bluuebunny/crossref_metadata_2025 huggingface dataset:
Long‐Term Safety, Efficacy, and Quality of Life in Patients With Juvenile Idiopathic Arthritis Treated With Intravenous Abatacept for Up to Seven Years
Authors: Lovell Daniel J. , Ruperto Nicolino , Mouy Richard , Paz Eliana , Rubio‐Pérez Nadina , Silva Clovis A. , Abud‐Mendoza Carlos , Burgos‐Vargas Ruben , Gerloni Valeria , Melo‐Gomes Jose A. , Saad‐Magalhaes Claudia , Chavez‐Corrales J. , Huemer Christian , Kivitz Alan , Blanco Francisco J. , Foeldvari Ivan , Hofer Michael , Huppertz Hans‐Iko , Job Deslandre Chantal , Minden Kirsten , Punaro Marilynn , Block Alan J. , Giannini Edward H. , Martini Alberto ,   for the Pediatric Rheumatology Collaborative Study Group and the Paediatric Rheumatology International Trials Organisation
Published: June 2015

Objective

The efficacy and safety of abatacept in patients with juvenile idiopathic arthritis (JIA) who experienced an inadequate response to disease‐modifying antirheumatic drugs were previously established in a phase III study that included a 4‐month open‐label lead‐in period, a 6‐month double‐blind withdrawal period, and a long‐term extension (LTE) phase. The aim of this study was to present the safety, efficacy, and patient‐reported outcomes of abatacept treatment (10 mg/kg every 4 weeks) during the LTE phase, for up to 7 years of followup.

Methods

Patients enrolled in the phase III trial could enter the open‐label LTE phase if they had not achieved a response to treatment at month 4 or if they had received abatacept or placebo during the double‐blind period.

Results

One hundred fifty‐three (80.5%) of 190 patients entered the LTE phase, and 69 patients (36.3%) completed it. The overall incidence rate (events per 100 patient‐years) of adverse events decreased during the LTE phase (433.61 events during the short‐term phase [combined lead‐in and double‐blind periods] versus 132.39 events during the LTE phase). Similar results were observed for serious adverse events (6.82 versus 5.60), serious infections (1.13 versus 1.72), malignancies (1.12 versus 0), and autoimmune events (2.26 versus 1.18). American College of Rheumatology (ACR) Pediatric 30 (Pedi 30) responses, Pedi 70 responses, and clinically inactive disease status were maintained throughout the LTE phase in patients who continued to receive therapy. Improvements in the Child Health Questionnaire physical and psychosocial summary scores were maintained over time.

Conclusion

Long‐term abatacept treatment for up to 7 years was associated with consistent safety, sustained efficacy, and quality‐of‐life benefits in patients with JIA.
Use of Ultrasound‐Guided Small Joint Biopsy to Evaluate the Histopathologic Response to Rheumatoid Arthritis Therapy: Recommendations for Application to Clinical Trials
Authors: Humby Frances , Kelly Stephen , Hands Rebecca , Rocher Vidalba , DiCicco Maria , Ng Nora , Zou Lu , Bugatti Serena , Manzo Antonio , Caporali Roberto , Montecucco Carlomaurizio , Bombardieri Michele , Pitzalis Costantino
Published: June 2015

Objective

To examine in a cohort of rheumatoid arthritis (RA) patients undergoing serial ultrasound (US)–guided biopsies of small joints in the context of clinical trials whether sufficient synovial tissue could be obtained at both baseline and second biopsy to: 1) accurately evaluate the synovial immune phenotype, 2) permit adequate RNA extraction to determine molecular signatures, and 3) sensitively detect change in the number of synovial sublining macrophages (CD68+) following effective therapy.

Methods

Synovial samples from RA patients undergoing US‐guided biopsy of small joints as part of 2 clinical trials (Barts Early Arthritis Cohort [n = 18] and the Clinical and Pathological Response to Certolizumab Pegol (CLIP‐Cert) study [n = 17]) were examined, and the quality and quantity of histologic samples and RNA extracted per joint were determined and compared to synovial thickness and power Doppler scores determined by US before biopsy. Modulation of the number of CD68+ sublining macrophages was correlated with clinical response to treatment.

