bluuebunny/crossref_metadata_2025_split huggingface dataset:
Targeted Delivery to Cartilage Is Critical for In Vivo Efficacy of Insulin‐like Growth Factor 1 in a Rat Model of Osteoarthritis
Authors: Loffredo Francesco S. , Pancoast James R. , Cai Lei , Vannelli Todd , Dong Jesse Z. , Lee Richard T. , Patwari Parth 
Published: January 2014

ObjectiveAcute articular injuries lead to an increased risk of progressive joint damage and osteoarthritis (OA), and no therapies are currently available to repair or protect the injured joint tissue. Intraarticular delivery of therapeutic proteins has been limited by their rapid clearance from the joint space and lack of retention within cartilage. The aim of this study was to test whether targeted delivery to cartilage by fusion with a heparin‐binding domain would be sufficient to prolong the in vivo function of the insulin‐like growth factor 1 (IGF‐1).MethodsWe produced a humanized and optimized recombinant HB‐IGF‐1 fusion protein. By injecting HB‐IGF‐1, IGF‐1, or saline alone into the knee joints of adult Lewis rats, we tested whether fusion with a heparin‐binding domain 1) altered the kinetics of retention in joint tissues, 2) prolonged functional stimulation as measured by radiolabel incorporation, and 3) enhanced efficacy in a rat model of surgically induced OA, using weekly injections.ResultsFusion of heparin‐binding domain with IGF‐1 prolonged retention in articular and meniscal cartilage from <1 day to 8 days after injection. Unmodified IGF‐1 had no functional effect 2 days after injection, whereas HB‐IGF‐1 stimulated meniscal cartilage at least 4 days after injection. HB‐IGF‐1, but not IGF‐1, significantly slowed cartilage damage in a rat model of OA.ConclusionHeparin‐binding domain fusions can transform rapidly cleared proteins into potential intraarticular therapies by targeting them to cartilage.
Systemic Juvenile Idiopathic Arthritis–like Syndrome in Mice Following Stimulation of the Immune System With Freund's Complete Adjuvant: Regulation by Interferon‐γ
Authors: Avau Anneleen , Mitera Tania , Put Stéphanie , Put Karen , Brisse Ellen , Filtjens Jessica , Uyttenhove Catherine , Van Snick Jacques , Liston Adrian , Leclercq Georges , Billiau An D. , Wouters Carine H. , Matthys Patrick 
Published: January 2014

ObjectiveSystemic juvenile idiopathic arthritis (JIA) is unique among the rheumatic diseases of childhood, given its distinctive systemic inflammatory character. Inappropriate control of innate immune responses following an initially harmless trigger is thought to account for the excessive inflammatory reaction. The aim of this study was to generate a similar systemic inflammatory syndrome in mice by injecting a relatively innocuous, yet persistent, immune system trigger: Freund's complete adjuvant (CFA), containing heat‐killed mycobacteria.MethodsGiven the central role of interferon‐γ (IFNγ) in immune regulation, we challenged wild‐type (WT) and IFNγ‐knockout (KO) BALB/c mice with CFA, and analyzed their clinical symptoms and biologic characteristics. The production of cytokines and the effects of anticytokine antibodies were investigated.ResultsIn WT mice, CFA injection resulted in splenomegaly, lymphadenopathy, neutrophilia, thrombocytosis, and increased cytokine expression. In the absence of IFNγ, these symptoms were more pronounced and were accompanied by weight loss, arthritis, anemia, hemophagocytosis, abundance of immature blood cells, and increased levels of interleukin‐6 (IL‐6), all of which are reminiscent of the symptoms of systemic JIA. CFA‐challenged IFNγ‐KO mice showed increased expression of IL‐17 by CD4+ T cells and by innate γ/δ T cells. Inflammatory and hematologic changes were prevented by treatment with anti–IL‐12/IL‐23p40 and anti–IL‐17 antibodies.ConclusionImmune stimulation of IFNγ‐KO mice with CFA produces a systemic inflammatory syndrome reflecting the clinical, biologic, and histopathologic picture of systemic JIA. The protective function of IFNγ in preventing anemia and overall systemic inflammation is a striking observation. The finding that both adaptive and innate T cells are important sources of IL‐17 may be of relevance in the pathogenesis of systemic JIA.
Lithium Protects Against Cartilage Degradation in Osteoarthritis
Authors: Minashima Takeshi , Zhang Ying , Lee Youjin , Kirsch Thorsten 
Published: January 2014

