bluuebunny/crossref_metadata_2025 huggingface dataset:
Results of a pilot investigation into a complex intervention for breathlessness in advanced chronic obstructive pulmonary disease (COPD): Brief report
Authors: Farquhar Morag , Higginson Irene J. , Fagan Petrea , Booth Sara
Published: March 2010

Objective:

Breathlessness is the most common devastating symptom of advanced chronic obstructive pulmonary disease (COPD). The Breathlessness Intervention Service (BIS) is a multidisciplinary service that uses both pharmacological and non-pharmacological evidence-based interventions to reduce the impact of the symptom. The results of a Phase II evaluation of the service are reported.

Method:

Pretest - posttest analysis of non-randomized data was performed for 13 patients with severe advanced COPD referred to BIS.

Results:

Mean VAS-Distress scores (primary outcome measure) decreased (improved) for the group between baseline and follow up suggesting a clinically significant improvement: 6.88 (SD = 2.50) to 5.25 (SD = 2.99). At an individual level, 11 of the 13 patients showed a decrease in their distress due to breathlessness, and for eight of these this was clinically significant (range of all decreases 0.3–7.1 cm). Changes in secondary outcome measures are also reported.

Significance of results:

The Breathlessness Intervention Service appears to reduce distress due to breathlessness among patients with advanced COPD. A Phase III fully-powered randomized controlled trial is warranted.
Large-signal modeling of large-size GaN HEMTs with a comprehensive extrinsic elements extraction algorithm
Authors: Zamudio-Flores J. Alberto , Dahmani Samir , Kompa Günter
Published: March 2010

This work presents a measurement-based physics-oriented large-signal modeling technique for GaN HEMTs. All the model elements are derived directly from pulsed-DC measurements and bias dependent small-signal model elements. The proposed small-signal model features a 12-element extrinsic network, which allows proper modeling of the complex parasitic effects present in large gate-width devices. A reliable generally applicable extrinsic extraction algorithm is presented. It is based on pinch-off S-parameter measurements and on a scanning procedure to find the optimal capacitance distribution. Results of applying the algorithm with measured data of a GaN HEMT with gate width of 3.2-mm prove the consistency of the formulation. Successful model verification is shown under pulsed-DC, single- and two-tone operations, showing accurate predictions versus measurements of IDS, Pout, gain, harmonics and IMD products.
Trying to Discover Sufficient Condition Causes
Authors: Krause Merton S.
Published: March 2010

Scientific human psychology is ultimately obligated to be able to describe, predict, and causally explain the psychological phenomena of every individual person. If all of this can be done in terms of the interrelations of linear combinations of variables, then our heavy reliance on statistical linear models will have been justified. But can it? The rather imperfect fits of such models to our data do not provide such justification, so perhaps more fundamental forms of data representation would be prudent to look into, given our modern computing capabilities. Such a form is offered in this paper: point-to-point mappings from independent-variable to dependent-variable hyperspaces. Its mathematical relationship to linear models is defined and explains why linear models may often not be capable of fitting psychological data.
How a Bayesian Might Estimate the Distribution of Cronbach’s Alpha From Ordinal-Dynamic Scaled Data
Authors: Gajewski Byron J. , Boyle Diane K. , Thompson Sarah
Published: March 2010

We demonstrate the utility of a Bayesian-based approach for calculating intervals of Cronbach’s alpha from a psychological instrument having ordinal responses with a dynamic scale. A small number of response options on an instrument will cause traditional-based interval estimates to be biased. Ordinal-based solutions are problematic because there is no clear mechanism for handling the dynamic scale. One way to remedy the bias is to adjust with a Bayesian approach. The Bayesian approach adjusts the bias and allows theoretically simple calculations of Cronbach’s alpha and intervals. We demonstrate the calculations of the Bayesian approach while at the same time offer a comparison to more traditional-based methods using both credible (or confidence) intervals and mean squared error. Practical advice is offered.
Higher‐order ionospheric effects on the GPS reference frame and velocities
Authors: Petrie Elizabeth J. , King Matt A. , Moore Philip , Lavallée David A.
Published: March 2010

We describe how GPS time series are influenced by higher‐order ionospheric effects over the last solar cycle (1995–2008) and examine implications for geophysical studies. Using 14 years of globally reprocessed solutions, we demonstrate the effect on the reference frame. Including second‐ and third‐order ionospheric terms causes up to 10 mm difference in the smoothed transformation to the International Terrestrial Reference Frame (ITRF) 2005, with theZtranslation term dominant. Scale is also slightly affected, with a change of up to ∼0.05 ppb. After transformation to ITRF2005, residual effects on vertical site velocities are as high as 0.34 mm yr−1. We assess the effect of the magnetic field model on the second‐order term and find a time‐varying difference of 0–2 mm in theZtranslation. We also assess the effect of omitting the third‐order term. We find that while the second‐order term is responsible for almost all theZtranslation effects, it is the combination of the second‐ and third‐order terms that causes the effect on scale. Comparison of our GPS reprocessing with ITRF2005 suggests that GPS origin rates may vary with time period. For example, we findZtranslation rates of −0.82 ± 0.17 mm yr−1for 1995–2008 and 0.17 ± 0.24 mm yr−1for 1995–2005. If GPS were to contribute to origin rate definition for future ITRFs, higher‐order ionospheric corrections would need to be applied due to their effect on translation parameters during solar maximum.
Assessing past temperature and soil pH estimates from bacterial tetraether membrane lipids: Evidence from the recent lake sediments of Lochnagar, Scotland
Authors: Tyler Jonathan J. , Nederbragt Alexandra J. , Jones Vivienne J. , Thurow Jürgen W.
Published: March 2010

