bluuebunny/crossref_metadata_2025 huggingface dataset:
Synthesis, Gastroprotective Effect and Cytotoxicity of New Amino Acid Diterpene Monoamides and Diamides
Authors: Schmeda-Hirschmann Guillermo , Pertino Mariano Walter , Rodriguez Jaime A. , Monsalve Francisco , Droguett Daniel , Theoduloz Cristina
Published: October 2010

Following our studies on the gastroprotective effect and cytotoxicity of terpene derivatives, new amides were prepared from the diterpene 8(17)-labden-15,19-dioic acid (junicedric acid) and its 8(9)-en isomer with C-protected amino acids (amino acid esters). The new compounds were evaluated for their gastroprotective effect in the ethanol/HCl-induced gastric lesions model in mice, as well as for cytotoxicity using the following human cell lines: normal lung fibroblasts (MRC-5), gastric adenocarcinoma cells (AGS) and liver hepatocellular carcinoma (Hep G2). A dose-response experiment showed that at 25 mg/kg the C-15 leucyl and C-15,19-dileucylester amides of junicedric acid reduced gastric lesions by about 65.6 and 49.6%, respectively, with an effect comparable to lansoprazole at 20 mg/kg (79.3% lesion reduction). The comparison of the gastroprotective effect of 18 new amino acid ester amides was carried out at a single oral dose of 25 mg/kg. Several compounds presented a strong gastroprotective effect, reducing gastric lesions in the 70.9-87.8% range. The diprolyl derivative of junicedric acid, the most active product of this study (87.8% lesion reduction at 25 mg/kg) presented a cytotoxicity value comparable with that of the reference compound lansoprazole. The structure-activity relationships are discussed.
Antibacterial Activity of Phytochemicals Isolated from Atractylodes japonica against Methicillin-Resistant Staphylococcus aureus
Authors: Jeong Seung-Il , Kim Seon-Young , Kim Sang-Jun , Hwang Byung-Soon , Kwon Tae-Ho , Yu Kang-Yeol , Hang Seung-Ho , Suzuki Koji , Kim Kang-Ju
Published: October 2010

Methicillin-resistant Staphylococcus aureus (MRSA) has been emerging worldwide as one of the most important problems in communities and hospitals. Therefore, new agents are needed to treat acute oral infections from MRSA. In this study, antibacterial compounds from the roots of Atractylodes japonica (A. japonica) were isolated and characterized. The compounds were isolated from the root extracts using HPLC-piloted activity-guided fractionations. Four A. japonica compounds were isolated and identified as atractylenolide III (1), atractylenolide I (2), diacetylatractylodiol [(6E,12E)-tetradeca-6,12-diene-8,10-diyne-1,3-diol diacetate, TDEYA, 3). and (6E,12E)-tetradecadiene-8,10-diyne-1,3-diol (TDEA, 4), which was obtained by hydrolysis of TDEYA. The minimum inhibitory concentrations (MICs) was determined in the setting of clinical MRSA isolates. Compound 4 showed anti-MRSA activity with a MIC value of 4-32 μg/mL. The overall results provide promising baseline information for the potential use of the extract of A. japonica as well as some of the isolated compounds in the treatment of bacterial infections.
E-Beam Patterned Gold Nanodot Arrays on Optical Fiber Tips for Localized Surface Plasmon Resonance Biochemical Sensing
Authors: Lin Yongbin , Zou Yang , Mo Yuanyao , Guo Junpeng , Lindquist Robert G.
Published: October 2010

Electron beam lithography (EBL) was used to directly pattern periodic gold nanodot arrays on optical fiber tips. Localized surface plasmon resonance of the E-beam patterned gold nanodot arrays on optical fiber tips was utilized for biochemical sensing. The advantage of the optical fiber based localized surface plasmon resonance (LSPR) sensors is the convenience to work with and work in harsh environments. An optical fiber tip LSPR refractive index sensor of 196 nm per refractive index unit (RIU) sensitivity has been demonstrated. The affinity sensing property of the fiber tip sensor was demonstrated using biotin/streptavidin as the receptor/analyte. The detection limit for streptavidin was determined to be 6 pM.
Study on a Luminol-based Electrochemiluminescent Sensor for Label-Free DNA Sensing
Authors: Chu Hai-Hong , Yan Ji-Lin , Tu Yi-Feng
Published: October 2010

Automatic, inexpensive, simple and sensitive methods for DNA sensing and quantification are highly desirable for biomedical research. The rapid development of both the fundamentals and applications of electrochemiluminescence (ECL) over the past years has demonstrated its potential for analytical and bio-analytical chemistry. This paper reports the quenching effect of DNA on the ECL of luminol and the further development of a DNA sensing device. With the pre-functionalization by a composite of carbon nano-tubes (CNTs) and Au nanoparticles (AuNPs), the sensor provides a novel and valuable label-free approach for DNA sensing. Here the ECL intensity was remarkably decreased when more than 1.0 × 10−12 molar of DNA were adsorbed on the sensor. Linearity of the DNA amount with the reciprocal of ECL intensity was observed. A saturated sensor caused a 92.8% quenching effect. The research also proposes the mechanism for the quenching effect which could be attributed to the interaction between luminol and DNA and the elimination of reactive oxygen species (ROSs) by DNA.
An Application of Symmetry Approach to Finance: Gauge Symmetry in Finance
Authors: Zhou Shipeng , Xiao Liuqing
Published: October 2010

