bluuebunny/crossref_metadata_2025 huggingface dataset:
Anti-interleukin-8 autoantibody:interleukin-8 immune complexes in acute lung injury/acute respiratory distress syndrome
Authors: Fudala Rafal , Krupa Agnieszka , Stankowska Dorota , Allen Timothy C. , Kurdowska Anna K.
Published: February 2008

ALI/ARDS (acute lung injury/acute respiratory distress syndrome) is a severe inflammatory lung disease associated with very high mortality. Importantly, no effective therapy has been developed to date for ALI/ARDS. Neutrophils have been implicated in the pathogenesis of ALI/ARDS, and IL-8 (interleukin-8) has been identified as the main chemotactic factor for neutrophils in lung fluids of patients with ALI/ARDS. Significantly, studies from our laboratory have revealed the presence of anti-IL-8 autoantibody:IL-8 immune complexes in lung fluids from patients with ALI/ARDS. Autoantibodies to several cytokines, including IL-8, have been found in human plasma and other tissues. The function of anticytokine autoantibodies is far from clear; however, in some instances, it has been suggested that such autoantibodies may contribute to the pathogenesis of variety of human diseases. In addition, many of these autoantibodies can form immune complexes with target cytokines. Furthermore, immune complexes consisting of anti-IL-8 autoantibodies and IL-8 are very stable due to the high affinity of autoantibodies against IL-8. These complexes are present in various human tissues, including the lung, as they have been detected in lung fluids from patients with ALI/ARDS. In this review, the significance of the latter findings are explored, and the possible involvement of anti-IL-8 autoantibody:IL-8 immune complexes in pathogenesis of ALI/ARDS is discussed.
Association of low-grade inflammation and platelet activation in patients with hypertension with microalbuminuria
Authors: Ferroni Patrizia , Guagnano Maria Teresa , Falco Angela , Paoletti Vincenzo , Manigrasso Maria Rosaria , Michetti Noemi , Santilli Francesca , Guadagni Fiorella , Basili Stefania , Davì Giovanni
Published: February 2008

Increased levels of sCD40L (soluble CD40 ligand) have been associated with enhanced in vivo platelet activation, and may represent a molecular link between inflammation and a prothrombotic state. The aim of the present study was to analyse the relationship between platelet activation, endothelial dysfunction, low-grade inflammation and sCD40L in patients with hypertension with or without MA (microalbuminuria). A cross-sectional comparison of sCD40L levels was performed in 25 patients with MH (essential hypertension with MA) pair-matched for gender and age with 25 patients with EH (essential hypertension) and 25 HS (healthy subjects with normotension). Circulating levels of CRP (C-reactive protein), a marker of inflammation, sP-selectin (soluble P-selectin), a marker of in vivo platelet activation, and ADMA (asymmetric dimethylarginine) and vWF (von Willebrand factor), markers of endothelial dysfunction, were analysed in each subject. sCD40L levels were increased in patients with MH compared with either patients with EH (P<0.001) or HS (P<0.0001). A highly significant correlation between plasma sCD40L and sP-selectin (P<0.0001), vWF (P<0.001) or CRP levels (P<0.05) was observed in patients with MH. Multivariate regression analysis showed that sP-selectin was the strongest independent predictor of sCD40L levels (P<0.0001) in patients with MH. Patients with hypertension with both vWF and CRP levels above the median had the highest sCD40L levels (P<0.0001). Factorial ANOVA of all of the patients with hypertension confirmed that only patients with MH with low-grade inflammation had elevated levels of sCD40L. In conclusion, sCD40L levels appear to discriminate a subset of patients characterized by MA and low-grade inflammation, suggesting that inhibition of the CD40/CD40L system may represent a potential therapeutic target in subjects with hypertension at a high risk of cardiovascular events.
Preparation and magnetic properties of monodisperse Permalloy hollow spheres
Authors: Lin Chun-Rong , Hsieh Ming-Hsiu , Siao Yu-Jhan , Wang Cheng-Chien
Published: February 2008

The ionic poly(methyl methacrylate-co-methacrylic acid) copolymer sphere (500nm) was used as a core template to prepare monodisperse Ni80Fe20∕SiO2 hollow spheres. The hollow Ni80Fe20∕SiO2 spherical structures were synthesized by coprecipitating metallic oxides of nickel and iron on the surface of the ionic polymer spheres and reducing in H2∕Ar mixed gas following heat treatment in air. The Ni80Fe20 nanoparticles involved in hollow spheres have face-centered-cubic structure and mean crystallite sizes ranging from 5.5to22.1nm. In addition, these hollow spheres have uniform size with shell thickness of 80nm and contain 71wt% of Ni80Fe20 alloy. Magnetic measurements show that the hollow spheres containing Ni80Fe20 nanoparticles with crystallite size d⩾10.9nm reveal ferromagnetic property, while those with d⩽6.7nm display a superparamagnetic behavior.
Microtexture of magnetite thin films of (001) and (111) orientations on MgO substrates studied by electron-backscatter diffraction
Authors: Koblischka-Veneva A. , Koblischka M. R. , Murphy S. , Arora S. K. , Mücklich F. , Hartmann U. , Shvets I. V.
Published: February 2008