Past variation in soil pH and air temperature can potentially be reconstructed from the relative abundance in sediments of branched glycerol dialkyl glycerol tetraethers (GDGTs), synthesized by anaerobic bacteria. Specifically, the cyclization of branched tetraethers (CBT) is believed to be a function of pH, whereas temperature can be estimated from a combination of the extent of both the CBT and methylation of branched tetraethers. Here we explore this potential by comparing a recent sedimentary GDGT profile from Lochnagar, Scotland, with reconstructed air temperature (statistically extrapolated from regional instrumental data sets) and diatom‐inferred lake water pH for the past ∼200 years. Branched glycerol dialkyl glycerol tetratether and diatom‐inferred pH generally agree throughout the core, supporting the use of cyclization of branched tetraethers to reconstruct pH. During the period of rapid industrial acidification (∼1860–1970 A.D.), changes in diatom‐inferred pH lag behind those inferred using branched tetraethers by between 10 and 50 years, possibly due to differing nonlinear responses to acid deposition within soil and lake water environments. However, branched‐GDGT‐derived temperatures are both lower than extrapolated mean annual air temperature estimates (by ∼5°C) and exhibit at least double the rate of reconstructed warming (∼2.5°C in 200 years). At Lochnagar, methylation and cyclization of branched tetraethers are closely correlated (r2 = 0.96) suggesting that in this setting the underlying controls over the two indices may not significantly differ. Therefore the validity of branched‐GDGT‐derived temperature is uncertain and further research is required to address the environmental controls over branched glycerol dialkyl glycerol tetratether synthesis and thus their value as palaeoclimate proxies.
Distinct roles of cytolytic effector molecules for antigen‐restricted killing by CTL in vivo
Authors: Janssen Edith M , Lemmens Ed E , Gour Naina , Reboulet Rachel A , Green Douglas R , Schoenberger Stephen P , Pinkoski Michael J
Published: March 2010

Cytotoxic T lymphocytes (CTLs) represent one of the front lines of defense for the immune system, killing virus‐infected and tumor‐transformed cells. CTL use at least two mechanisms to induce apoptosis in their targets, one mediated by perforin and granzymes, and the other triggered by the death ligand, CD95 ligand (CD95L). Here, we used an in vivo cytotoxicity assay to measure specific clearance of antigen‐bearing target cells in mice that had previously been immunized with noninfectious cell‐associated antigens. We found that perforin was dispensable for efficient clearance of antigen‐bearing cells from immunized mice, but only if CD95/CD95L was functional; however, there was a delay in target cell clearance in the absence of perforin. In addition, we observed ∼35% target cell clearance in the absence of both perforin and CD95L, which was only slightly abrogated in the presence of a neutralizing anti‐tumor necrosis factor (TNF) antibody. The presence of a dominant negative Fas‐associated death domain (FADD) did not block target cell clearance and therefore cannot be attributed to known death receptors. Taken together, these data suggest that perforin‐ and CD95L‐dependent killing are complementary at early time points, each can compensate for the absence of the other at later time points, and that there is an additional component of antigen‐restricted CTL killing independent of perforin, CD95L, and TNFα.
Design and control of six degree-of-freedom active vibration isolation table
Authors: Hong Jinpyo , Park Kyihwan
Published: March 2010

A six-axis active vibration isolation system (AVIS) is designed by using the direct driven guide and ball contact mechanisms in order to have no cross-coupling between actuators. The point contact configuration gives an advantage of having an easy assembly of eight voice coil actuators to an upper and a base plate. A voice coil actuator is used since it can provide a large displacement and sufficient bandwidth required for vibration control. The AVIS is controlled considering the effect of flexible vibration mode in the upper plate and velocity sensor dynamics. A loop shaping technique and phase margin condition are applied to design a vibration controller. The performances of the AVIS are investigated in the frequency domain and finally validated by comparing with the passive isolation system. The scanning profiles of the specimen are compared together by using the atomic force microscope. The robustness of the AVIS is verified by showing the impulse response.
Influence of the Si(100)-c(4×12)-Al surface phase on formation and electrical properties of thin iron films
Authors: Goroshko D. L. , Galkin N. G. , Gouralnik A. S.
Published: March 2010

The electrical properties of thin iron films deposited at room temperature (RT) on clean Si(100) and on the prefabricated Si(100)-c(4×12)-Al surface phase (SP) have been studied by means of in situ Hall effect and conductance measurements for iron coverage (0–2.3) nm. It is shown that the Si(100)-c(4×12)-Al SP blocks intermixing of iron and substrate atoms. The conductance and mobility of the majority carriers in this SP are higher than those in Si(100)2×1, within the temperature range from RT to 460 K. For iron coverage below 2 nm, the sample conductance is significantly lower than that for the bare Si(100). The iron film grown on the Si(100)-c(4×12)-Al becomes continuous at a coverage approximately half as thick as for the film grown on the Si(100)2×1 surface.
Structural and magnetic properties of Co1−xFexSr2YCu2O7+δ compounds
Authors: Singh Shiva Kumar , Kumar Praveen , Husain M. , Kishan Hari , Awana V. P. S.
Published: March 2010