The paper presents an application of symmetry approach to finance. This symmetry approach comes from the gauge field theory in Physics. We revise the pricing model of financial derivatives in a financial market in a gauge symmetry view, and rewrite it as a partial differential equation on a fiber bundle in covariant differential form so as to have invariance in form. The paper shows the form of the pricing equation can keep invariant under all the local num´eraire transformations, this symmetry behind the pricing equation of derivatives is revealed. In addition a corresponding relationship between the curvature of the fiber bundle and the arbitrage in finance arises.
Evolution of Avian Conservation Breeding With Insights for Addressing the Current Extinction Crisis
Authors: D'Elia Jesse
Published: October 2010

Birds have been bred in captivity since the dawn of civilization. In the nineteenth century, breeding rare and exotic animals for the menageries of royalty and aristocrats transitioned to the formation of public zoological gardens and natural history museums. With industrialization and human population expansion, some bird species became rare or disappeared entirely. Once the magnitude of the destructive forces of humans became evident, concerted efforts were initiated to restore depleted bird populations by using, among other techniques, captive breeding. In this article, I explore the evolution of avian conservation breeding programs and evaluate how this historical review informs our outlook for addressing the current extinction crisis.
An Inflammasome-Independent Role for Epithelial-Expressed Nlrp3 in Renal Ischemia-Reperfusion Injury
Authors: Shigeoka Alana A. , Mueller James L. , Kambo Amanpreet , Mathison John C. , King Andrew J. , Hall Wesley F. , Correia Jean da Silva , Ulevitch Richard J. , Hoffman Hal M. , McKay Dianne B.
Published: October 2010

Cytoplasmic innate immune receptors are important therapeutic targets for diseases associated with overproduction of proinflammatory cytokines. One cytoplasmic receptor complex, the Nlrp3 inflammasome, responds to an extensive array of molecules associated with cellular stress. Under normal conditions, Nlrp3 is autorepressed, but in the presence of its ligands, it oligomerizes, recruits apoptosis-associated speck-like protein containing a caspase recruitment domain (Asc), and triggers caspase 1 activation and the maturation of proinflammatory cytokines such as IL-1β and IL-18. Because ischemic tissue injury provides a potential source for Nlrp3 ligands, our study compared and contrasted the effects of renal ischemia in wild-type mice and mice deficient in components of the Nlrp3 inflammasome (Nlrp3−/− and Asc−/− mice). To examine the role of the inflammasome in renal ischemia-reperfusion injury (IRI) we also tested its downstream targets caspase 1, IL-1β, and IL-18. Both Nlrp3 and Asc were highly expressed in renal tubular epithelium of humans and mice, and the absence of Nlrp3, but not Asc or the downstream inflammasome targets, dramatically protected from kidney IRI. We conclude that Nlrp3 contributes to renal IRI by a direct effect on renal tubular epithelium and that this effect is independent of inflammasome-induced proinflammatory cytokine production.
Roles of Beta2- and Beta3-Adrenoceptor Polymorphisms in Hypertension and Metabolic Syndrome
Authors: Masuo Kazuko
Published: October 2010

Hypertension, diabetes mellitus (especially type 2 diabetes mellitus), metabolic syndrome and obesity are rapidly growing public health problems. Sympathetic nerve activation is observed in obesity, hypertension and diabetes mellitus, which have strong genetic as well as environmental determinants. Reduced energy expenditure and resting metabolic rate are predictive of weight gain, and the sympathetic nervous system participates in regulating energy balance through thermogenesis. The thermogenic effects of catecholamines in obesity have been mainly mediated via the 2- and 3-adrenergic receptors in humans. Further, 2-adrenoceptors importantly influence vascular reactivity and may regulate blood pressure. Genetic polymorphistns of the -adrenoceptor gene have been shown to alter the function of several adrenoceptor subtypes and thus to modify the response to catecholamine. 2-adrenoceptor polymorphisms (Arg16Gly, Gln27Glu, and Thr164Ile) have been studied in relation to hypertension. Genetic variations in the 3-adrenoceptor (i.e. Try64Arg variant) are also associated with both obesity and hypertension. However, the precise relationships of the polymorphisms of 2- and 3-adrenoceptor genes with sympathetic nervous system activity, hypertension, and metabolic syndrome have not been fully clarified. This paper will discuss the current topics involving the influence of the sympathetic nervous system and 2- and 3- adrenoceptor polymorphisms in hypertension and metabolic syndrome.
Hölder continuity of solutions of second-order non-linear elliptic integro-differential equations
Authors: Barles Guy , Chasseigne Emmanuel , Imbert Cyril
Published: October 2010

This paper is concerned with the Hölder regularity of viscosity solutions of second-order, fully non-linear elliptic integro-differential equations. Our results rely on two key ingredients: first we assume that, at each point of the domain, either the equation is strictly elliptic in the classical fully non-linear sense, or (and this is the most original part of our work) the equation is strictly elliptic in a non-local non-linear sense we make precise. Next we impose some regularity and growth conditions on the equation. These results are concerned with a large class of integro-differential operators whose singular measures depend on
x
and also a large class of equations, including Bellman–Isaacs equations.
Parapuzzle of the multibrot set and typical dynamics of unimodal maps
Authors: Avila Artur , Lyubich Mikhail , Shen Weixiao
Published: October 2010

We study the parameter space of unicritical polynomials

f_c : z ↦ z^d + c

. For complex parameters, we prove that for Lebesgue almost every

c

, the map

f_c

is either hyperbolic or infinitely renormalizable. For real parameters, we prove that for Lebesgue almost every

c

, the map

f_c

is either hyperbolic, or Collet–Eckmann, or infinitely renormalizable. These results are based on controlling the spacing between consecutive elements in the “principal nest” of parapuzzle pieces.
Positivity and Kleiman transversality in equivariant $K$-theory of homogeneous spaces
Authors: Anderson Dave , Griffeth Stephen , Miller Ezra
Published: October 2010