The grain orientation of (001)- and (111)-oriented magnetite thin films grown on MgO substrates (film thickness of 100–400nm) is analyzed by means of the electron-backscatter diffraction (EBSD) technique. The (001) surface after a short annealing in air (1min, 250°C) is characterized by the presence of tiny (diameter of 100–200nm) misoriented islands, which have an influence on the antiferromagnetic coupling within the film. In the (111)-oriented films, such defects are found to be absent, and the films show a very homogeneous surface. The achieved spatial resolution enables further a cross-section analysis of a 400-nm-thick film with (001) orientation, even close to the interface MgO-magnetite.
Effects of an external electric field on the ferroelectric-paraelectric phase transition in polyvinylidene fluoride-trifluoroethylene copolymer Langmuir–Blodgett films
Authors: Poulsen Matt , Sorokin A. V. , Adenwalla S. , Ducharme Stephen , Fridkin V. M.
Published: February 2008

X-ray diffraction and capacitance measurements have been employed to study the structural and dielectric behavior of the ferroelectric-paraelectric phase transition under the influence of a large external electric field. The samples under study are ultrathin (15–100nm) Langmuir–Blodgett films of a copolymer of vinylidene fluoride (70%) with trifluoroethylene (30%) deposited on aluminum-coated silicon. In situ θ-2θ x-ray diffraction was used to measure the change in interlayer spacing perpendicular to the film surface, corresponding to the (110) direction and indicating that the polymer chains along (001) lie predominantly in the plane, while capacitance measurements were used to monitor the behavior of the dielectric constant of the film. Application of a large electric field, up to 265MV∕m, raises the phase transition temperature and can convert the nonpolar trans-gauche paraelectric phase to the polar all-trans ferroelectric phase in a reversible manner.
Effect of interstitial C incorporation on the Raman scattering of Si1−x−yGexCy epitaxial layer
Authors: Choi Suk , Kim Hyun Woo , Kim Hee Jin , Hong Sukwon , Lee Gun-Do , Yoon Euijoon
Published: February 2008

We performed Raman spectroscopy on the Si1−x−yGexCy epitaxial layers grown on Si substrates by ultrahigh vacuum chemical vapor deposition. The incorporation of substitutional C atoms reduces the Si–Si mode frequency of Si1−x−yGexCy, whereas the interstitial C incorporation shifts it up. The ab initio phonon frequency calculation considering the most stable interstitial C site was performed to verify our results and we showed that the V-shaped behavior, showing the decrease and increase of Si–Si mode frequency as the amount of C, originated from the effect of interstitial C incorporation and proposed that the Si–Si Raman vibrational mode frequency shift can be used as a tool to observe interstitial C atoms.
Laminated active matrix organic light-emitting devices
Authors: Liu Hongyu , Sun Runguang
Published: February 2008

Laminated active matrix organic light-emitting device (AMOLED) realizing top emission by using bottom-emitting organic light-emitting diode (OLED) structure was proposed. The multilayer structure of OLED deposited in the conventional sequence is not on the thin film transistor (TFT) backplane but on the OLED plane. The contact between the indium tin oxide (ITO) electrode of TFT backplane and metal cathode of OLED plane is implemented by using transfer electrode. The stringent pixel design for aperture ratio of the bottom-emitting AMOLED, as well as special technology for the top ITO electrode of top-emitting AMOLED, is unnecessary in the laminated AMOLED.
Aerosol immunization with NYVAC and MVA vectored vaccines is safe, simple, and immunogenic
Authors: Corbett Max , Bogers Willy M. , Heeney Jonathan L. , Gerber Stefan , Genin Christian , Didierlaurent Arnaud , Oostermeijer Herman , Dubbes Rob , Braskamp Gerco , Lerondel Stéphanie , Gomez Carmen E. , Esteban Mariano , Wagner Ralf , Kondova Ivanella , Mooij Petra , Balla-Jhagjhoorsingh Sunita , Beenhakker Niels , Koopman Gerrit , van der Burg Sjoerd , Kraehenbuhl Jean-Pierre , Le Pape Alain
Published: February 2008

Each year, approximately five million people die worldwide from putatively vaccine-preventable mucosally transmitted diseases. With respect to mass vaccination campaigns, one strategy to cope with this formidable challenge is aerosol vaccine delivery, which offers potential safety, logistical, and cost-saving advantages over traditional vaccination routes. Additionally, aerosol vaccination may elicit pivotal mucosal immune responses that could contain or eliminate mucosally transmitted pathogens in a preventative or therapeutic vaccine context. In this current preclinical non-human primate investigation, we demonstrate the feasibility of aerosol vaccination with the recombinant poxvirus-based vaccine vectors NYVAC and MVA. Real-timein vivoscintigraphy experiments with radiolabeled, aerosol-administered NYVAC-C (Clade C, HIV-1 vaccine) and MVA-HPV vaccines revealed consistent mucosal delivery to the respiratory tract. Furthermore, aerosol delivery of the vaccines was safe, inducing no vaccine-associated pathology, in particular in the brain and lungs, and was immunogenic. Administration of a DNA-C/NYVAC-C prime/boost regime resulted in both systemic and anal-genital HIV-specific immune responses that were still detectable 5 months after immunization. Thus, aerosol vaccination with NYVAC and MVA vectored vaccines constitutes a tool for large-scale vaccine efforts against mucosally transmitted pathogens.
Enzymes of the shikimic acid pathway encoded in the genome of a basal metazoan,
Nematostella vectensis
, have microbial origins
Authors: Starcevic Antonio , Akthar Shamima , Dunlap Walter C. , Shick J. Malcolm , Hranueli Daslav , Cullum John , Long Paul F.
Published: February 2008