Here we study the structural and magnetic properties of the Co1−xFexSr2YCu2O7+δ compound (0≤x≤1). X-ray diffraction patterns and simulated data obtained from Rietveld refinement of the same indicate that the iron ion replacement in Co1−xFexSr2YCu2O7+δ induces a change in crystal structure. The orthorhombic Ima2 space group structure of Co-1212 changes to tetragonal P4/mmm with increasing Fe (x≥0.5) ion. The XPS studies reveal that both Co and Fe ions are in mixed states of 3+/4+ for the former and 2+/3+ in case of later. The magnetization with temperature follows Curie–Weiss behavior, in the range of 150–300 K and short magnetic correlations/spin glasslike features below 150 K. The observed magnetic behavior is due to competition of antiferro/ferromagnetic exchange interaction of Co3+ [intermediate spin (IS)]-O–Co3+ (IS)/Co4+ [low spin (LS)] and Fe3+ [high spin (HS)]-O–Fe2+ (LS)/Fe3+ (HS)/Co3+ (IS)/Co4+ (LS) states. Although none of the studied as synthesized samples in Co1−xFexSr2YCu2O7+δ are superconducting, the interesting structural changes in terms of their crystallization space groups and the weak magnetism highlights the rich solid state chemistry of this class of materials.
New stability criteria and bifurcation analysis for nonlinear discrete-time coupled loops with multiple delays
Authors: Peng Mingshu , Yang Xiaozhong
Published: March 2010

A detailed analysis of zero distributions in a special polynomial of the form λτ(λ−a1)(λ−a2)⋯(λ−an)−(c+id) is proposed, where all ai(i=1,2,…,) have the same sign. As its applications, new criteria for asymptotic behavior of nonlinear delayed coupled systems with different topological structures are established. All possible bifurcations, including codimension-two bifurcations with 1:4/1:3 strong resonance in such a delayed difference system, are discussed. Numerical simulation gives a solid verification of the theoretical analysis.
Scytale decodes chaos: A method for estimating unstable symmetric solutions
Authors: Morita Yasuaki , Fujiwara Naoya , Kobayashi Miki U. , Mizuguchi Tsuyoshi
Published: March 2010

A method for estimating a period of unstable periodic solutions is suggested in continuous dissipative chaotic dynamical systems. The measurement of a minimum distance between a reference state and an image of transformation of it exhibits a characteristic structure of the system, and the local minima of the structure give candidates of period and state of corresponding symmetric solutions. Appropriate periods and initial states for the Newton method are chosen efficiently by setting a threshold to the range of the minimum distance and the period.
Investigation of the electroforming process in resistively switching TiO2 nanocrosspoint junctions
Authors: Nauenheim C. , Kuegeler C. , Ruediger A. , Waser R.
Published: March 2010

We report on the electroforming in resistively switching nanocrosspoint devices made of a reactively sputtered TiO2 thin film between Pt and Ti/Pt electrodes, respectively. As most resistance switching materials, TiO2 needs to be electroformed before it can be switched. This paper presents and compares current and voltage controlled electroforming with regard to the polarity. We show that a current-driven electroforming with negative polarities leads into the switchable high resistive state without need for a current compliance. These devices show an improved stability and reliability in bipolar resistive switching performance.
Hydration and coordination of K+ solvation in water from ab initio molecular-dynamics simulation
Authors: Liu Yi , Lu Haigang , Wu Yanbo , Hu Tuoping , Li Qiaoling
Published: March 2010

Potassium ion in water plays a very important role in chemistry and biology. In this paper, we investigated the hydration structure and coordination of K+ solvation in water at 300 and 450 K using ab initio Car–Parrinello molecular dynamics. The K+-oxygen radial distribution function indicated that the perturbation of K+ on the water structure is strong in the first hydration shells, while it is mild outside of this region in normal liquid. According to our natural geometric criterion for the coordinated oxygen atom, the average coordination number of K+ is 6.24 and 6.53 at 300 and 450 K, respectively, which agrees with the experimental value (6.1). This geometric criterion can also be used to define strong, moderate and weak hydrogen bonds in liquid.
Using indentation to characterize the poroelasticity of gels
Authors: Hu Yuhang , Zhao Xuanhe , Vlassak Joost J. , Suo Zhigang
Published: March 2010

When an indenter is pressed into a gel to a fixed depth, the solvent in the gel migrates, and the force on the indenter relaxes. Within the theory of poroelasticity, the force relaxation curves for indenters of several types are obtained in a simple form, enabling indentation to be used with ease as a method for determining the elastic constants and permeability of the gel. The method is demonstrated with a conical indenter on an alginate hydrogel.
Semiconductor snail lasers
Authors: Strain M. J. , Mezősi G. , Javaloyes J. , Sorel M. , Pérez-Serrano A. , Scirè A. , Balle S. , Danckaert J. , Verschaffelt G.
Published: March 2010

A modified ring laser geometry is presented to promote stable unidirectional lasing. The effects of directional coupling and facet reflectivities are investigated with respect to quantum efficiency, directionality, and side-mode suppression ratio of the lasing spectra. Simulation and experimental results are presented showing single mode (>20 dB side-mode suppression ratio), unidirectional lasing on an InP based multiple quantum well material.
Movements and landscape use of camels in central Australia revealed by GPS satellite
Authors: Lethbridge Mark R. , Anderson Nicole , Harper Megan L. , Gee Phil
Published: March 2010