Results

Good quality synovial tissue that accurately reflected the synovial immune phenotype of the total joint was obtained in 80% of US‐guided procedures when synovial thickness (higher than grade 2) was documented before biopsy. In 100% of the procedures, sufficient RNA was extracted to permit molecular analysis. There was a significant correlation between change in CD68+ sublining macrophage number and clinical response to treatment.

Conclusion

This study provides minimum standards for sample retrieval for small joint biopsy. Furthermore, our findings confirm the clinical utility of the procedure in the largest reported cohort of US‐guided small joint biopsies. The demonstration that small joint synovial tissue can be readily accessed by a technically simple, minimally invasive procedure is likely to facilitate critical advancements in the knowledge of RA pathobiology and personalized health care.
Promotion of Hypercoagulability in Antineutrophil Cytoplasmic Antibody–Associated Vasculitis by C5a‐Induced Tissue Factor–Expressing Microparticles and Neutrophil Extracellular Traps
Authors: Huang Yi‐Min , Wang Huan , Wang Chen , Chen Min , Zhao Ming‐Hui
Published: June 2015

Objective

Patients with antineutrophil cytoplasmic antibody–associated vasculitis (AAV) have a high frequency of venous thromboembolic events and a hypercoagulable state. As C5a‐primed neutrophils play an important role in the development of AAV, we investigated whether C5a‐induced neutrophil tissue factor (TF)–expressing microparticles (MPs) and neutrophil extracellular traps (NETs) might promote hypercoagulability in AAV.

Methods

TF‐expressing MPs were measured by flow cytometry. TF‐expressing NETs were assessed by confocal microscopy. Levels of thrombin–antithrombin complexes were determined by enzyme‐linked immunosorbent assay. The effect of C5a in sera from AAV patients was evaluated by treating neutrophils with C5a receptor antagonist before incubation with sera from AAV patients with active disease.

Results

Treatment of C5a‐primed neutrophils with antineutrophil cytoplasmic antibody (ANCA)–positive IgG resulted in the release of TF‐bearing MPs and NETs. Neutrophils from healthy donors treated with sera from patients with active AAV released TF‐bearing MPs and NETs, which were abolished by treatment with C5a receptor antagonist. Involvement of TF in MP‐ or NET‐dependent thrombin generation was indicated by the findings of antibody neutralization studies. NETs with thrombin‐generating capacity were demonstrated by DNase I treatment.

Conclusion

C5a‐primed neutrophils produce TF‐expressing MPs and NETs after stimulation with ANCAs, indicating a mechanism for hypercoagulability in AAV that was not previously recognized.
Brief Report: Association of CCR1, KLRC4, IL12A–AS1, STAT4, and ERAP1 With Behçet's Disease in Iranians
Authors: Sousa Inês , Shahram Farhad , Francisco David , Davatchi Fereydoun , Abdollahi Bahar Sadeghi , Ghaderibarmi Fahmida , Nadji Abdolhadi , Mojarad Shafiee Niloofar , Xavier Joana M. , Oliveira Sofia A.
Published: June 2015

Objective

To independently replicate the top findings from 4 published genome‐wide association studies (GWAS) of susceptibility genes in Behçet's disease (BD).

Methods

We tested 14 single‐nucleotide polymorphisms (SNPs) in 13 genomic loci (excluding the major histocompatibility complex [MHC], IL10, and IL23R–IL12RB2, which have already been associated with BD in Iranians) for allelic and genotypic associations with BD in 973 patients and 828 controls from Iran and performed meta‐analyses of the significantly associated markers.