The shikimic acid pathway is responsible for the biosynthesis of many aromatic compounds by a broad range of organisms, including bacteria, fungi, plants, and some protozoans. Animals are considered to lack this pathway, as evinced by their dietary requirement for shikimate-derived aromatic amino acids. We challenge the universality of this traditional view in this report of genes encoding enzymes for the shikimate pathway in an animal, the starlet sea anemone
Nematostella vectensis
. Molecular evidence establishes horizontal transfer of ancestral genes of the shikimic acid pathway into the
N. vectensis
genome from both bacterial and eukaryotic (dinoflagellate) donors. Bioinformatic analysis also reveals four genes that are closely related to those of
Tenacibaculum
sp. MED152, raising speculation for the existence of a previously unsuspected bacterial symbiont. Indeed, the genome of the holobiont (i.e., the entity consisting of the host and its symbionts) comprises a high content of
Tenacibaculum
-like gene orthologs, including a 16S rRNA sequence that establishes the phylogenetic position of this associate to be within the family Flavobacteriaceae. These results provide a complementary view for the biogenesis of shikimate-related metabolites in marine Cnidaria as a “shared metabolic adaptation” between the partners.
Discovery of a rare arboreal forest-dwelling flying reptile (Pterosauria, Pterodactyloidea) from China
Authors: Wang Xiaolin , Kellner Alexander W. A. , Zhou Zhonghe , de Almeida Campos Diogenes
Published: February 2008

A previously undescribed toothless flying reptile from northeastern China,
Nemicolopterus crypticus
gen. et sp. nov., was discovered in the lacustrine sediments of the Early Cretaceous Jiufotang Formation, western Liaoning, China. The specimen consists of an almost complete articulated skeleton (IVPP V14377) and, despite representing an immature individual, based on the ossification of the skeleton, it is not a hatchling or newborn, making it one of the smallest pterosaurs known so far (wing span ≈250 mm). It can be distinguished from all other pterosaurs by the presence of a short medial nasal process, an inverted “knife-shaped” deltopectoral crest of the humerus, and the presence of a well developed posterior process on the femur above the articulation with the tibia. It further shows the penultimate phalanges of the foot curved in a degree not reported in any pterosaur before, strongly indicating that it had an arboreal lifestyle, more than any other pterodactyloid pterosaur known so far. It is the sister-group of the Ornithocheiroidea and indicates that derived pterosaurs, including some gigantic forms of the Late Cretaceous with wingspans of >6 m, are closely related to small arboreal toothless creatures that likely were living in the canopies of the ancient forests feeding on insects.
Bayesian learning of visual chunks by human observers
Authors: Orbán Gergő , Fiser József , Aslin Richard N. , Lengyel Máté
Published: February 2008

Efficient and versatile processing of any hierarchically structured information requires a learning mechanism that combines lower-level features into higher-level chunks. We investigated this chunking mechanism in humans with a visual pattern-learning paradigm. We developed an ideal learner based on Bayesian model comparison that extracts and stores only those chunks of information that are minimally sufficient to encode a set of visual scenes. Our ideal Bayesian chunk learner not only reproduced the results of a large set of previous empirical findings in the domain of human pattern learning but also made a key prediction that we confirmed experimentally. In accordance with Bayesian learning but contrary to associative learning, human performance was well above chance when pair-wise statistics in the exemplars contained no relevant information. Thus, humans extract chunks from complex visual patterns by generating accurate yet economical representations and not by encoding the full correlational structure of the input.
Temporal and spatial changes in social vulnerability to natural hazards
Authors: Cutter Susan L. , Finch Christina
Published: February 2008

During the past four decades (1960–2000), the United States experienced major transformations in population size, development patterns, economic conditions, and social characteristics. These social, economic, and built-environment changes altered the American hazardscape in profound ways, with more people living in high-hazard areas than ever before. To improve emergency management, it is important to recognize the variability in the vulnerable populations exposed to hazards and to develop place-based emergency plans accordingly. The concept of social vulnerability identifies sensitive populations that may be less likely to respond to, cope with, and recover from a natural disaster. Social vulnerability is complex and dynamic, changing over space and through time. This paper presents empirical evidence on the spatial and temporal patterns in social vulnerability in the United States from 1960 to the present. Using counties as our study unit, we found that those components that consistently increased social vulnerability for all time periods were density (urban), race/ethnicity, and socioeconomic status. The spatial patterning of social vulnerability, although initially concentrated in certain geographic regions, has become more dispersed over time. The national trend shows a steady reduction in social vulnerability, but there is considerable regional variability, with many counties increasing in social vulnerability during the past five decades.
An experimental survey of the transition between two-state and downhill protein folding scenarios
Authors: Liu Feng , Du Deguo , Fuller Amelia A. , Davoren Jennifer E. , Wipf Peter , Kelly Jeffery W. , Gruebele Martin
Published: February 2008

A kinetic and thermodynamic survey of 35 WW domain sequences is used in combination with a model to discern the energetic requirements for the transition from two-state folding to downhill folding. The sequences used exhibit a 600-fold range of folding rates at the temperature of maximum folding rate. Very stable proteins can achieve complete downhill folding when the temperature is lowered sufficiently below the melting temperature, and then at even lower temperatures they become two-state folders again because of cold denaturation. Less stable proteins never achieve a sufficient bias to fold downhill because of the onset of cold denaturation. The model, considering both heat and cold denaturation, reveals that to achieve incipient downhill folding (barrier <3
RT
) or downhill folding (no barrier), the WW domain average melting temperatures have to be ≥50°C for incipient downhill folding and ≥90°C for downhill folding.
The PD-1/PD-L costimulatory pathway critically affects host resistance to the pathogenic fungusHistoplasma capsulatum
Authors: Lázár-Molnár Eszter , Gácser Attila , Freeman Gordon J. , Almo Steven C. , Nathenson Stanley G. , Nosanchuk Joshua D.
Published: February 2008