We analysed the movement of seven female camels collared in the Anangu Pitjantjatjara Yankunytjatjara Lands of South Australia. Understanding the movement patterns of feral camels and subsequently where high densities are likely to threaten biodiversity and cultural assets, provides land managers and government agencies with information and decision support tools to manage camel impacts. Accordingly, we tested if there were any seasonal changes in camel movement, any measurable separation between home range and migration, and any relationship between broader camel landscape use, rainfall and mountainous terrain. We fitted ARGOS GPS satellite collars to seven female camels in South Australia during August 2007 and found evidence to suggest that over a 12-month study period, some camels had returned to locations that they had previously visited. This cyclic movement pattern was more regular up to ~50 days, however, one collared individual returned to a previous location after 300 days. Despite only having a small sample size, we did find camels moving into areas that received higher rainfalls in the warmer months and possibly some attraction of these camels to steep mountainous terrain over this period.
Modelling the distribution and relative abundance of feral camels in the Northern Territory using count data
Authors: McLeod S. R. , Pople A. R.
Published: March 2010

The objectives of this study were to predict the potential distribution, relative abundance and probability of habitat use by feral camels in southern Northern Territory. Aerial survey data were used to model habitat association. The characteristics of ‘used’ (where camels were observed) v. ‘unused’ (pseudo-absence) sites were compared. Habitat association and abundance were modelled using generalised additive model (GAM) methods. The models predicted habitat suitability and the relative abundance of camels in southern Northern Territory. The habitat suitability maps derived in the present study indicate that camels have suitable habitat in most areas of southern Northern Territory. The index of abundance model identified areas of relatively high camel abundance. Identifying preferred habitats and areas of high abundance can help focus control efforts.
ATP-gated P2X3receptors constitute a positive autocrine signal for insulin release in the human pancreatic β cell
Authors: Jacques-Silva M. Caroline , Correa-Medina Mayrin , Cabrera Over , Rodriguez-Diaz Rayner , Makeeva Natalia , Fachado Alberto , Diez Juan , Berman Dora M. , Kenyon Norma S. , Ricordi Camillo , Pileggi Antonello , Molano R. Damaris , Berggren Per-Olof , Caicedo Alejandro
Published: March 2010

Extracellular ATP has been proposed as a paracrine signal in rodent islets, but it is unclear what role ATP plays in human islets. We now show the presence of an ATP signaling pathway that enhances the human β cell's sensitivity and responsiveness to glucose fluctuations. By using in situ hybridization, RT-PCR, immunohistochemistry, and Western blotting as well as recordings of cytoplasmic-free Ca2+concentration, [Ca2+]i, and hormone release in vitro, we show that human β cells express ionotropic ATP receptors of the P2X3type and that activation of these receptors by ATP coreleased with insulin amplifies glucose-induced insulin secretion. Released ATP activates P2X3receptors in the β-cell plasma membrane, resulting in increased [Ca2+]iand enhanced insulin secretion. Therefore, in human islets, released ATP forms a positive autocrine feedback loop that sensitizes the β cell's secretory machinery. This may explain how the human pancreatic β cell can respond so effectively to relatively modest changes in glucose concentration under physiological conditions in vivo.
P53-induced microRNA-107 inhibits HIF-1 and tumor angiogenesis
Authors: Yamakuchi Munekazu , Lotterman Craig D. , Bao Clare , Hruban Ralph H. , Karim Baktiar , Mendell Joshua T. , Huso David , Lowenstein Charles J.
Published: March 2010

The pathway involving the tumor suppressor gene
TP53
can regulate tumor angiogenesis by unclear mechanisms. Here we show that p53 regulates hypoxic signaling through the transcriptional regulation of microRNA-107 (miR-107). We found that miR-107 is a microRNA expressed by human colon cancer specimens and regulated by p53. miR-107 decreases hypoxia signaling by suppressing expression of hypoxia inducible factor-1β (HIF-1β). Knockdown of endogenous miR-107 enhances HIF-1β expression and hypoxic signaling in human colon cancer cells. Conversely, overexpression of miR-107 inhibits HIF-1β expression and hypoxic signaling. Furthermore, overexpression of miR-107 in tumor cells suppresses tumor angiogenesis, tumor growth, and tumor VEGF expression in mice. Finally, in human colon cancer specimens, expression of miR-107 is inversely associated with expression of HIF-1β. Taken together these data suggest that miR-107 can mediate p53 regulation of hypoxic signaling and tumor angiogenesis.
A sense of direction in human entorhinal cortex
Authors: Jacobs Joshua , Kahana Michael J. , Ekstrom Arne D. , Mollison Matthew V. , Fried Itzhak
Published: March 2010

Finding our way in spatial environments is an essential part of daily life. How do we come to possess this sense of direction? Extensive research points to the hippocampus and entorhinal cortex (EC) as key neural structures underlying spatial navigation. To better understand this system, we examined recordings of single-neuron activity from neurosurgical patients playing a virtual-navigation video game. In addition to place cells, which encode the current virtual location, we describe a unique cell type, EC path cells, the activity of which indicates whether the patient is taking a clockwise or counterclockwise path around the virtual square road. We find that many EC path cells exhibit this directional activity throughout the environment, in contrast to hippocampal neurons, which primarily encode information about specific locations. More broadly, these findings support the hypothesis that EC encodes general properties of the current context (e.g., location or direction) that are used by hippocampus to build unique representations reflecting combinations of these properties.
Zbtb20 is essential for the specification of CA1 field identity in the developing hippocampus
Authors: Xie Zhifang , Ma Xianhua , Ji Wenli , Zhou Guangdi , Lu Yinzhong , Xiang Zhenghua , Wang Yan X. , Zhang Lei , Hu Yiping , Ding Yu-Qiang , Zhang Weiping J.
Published: March 2010