We prove the conjectures of Graham–Kumar [GrKu08] and Griffeth–Ram [GrRa04] concerning the alternation of signs in the structure constants for torus-equivariant
K
-theory of generalized ﬂag varieties
G
/
P
. These results are immediate consequences of an equivariant homological Kleiman transversality principle for the Borel mixing spaces of homogeneous spaces, and their subvarieties, under a natural group action with ﬁnitely many orbits. The computation of the coefficients in the expansion of the equivariant
K
-class of a subvariety in terms of Schubert classes is reduced to an Euler characteristic using the homological transversality theorem for non-transitive group actions due to S. Sierra. A vanishing theorem, when the subvariety has rational singularities, shows that the Euler characteristic is a sum of at most one term—the top one—with a well-deﬁned sign. The vanishing is proved by suitably modifying a geometric argument due to M. Brion in ordinary
K
-theory that brings Kawamata–Viehweg vanishing to bear.
A sharp isoperimetric inequality in the plane
Authors: Alvino Angelo , Ferone Vincenzo , Nitsch Carlo
Published: October 2010

We show that among all the convex bounded domain in

ℝ^2

having an assigned Fraenkel asymmetry index, there exists only one convex set (up to a similarity) which minimizes the isoperimetric deficit. We also show how to construct this set. The result can be read as a sharp improvement of the isoperimetric inequality for convex planar domain.
Kazhdan–Lusztig basis and a geometric filtration of an affine Hecke Algebra, II
Authors: Xi Nanhua
Published: October 2010

An affine Hecke algebras can be realized as an equivariant K-group of the corresponding Steinberg variety. This gives rise naturally to some two-sided ideals of the affine Hecke algebra by means of the closures of nilpotent orbits of the corresponding Lie algebra. In this paper we will show that the two-sided ideals are in fact the two-sided ideals of the affine Hecke algebra defined through two-sided cells of the corresponding affine Weyl group after the two-sided ideals are tensored by

ℚ

. This proves a weak form of a conjecture of Ginzburg proposed in 1987.
A note on Ricci flow and optimal transportation
Authors: Brendle Simon
Published: October 2010

We describe a new link between Perelman’s monotonicity formula for the reduced volume and ideas from optimal transport theory.
The ice nucleation ability of one of the most abundant types of fungal spores found in the atmosphere
Authors: Iannone R. , Chernoff D. I. , Pringle A. , Martin S. T. , Bertram A. K.
Published: October 2010

Abstract. Recent atmospheric measurements show that biological particles are important ice nuclei. Types of biological particles that may be good ice nuclei include bacteria, pollen and fungal spores. We studied the ice nucleation properties of water droplets containing fungal spores from the genus Cladosporium, one of the most abundant types of spores found in the atmosphere. For water droplets containing a Cladosporium spore surface area of ~217 μm2 (equivalent to ~5 spores with average diameters of 3.2 μm), 1% of the droplets froze by −28.5 °C and 10% froze by −30.1 °C. However, there was a strong dependence on freezing temperature with the spore surface area of Cladosporium within a given droplet. As such, freezing temperatures for droplets containing 1–5 spores are expected to be approximately −35.1±2.3 °C (1σ S.D.). Atmospheric ice nucleation on spores of Cladosporium sp., or other spores with similar surface properties, do not appear to explain recent atmospheric measurements showing that biological particles are important ice nuclei. The poor ice nucleation ability of Cladosporium sp. spores may be attributed to the surface which is coated with hydrophobins (a class of hydrophobic proteins that appear to be widespread in filamentous fungi). Given the ubiquity of hydrophobins on spore surfaces, the current study may be applicable to many fungal species of atmospheric importance.
Data assimilation using a hybrid ice flow model
Authors: Goldberg D. N. , Sergienko O. V.
Published: October 2010

Abstract. Hybrid models, or depth-integrated flow models that include the effect of both longitudinal stresses and vertical shearing, are becoming more prevalent in dynamical ice modeling. Under a wide range of conditions they closely approximate the well-known First Order stress balance, yet are of computationally lower dimension, and thus require less intensive resources. Concomitant with the development and use of these models is the need to perform inversions of observed data. Here, an inverse control method is extended to use a hybrid flow model as a forward model. We derive an adjoint of a hybrid model and use it for inversion of ice-stream basal traction from observed surface velocities. A novel aspect of the adjoint derivation is a retention of non-linearities in Glen's flow law. Experiments show that including those nonlinearities is advantageous in minimization of the cost function, yielding a more efficient inversion procedure.
Technical Vocational Education and Training for Micro-Enterprise Development in Ethiopia
Authors: Gondo Tendayi , Dafuleya Gift
Published: October 2010

Technical vocational education and training (TVET) programmes have recently received increased attention as an area of priority for stimulating growth in developed and developing countries. This paper considers the situation in Ethiopia where the promotion of micro and small-sized enterprises (MSEs) has been central to the development and expansion of TVET centres throughout the country. The extent to which efforts relating to TVET made by Ethiopian policy makers, higher education institutions and MSEs have enhanced the development of the micro-enterprise sector is considered, using empirical evidence gathered from nine Ethiopian cities. It is argued that the existing relationship between TVET and micro-enterprise cannot be regarded only as one of constrained capacity, usage and transformation. The authors argue further that the development of micro and small-sized enterprises requires approaches extending beyond the simple expansion and development of TVET institutions.
A Study on Methodologies for Research Impact Assessment: Responses of the UK Research Councils to the Warry Report
Authors: de Campos André Luiz
Published: October 2010