ObjectiveTo determine the actions of lithium chloride (LiCl) on catabolic events in human articular chondrocytes, and the effects of LiCl on the progression and severity of cartilage degradation in interleukin‐1β (IL‐1β)–treated mouse knee joints and after surgical induction of osteoarthritis (OA) in a mouse model.MethodsHuman articular chondrocytes were treated with LiCl followed by IL‐1β, and the expression levels of catabolic genes were determined by real‐time polymerase chain reaction. To understand the mechanism by which LiCl affects catabolic events in articular chondrocytes after IL‐1β treatment, the activation of NF‐κB was determined using luciferase reporter assays, and the activities of MAPKs and the STAT‐3 signaling pathway were determined by immunoblot analysis of total cell lysates. Cultures of mouse femoral head explants treated with IL‐1β and a mouse model of surgically induced OA were used to determine the effects of LiCl on proteoglycan loss and cartilage degradation.ResultsLiCl treatment resulted in decreased catabolic marker messenger RNA levels and activation of NF‐κB, p38 MAPK, and STAT‐3 signaling in IL‐1β–treated articular chondrocytes. Furthermore, LiCl directly inhibited IL‐6–stimulated activation of STAT‐3 signaling. Consequently, the loss of proteoglycan and severity of cartilage destruction in LiCl‐treated mouse knee joints 8 weeks after OA induction surgery or in LiCl‐treated mouse femoral head explants after IL‐1β treatment were markedly reduced compared to that in vehicle‐treated joints or explants.ConclusionLiCl reduced catabolic events in IL‐1β–treated human articular chondrocytes and attenuated the severity of cartilage destruction in IL‐1β–treated mouse femoral head explants and in the knee joints of mice with surgically induced OA, acting via inhibition of the activities of the NF‐κB, p38, and STAT‐3 signaling pathways.
Interleukin‐17+CD8+ T Cells Are Enriched in the Joints of Patients With Psoriatic Arthritis and Correlate With Disease Activity and Joint Damage Progression
Authors: Menon Bina , Gullick Nicola J. , Walter Gina J. , Rajasekhar Megha , Garrood Toby , Evans Hayley G. , Taams Leonie S. , Kirkham Bruce W. 
Published: January 2014

ObjectivePsoriatic arthritis (PsA) is associated with HLA class I genes, in contrast to the association with HLA class II in rheumatoid arthritis (RA). Since IL‐17+ cells are considered important mediators of synovial inflammation, we sought to determine whether IL‐17–producing CD8+ T cells may be found in the joints of patients with PsA and whether these cells might contribute to the disease process.MethodsMononuclear cells from paired samples of synovial fluid (SF) and peripheral blood (PB) from patients with PsA or patients with RA were stimulated ex vivo, and CD4− T cells were examined by flow cytometry for cytokine expression, cytotoxic markers, and frequencies of γ/δ or mucosal‐associated invariant T cells. Clinical measures of arthritis activity (C‐reactive protein [CRP] level, erythrocyte sedimentation rate [ESR], Disease Activity Score in 28 joints [DAS28]) and power Doppler ultrasound (PDUS) scores for the presence of active synovitis in the aspirated knee were recorded and assessed for correlations with immunologic markers.ResultsWithin the CD3+ T cell compartment, both IL‐17+CD4− (predominantly CD8+) and IL‐17+CD4+ T cells were significantly enhanced in the SF compared to the PB of patients with PsA (P = 0.0003 and P = 0.002, respectively; n = 21), whereas in patients with RA, only IL‐17+CD4+ T cells were increased in the SF compared to the PB (P = 0.008; n = 14). The frequency of IL‐17+CD4− T cells in PsA SF was positively correlated with the CRP level (r = 0.52, P = 0.01), ESR (r = 0.59, P = 0.004), and DAS28 (r = 0.52, P = 0.01), and was increased in patients with erosive disease (P < 0.05). In addition, the frequency of IL‐17+CD4− T cells positively correlated with the PDUS score, a marker for active synovitis (r = 0.49, P = 0.04).ConclusionThese results show, for the first time, that the PsA joint, but not the RA joint, is enriched for IL‐17+CD8+ T cells. Moreover, the findings reveal that the levels of this T cell subset are correlated with disease activity measures and the radiographic erosion status after 2 years, suggesting a previously unrecognized contribution of these cells to the pathogenesis of PsA.
Identification of New Citrulline‐Specific Autoantibodies, Which Bind to Human Arthritic Cartilage, by Mass Spectrometric Analysis of Citrullinated Type II Collagen
Authors: Haag Sabrina , Schneider Nadine , Mason Daniel E. , Tuncel Jonatan , Andersson Ida E. , Peters Eric C. , Burkhardt Harald , Holmdahl Rikard 
Published: January 2014