The development of hippocampal circuitry depends on the proper assembly of correctly specified and fully differentiated hippocampal neurons. Little is known about factors that control the hippocampal specification. Here, we show that zinc finger protein Zbtb20 is essential for the specification of hippocampal CA1 field identity. We found that
Zbtb20
expression was initially activated in the hippocampal anlage at the onset of corticogenesis, and persisted in immature hippocampal neurons. Targeted deletion of
Zbtb20
in mice did not compromise the progenitor proliferation in the hippocampal and adjacent transitional ventricular zone, but led to the transformation of the hippocampal CA1 field into a transitional neocortex-like structure, as evidenced by cytoarchitectural, neuronal migration, and gene expression phenotypes. Correspondingly, the subiculum was ectopically located adjacent to the CA3 in mutant. Although the field identities of the mutant CA3 and dentate gyrus (DG) were largely maintained, their projections were severely impaired. The hippocampus of Zbtb20 null mice was reduced in size, and exhibited increased apoptotic cell death during postnatal development. Our data establish an essential role of
Zbtb20
in the specification of CA1 field identity by repressing adjacent transitional neocortex-specific fate determination.
Short N-terminal sequences package proteins into bacterial microcompartments
Authors: Fan Chenguang , Cheng Shouqiang , Liu Yu , Escobar Cristina M. , Crowley Christopher S. , Jefferson Robert E. , Yeates Todd O. , Bobik Thomas A.
Published: March 2010

Hundreds of bacterial species produce proteinaceous microcompartments (MCPs) that act as simple organelles by confining the enzymes of metabolic pathways that have toxic or volatile intermediates. A fundamental unanswered question about bacterial MCPs is how enzymes are packaged within the protein shell that forms their outer surface. Here, we report that a short N-terminal peptide is necessary and sufficient for packaging enzymes into the lumen of an MCP involved in B12-dependent 1,2-propanediol utilization (Pdu MCP). Deletion of 10 or 14 amino acids from the N terminus of the propionaldehyde dehydrogenase (PduP) enzyme, which is normally found within the Pdu MCP, substantially impaired packaging, with minimal effects on its enzymatic activity. Fusion of the 18 N-terminal amino acids from PduP to GFP, GST, or maltose-binding protein resulted in their encapsulation within MCPs. Bioinformatic analyses revealed N-terminal extensions in two additional Pdu proteins and three proteins from two unrelated MCPs, suggesting that N-terminal peptides may be used to package proteins into diverse MCPs. The potential uses of MCP assembly principles in nature and in biotechnology are discussed.
Toll-like receptor 8-mediated activation of murine plasmacytoid dendritic cells by vaccinia viral DNA
Authors: Martinez Jennifer , Huang Xiaopei , Yang Yiping
Published: March 2010

Plasmacytoid dendritic cells (pDCs) play a critical role in antiviral immunity through their ability to produce large amounts of type I IFNs. Activation of pDCs upon viral infection has been shown to be dependent on MyD88 and mediated by Toll-like receptors (TLR) 7 and 9, which sense viral ssRNA and CpG DNA, respectively. In this study, we showed that murine pDC recognition of vaccinia virus (VV), a dsDNA virus, was MyD88-dependent but TLR9-independent. Using HEK293 cells transfected with murine TLR7 or TLR8 and a NF-κB luciferase reporter, we demonstrated that stimulation of TLR8-, but not TLR7-, transfected cells with either VV or VV DNA resulted in substantial NF-κB activation, and that siRNA-mediated knockdown of TLR8 expression in pDCs led to a complete ablation of VV-induced type I IFN production. We further identified that the VV genome was rich in poly(A)/T sequences, and synthetic poly(A) and poly T oligodeoxynucleotides were capable of activating pDCs in a TLR8-dependent manner. In vivo, TLR8-MyD88-dependent pDC activation played a critical role in innate immune control of VV infection. Collectively, our data are unique in demonstrating that TLR8 is required for sensing poly(A)/T-rich DNA in pDCs, and that murine TLR8 is functional in the context of a viral infection.
Combinatorial libraries against libraries for selecting neoepitope activation-specific antibodies
Authors: Hu Xuebo , Kang Sungkwon , Lefort Craig , Kim Minsoo , Jin Moonsoo M.
Published: March 2010

A systematic approach to the discovery of conformation-specific antibodies or those that recognize activation-induced neoepitopes in signaling molecules and enzymes will be a powerful tool in developing antibodies for basic science and therapy. Here, we report the isolation of antibody antagonists that preferentially bind activated integrin Mac-1 (αMβ2) and are potent in blocking neutrophil adhesion and migration. A novel strategy was developed for this task, consisting of yeast surface display of Mac-1 inserted (I) domain library, directed evolution to isolate active mutants of the I domain, and screening of phage display of human antibody library against the active I domain in yeast. Enriched antibody library was then introduced into yeast surface two-hybrid system for final quantitative selection of antibodies from monomeric antigen–antibody interaction. This led to highly efficient isolation of intermediate to high affinity antibodies, which preferentially reacted with the active I domain, antagonized the I domain binding to intercellular adhesion molecule (ICAM)-1, complement C3 fragment iC3b, and fibronectin, and potently inhibited neutrophil migration on fibrinogen. The strategy demonstrated herein can be broadly applicable to developing antibodies against modular domains that switch between inactive and active conformations, particularly toward the discovery of antibody antagonists in therapeutic and diagnostic applications.
Subunit interactions in bovine papillomavirus
Authors: Wolf Matthias , Garcea Robert L. , Grigorieff Nikolaus , Harrison Stephen C.
Published: March 2010