Results

Six SNPs (in decreasing order of significance, rs7616215 located 38 kb downstream of CCR1, rs2617170 [p.Asn104Ser] in KLRC4, rs17810546 in IL12A–AS1, rs7574070 in STAT4, and rs10050860 [p.Asp575Asn] and rs13154629 in ERAP1) were nominally associated with BD in both allelic association tests (5.05 × 10−9 ≤ Pallele ≤ 7.55 × 10−3) and sex‐adjusted genotypic association tests (6.01 × 10−9 ≤ adjusted P value ≤ 1.30 × 10−2). For all 6 SNPs tested by meta‐analysis (Pmeta), the association with BD was strengthened, because the direction and magnitude of association were similar across populations (e.g., for rs7574070, odds ratio [OR] for A allele 1.29 [95% confidence interval (95% CI) 1.21–1.37], Pmeta = 2.34 × 10−16; for rs7616215, OR for C allele 0.70 [95% CI 0.65–0.76], Pmeta = 1.54 × 10−19; for rs17810546, OR for A allele 0.60 [95% CI 0.52–0.70], Pmeta = 6.34 × 10−11; for rs2617170, OR for T allele 0.76 [95% CI 0.70–0.81], Pmeta = 2.75 × 10−14; for rs13154629, OR for TT genotype 2.76 [95% CI 2.01–3.80], Pmeta = 3.57 × 10−10).

Conclusion

This study reinforces the notion that CCR1, KLRC4, IL12A–AS1, STAT4, and ERAP1 are bona fide susceptibility genes for BD, in addition to the MHC, IL10, and IL23R–IL12RB2 loci. Future genetic and functional studies are now warranted to uncover the roles of these genes in the pathogenesis of BD.
Increased Expression of NAPDH Oxidase 4 in Systemic Sclerosis Dermal Fibroblasts: Regulation by Transforming Growth Factor β
Authors: Piera‐Velazquez Sonsoles , Makul Alma , Jiménez Sergio A.
Published: June 2015

Objective

Systemic sclerosis (SSc) is characterized by severe and often progressive fibrosis of the skin and multiple internal organs. The mechanisms responsible for these alterations remain obscure, although excessive reactive oxygen species (ROS)–mediated oxidative stress has been implicated. NOX‐4 is 1 of 7 isoforms of NADPH oxidase responsible for the generation of ROS. The purpose of this study was to examine NOX‐4 expression in skin and cultured dermal fibroblasts from SSc patients and to examine its regulation by transforming growth factor β1 (TGFβ1).

Methods

NOX‐4 was assessed in normal and SSc skin by immunohistologic analysis and in normal and SSc cultured dermal fibroblasts by quantitative polymerase chain reaction analysis, fluorescence microscopy, and Western blotting. ROS levels were assessed by fluorescence measurement of H2O2 production. Specific kinase inhibitors were used to study the TGFβ1 signaling involved in NOX‐4 stimulation. NOX‐4 inhibition/down‐regulation was induced with a selective NOX‐4 small‐molecule inhibitor and NOX‐4 small interfering RNA (siRNA).

Results

In contrast with normal skin fibroblasts, those from SSc skin showed intense NOX‐4 staining. Cultured SSc fibroblasts displayed increased NOX‐4 expression. TGFβ1 caused potent NOX‐4 protein and messenger RNA stimulation in normal and SSc fibroblasts, which was mediated by the protein kinase Cδ (PKCδ) and Smad2/3 pathways. NOX‐4 knockdown in SSc fibroblasts reduced the production of ROS and lowered the expression of type I collagen.

Conclusion

NOX‐4 expression and production were found to be constitutively elevated in SSc skin and cultured SSc dermal fibroblasts. TGFβ1 stimulated NOX‐4 expression in normal and SSc fibroblasts through PKCδ and Smad2/3 signaling pathways. A small‐molecule NOX‐4 inhibitor decreased collagen and fibronectin production by normal and SSc fibroblasts, and NOX‐4 siRNA knockdown reduced ROS and collagen production by SSc fibroblasts. These results demonstrate the involvement of NOX‐4 in SSc‐associated fibrosis and indicate NOX‐4 inhibitors as novel therapeutic approaches for SSc.
Articular Cartilage Endurance and Resistance to Osteoarthritic Changes Require Transcription Factor Erg
Authors: Ohta Yoichi , Okabe Takahiro , Larmour Colleen , Di Rocco Agnese , Maijenburg Marijke W. , Phillips Amanda , Speck Nancy A. , Wakitani Shigeyuki , Nakamura Takashi , Yamada Yoshihiko , Enomoto‐Iwamoto Motomi , Pacifici Maurizio , Iwamoto Masahiro
Published: June 2015

Objective

To determine whether and how the transcription factor Erg participates in the genesis, establishment, and maintenance of articular cartilage.