ObjectiveTo investigate type II collagen (CII) as a joint‐specific target of the anti–citrullinated protein antibody (ACPA) response in rheumatoid arthritis (RA).MethodsPotential citrullinated neoepitopes were identified by high‐resolution tandem mass spectrometry (MS/MS) of in vitro peptidylarginine deiminase 2 (PAD‐2)–treated CII, and the relationship between citrullination and CII conformation was investigated by circular dichroism and conformation‐dependent antibodies. Based on the MS analyses, synthetic peptides were designed and analyzed for serum IgG reactivity in the Epidemiological Investigation of RA (EIRA) case–control cohort of 1,949 RA patients and 278 healthy controls. Peptide‐specific antibodies were purified from RA patient serum and used to stain RA cartilage specimens.ResultsWe described the conformation‐dependent citrullination pattern of CII after PAD‐2 treatment at room temperature and 37°C and showed that CII could be citrullinated in its native triple‐helical conformation. Screening of Arg and Cit pairs of synthetic peptides revealed new citrullinated B cell epitopes on CII. Antibodies directed to 2 proximal epitopes close to the C‐terminus of the CII triple helix were recognized by autoantibodies in 21% and 17% of RA patients, respectively. Affinity‐purified antibodies from RA sera directed to these 2 epitopes, but not antibodies directed to citrullinated α‐enolase peptide 1, bound to RA cartilage.ConclusionThese findings suggest that cartilage‐directed anticitrulline immunity contributes to the induction of joint inflammation in RA.
Few‐Layer Borocarbonitride Nanosheets: Platinum‐Free Catalyst for the Oxygen Reduction Reaction
Authors: Moses Kota , Kiran Vankayala , Sampath S. , Rao C. N. R. 
Published: January 2014

AbstractThe present study demonstrates the use of few‐layer borocarbonitride nanosheets synthesized by a simple method as non‐platinum cathode catalysts for the oxygen reduction reaction (ORR) in alkaline medium. Composition‐dependent ORR activity is observed and the best performance was found when the composition was carbon‐rich. Mechanistic aspects reveal that ORR follows the 4 e− pathway with kinetic parameters comparable to those of the commercial Pt/C catalyst. Excellent methanol tolerance is observed with the BCN nanosheets unlike with Pt/C.
Phosphane‐Catalyzed [4+1] Annulation between Nitroalkenes and Morita–Baylis–Hillman Carbonates: Facile Synthesis of Isoxazoline N‐Oxides by Phosphorus Ylides
Authors: Zhou Rong , Duan Chong , Yang Changjiang , He Zhengjie 
Published: January 2014

AbstractA phosphane‐catalyzed [4+1] annulation between nitroalkenes and Morita–Baylis–Hillman carbonates has been realized; this provides facile and diastereoselective access to polysubstituted isoxazoline N‐oxides in moderate to excellent yields. In the annulation, an in situ formed allylic phosphorus ylide presumably serves as a pivotal active intermediate. This reaction accordingly represents the first example of phosphorus ylide initiated [4+1] cyclization of nitroalkenes to give isoxazoline N‐oxides.
Autoregressive model for a finite random sequence on the unit circle for investigating the fluctuations of residual stresses in the rims of new railroad wheels
Authors: Koshulyan Alexey V. , Malajchuk Valentin P. 
Published: January 2014

AbstractThis paper presents an autoregressive model for a finite sequence of random variables that are observed at points equally spaced on the unit circle. The proposed model is an extension of the well‐known autoregressive model of time series. We demonstrate that this model amounts to a linear transformation of a vector of independent and identically distributed random variables. The second‐order properties of the multivariate distribution were examined. The least squares estimators of the model parameters were obtained. The connection between the proposed first‐order model and a second‐order, stationary, mean‐square‐continuous, real‐valued random process on the unit circle was considered. We used the model presented to describe the fluctuations of hoop residual stresses in the rims of new railroad wheels. The stress measurement was performed using an ultrasonic method. The stress fluctuation model allowed us to determine the number of measurement points required to assess residual stress levels in the wheels. Copyright © 2014 John Wiley & Sons, Ltd.
Surface display of small peptides on Escherichia coli for enhanced calcite precipitation rates
Authors: Patel Tushar N. , Alissa Park Ah‐Hyung , Banta Scott 
Published: January 2014