The experience of the UK Research Councils in assessing the impacts of their research funding is discussed, including a report on the findings of research which reviewed the impact studies implemented by the Research Councils. The response of the Councils to the challenge of demonstrating the impacts of their funding and the main methodologies used are presented and the implications of both for the Research Councils and policy makers elsewhere are outlined.
Enterprise Professional Development – Evaluating Learning
Authors: Murphy Gerald A. , Calway Bruce A.
Published: October 2010

Whilst professional development (PD) is an activity required by many regulatory authorities, the value that enterprises obtain from PD is often unknown, particularly when it involves development of knowledge. This paper discusses measurement techniques and processes and provides a review of established evaluation techniques, highlighting deficiencies in these methods for evaluating the ongoing long-term impact of PD. Enterprises need to understand the risks associated with PD as well as the impact of policies, processes and practices. The paper sets out the factors that affect the value added to the enterprise by PD and provides details of how this may be measured by developing an Enterprise PD profile.
Primary Recrystallization of Invar, Fe‐36%Ni Alloy: Origin and Development of the Cubic Texture
Authors: Penelle Richard , Baudin Thierry
Published: October 2010

This short review summarizes the main results acquired by Penelle's group at the Université Paris Sud 11 in Orsay during the last 10 years on recrystallization of the Fe‐36%Ni so‐called Invar alloy. The formation and the development of the cube texture after high deformation by cold rolling (CR) and subsequent annealing is interpreted from a multiscale analysis based on TEM, SEM/EBSD, X‐ray, and neutron diffraction measurements coupled with a Monte Carlo simulation. It is shown that the cube orientation which presents a cellular deformation substructure consumes the noncube matrix. This is interpreted by the high difference of stored deformation energy between the cube and the recovered matrix which is the main driving force for recrystallization. The parameters disorientation and subgrain size are also discussed. For low CR reductions, the difference of stored energy is weaker and as a consequence other orientations of the matrix have time to develop which leads to a softening of the recrystallization texture, the texture randomization is intensified by annealing twinning.
Organic FETs: Functional Organic Field‐Effect Transistors (Adv. Mater. 40/2010)
Authors: Guo Yunlong , Yu Gui , Liu Yunqi
Published: October 2010

Functional organic field‐effect transistors (OFETs) have attracted increasing attention in the past few years due to their wide variety of potential applications. Research on functional OFETs underpins future advances in organic electronics. In this review, different types of functional OFETs including organic phototransistors, organic memory FETs, organic light emitting FETs, sensors based on OFETs and other functional OFETs are introduced. In order to provide a comprehensive overview of this field, the history, current status of research, main challenges and prospects for functional OFETs are all discussed
Synthesis of hybrid polyaniline/carbon nanotube nanocomposites by dynamic interfacial inverse emulsion polymerization under sonication
Authors: Suckeveriene R. Y. , Zelikman E. , Mechrez G. , Tzur A. , Frisman I. , Cohen Y. , Narkis M.
Published: October 2010

This article describes an ultrasonically assisted in situ interfacial dynamic inverse emulsion polymerization process of aniline in the presence of multiwalled carbon nanotubes (MWNT) in chloroform. During polymerization, MWNT are coated with polyaniline (PANI) forming a core‐shell structure of nanowires, as evidenced by cryogenic transmission electron microscopy. Thermogravimetric analysis curves and conversion measurements provided important knowledge regarding the unique polymerization method. Scanning electron microscopy images and surface resistivity imply that PANI/MWNTs are characterized by a structural synergistic effect. The PANI coating of MWNT leads to a remarkable improvement in separation and dispersion of MWNT in chloroform, which otherwise would rapidly coagulate and settle. The presented interfacial dynamic polymerization process is very fast, reaching 82% conversion within 5 min of sonication and produces stable clear dispersions of doped PANI in chloroform. © 2010 Wiley Periodicals, Inc. J Appl Polym Sci, 2011
Spatial variation in abundance and diversity of the smaller surface and near‐surface eelgrass‐associated intertidal macrobenthos within a warm‐temperate estuarine bay in the Garden Route National Park, RSA
Authors: Barnes R. S. K.
Published: October 2010

Smaller members (<10 mm) of the sediment‐surface macrobenthos of Nanozostera capensis meadows across 9 km2 of the marine Outer Basin of the Knysna estuarine bay (Garden Route National Park, Western Cape, South Africa) were investigated at a series of 24 stations.

Ordination (nMDS) disclosed the existence of five clusters of stations related to degree of exposure. Relatively sheltered stations were dominated by two endemic species of deposit‐feeding microgastropod, and they supported significantly higher macrobenthic densities but lower species diversity and less evenness than relatively exposed stations. The latter were dominated by polychaetes and also possessed more suspension feeders, equivalent to more open seagrass beds in other latitudes. Species richness per station, however, was relatively constant across the whole basin.

The smaller benthic macrofauna, totalling 82 species, was found to include several animals (<5 mm) hitherto unknown from the region, including one gastropod genus (Cornirostra) not previously known from Africa.

Species were patchily distributed across all scales from 1 m to >1 km, but variance partitioning showed components of total variance to decrease with increasing spatial scale: sample (46.5%), station (30.0%), site (23.5%).