The PD-1 costimulatory receptor inhibits T cell receptor signaling upon interacting with its ligands PD-L1 and PD-L2. The PD-1/PD-L pathway is critical in maintaining self-tolerance. In this study, we examined the role of PD-1 in a mouse model of acute infection withHistoplasma capsulatum, a major human pathogenic fungus. In a lethal model of histoplasmosis, all PD-1-deficient mice survived infection, whereas the wild-type mice died with disseminated disease. PD-L expression on macrophages and splenocytes was up-regulated during infection, and macrophages from infected mice inhibitedin vitroT cell activation. Of interest, antibody blocking of PD-1 significantly increased survival of lethally infected wild-type mice. Thus, our studies extend the role of the PD-1/PD-L pathway in regulating antimicrobial immunity to fungal pathogens. The results show that the PD-1/PD-L pathway has a key role in the regulation of antifungal immunity, and suggest that manipulation of this pathway represents a strategy of immunotherapy for histoplasmosis.
Amyloid of Rnq1p, the basis of the [
PIN
+
] prion, has a parallel in-register β-sheet structure
Authors: Wickner Reed B. , Dyda Fred , Tycko Robert
Published: February 2008

The [PIN
+
] prion, a self-propagating amyloid form of Rnq1p, increases the frequency with which the [
PSI
+
] or [URE3] prions arise
de novo
. Like the prion domains of Sup35p and Ure2p, Rnq1p is
r
ich in
N
and
Q
residues, but
rnq1
Δ strains have no known phenotype except for inability to propagate the [PIN
+
] prion. We used solid-state NMR methods to examine amyloid formed
in vitro
from recombinant Rnq1 prion domain (residues 153–405) labeled with Tyr-1–
13
C (14 residues), Leu-1–
13
C (7 residues), or Ala-3–
13
C (13 residues). The carbonyl chemical shifts indicate that most Tyr and Leu residues are in β-sheet conformation. Experiments designed to measure the distance from each labeled residue to the next nearest labeled carbonyl showed that almost all Tyr and Leu carbonyl carbon atoms were ≈0.5 nm from the next nearest Tyr and Leu residues, respectively. This result indicates that the Rnq1 prion domain forms amyloid consisting of parallel β-strands that are either in register or are at most one amino acid out of register. Similar experiments with Ala-3–
13
C indicate that the β-strands are indeed in-register. The parallel in-register structure, now demonstrated for each of the yeast prions, explains the faithful templating of prion strains, and suggests as well a mechanism for the rare hetero-priming that is [
PIN
+
]'s defining characteristic.
Mechanisms of prion protein assembly into amyloid
Authors: Stöhr Jan , Weinmann Nicole , Wille Holger , Kaimann Tina , Nagel-Steger Luitgard , Birkmann Eva , Panza Giannantonio , Prusiner Stanley B. , Eigen Manfred , Riesner Detlev
Published: February 2008

The conversion of the α-helical, cellular isoform of the prion protein (PrP
C
) to the insoluble, β-sheet-rich, infectious, disease-causing isoform (PrP
Sc
) is the key event in prion diseases. In an earlier study, several forms of PrP were converted into a fibrillar state by using an
in vitro
conversion system consisting of low concentrations of SDS and 250 mM NaCl. Here, we characterize the structure of the fibril precursor state, that is, the soluble state under fibrillization conditions. CD spectroscopy, analytical ultracentrifugation, and chemical cross-linking indicate that the precursor state exists in a monomer-dimer equilibrium of partially denatured, α-helical PrP, with a well defined contact site of the subunits in the dimer. Using fluorescence with thioflavin T, we monitored and quantitatively described the kinetics of seeded fibril formation, including dependence of the reaction on substrate and seed concentrations. Exponential, seed-enhanced growth can be achieved in homogeneous solution, which can be enhanced by sonication. From these data, we propose a mechanistic model of fibrillization, including the presence of several intermediate structures. These studies also provide a simplified amplification system for prions.
IKKα is a critical coregulator of a Smad4-independent TGFβ-Smad2/3 signaling pathway that controls keratinocyte differentiation
Authors: Descargues Pascal , Sil Alok K. , Sano Yuji , Korchynskyi Olexandr , Han Gangwen , Owens Philip , Wang Xiao-Jing , Karin Michael
Published: February 2008

Cell-cycle exit and differentiation of suprabasal epidermal keratinocytes require nuclear IκB kinase α (IKKα), but not its protein kinase activity. IKKα also is a suppressor of squamous cell carcinoma (SCC), but its mode of action remains elusive. Postulating that IKKα may serve as a transcriptional regulator in keratinocytes, we searched for cell-cycle-related genes that could illuminate this function. IKKα was found to control several Myc antagonists, including
Mad1
,
Mad2
, and
Ovol1
, through the association with TGFβ-regulated Smad2/3 transcription factors and is required for Smad3 recruitment to at least one of these targets. Surprisingly, Smad2/3-dependent
Mad1
induction and keratinocyte differentiation are independent of Smad4, the almost universal coregulator of canonical TGFβ signaling. IKKα also is needed for nuclear accumulation of activated Smad2/3 in the epidermis, and Smad2/3 are required for epidermal differentiation. We suggest that a TGFβ–Smad2/3–IKKα axis is a critical Smad4-independent regulator of keratinocyte proliferation and differentiation.
The genome landscape of ERα- and ERβ-binding DNA regions
Authors: Liu Yawen , Gao Hui , Marstrand Troels Torben , Ström Anders , Valen Eivind , Sandelin Albin , Gustafsson Jan-Åke , Dahlman-Wright Karin
Published: February 2008