Papillomaviruses, members of a group of dsDNA viruses associated with epithelial growths and tumors, have compact capsids assembled from 72 pentamers of the protein L1. We have determined the structure of bovine papillomavirus by electron cryomicrosopy (cryoEM), at ∼3.6 
Å
resolution. The density map, obtained from single-particle analysis of ∼4,000 particle images, shows the trace of the L1 polypeptide chain and reveals how the N- and C-terminal “arms” of a subunit (extensions from its β-jelly-roll core) associate with a neighboring pentamer. Critical contacts come from the C-terminal arm, which loops out from the core of the subunit, forms contacts (including a disulfide) with two subunits in a neighboring pentamer, and reinserts into the pentamer from which it emanates. This trace corrects one feature of an earlier model. We discuss implications of the structure for virion assembly and for pathways of infectious viral entry. We suggest that it should be possible to obtain image reconstructions of comparable resolution from cryoEM images of asymmetric particles. From the work on papillomavirus described here, we estimate that such a reconstruction will require about 1.5 million images to achieve the same number of averaged asymmetric units; structural variability will increase this number substantially.
Biosynthesis and functions of bacillithiol, a major low-molecular-weight thiol in Bacilli
Authors: Gaballa Ahmed , Newton Gerald L. , Antelmann Haike , Parsonage Derek , Upton Heather , Rawat Mamta , Claiborne Al , Fahey Robert C. , Helmann John D.
Published: March 2010

Bacillithiol (BSH), the α-anomeric glycoside of L-cysteinyl-D-glucosamine with L-malic acid, is a major low-molecular-weight thiol in
Bacillus subtilis
and related bacteria. Here, we identify genes required for BSH biosynthesis and provide evidence that the synthetic pathway has similarities to that established for the related thiol (mycothiol) in the Actinobacteria. Consistent with a key role for BSH in detoxification of electrophiles, the BshA glycosyltransferase and BshB1 deacetylase are encoded in an operon with methylglyoxal synthase. BshB1 is partially redundant in function with BshB2, a deacetylase of the LmbE family. Phylogenomic profiling identified a conserved unknown function protein (COG4365) as a candidate cysteine-adding enzyme (BshC) that co-occurs in genomes also encoding BshA, BshB1, and BshB2. Additional evolutionarily linked proteins include a thioredoxin reductase homolog and two thiol:disulfide oxidoreductases of the DUF1094 (CxC motif) family. Mutants lacking BshA, BshC, or both BshB1 and BshB2 are devoid of BSH. BSH is at least partially redundant in function with other low-molecular-weight thiols: redox proteomics indicates that protein thiols are largely reduced even in the absence of BSH. At the transcriptional level, the induction of genes controlled by two thiol-based regulators (OhrR, Spx) occurs normally. However, BSH null cells are significantly altered in acid and salt resistance, sporulation, and resistance to electrophiles and thiol reactive compounds. Moreover, cells lacking BSH are highly sensitive to fosfomycin, an epoxide-containing antibiotic detoxified by FosB, a prototype for bacillithiol-
S
-transferase enzymes.
Hypoxia inducible microRNA 210 attenuates keratinocyte proliferation and impairs closure in a murine model of ischemic wounds
Authors: Biswas Sabyasachi , Roy Sashwati , Banerjee Jaideep , Hussain Syed-Rehan A. , Khanna Savita , Meenakshisundaram Guruguhan , Kuppusamy Periannan , Friedman Avner , Sen Chandan K.
Published: March 2010

Ischemia complicates wound closure. Here, we are unique in presenting a murine ischemic wound model that is based on bipedicle flap approach. Using this model of ischemic wounds we have sought to elucidate how microRNAs may be implicated in limiting wound re-epithelialization under hypoxia, a major component of ischemia. Ischemia, evaluated by laser Doppler as well as hyperspectral imaging, limited blood flow and lowered tissue oxygen saturation. EPR oximetry demonstrated that the ischemic wound tissue had
p
O
2
<10 mm Hg. Ischemic wounds suffered from compromised macrophage recruitment and delayed wound epithelialization. Specifically, epithelial proliferation, as determined by Ki67 staining, was compromised. In vivo imaging showed massive hypoxia inducible factor-1α (HIF-1α) stabilization in ischemic wounds, where HIF-1α induced miR-210 expression that, in turn, silenced its target E2F3, which was markedly down-regulated in the wound-edge tissue of ischemic wounds. E2F3 was recognized as a key facilitator of cell proliferation. In keratinocytes, knock-down of E2F3 limited cell proliferation. Forced stabilization of HIF-1α using Ad-VP16- HIF-1α under normoxic conditions up-regulated miR-210 expression, down-regulated E2F3, and limited cell proliferation. Studies using cellular delivery of miR-210 antagomir and mimic demonstrated a key role of miR-210 in limiting keratinocyte proliferation. In summary, these results are unique in presenting evidence demonstrating that the hypoxia component of ischemia may limit wound re-epithelialization by stabilizing HIF-1α, which induces miR-210 expression, resulting in the down-regulation of the cell-cycle regulatory protein E2F3.
Integrating Spirituality into the Workplace: Theory and Practice
Authors: Bandsuch Mark R. , Cavanagh Gerald F.
Published: March 2010

The presence of spirituality in the workplace meets a variety of personal and professional business objectives, including meaningfulness of work, ethics and productivity. Three essential dimensions of spirituality—beliefs, rituals and community—can be developed in the workplace.
It is the clear, coordinated, comprehensive and continued development of these dimensions that cultivates workplace spirituality and promotes the related individual and organizational business benefits.
Entrepreneurship and Spirituality: Integration of Spirituality into the Workplace
Authors: King-Kauanui Sandra , Thomas Kevin D. , Waters Gail Ross
Published: March 2010