These findings are discussed in relation to conservation site selection in rich but faunistically heterogeneous seagrass beds that are impacted by bait collection or other human disturbance. Copyright © 2010 John Wiley & Sons, Ltd.
Selective ERK activation differentiates mouse and human tolerogenic dendritic cells, expands antigen‐specific regulatory T cells, and suppresses experimental inflammatory arthritis
Authors: Arce Frederick , Breckpot Karine , Stephenson Holly , Karwacz Katarzyna , Ehrenstein Michael R. , Collins Mary , Escors David
Published: October 2010

Objective

Most therapeutic treatments for autoimmune arthritis rely on immunosuppressive drugs, which have side effects. Although a previous study by our group showed that specific ERK activation suppressed immune responses, its application in a therapeutic setting has never been tested. The aim of the present study was to define the ERK‐dependent immunosuppressive mechanisms and to apply selective ERK activation for the treatment of experimental inflammatory arthritis.

Methods

A constitutively active ERK activator was coexpressed with a model antigen using lentivectors. Immunosuppressive mechanisms were characterized at the level of dendritic cell (DC) function, differentiation of antigen‐specific Treg cells, and inhibition of inflammatory T cells. Administration of the ERK activator with antigen as a strategy to suppress inflammatory arthritis was tested in an experimental mouse model.

Results

Selective ERK activation induced mouse and human DCs to secrete bioactive transforming growth factor β, a process required for suppression of T cell responses and differentiation of antigen‐specific Treg cells. Treg cells strongly proliferated after antigen reencounter in inflammatory conditions, and these cells exhibited antigen‐dependent suppressive activities. Inflammatory arthritis was effectively inhibited through antigen‐specific mechanisms. Importantly, this strategy did not rely on identification of the initiating arthritogenic antigen. Equivalent mechanisms were demonstrated in human monocyte–derived DCs, setting the scene for a possible rapid translation of this approach to patients with rheumatoid arthritis.

Conclusion

This strategy of selective ERK activation resulted in an effective therapeutic protocol, with substantial advantages over DC or T cell vaccination.
Classification of rheumatoid arthritis: Comparison of the 1987 American College of Rheumatology criteria and the 2010 American College of Rheumatology/European League Against Rheumatism criteria
Authors: van der Linden M. P. M. , Knevel R. , Huizinga T. W. J. , van der Helm‐van Mil A. H. M
Published: October 2010

Objective

New criteria to classify rheumatoid arthritis (RA) have been derived in order to increase the specificity and sensitivity for early RA compared with the 1987 American College of Rheumatology (ACR) criteria. The aim of this study was to evaluate differences in classification between the 1987 ACR criteria and the 2010 ACR/European League Against Rheumatism (EULAR) criteria in an early arthritis cohort and to determine the test characteristics of the 2010 ACR/EULAR criteria.

Methods

A total of 2,258 patients with early arthritis included in the Leiden Early Arthritis Clinic cohort were studied. Fulfillment of the 1987 and 2010 criteria for the classification of RA was determined at baseline. The diagnosis of each patient at 1 year was assessed. The sensitivity and specificity of the 2010 criteria were determined using the following outcome measures: initiation of methotrexate therapy or any disease‐modifying antirheumatic drug (DMARD) therapy during the first year of followup and having persistent arthritis during 5 years of followup.

Results

At their first presentation, 1,099 patients fulfilled the 2010 criteria, and 726 patients fulfilled the 1987 criteria for RA. Eighty‐two of the 726 patients fulfilling the 1987 criteria did not fulfill the 2010 criteria. Sixty‐eight percent of the patients who fulfilled the 1987 criteria during the first year of disease but not at baseline did fulfill the 2010 criteria at baseline. In 18% of patients, use of the 2010 classification criteria also led to a revoked classification at 1 year. The sensitivity and specificity of the 2010 criteria were 0.84 and 0.60, respectively, with methotrexate therapy as the outcome and 0.74 and 0.74, respectively, with DMARD therapy as the outcome. With persistent arthritis as the outcome, the sensitivity and specificity of the 2010 criteria were 0.71 and 0.65, respectively.

Conclusion

Compared with the 1987 criteria, the 2010 criteria classify more patients with RA and at an earlier phase of the disease. The discriminative ability of the 2010 criteria is acceptable.
A genetic variation located in the promoter region of the UPAR (CD87) gene is associated with the vascular complications of systemic sclerosis
Authors: Manetti Mirko , Allanore Yannick , Revillod Lucile , Fatini Cinzia , Guiducci Serena , Cuomo Giovanna , Bonino Claudia , Riccieri Valeria , Bazzichi Laura , Liakouli Vasiliki , Cipriani Paola , Giacomelli Roberto , Abbate Rosanna , Bombardieri Stefano , Valesini Guido , Montecucco Carlomaurizio , Valentini Gabriele , Ibba‐Manneschi Lidia , Matucci‐Cerinic Marco
Published: October 2010

Objective

The UPAR gene encodes a pleiotropic receptor (urokinase‐type plasminogen activator receptor [uPAR]) involved in fibrosis, immunity, angiogenesis, and vascular remodeling. Previous studies have implicated uPAR in systemic sclerosis (SSc) vasculopathy and impaired angiogenesis. We undertook this study to investigate whether UPAR gene promoter polymorphisms might be associated with SSc phenotypes in the European Caucasian population.

Methods

We studied a total population of 1,339 individuals. The Italian discovery cohort comprised 388 SSc patients and 391 healthy controls. The French replication cohort consisted of 344 SSc patients and 216 healthy controls. The UPAR rs344781 and rs4251805 single‐nucleotide polymorphisms were genotyped by polymerase chain reaction–restriction fragment length polymorphism assay.