In this article, we have applied the ChIP-on-chip approach to pursue a large scale identification of ERα- and ERβ-binding DNA regions in intact chromatin. We show that there is a high degree of overlap between the regions identified as bound by ERα and ERβ, respectively, but there are also regions that are bound by ERα only in the presence of ERβ, as well as regions that are selectively bound by either receptor. Analysis of bound regions shows that regions bound by ERα have distinct properties in terms of genome landscape, sequence features, and conservation compared with regions that are bound by ERβ. ERβ-bound regions are, as a group, located more closely to transcription start sites. ERα- and ERβ-bound regions differ in sequence properties, with ERα-bound regions having an overrepresentation of TA-rich motifs including forkhead binding sites and ERβ-bound regions having a predominance of classical estrogen response elements (EREs) and GC-rich motifs. Differences in the properties of ER bound regions might explain some of the differences in gene expression programs and physiological effects shown by the respective estrogen receptors.
Remote detection of nuclear magnetic resonance with an anisotropic magnetoresistive sensor
Authors: Verpillat F. , Ledbetter M. P. , Xu S. , Michalak D. J. , Hilty C. , Bouchard L.-S. , Antonijevic S. , Budker D. , Pines A.
Published: February 2008

We report the detection of nuclear magnetic resonance (NMR) using an anisotropic magnetoresistive (AMR) sensor. A “remote-detection” arrangement was used in which protons in flowing water were prepolarized in the field of a superconducting NMR magnet, adiabatically inverted, and subsequently detected with an AMR sensor situated downstream from the magnet and the adiabatic inverter. AMR sensing is well suited for NMR detection in microfluidic “lab-on-a-chip” applications because the sensors are small, typically on the order of 10 μm. An estimate of the sensitivity for an optimized system indicates that ≈6 × 10
13
protons in a volume of 1,000 μm
3
, prepolarized in a 10-kG magnetic field, can be detected with a signal-to-noise ratio of 3 in a 1-Hz bandwidth. This level of sensitivity is competitive with that demonstrated by microcoils in superconducting magnets and with the projected sensitivity of microfabricated atomic magnetometers.
Chemically modified β-glucuronidase crosses blood–brain barrier and clears neuronal storage in murine mucopolysaccharidosis VII
Authors: Grubb Jeffrey H. , Vogler Carole , Levy Beth , Galvin Nancy , Tan Yun , Sly William S.
Published: February 2008

Enzyme replacement therapy has been used successfully in many lysosomal storage diseases. However, correction of brain storage has been limited by the inability of infused enzyme to cross the blood–brain barrier. The newborn mouse is an exception because recombinant enzyme is delivered to neonatal brain after mannose 6-phosphate receptor-mediated transcytosis. Access to this route is very limited after 2 weeks of age. Recently, several studies showed that multiple infusions of high doses of enzyme partially cleared storage in adult brain. These results raised the question of whether correction of brain storage by repeated high doses of enzyme depends on mannose 6-phosphate receptor-mediated uptake or whether enzyme gains access to brain storage by another route when brain capillaries are exposed to prolonged, high levels of circulating enzyme. To address this question, we used an enzyme whose carbohydrate-dependent receptor-mediated uptake was inactivated by chemical modification. Treatment of human β-glucuronidase (GUS) with sodium metaperiodate followed by sodium borohydride reduction (PerT-GUS) eliminated uptake by mannose 6-phosphate and mannose receptors in cultured cells and dramatically slowed its plasma clearance from a
t
½ of <10 min to 18 h. Surprisingly, PerT-GUS infused weekly for 12 weeks was more effective in clearing central nervous system storage than native GUS at the same dose. In fact, PerT-GUS resulted in almost complete reversal of storage in neocortical and hippocampal neurons. This enhanced correction of neuronal storage by long-circulating enzyme, which targets no known receptor, suggests a delivery system across the blood–brain barrier that might be exploited therapeutically.
ATF3 regulates MCMV infection in mice by modulating IFN-γ expression in natural killer cells
Authors: Rosenberger Carrie M. , Clark April E. , Treuting Piper M. , Johnson Carrie D. , Aderem Alan
Published: February 2008

Activating transcription factor 3 (ATF3) is a negative regulator of proinflammatory cytokine expression in macrophages, and ATF3-deficient mice are more susceptible to endotoxic shock. Here, we demonstrate that ATF3 interacts with acis-regulatory element of the IFN-γ gene in natural killer (NK) cells, and that ATF3null NK cells show increased transcription and secretion of IFN-γ. NK cell-derived IFN-γ has previously been demonstrated to be protective against murine cytomegalovirus (MCMV) infection, and we show here that ATF3null mice exhibit decreased hepatic viral load and reduced liver histopathology upon challenge with MCMV. Reconstitution of NK-deficient mice with ATF3null NK cells more effectively controlled MCMV infection than mice reconstituted with WT cells, indicating that ATF3 acts within NK cells to regulate antiviral responses.
Role of Bv8 in neutrophil-dependent angiogenesis in a transgenic model of cancer progression
Authors: Shojaei Farbod , Singh Mallika , Thompson Jennifer D. , Ferrara Napoleone
Published: February 2008