Methods

Floxed Erg mice were mated with Gdf5‐Cre mice to generate conditional mutants lacking Erg in their joints. Joints of mutant and control mice were subjected to morphologic and molecular characterization and also to experimental surgically induced osteoarthritis (OA). Gene expression, promoter reporter assays, and gain‐ and loss‐of‐function in vitro tests were used to characterize molecular mechanisms of Erg action.

Results

Conditional Erg ablation did not elicit obvious changes in limb joint development and overall phenotype in juvenile mice. However, as mice aged, joints of mutant mice degenerated spontaneously and exhibited clear OA‐like phenotypic defects. Joints in juvenile mutant mice were more sensitive to surgically induced OA and became defective sooner than operated joints in control mice. Global gene expression data and other studies identified parathyroid hormone–related protein (PTHrP) and lubricin as possible downstream effectors and mediators of Erg action in articular chondrocytes. Reporter assays using control and mutated promoter‐enhancer constructs indicated that Erg acted on Ets DNA binding sites to stimulate PTHrP expression. Erg was up‐regulated in severely affected areas in human OA articular cartilage but remained barely appreciable in areas of less affected cartilage.

Conclusion

The study shows for the first time that Erg is a critical molecular regulator of the endurance of articular cartilage during postnatal life and that Erg can mitigate spontaneous and experimental OA. Erg appears to do this through regulating expression of PTHrP and lubricin, factors known for their protective roles in joints.
Dysregulated Osteoclastogenesis Is Related to Natural Killer T Cell Dysfunction in Rheumatoid Arthritis
Authors: Jin Hye‐Mi , Kee Seung‐Jung , Cho Young‐Nan , Kang Jeong‐Hwa , Kim Moon‐Ju , Jung Hyun‐Ju , Park Ki‐Jeong , Kim Tae‐Jong , Lee Sang‐Il , Choi Hyuck , Koh Jeong‐Tae , Kim Nacksung , Park Yong‐Wook
Published: June 2015

Objective

To investigate the role played by natural killer T (NKT) cells in osteoclastogenesis and their effects on inflammatory bone destruction.

Methods

Patients with rheumatoid arthritis (RA) (n = 25) and healthy controls (n = 12) were enrolled in this study. In vitro osteoclastogenesis experiments were performed using peripheral blood mononuclear cells (PBMCs) in the presence of macrophage colony‐stimulating factor and RANKL. PBMCs were cultured in vitro with α‐galactosylceramide (αGalCer), and proliferation indices of NKT cells were estimated by flow cytometry. In vivo effects of αGalCer‐stimulated NKT cells on inflammation and bone destruction were determined in mice with collagen‐induced arthritis.

Results

In vitro osteoclastogenesis was found to be significantly inhibited by αGalCer in healthy controls but not in RA patients. Proliferative responses of NKT cells and STAT‐1 phosphorylation in monocytes in response to αGalCer were impaired in RA patients. Notably, αGalCer‐stimulated NKT cells inhibited osteoclastogenesis mainly via interferon‐γ production in a cytokine‐dependent manner (not by cell–cell contact) and down‐regulated osteoclast‐associated genes. Mice treated with αGalCer showed less severe arthritis and reduced bone destruction. Moreover, proinflammatory cytokine expression in arthritic joints was found to be reduced by αGalCer treatment.