Results

In the Italian cohort, the rs344781 G allele was associated with SSc‐related digital ulceration (odds ratio [OR] 1.39), pulmonary arterial hypertension (PAH) (OR 1.81), anticentromere antibody (ACA) positivity (OR 1.45), and limited cutaneous SSc (lcSSc) (OR 1.37). The rs344781 GG genotype was associated with SSc‐related (OR 3.79), ACA‐positive SSc (OR 2.17), and lcSSc (OR 1.96). Allelic and genotypic associations with SSc‐related digital ulceration and ACA‐positive SSc were replicated in the French sample. Combined analyses showed an association of the rs344781 G allele and GG genotype with SSc‐related digital ulceration (allele OR 1.41, genotype OR 2.15), SSc‐related PAH (allele OR 1.65, genotype OR 3.16), ACA‐positive SSc (allele OR 1.47, genotype OR 2.40), and lcSSc (allele OR 1.34, genotype OR 1.77). In a multivariate logistic regression analysis model including the above associated phenotypes of SSc patients, the rs344781 GG genotype remained an independent risk factor for SSc‐related digital ulceration (OR 1.96) and SSc‐related PAH (OR 2.68).

Conclusion

The UPAR rs344781 gene variant is associated with the SSc vascular phenotype.
Ablation of the Ccr2 gene exacerbates polyarthritis in interleukin‐1 receptor antagonist–deficient mice
Authors: Fujii Hiroshi , Baba Tomohisa , Ishida Yuko , Kondo Toshikazu , Yamagishi Masakazu , Kawano Mitsuhiro , Mukaida Naofumi
Published: October 2010

Objective

The pathogenesis of rheumatoid arthritis (RA) involves cytokines and chemokines. Given the role of intraarticular macrophage infiltration in RA, this study was undertaken to address the pathogenic role of CCR2, a chemokine receptor that is abundantly expressed by macrophages, in Il1rn‐deficient mice, a mouse model of RA.

Methods

Il1rn‐deficient and Il1rn and Ccr2–double‐deficient mice were subjected to clinical assessment of arthritis and histologic examination. Bone mineral density was measured with computed tomography. The types of cells infiltrating joints were determined by immunohistochemical analysis and flow cytometric analysis. Osteoclasts in joints were quantified after tartrate‐resistant acid phosphatase staining. Cytokine and chemokine levels were measured by enzyme‐linked immunosorbent assay and multiplex suspension array assay. The expression patterns of chemokines and osteoclastogenic factors were determined by double‐color immunofluorescence analysis. Anti‐mouse CXCR2 antibody was injected into Il1rn and Ccr2–double‐deficient mice for blocking experiments.

Results

Ablation of the Ccr2 gene actually exacerbated arthritis and intraarticular osteoclastogenesis, while it enhanced intraarticular neutrophil but not macrophage accumulation in Il1rn‐deficient mice. Infiltrated neutrophils expressed the osteoclastogenic factors RANKL and ADAM‐8, thereby augmenting intraarticular osteoclastogenesis in Il1rn and Ccr2–double‐deficient mice. Moreover, the double‐deficient mice exhibited enhanced expression of the neutrophilic chemokines keratinocyte chemoattractant and macrophage inflammatory protein 2 (MIP‐2), compared with Il1rn‐deficient mice. Finally, neutralizing antibodies to CXCR2, the receptor for keratinocyte chemoattractant and MIP‐2, dramatically attenuated arthritis in Il1rn and Ccr2–double‐deficient mice.

Conclusion

Our findings indicate that CCR2‐mediated signals can modulate arthritis in Il1rn‐deficient mice by negatively regulating neutrophil infiltration.
The incidence of gastrointestinal perforations among rheumatoid arthritis patients
Authors: Curtis Jeffrey R. , Xie Fenglong , Chen Lang , Spettell Claire , McMahan Raechele M. , Fernandes Joaquim , Delzell Elizabeth
Published: October 2010

Objective

Gastrointestinal (GI) perforation has emerged as a novel safety concern in relation to medications used to treat rheumatoid arthritis (RA). This study was undertaken to characterize the incidence and risk factors for GI perforation in RA patients.

Methods

Using administrative databases of a large US health plan, we identified RA patients treated with biologic agents, methotrexate (MTX), oral glucocorticoids, and nonsteroidal antiinflammatory drugs (NSAIDs). Additional risk factors we evaluated included diverticulitis. Hospitalization with GI perforation was identified using a validated algorithm. Incidence rates and risk factors were evaluated using Cox proportional hazards models.

Results

Among 40,841 RA patients, 37 hospitalizations with GI perforation were identified. The rate of GI perforation among patients currently being treated with biologic agents who were also receiving oral glucocorticoids was higher (1.12 per 1,000 person‐years [95% confidence interval (95% CI) 0.50–2.49]) than for patients being treated with biologic agents who were not also receiving glucocorticoids (0.47 per 1,000 person‐years [95% CI 0.22–0.98]) or for patients being treated with MTX who were also receiving glucocorticoids (0.87 per 1,000 person‐years [95% CI 0.36–2.10]). Neither biologic agents nor MTX was significantly associated with GI perforation, in contrast to current treatment with glucocorticoids and NSAIDs together (hazard ratio 4.7 [95% CI 1.9–12.0]) or glucocorticoids alone (hazard ratio 2.8 [95% CI 1.3–6.1]). Diverticulitis also was a strong risk factor (hazard ratio 9.1 [95% CI 3.1–26.4]). Seventy percent of patients with GI perforation received glucocorticoids, had antecedent diverticulitis, or both.