AbstractMineralization has emerged as a promising strategy for long‐term carbon sequestration. These processes involve carbon dioxide hydration followed by mineral precipitation. We have explored the production of whole‐cell biocatalysts engineered with carbonic anhydrase (CA) activity to accelerate the CO2 hydration reaction. In this study, short polypeptides were displayed on the surface of E. coli cells and whole‐cell biocatalysts containing periplasmically expressed CAs in an attempt to enhance calcite mineral formation. It was found that cells coexpressing recombinant periplasmic CA and surface‐displayed GPA peptide (PEVPEGAFDTAI) outperformed other peptide‐expressing biocatalysts evaluated in terms of the amount of precipitate formed, as well as the overall formation rate of solids. Cells expressing the Cab CA isoform (BLR‐pCab) and Cam isoform (BLR‐pCam) with the surface‐displayed GPA peptide exhibited 36 and 59% improvements in precipitation amounts, as well as 18 and 60% improvements in overall formation rates, respectively, over similar biocatalysts without GPA expression. The biocatalyst with the best performance was BLR‐pCam/GPA, which generated 0.15 g of CaCO3, while BLR cells generated only 0.08 g of CaCO3 under the same small batch reaction conditions. The BLR‐pCam/GPA cells also exhibited the fastest formation rates, achieving the maximum change in solution turbidity after only 2.2 min, as opposed to 6.3 min for BLR cells. These results demonstrate that synthetic biology approaches can be used to create novel biocatalysts with the ability to enhance both catalysis and precipitation activities. © 2014 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 102: 191–196, 2014.
Mid-term cost-effectiveness analysis of open and endovascular repair for ruptured abdominal aortic aneurysm
Authors: Rollins K E , Shak J , Ambler G K , Tang T Y , Hayes P D , Boyle J R 
Published: January 2014

AbstractBackgroundEmergency endovascular repair (EVAR) for ruptured abdominal aortic aneurysm (rAAA) may have lower operative mortality rates than open surgical repair. Concerns remain that the early survival benefit after EVAR for rAAA may be offset by late reinterventions. The aim of this study was to compare reintervention rates and cost-effectiveness of EVAR and open repair for rAAA.MethodsA retrospective analysis was undertaken of patients with rAAA undergoing EVAR or open repair over 6 years. A health economic model developed for the cost-effectiveness of elective EVAR was used in the emergency setting.ResultsSixty-two patients (mean age 77·9 years) underwent EVAR and 85 (mean age 75·9 years) had open repair of rAAA. Median follow-up was 42 and 39 months respectively. There was no significant difference in 30-day mortality rates after EVAR and open repair (18 and 26 per cent respectively; P = 0·243). Reintervention rates were also similar (32 and 31 per cent; P = 0·701). The mean cost per patient was €26 725 for EVAR and €30 297 for open repair, and the cost per life-year gained was €7906 and €9933 respectively (P = 0·561). Open repair had greater initial costs: longer procedural times (217 versus 178·5 min; P &lt; 0·001) and intensive care stay (5·0 versus 1·0 days; P = 0·015). Conversely, EVAR had greater reintervention (€156 939 versus €35 335; P = 0·001) and surveillance (P &lt; 0·001) costs.ConclusionThere was no significant difference in reintervention rates after EVAR or open repair for rAAA. EVAR was as cost-effective at mid-term follow-up. The increased procedural costs of open repair are not outweighed by greater surveillance and reintervention costs after EVAR.
Mine simulation for educational purposes: A case study
Authors: Akkoyun Ozgur , Careddu Nicola 
Published: January 2014

ABSTRACTThis paper presents a new simulation‐based computer program that provides an interactive and visual environment for teaching and learning of mining engineering related subjects. An actual open pit magnesite mine was selected and whole simulation data were obtained from this mine in order to create a simulation application. The program represents this open pit mine in detail using more than hundred variables, 14 windows, and several modules. It is believed that, with its all components, this educational tool can be used for several mining‐related subjects such as drilling and blasting, excavation and haulage, size reduction and magnetic separation at universities to provide fundamental information to the students and anyone dealing with mining engineering related subjects. It may also be used for mining related departments such as geology and geophysics for giving brief information about mining. © 2014 Wiley Periodicals, Inc. Comput Appl Eng Educ 23:286–293, 2015; View this article online at wileyonlinelibrary.com/journal/cae; DOI 10.1002/cae.21598
Well‐Directed Adjusting of Graining and Mechanical Strength of Lignite Granules
Authors: Fehse Franz , Herdegen Volker , Schröder Hans‐Werner , Repke Jens‐Uwe 
Published: January 2014