Conclusion

This study primarily demonstrates that αGalCer‐stimulated NKT cells have a regulatory effect on osteoclastogenesis and a protective effect against inflammatory bone destruction. However, it also shows that these effects of αGalCer are diminished in RA patients and that this is related to NKT cell dysfunction. These findings provide important information for those searching for novel therapeutic strategies to prevent bone destruction in RA.
Release of Neutrophil Extracellular Traps by Neutrophils Stimulated With Antiphospholipid Antibodies: A Newly Identified Mechanism of Thrombosis in the Antiphospholipid Syndrome
Authors: Yalavarthi Srilakshmi , Gould Travis J. , Rao Ashish N. , Mazza Levi F. , Morris Alexandra E. , Núñez‐Álvarez Carlos , Hernández‐Ramírez Diego , Bockenstedt Paula L. , Liaw Patricia C. , Cabral Antonio R. , Knight Jason S.
Published: June 2015

Objective

Antiphospholipid antibodies (aPL), especially those targeting β2‐glycoprotein I (β2GPI), are well known to activate endothelial cells, monocytes, and platelets, with prothrombotic implications. In contrast, the interaction of aPL with neutrophils has not been extensively studied. Neutrophil extracellular traps (NETs) have recently been recognized as an important activator of the coagulation cascade, as well as an integral component of arterial and venous thrombi. This study was undertaken to determine whether aPL activate neutrophils to release NETs, thereby predisposing to the arterial and venous thrombosis inherent in the antiphospholipid syndrome (APS).

Methods

Neutrophils, sera, and plasma were prepared from patients with primary APS (n = 52) or from healthy volunteers and characterized. No patient had concomitant systemic lupus erythematosus.

Results

Sera and plasma from patients with primary APS had elevated levels of both cell‐free DNA and NETs, as compared to healthy volunteers. Freshly isolated neutrophils from patients with APS were predisposed to high levels of spontaneous NET release. Further, APS patient sera, as well as IgG purified from APS patients, stimulated NET release from control neutrophils. Human aPL monoclonal antibodies, especially those targeting β2GPI, also enhanced NET release. The induction of APS NETs was abrogated with inhibitors of reactive oxygen species formation and Toll‐like receptor 4 signaling. Highlighting the potential clinical relevance of these findings, APS NETs promoted thrombin generation.

Conclusion

Our findings indicate that NET release warrants further investigation as a novel therapeutic target in APS.
Data sharing for the advancement of science: Overcoming barriers for citizen scientists
Authors: Williamson Kirsty , Kennan Mary Anne , Johanson Graeme , Weckert John
Published: June 2015

Systematic study of data sharing by citizen scientists will make a significant contribution to science because of the growing importance of aggregated data in data‐intensive science. This article expands on the data sharing component of a paper presented at the 2013ASISTconference. A three‐phase project is reported. Conducted between 2011 and 2013 within an environmental voluntary group, theAustralianPlantsSocietyVictoria (APSV), the interviews of the first phase are the major data source. Because the project revealed the importance of data sharing with professional scientists, their views are included in the literature review where four themes are explored: lack of shared disciplinary culture, trust, responsibility and controlled access to data, and describing data to enable reuse. The findings, presented under these themes, revealed that, withinAPSV, sharing among members is mostly generous and uninhibited. BeyondAPSV, when online repositories were involved, barriers came very strongly into play. Trust was weaker and barriers also included issues of data quality, data description, and ownership and control. The conclusion is that further investigation of these barriers, including the attitudes of professional scientists to using data contributed by citizen scientists, would indicate how more extensive and useful data sharing could be achieved.
Direct Synthesis of Palladium Catalyst on Supporting WS2 Nanotubes and its Reactivity in Cross‐Coupling Reactions
Authors: Višić Bojana , Cohen Hagai , Popovitz‐Biro Ronit , Tenne Reshef , Sokolov Viacheslav I. , Abramova Natalya V. , Buyanovskaya Anastasiya G. , Dzvonkovskii Sergei L. , Lependina Olga L.
Published: June 2015