The secreted Bv8 protein has been recently characterized as a regulator of myeloid cell mobilization and a neutrophil-derived mediator of tumor angiogenesis in several xenografts, but its role in tumor progression in an endogenous setting was unknown. The rat insulin promoter (RIP)–T-antigen (Tag) is a well characterized transgenic mouse model of multistage pancreatic β-cell tumorigenesis. Also, the role of neutrophils in RIP-Tag angiogenic switching, as assessed by systemic ablation using anti-Gr1 antibodies at different stages of tumor progression, has been recently described. Here, we show that early treatment of RIP-Tag mice with anti-Bv8 antibodies resulted in a significant reduction in the number of angiogenic islets relative to control antibody-treated mice, implicating Bv8 in the angiogenic switch during neoplasia. Histological analysis showed a significant reduction in vascular surface areas in hyperplastic and angiogenic lesions in pancreatic islets from anti-Bv8-treated mice. Anti-Bv8 treatment also inhibited the mobilization and homing of CD11b+Gr1+ cells to the peripheral blood and the emerging neoplastic lesions. However, anti-Bv8 treatment had no effect on tumor vascularization or burden when initiated at later stages of tumor progression. The stage-dependent efficacy of anti-Bv8 treatment appears remarkably similar to that reported after neutrophil ablation, suggesting that Bv8 is an important mediator of neutrophil-dependent angiogenesis in this transgenic model. In summary, our studies verify a role for Bv8 in the mobilization and recruitment of myeloid cells and in the induction of tumor angiogenesis in the early stages of neoplastic progression.
Anthrax lethal toxin induces cell death-independent permeability in zebrafish vasculature
Authors: Bolcome Robert E. , Sullivan Sarah E. , Zeller René , Barker Adam P. , Collier R. John , Chan Joanne
Published: February 2008

Vascular dysfunction has been reported in human cases of anthrax, in mammalian models of
Bacillus anthracis
, and in animals injected with anthrax toxin proteins. To examine anthrax lethal toxin effects on intact blood vessels, we developed a zebrafish model that permits
in vivo
imaging and evaluation of vasculature and cardiovascular function. Vascular defects monitored in hundreds of embryos enabled us to define four stages of phenotypic progression leading to circulatory dysfunction. We demonstrated increased endothelial permeability as an early consequence of toxin action by tracking the extravasation of fluorescent microspheres in toxin-injected embryos. Lethal toxin did not induce a significant amount of cell death in embryonic tissues or blood vessels, as shown by staining with acridine orange, and endothelial cells in lethal toxin-injected embryos continued to divide at the normal rate. Vascular permeability is strongly affected by the VEGF/vascular permeability factor (VPF) signaling pathway, and we were able to attenuate anthrax lethal toxin effects with chemical inhibitors of VEGFR function. Our study demonstrates the importance of vascular permeability in anthrax lethal toxin action and the need for further investigation of the cardiovascular component of human anthrax disease.
Gene deletion of inositol hexakisphosphate kinase 1 reveals inositol pyrophosphate regulation of insulin secretion, growth, and spermiogenesis
Authors: Bhandari Rashna , Juluri Krishna R. , Resnick Adam C. , Snyder Solomon H.
Published: February 2008

Inositol pyrophosphates, also designated inositol diphosphates, possess high-energy β-phosphates that can pyrophosphorylate proteins and regulate various cellular processes. They are formed by a family of inositol hexakisphosphate kinases (IP6Ks). We have created mice with a targeted deletion of IP6K1 in which production of inositol pyrophosphates is markedly diminished. Defects in the mutants indicate important roles for IP6K1 and inositol pyrophosphates in several physiological functions. Male mutant mice are sterile with defects in spermiogenesis. Mutant mice are smaller than wild-type despite normal food intake. The mutants display markedly lower circulating insulin.
A W-linked DM-domain gene, DM-W, participates in primary ovary development in
Xenopus laevis
Authors: Yoshimoto Shin , Okada Ema , Umemoto Hirohito , Tamura Kei , Uno Yoshinobu , Nishida-Umehara Chizuko , Matsuda Yoichi , Takamatsu Nobuhiko , Shiba Tadayoshi , Ito Michihiko
Published: February 2008

In the XX/XY sex-determining system, the Y-linked
SRY
genes of most mammals and the
DMY
/
Dmrt1bY
genes of the teleost fish medaka have been characterized as sex-determining genes that trigger formation of the testis. However, the molecular mechanism of the ZZ/ZW-type system in vertebrates, including the clawed frog
Xenopus laevis
, is unknown. Here, we isolated an
X. laevis
female genome-specific DM-domain gene,
DM-W
, and obtained molecular evidence of a W-chromosome in this species. The DNA-binding domain of DM-W showed a strikingly high identity (89%) with that of DMRT1, but it had no significant sequence similarity with the transactivation domain of DMRT1. In nonmammalian vertebrates, DMRT1 expression is connected to testis formation. We found
DMRT1
or
DM-W
to be expressed exclusively in the primordial gonads of both ZZ and ZW or ZW tadpoles, respectively. Although
DMRT1
showed continued expression after sex determination,
DM-W
was expressed transiently during sex determination. Interestingly,
DM-W
mRNA was more abundant than
DMRT1
mRNA in the primordial gonads of ZW tadpoles early in sex determination. To assess the role of DM-W, we produced transgenic tadpoles carrying a DM-W expression vector driven by ≈3 kb of the 5′-flanking sequence of
DM-W
or by the cytomegalovirus promoter. Importantly, some developing gonads of ZZ transgenic tadpoles showed ovarian cavities and primary oocytes with both drivers, suggesting that DM-W is crucial for primary ovary formation. Taken together, these results suggest that
DM-W
is a likely sex (ovary)-determining gene in
X. laevis
.
A cell-type-specific requirement for IFN regulatory factor 5 (IRF5) in Fas-induced apoptosis
Authors: Couzinet Arnaud , Tamura Kaoru , Chen Hui-min , Nishimura Keishiro , Wang ZhiChao , Morishita Yasuyuki , Takeda Kazuyoshi , Yagita Hideo , Yanai Hideyuki , Taniguchi Tadatsugu , Tamura Tomohiko
Published: February 2008