AbstractBraunkohlengranulate mit gleichmäßiger Körnung und hoher Festigkeit können als neuartige Produkte vielseitigen Verwendungen zugeführt werden. Neben dem Einsatz als kleinstückiger Brennstoff rückt insbesondere die stoffliche Nutzung, zum Beispiel als Dämmstoff oder Adsorbens zur SO2‐Abscheidung, in den Fokus der Forschung. Zur Herstellung qualitativ hochwertiger Granulate ist es notwendig, Wechselwirkungen der Prozessparameter auf die Granulatqualität zu kennen. Im Folgenden werden der Einfluss der Zerkleinerungsart der Rohkohle und des Dampfanteils sowie der Dampfzugabedauer auf die Granulatqualität systematisch untersucht.
Design and Synthesis of C3‐Pyrazole/Chalcone‐Linked Beta‐Carboline Hybrids: Antitopoisomerase I, DNA‐Interactive, and Apoptosis‐Inducing Anticancer Agents
Authors: Kamal Ahmed , Srinivasulu Vunnam , Nayak V. Lakshma , Sathish Manda , Shankaraiah Nagula , Bagul Chandrakant , Reddy N. V. Subba , Rangaraj Nandini , Nagesh Narayana 
Published: January 2014

AbstractA series of β‐carboline hybrids bearing a substituted phenyl and a chalcone/(N‐acetyl)‐pyrazole moiety at the C1 and C3 positions, respectively, was designed, synthesized, and evaluated for anticancer activity. These new hybrid molecules showed significant cytotoxic activity, with IC50 values ranging from <2.0 μM to 80 μM, and the structure–activity relationships (SAR) associated with substitutions at positions 1 and 3 of these hybrids was clearly addressed. Further, induction of apoptosis was confirmed by Annexin V‐FITC, Hoechst staining, and DNA fragmentation analysis. In addition, DNA photocleavage studies proved that two of the hybrids, (E)‐1‐(furan‐2‐yl)‐3‐(1‐(4‐(trifluoromethyl)phenyl)‐9H‐pyrido[3,4‐b]indol‐3‐yl)prop‐2‐en‐1‐one (7 d) and 1‐(3‐(furan‐2‐yl)‐5‐(1‐(4‐(trifluoromethyl)phenyl)‐9H‐pyrido[3,4‐b]indol‐3‐yl)‐4,5‐dihydro‐1H‐pyrazol‐1‐yl)ethanone (8 d) could effectively cleave pBR322 plasmid DNA upon irradiation with UV light. Active hybrid 8 d inhibited DNA topoisomerase I activity efficiently and preserved DNA in the supercoiled form. To further corroborate the biological activities, as well as to understand the nature of the interaction of these hybrids with DNA, spectroscopic studies were also performed. Unlike simple β‐carboline alkaloids, the binding mode of these new hybrid molecules with DNA was not similar, and both biophysical as well as molecular docking studies speculated a combilexin‐type of interaction with DNA. Further, an in silico study of these β‐carboline hybrids revealed their drug‐like properties.
Prospective Virtual Screening in a Sparse Data Scenario: Design of Small‐Molecule TLR2 Antagonists
Authors: Murgueitio Manuela S. , Henneke Philipp , Glossmann Hartmut , Santos‐Sierra Sandra , Wolber Gerhard 
Published: January 2014

AbstractToll‐like receptors (TLRs) are critical signaling molecules with roles in various severe clinical conditions such as sepsis and rheumatoid arthritis, and have therefore been advocated as promising drug targets for the treatment of these diseases. The aim of this study was to discover small‐molecule antagonists of TLR2 by computer‐aided drug design. This goal poses several challenges due to the lack of available data on TLR2 modulators. To overcome these hurdles we developed a combined structure‐ and ligand‐based virtual screening approach. First, we calculated molecular interaction fields of the TLR2 binding site to derive a structure‐based 3D pharmacophore, which was then used for virtual screening. We then performed a two‐step shape‐ and feature‐based similarity search using known TLR2 ligands as query structures. A selection of virtual screening hits was biologically tested in a cell‐based assay for TLR2 signaling inhibition, leading to the identification of several compounds with antagonistic activity (IC50 values) in the low‐micromolar range.