This qualitative exploratory study is based on interviews with 35 entrepreneurs on spirituality and work. Specific questions included (1) What visible actions and behaviors do entrepreneurs employ to espouse spirituality in their organizations, especially with employees, suppliers and
customers? (2) How do entrepreneurs define spirituality at work? (3) How do entrepreneurs integrate personal spiritual values into their organization's culture? Information from the interviews was organized using Atlas.ti software, resulting in an interesting conceptual framework of spirituality
at work.All entrepreneurs who embraced spirituality found a way to integrate it into relationships with their employees, customers and suppliers. Spiritual entrepreneurs appear to make a conscious effort to develop actions and initiatives to bring spirituality to those people and communities
with whom they work. Entrepreneurs with religious beliefs were slightly less likely than others to say they bring personal spirituality to the workplace. This paper provides numerous examples of spiritually based behaviors.
A novel Rac-dependent checkpoint in B cell development controls entry into the splenic white pulp and cell survival
Authors: Henderson Robert B. , Grys Katarzyna , Vehlow Anne , de Bettignies Carine , Zachacz Agnieszka , Henley Tom , Turner Martin , Batista Facundo , Tybulewicz Victor L.J.
Published: March 2010

Rac1 and Rac2 GTPases transduce signals from multiple receptors leading to cell migration, adhesion, proliferation, and survival. In the absence of Rac1 and Rac2, B cell development is arrested at an IgD− transitional B cell stage that we term transitional type 0 (T0). We show that T0 cells cannot enter the white pulp of the spleen until they mature into the T1 and T2 stages, and that this entry into the white pulp requires integrin and chemokine receptor signaling and is required for cell survival. In the absence of Rac1 and Rac2, transitional B cells are unable to migrate in response to chemokines and cannot enter the splenic white pulp. We propose that loss of Rac1 and Rac2 causes arrest at the T0 stage at least in part because transitional B cells need to migrate into the white pulp to receive survival signals. Finally, we show that in the absence of Syk, a kinase that transduces B cell antigen receptor signals required for positive selection, development is arrested at the same T0 stage, with transitional B cells excluded from the white pulp. Thus, these studies identify a novel developmental checkpoint that coincides with B cell positive selection.
Subcellular distribution and expression of prenylated Rab acceptor 1 domain family, member 2 (PRAF2) in malignant glioma: Influence on cell survival and migration
Authors: Borsics Tamás , Lundberg Emma , Geerts Dirk , Koomoa Dana‐Lynn T. , Koster Jan , Wester Kenneth , Bachmann André S.
Published: March 2010

Our previous studies revealed that the expression of the 19‐kDa protein prenylated Rab acceptor 1 domain family, member 2 (PRAF2) is elevated in cancer tissues of the breast, colon, lung, and ovary, when compared to noncancerous tissues of paired samples. PRAF2 mRNA expression also correlated with several genetic and clinical features and is a candidate prognostic marker in the pediatric cancer neuroblastoma. The PRAF2‐related proteins, PRAF1 and PRAF3, play multiple roles in cellular processes, including endo/exocytic vesicle trafficking and glutamate uptake. PRAF2 shares a high sequence homology with these family members, but its function remains unknown. In this study, we examined PRAF2 mRNA and protein expression in 20 different human cancer types using Affymetrix microarray and human tissue microarray (TMA) analyses, respectively. In addition, we investigated the subcellular distribution of PRAF2 by immunofluorescence microscopy and cell fractionation studies. PRAF2 mRNA and protein expression was elevated in several cancer tissues with highest levels in malignant glioma. At the molecular level, we detected native PRAF2 in small, vesicle‐like structures throughout the cytoplasm as well as in and around cell nuclei of U‐87 malignant glioma cells. We further found that monomeric and dimeric forms of PRAF2 are associated with different cell compartments, suggesting possible functional differences. Importantly, PRAF2 down‐regulation by RNA interference significantly reduced the cell viability, migration, and invasiveness of U‐87 cells. This study shows that PRAF2 expression is elevated in various tumors with exceptionally high expression in malignant gliomas, and PRAF2 therefore presents a candidate molecular target for therapeutic intervention. (Cancer Sci2010)
Establishment of functional telomerase immortalized human hepatocytes and a hepatic stellate cell line for telomere‐targeting anticancer drug development
Authors: Waki Koji , Anno Kumiko , Ono Taeko , Ide Toshinori , Chayama Kazuaki , Tahara Hidetoshi
Published: March 2010

We previously reported that the telomere‐targeting drug telomestatin induces apoptosis accompanied by G‐tail reduction and dissociation of binding protein TRF2 from telomeres in cancer cell lines but not normal or human telomerase reverse transcriptase (hTERT)‐immortalized cells. Because telomere‐targeting drugs induce growth arrest in normal cells at higher doses, their development is dependent on the ability to predict toxicity before in vivo use, but no models for this are available. Here, we established two new cell lines, telomerase immortalized human fetal hepatocytes, Hc3716‐hTERT, and telomerase immortalized hepatic stellate cells, NPC‐hTERT. Examinations showed that Hc3716‐hTERT maintained normal mammalian cell morphology, cell growth, albumin expression, and wild‐type p53 responsiveness, whereas NPC‐hTERT maintained hepatic stellate‐like morphology, expression of hepatic stellate markers, α‐smooth muscle actin, and secretion of type I collagen, an extracellular matrix protein. Given our finding that telomere G‐tail length in Hc3716 cells was decreased in senescence and increased by hTERT infection, we next examined the effect of high‐dose telomestatin‐induced telomere dysfunction and G‐tail shortening on cellular functions in Hc3716‐hTERT cells. Interestingly, telomestatin decreased expression of cytochrome P450 (CYP) family members CYP3A3/4, CYP3A5, and CYP3A7, mRNA and induced albumin expression at both mRNA and protein levels. These gene expression responses to telomestatin were similar to those of the normal parental cell Hc3716. These established cell lines thus represent the first model for predicting the side‐effects of telomere‐targeting drugs in normal cells, and should be powerful tools in the development of these drugs. (Cancer Sci 2010)
In vitro study of magnetic resonance imaging artefacts of six supraglottic airway devices
Authors: Zaballos M. , Bastida E. , Del Castillo T. , De Villoria J. G. , Jiménez C.
Published: March 2010