Apoptosis is a highly regulated process of cell suicide that occurs during development, host defense, and pathophysiology. The transcription factor IFN regulatory factor 5 (IRF5), known to be involved in the activation of innate immune responses, recently has been shown to be critical for DNA damage-induced apoptosis and tumor suppression. Here, we report on a cell-type-specific role of IRF5 in promoting apoptosis upon signaling through the death receptor Fas (CD95/APO-1/TNFRSF6). In particular, we show that mice deficient in the
Irf5
gene are resistant to hepatic apoptosis and lethality in response to the
in vivo
administration of a Fas-activating monoclonal antibody, and that IRF5 is involved in a stage of Fas signaling that precedes the activation of caspase 8 and c-Jun N-terminal kinase (JNK). In addition to hepatocytes, IRF5 is also required for apoptosis in dendritic cells activated by hypomethylated CpG but not in thymocytes and embryonic fibroblasts
in vitro
. Thus, these findings reveal a cell-type-specific function for IRF5 in the complex regulatory mechanism of death-receptor-induced apoptosis.
Developing understanding about learning to teach in a university–schools partnership in England
Authors: Taylor Alexis
Published: February 2008

This study aims to provide some clarity about how learning to teach is understood by university teacher educators, mentors and students. Initial teacher education (ITE) in England is subject to central government legislation but without prescription for local implementation. Semi‐structured interview data was collected from key partners in a local university–schools partnership working within this central framework. Four ways of understanding learning to teach were identified, labelled: Cascading Expertise; Enabling Students' Individual Growth as a Teacher; Developing Student Teaching; and Student as Teacher and Learner. Each is characterised by an internal relationship between how teaching, student learning and partnership are understood, and relate across the groups, and not between the groups of the key partners. Each of these ways of understanding is discussed in relation to teaching, student learning and partnership development within a centrally imposed model. The possibility of a hierarchical relationship between these ways of understanding is highlighted and, along with other associated possibilities, is suggested as an area for further research.
Does school‐based initial teacher training affect secondary school performance?
Authors: Hurd Steve
Published: February 2008

This article investigates the effects of trainee teachers on secondary school student outcomes. The additional resources which schools receive from being involved in teacher training offer them an opportunity to raise standards, but this has to be set against the possible losses due to school students being taught by inexperienced beginning teachers and the diversion of mentors' efforts away from the classroom. Inspection evidence is used to assess whether trainee teachers affect school students' test and examination results. The findings of this research are that the number of trainees has no significant effect on school results at A‐level or General Certificate of Secondary Education (GCSE), or on the overall value added between Key Stage 3 and GCSE level. However, at Key Stage 3 level at age 14, while there appears to be a very small depressing effect on achievement in schools with low numbers of trainees, there is a significant positive effect on achievement in schools with larger numbers of trainees.
Reinventing Japan Inc.: Twenty‐First Century Innovation Strategies in Japan
Authors: Holroyd Carin
Published: February 2008

Japan has been a key player in the global competition based on scientific and technological innovation. Through a series of Science and Technology Basic Plans, the national government sought to restructure the country’s approach to scientific and technological development, with initiatives ranging from a fundamental restructuring of public universities to major investments in regional clusters. Collaboration with business has likewise been a centerpiece of the Japan strategy, as has high level political leadership of the broad initiative. This paper examines the international and national context of Japanese innovation, outlines the core elements of the Japanese innovation strategy, and provides preliminary observations about the first decade of the country’s extensive efforts to establish Japan as a global leader in the commercialization of science and technology.
Promoting University–Industry Linkages in Japan: Faculty Responses to a Changing Policy Environment
1
Authors: Walsh John P. , Baba Yasunori , Goto Akira , Yasaki Yoshihito
Published: February 2008

Since the mid‐1990s, Japan has instituted a series of policy reforms in order to encourage greater university participation in commercial activity. Using data from a survey of scientists in engineering and biomedical fields in Japanese universities, we find that there has been a significant increase in commercial activity during this period, in particular, links to small‐ and medium‐sized enterprises. We also find that scientists are increasingly considering business potential when choosing projects. However, we find little evidence of the increasing commercialization leading to barriers to access to research tools. We also find that, despite the growing importance of formalized university–industry ties, university–industry linkages continue to be dominated by informal ties and gift‐exchange.
The Kyoto Model of Innovation and Entrepreneurship: Regional Innovation Systems and Cluster Culture
Authors: Ibata‐Arens Kathryn
Published: February 2008

Why is it that Kyoto, ancient cultural capital of Japan, a conservative and traditional place in many ways, manages to produce Japan’s most innovative (and profitable) high technology entrepreneurial firms? Further, what causes regions such as Kyoto to create a self‐sustaining critical mass, or cluster, of new venture start‐ups in emerging sectors? Can this success in ‘clustering’ entrepreneurial businesses be replicated elsewhere? For example, what are the most effective ways to encourage new start‐ups and connect fledgling firms to critical resources? The findings herein are based primarily on original case study survey and interview data from 29 life science start‐ups and the entrepreneurs at their helms, representing more than half of all life science start‐ups in Kyoto. I identify best practices in firm‐level strategy and entrepreneurship policy in what I call the Kyoto Model of Entrepreneurship and Innovation, highlighting entrepreneurial case studies of successful start‐ups. I also analyze factors leading to successful new business clusterization through analysis of entrepreneurial social networks and resource environments. Situating the findings within national innovation and entrepreneurship policies in Japan, I present a new model for regional innovation systems (RIS) and cluster emergence. I also include brief comparisons to life science clusters (and want‐to‐be clusters) in Japan and the United States, based on additional original survey and interview research in other regional clusters in each country.
Microbe sampling by mucosal dendritic cells is a discrete, MyD88-independent stepin ΔinvG S. Typhimurium colitis
Authors: Hapfelmeier Siegfried , Müller Andreas J. , Stecher Bärbel , Kaiser Patrick , Barthel Manja , Endt Kathrin , Eberhard Matthias , Robbiani Riccardo , Jacobi Christoph A. , Heikenwalder Mathias , Kirschning Carsten , Jung Steffen , Stallmach Thomas , Kremer Marcus , Hardt Wolf-Dietrich
Published: February 2008