Palladium nanoparticles were deposited on multiwall WS2 nanotubes. The composite nanoparticles were characterized by a variety of techniques. The Pd nanoparticles were deposited uniformly on the surface of WS2 nanotubes. An epitaxial relationship between the (111) plane of Pd and the (013) plane of WS2 was mostly observed. The composite nanoparticles were found to perform efficiently as catalysts for cross‐coupling (Heck and Suzuki) reactions. The role of the nanotubes′ support in the catalytic process is briefly discussed.
Photon‐Quantitative 6π‐Electrocyclization of a Diarylbenzo[b]thiophene in Polar Medium
Authors: Li Ruiji , Nakashima Takuya , Galangau Olivier , Iijima Shunsuke , Kanazawa Rui , Kawai Tsuyoshi
Published: June 2015

The high reactivity of 6π‐electrocyclization in polar solvents has remained one of the important challenges for diarylethenes because of the emergence of a twisted intramolecular charge transfer (TICT) state at the excited state in such polar media, which usually quenches the photocyclization reaction. Herein we report on the preparation and highly efficient photocyclization of 2,3‐diarylbenzo[b]thiophenes with nonsymmetric side‐aryl units in a polar solvent. While the dithiazolylbenzo[b]thiophene showed a suppressed quantum yield of 6π‐electrocyclization of 54 % in methanol, the replacement of a thiazole unit with a thiophene ring led to a photon‐quantitative 6π‐cyclization reaction. The nonsymmetrical modification into the side‐aryl units was considered to enhance the CH/π interactions between side‐aryl units to support a photoreactive conformation in methanol. The stabilization of the photochromic reactive conformation is expected to suppress the formation of the TICT state at the excited state, leading to highly efficient photoreactivity.
Amine‐Catalyzed Highly Regioselective and Stereoselective C(sp2)–C(sp2) Cross‐Coupling of Naphthols with trans‐α,β‐Unsaturated Aldehydes
Authors: Hu Yang , Ma Yueyue , Sun Rengwei , Yu Xinhong , Xie Hexin , Wang Wei
Published: June 2015

A metal‐free C(sp2)–C(sp2) cross‐coupling approach to highly congested (E)‐α‐naphtholylenals from simple naphthols and enals is described. The mild reaction conditions with pyridine hydrobromideperbromide (PHBP) as the bromination reagent in the presence of piperidine or diphenylprolinol trimethylsilyl (TMS) ether as promoters enable the process in good yields and with high chemoselectivity, regioselectivity, and stereoselectivity. The process involves an unprecedented pathway of in situ regioselective 4‐bromination of 1‐naphthols and the subsequent unusual aromatic nucleophilic substitution of the resulting 4‐bromo‐1‐naphthols with the α‐C(sp2) of enals through a Michael‐type Friedel–Crafts alkylation–dearomatization followed by a cyclopropanation ring‐opening cascade process. The noteworthy features of this strategy are highlighted by the highly efficient creation of a C(sp2)–C(sp2) bond from readily available unfunctionalized naphthols and enals catalyzed by non‐metal, readily available cyclic secondary amines under mild reaction conditions.
Visible‐Light Photoredox Catalysis: Direct Synthesis of Sulfonated Oxindoles from N‐Arylacrylamides and Arylsulfinic Acids by Means of a Cascade C−S/C−C Formation Process
Authors: Xia Dong , Miao Tao , Li Pinhua , Wang Lei
Published: June 2015

A novel photocatalytic synthesis of sulfonated oxindoles from N‐arylacrylamides and arylsulfinic acids was developed by means of a cascade C−S/C−C bond‐formation process. This method provides mild, efficient, and atom‐economical access to various sulfonated oxindoles in water.
Required traffic micro‐simulation runs for reliable multivariate performance estimates
Authors: Truong Long T. , Sarvi Majid , Currie Graham , Garoni Timothy M.
Published: June 2015