Conclusion

GI perforation is an uncommon but serious adverse event among RA patients. Because a majority of patients with GI perforation were being treated with glucocorticoids or had previously experienced diverticulitis, these individuals should be considered at higher risk.
Therapeutic potential of anti–interleukin‐17A aptamer: Suppression of interleukin‐17A signaling and attenuation of autoimmunity in two mouse models
Authors: Ishiguro Akira , Akiyama Taishin , Adachi Hironori , Inoue Jun‐Ichiro , Nakamura Yoshikazu
Published: October 2010

Objective

The proinflammatory cytokine interleukin‐17A (IL‐17A) is produced primarily by the CD4+ T cell subset called Th17 cells, which is involved in host defense, inflammation, and autoimmune disorders. This study was undertaken to investigate the effect of a high‐affinity RNA molecule, called an aptamer, against human IL‐17A on IL‐17A–induced signal transduction in vitro and its anti‐autoimmune efficacy in vivo in 2 mouse models of inflammation.

Methods

By screening a large library of nuclease‐resistant RNA oligonucleotides, we selected an RNA aptamer, Apt21‐2, that binds human and mouse IL‐17 and blocks the interaction between IL‐17A and its receptor. The inhibition of IL‐17A–mediated phosphorylation and marker protein production was analyzed in human and mouse cells. Mice with glucose‐6‐phosphate isomerase (GPI)–induced rheumatoid arthritis and myelin oligodendrocyte glycoprotein (MOG)–induced experimental autoimmune encephalomyelitis were used to assess efficacy.

Results

Apt21‐2 prevented efficient phosphorylation of the IL‐17A signaling factors IκB and JNK and inhibited the production of IL‐6 in human and mouse cells. A PEGylated form of Apt21‐2 (PEG21‐2idT) exhibited a 50% inhibition concentration (IC50) in the range of 1–2 nM and 70–80 nM in human and mouse cells, respectively. When administered immediately after immunization with GPI or MOG, PEG21‐2idT inhibited in a dose‐dependent manner the development of arthritic or neurologic symptoms. Significantly, PEG21‐2idT slowed the progression of arthritis when administered after the onset of GPI‐induced arthritis.

Conclusion

Our findings indicate that the chemically processed anti–IL‐17A aptamer PEG21‐2idT inhibits the actions of IL‐17A as well as the development of autoimmunity in 2 mouse models of inflammation. These results offer for the first time an aptamer‐based therapeutic approach to the treatment of Th17 cell–mediated autoimmune disorders.
Supramolecular Synthons in Designing Low Molecular Mass Gelling Agents: L‐Amino Acid Methyl Ester Cinnamate Salts and their Anti‐Solvent‐Induced Instant Gelation
Authors: Sahoo Pathik , Kumar D. Krishna , Raghavan Srinivasa R. , Dastidar Parthasarathi
Published: October 2010

Easy access to a class of chiral gelators has been achieved by exploiting primary ammonium monocarboxylate (PAM), a supramolecular synthon. A combinatorial library comprising of 16 salts, derived from 5 l‐amino acid methyl esters and 4 cinnamic acid derivatives, has been prepared and scanned for gelation. Remarkably, 14 out of 16 salts prepared (87.5 % of the salts) show moderate to good gelation abilities with various solvents, including commercial fuels, such as petrol. Anti‐solvent induced instant gelation at room temperature has been achieved in all the gelator salts, indicating that the gelation process is indeed an aborted crystallization phenomenon. Rheology, optical and scanning electron microscopy, small angle neutron scattering, and X‐ray powder diffraction have been used to characterize the gels. A structure‐property correlation has been attempted, based on these data, in addition to the single‐crystal structures of 5 gelator salts. Analysis of the FT‐IR and 1H NMR spectroscopy data reveals that some of these salts can be used as supramolecular containers for the slow release of certain pest sex pheromones. The present study clearly demonstrates the merit of crystal engineering and the supramolecular synthon approach in designing new materials with multiple properties.
The polypeptide tunnel exit of the mitochondrial ribosome is tailored to meet the specific requirements of the organelle
Authors: Gruschke Steffi , Ott Martin
Published: October 2010

The ribosomal polypeptide tunnel exit is the site where a variety of factors interact with newly synthesized proteins to guide them through the early steps of their biogenesis. In mitochondrial ribosomes, this site has been considerably modified in the course of evolution. In contrast to all other translation systems, mitochondrial ribosomes are responsible for the synthesis of only a few hydrophobic membrane proteins that are essential subunits of the mitochondrial respiratory chain. Membrane insertion of these proteins occurs co‐translationally and is connected to a sophisticated assembly process that not only includes the assembly of the different subunits but also the acquisition of redox co‐factors. Here, we describe how mitochondrial translation is organized in the context of respiratory chain assembly and speculate how alteration of the ribosomal tunnel exit might allow the establishment of a subset of specialized ribosomes that individually organize the early steps in the biogenesis of distinct mitochondrially‐encoded proteins.
Pathogenesis of CADASIL
Authors: Joutel Anne
Published: October 2010

Small vessel diseases (SVDs) of the brain are the leading cause of vascular cognitive impairment and a major contributor to stroke in the human adult, however, their pathogenesis is poorly understood. Dominant mutations in NOTCH3 cause CADASIL, one of the most prevalent inherited cerebral SVDs. The disease gene encodes a transmembrane receptor primarily expressed in smooth muscle cells of small arteries and pericytes of brain capillaries. Pathogenic mutations alter the number of cysteine residues in the extracellular domain of NOTCH3, leading to its abnormal accumulation in the vessels of patients. Mice lacking NOTCH3 have revealed a critical role for NOTCH3 in the elaboration of small arteries. Despite being incomplete disease models, transgenic mice expressing CADASIL‐associated NOTCH3 mutations, have provided important insights into specific aspects of CADASIL pathogenesis, including the functional significance of disease‐linked mutations and the earliest pathological events that initiate brain lesions. In this paper, I provide a critical overview of these studies. Moreover, I discuss future directions and further work that needs to be done.
Genome‐scale modeling and in silico analysis of ethanologenic bacteria Zymomonas mobilis
Authors: Widiastuti Hanifah , Kim Jae Young , Selvarasu Suresh , Karimi Iftekhar A. , Kim Hyungtae , Seo Jeong‐Sun , Lee Dong‐Yup
Published: October 2010