Intestinal dendritic cells (DCs) are believed to sample and present commensal bacteria to the gut-associated immune system to maintain immune homeostasis. How antigen sampling pathways handle intestinal pathogens remains elusive. We present a murine colitogenic Salmonella infection model that is highly dependent on DCs. Conditional DC depletion experiments revealed that intestinal virulence of S. Typhimurium SL1344 ΔinvG mutant lacking a functional type 3 secretion system-1 (ΔinvG)critically required DCs for invasion across the epithelium. The DC-dependency was limited to the early phase of infection when bacteria colocalized with CD11c+CX3CR1+ mucosal DCs. At later stages, the bacteria became associated with other (CD11c−CX3CR1−) lamina propria cells, DC depletion no longer attenuated the pathology, and a MyD88-dependent mucosal inflammation was initiated. Using bone marrow chimeric mice, we showed that the MyD88 signaling within hematopoietic cells, which are distinct from DCs, was required and sufficient for induction of the colitis. Moreover, MyD88-deficient DCs supported transepithelial uptake of the bacteria and the induction of MyD88-dependent colitis. These results establish that pathogen sampling by DCs is a discrete, and MyD88-independent, step during the initiation of a mucosal innate immune response to bacterial infection in vivo.
Essential but differential role for CXCR4 and CXCR7 in the therapeutic homingof human renal progenitor cells
Authors: Mazzinghi Benedetta , Ronconi Elisa , Lazzeri Elena , Sagrinati Costanza , Ballerini Lara , Angelotti Maria Lucia , Parente Eliana , Mancina Rosa , Netti Giuseppe Stefano , Becherucci Francesca , Gacci Mauro , Carini Marco , Gesualdo Loreto , Rotondi Mario , Maggi Enrico , Lasagni Laura , Serio Mario , Romagnani Sergio , Romagnani Paola
Published: February 2008

Recently, we have identified a population of renal progenitor cells in human kidneys showing regenerative potential for injured renal tissue of SCID mice. We demonstrate here that among all known chemokine receptors, human renal progenitor cells exhibit high expression of both stromal-derived factor-1 (SDF-1) receptors, CXCR4 and CXCR7. In SCID mice with acute renal failure (ARF), SDF-1 was strongly up-regulated in resident cells surrounding necrotic areas. In the same mice, intravenously injected renal stem/progenitor cells engrafted into injured renal tissue decreased the severity of ARF and prevented renal fibrosis. These beneficial effects were abolished by blocking either CXCR4 or CXCR7, which dramatically reduced the number of engrafting renal progenitor cells. However, although SDF-1–induced migration of renal progenitor cells was only abolished by an anti-CXCR4 antibody, transendothelial migration required the activity of both CXCR4 and CXCR7, with CXCR7 being essential for renal progenitor cell adhesion to endothelial cells. Moreover, CXCR7 but not CXCR4 was responsible for the SDF-1–induced renal progenitor cell survival. Collectively, these findings suggest that CXCR4 and CXCR7 play an essential, but differential, role in the therapeutic homing of human renal progenitor cells in ARF, with important implications for the development of stem cell–based therapies.
VEGF and TGF-β are required for the maintenance of the choroid plexus and ependyma
Authors: Maharaj Arindel S.R. , Walshe Tony E. , Saint-Geniez Magali , Venkatesha Shivalingappa , Maldonado Angel E. , Himes Nathan C. , Matharu Kabir S. , Karumanchi S. Ananth , D'Amore Patricia A.
Published: February 2008

Although the role of vascular endothelial growth factor (VEGF) in developmental and pathological angiogenesis is well established, its function in the adult is less clear. Similarly, although transforming growth factor (TGF) β is involved in angiogenesis, presumably by mediating capillary (endothelial cell [EC]) stability, its involvement in quiescent vasculature is virtually uninvestigated. Given the neurological findings in patients treated with VEGF-neutralizing therapy (bevacizumab) and in patients with severe preeclampsia, which is mediated by soluble VEGF receptor 1/soluble Fms-like tyrosine kinase receptor 1 and soluble endoglin, a TGF-β signaling inhibitor, we investigated the roles of VEGF and TGF-β in choroid plexus (CP) integrity and function in adult mice. Receptors for VEGF and TGF-β were detected in adult CP, as well as on ependymal cells. Inhibition of VEGF led to decreased CP vascular perfusion, which was associated with fibrin deposition. Simultaneous blockade of VEGF and TGF-β resulted in the loss of fenestrae on CP vasculature and thickening of the otherwise attenuated capillary endothelium, as well as the disappearance of ependymal cell microvilli and the development of periventricular edema. These results provide compelling evidence that both VEGF and TGF-β are involved in the regulation of EC stability, ependymal cell function, and periventricular permeability.