We investigated the artefacts created during magnetic resonance imaging by five different laryngeal mask airways: the Classic (cLMA™); the LMA ProSeal™; the LMA Unique™; the Ambu® Disposable Laryngeal Mask; the LMA Supreme™; and one other supraglottic airway device, the i‐gel supraglottic airway. The devices were placed on top of and inside a phantom simulator to resemble the position in vivo. The artefacts with the cLMA, Unique and Supreme were similar and related to ferromagnetic material in the pilot balloon valve. Artefacts were more prominent with the ProSeal. There were no artefacts with the Ambu Disposable Laryngeal Mask or the i‐gel.
Awake tracheal intubation using the Sensascope™ in 13 patients with an anticipated difficult airway
Authors: Greif R. , Kleine‐Brueggeney M. , Theiler L.
Published: March 2010

We present the use of the SensaScope™, an S‐shaped rigid fibreoptic scope with a flexible distal end, in a series of 13 patients at high risk of, or known to have, a difficult intubation. Patients received conscious sedation with midazolam or fentanyl combined with a remifentanil infusion and topical lidocaine to the oral mucosa and to the trachea via a trans‐cricoid injection. Spontaneous ventilation was maintained until confirmation of tracheal intubation. In all cases, tracheal intubation was achieved using the SensaScope. The median (IQR [range]) insertion time (measured from the time the facemask was taken away from the face until an end‐expiratory CO2 reading was visible on the monitor) was 58 s (38–111 [28–300]s). In nine of the 13 cases, advancement of the SensaScope into the trachea was easy. Difficulties included a poor view associated with a bleeding diathesis and saliva, transient loss of spontaneous breathing, and difficulty in advancing the tracheal tube in a patient with unforeseen tracheal narrowing. A poor view in two patients was partially improved by a high continuous flow of oxygen. The SensaScope may be a valuable alternative to other rigid or flexible fibreoptic scopes for awake intubation of spontaneously breathing patients with a predicted difficult airway.
Clinical assessment of a new anaesthetic drug administration system: a prospective, controlled, longitudinal incident monitoring study*
Authors: Webster C. S. , Larsson L. , Frampton C. M. , Weller J. , McKenzie A. , Cumin D. , Merry A. F.
Published: March 2010

A safety‐orientated system of delivering parenteral anaesthetic drugs was assessed in a prospective incident monitoring study at two hospitals. Anaesthetists completed an incident form for every anaesthetic, indicating if an incident occurred. Case mix data were collected and the number of drug administrations made during procedures estimated. From February 1998 at Hospital A and from June 1999 at Hospital B, until November 2003, 74 478 anaesthetics were included, for which 59 273 incident forms were returned (a 79.6% response rate). Fewer parenteral drug errors occurred with the new system than with conventional methods (58 errors in an estimated 183 852 drug administrations (0.032%, 95% CI 0.024–0.041%) vs 268 in 550 105 (0.049%, 95% CI 0.043–0.055%) respectively, p = 0.002), a relative reduction of 35% (difference 0.017%, 95% CI 0.006–0.028%). No major adverse outcomes from these errors were reported with the new system while 11 (0.002%) were reported with conventional methods (p = 0.055). We conclude that targeted system re‐design can reduce medical error.
Segregation of infectious pancreatic necrosis resistance QTL in the early life cycle of Atlantic Salmon (Salmo salar)
Authors: Gheyas A. A. , Houston R. D. , Mota‐Velasco J. C. , Guy D. R. , Tinch A. E. , Haley C. S. , Woolliams J. A.
Published: March 2010

In a previous study, three significant quantitative trait loci (QTL) associated with resistance to Infectious Pancreatic Necrosis (IPN) disease were identified by analysing challenge data from one sub‐population of Landcatch Atlantic salmon (Salmo salar) smolt. While these QTL were shown to affect the resistance in seawater, their effect in freshwater was unknown. This study investigates the effect of these QTL on IPN resistance in salmon fry in freshwater. Twenty families with intermediate levels of IPN mortality were analysed from a freshwater challenge trial undertaken on a different sup‐population of LNS salmon to that studied previously. Only the QTL from linkage group 21 (LG21) appeared to have a significant and large effect on resistance in freshwater; the same QTL was found to have the largest effect in seawater in the previous study. Variance component analysis showed a high heritability for the QTL: 0.45 ± 0.07 on the liability scale and 0.25 ± 0.05 on the observed scale. In a family where both parents were segregating for the QTL, there was a 0% vs. 100% mortality in homozygous offspring for resistant and susceptible QTL alleles. The finding that the same QTL has major effect in both freshwater and seawater has important practical implications, as this will allow the improvement of resistance in both phases through marker assisted selection by targeting this QTL. Moreover, the segregation of the LG21 QTL in a different sub‐population gives further evidence of its association with IPN‐resistance.