Bioethanol has been recognized as a potential alternative energy source. Among various ethanol‐producing microbes, Zymomonas mobilis has acquired special attention due to its higher ethanol yield and tolerance. However, cellular metabolism in Z. mobilis remains unclear, hindering its practical application for bioethanol production. To elucidate such physiological characteristics, we reconstructed and validated a genome‐scale metabolic network (iZM363) of Z. mobilis ATCC31821 (ZM4) based on its annotated genome and biochemical information. The phenotypic behaviors and metabolic states predicted by our genome‐scale model were highly consistent with the experimental observations of Z. mobilis ZM4 strain growing on glucose as well as NMR‐measured intracellular fluxes of an engineered strain utilizing glucose, fructose, and xylose. Subsequent comparative analysis with Escherichia coli and Saccharomyces cerevisiae as well as gene essentiality and flux coupling analyses have also confirmed the functional role of pdc and adh genes in the ethanologenic activity of Z. mobilis, thus leading to better understanding of this natural ethanol producer. In future, the current model could be employed to identify potential cell engineering targets, thereby enhancing the productivity of ethanol in Z. mobilis. Biotechnol. Bioeng. 2011; 108:655–665. © 2010 Wiley Periodicals, Inc.
Generation of stable, high‐producing cho cell lines by lentiviral vector‐mediated gene transfer in serum‐free suspension culture
Authors: Oberbek Agata , Matasci Mattia , Hacker David L. , Wurm Florian M.
Published: October 2010

Lentivirus‐derived vectors (LVs) were studied for the generation of stable recombinant Chinese hamster ovary (CHO) cell lines. Stable pools and clones expressing the enhanced green fluorescent protein (eGFP) were selected via fluorescence‐activated cell sorting (FACS). For comparison, cell pools and cell lines were also generated by transfection, using the LV transfer plasmid alone. The level and stability of eGFP expression was greater in LV‐transduced cell lines and pools than in those established by transfection. CHO cells were also infected at two different multiplicities of infection with an LV co‐expressing eGFP and a tumor necrosis factor receptor:Fc fusion protein (TNFR:Fc). At 2‐day post‐infection, clonal cell lines with high eGFP‐specific fluorescence were recovered by FACS. These clones co‐expressed TNFR:Fc with yields of 50–250 mg/L in 4‐day cultures. The recovered cell lines maintained stable expression over 3 months in serum‐free suspension culture without selection. In conclusion, LV‐mediated gene transfer provided an efficient alternative to plasmid transfection for the generation of stable and high‐producing recombinant cell lines. Biotechnol. Bioeng. 2011; 108:600–610. © 2010 Wiley Periodicals, Inc.
An active intracellular device to prevent lethal disease outcomes in virus‐infected bacterial cells
Authors: Bagh Sangram , Mandal Mahuya , Ang Jordan , McMillen David R.
Published: October 2010

Synthetic biology includes an effort to logically control cellular behavior. One long‐term goal is to implement medical interventions inside living cells, creating intracellular “disease fighters”; one may imagine a system that detects viral infection and responds to halt the spread of the virus. Here, we explore a system designed to display some of the qualitative features that such disease prevention systems should have, while not claiming that the system itself has any medical application. An intracellular disease prevention mechanism should: lie dormant in the absence of the disease state; detect the onset of a lethal disease pathway; respond to halt or mitigate the disease's effects; and be subject to external deactivation when required. We have created a device that displays these properties, in the highly simplified case of a bacterial viral disease. Our system detects the onset of the lytic phase of bacteriophage lambda in Escherichia coli, responds by preventing this lethal pathway from being followed, and is deactivated by a temperature shift. We have formulated a mathematical model of the engineered system, using parameters obtained from the literature and by local experimental measurement, and shown that the model captures the essential experimental behavior of the system in most parameter regimes. Biotechnol. Bioeng. 2011; 108:645–654. © 2010 Wiley Periodicals, Inc.
A new bioproduction route for a novel antimicrobial peptide
Authors: Tay Derrick Kok Sing , Rajagopalan Gobinath , Li Xiang , Chen Yu , Lua Linda H.L. , Leong Susanna Su Jan
Published: October 2010

Beta defensins are antimicrobial peptides (AMPs) with a broad spectrum antimicrobial behavior against pathogens while having minimal tendency to incur pathogen resistance. Human β‐defensin 28 (hBD28) is a strongly cationic AMP and hence hypothesized to be highly effective in permeabilizing negatively‐charged pathogen membranes. However, the scarcity of hBD28 in vivo has impeded detailed structure and antimicrobial studies of hBD28. Chemical synthesis of hBD28 rendered extremely poor yields due to inefficient cysteine oxidation. In this study, a rapid and scalable production route to produce bioactive hBD28 in Escherichia coli (E. coli) is reported. The design of a dual fusion tag expression construct was pivotal in enhancing soluble expression and easing purification of hBD28. The final hBD28 (purity >95%) displayed significant antimicrobial activity against E. coli K12 and showed dose‐dependent killing kinetics. Circular dichroism spectroscopy confirmed the presence of both β‐sheet and α‐helix conformations in the secondary structure of hBD28. Biotechnol. Bioeng. 2011; 108:572–581. © 2010 Wiley Periodicals, Inc.