Previous methods to calculate the minimum number of traffic micro‐simulation runs do not consider multiple measures of performance simultaneously at an overall confidence level, which can lead to unreliable simulation outputs. This paper describes new methodologies for calculating the minimum number of traffic micro‐simulation runs for multivariate estimates at an overall confidence level. Simultaneous confidence intervals obtained from multiple comparisons in statistical theory such as the Bonferroni inequality and simultaneous confidence interval method are used to estimate multiple measures of performance with allowable errors at an overall confidence level. Measures of performance can be means and standard deviations. Results of numerical analysis based on an example corridor suggest that the proposed methods provide improved means of assessing statistical accuracy of multiple measures of performance. Results also indicate that the minimum number of runs is influenced by not only the sample size issue but also the complexity of the traffic system. Copyright © 2015 John Wiley & Sons, Ltd.
Flexible integration of visual cues in adolescents with autism spectrum disorder
Authors: Bedford Rachael , Pellicano Elizabeth , Mareschal Denis , Nardini Marko
Published: June 2015

Although children with autism spectrum disorder (ASD) show atypical sensory processing, evidence for impaired integration of multisensory information has been mixed. In this study, we took a Bayesian model‐based approach to assess within‐modality integration of congruent and incongruent texture and disparity cues to judge slant in typical and autistic adolescents. Human adults optimally combine multiple sources of sensory information to reduce perceptual variance but in typical development this ability to integrate cues does not develop until late childhood. While adults cannot help but integrate cues, even when they are incongruent, young children's ability to keep cues separate gives them an advantage in discriminating incongruent stimuli. Given that mature cue integration emerges in later childhood, we hypothesized that typical adolescents would show adult‐like integration, combining both congruent and incongruent cues. For the ASD group there were three possible predictions (1) “no fusion”: no integration of congruent or incongruent cues, like 6‐year‐old typical children; (2) “mandatory fusion”: integration of congruent and incongruent cues, like typical adults; (3) “selective fusion”: cues are combined when congruent but not incongruent, consistent with predictions of Enhanced Perceptual Functioning (EPF) theory. As hypothesized, typical adolescents showed significant integration of both congruent and incongruent cues. The ASD group showed results consistent with “selective fusion,” integrating congruent but not incongruent cues. This allowed adolescents with ASD to make perceptual judgments which typical adolescents could not. In line with EPF, results suggest that perception in ASD may be more flexible and less governed by mandatory top‐down feedback. Autism Res 2016, 9: 272–281. © 2015 International Society for Autism Research, Wiley Periodicals, Inc.
Regulation of uridine diphosphate‐glucuronosyltransferase 1A3 activity by protein phosphorylation
Authors: Xiao Yongsheng , Yao Yan , Jiang Huidi , Lu Chuan , Zeng Su , Yu Lushan
Published: June 2015

Protein phosphorylation is a vital post‐translational modification. This study investigated the effect of phosphorylation on human uridine diphosphate (UDP)‐glucuronosyltransferase 1A3 (UGT1A3) activity. Curcumin and calphostin C suppressed the activity and phosphorylation of recombinant UGT1A3 expressed in Sf9 cells. These results indicate that UGT1A3 undergoes phosphorylation, which is required for its catalytic activity. Calphostin C is a highly specific protein kinase C (PKC) inhibitor, so three predicted PKC phosphorylation sites in UGT1A3 were examined. Site‐directed mutation analysis at residues 28, 43 and 436 (from serine to glycine) was conducted. Compared with the wild‐type, the S43G‐mutant showed significantly decreased UGT1A3 catalytic activity. Furthermore, the UGT1A3 activity of wild‐type and S43G‐mutant was down‐regulated by calphostin C, whereas the calphostin C inhibitory effect was much weaker on the S43G‐mutant than the wild‐type. In conclusion, phosphorylation plays an important role in UGT1A3 activity, and the serine at site 43 in UGT1A3 is most likely a phosphorylation site. Copyright © 2015 John Wiley & Sons, Ltd.
Unusual trend in the prevalence of trisomy 13 in mothers aged 35 and older: A population based study of national congenital anomaly data
Authors: Nair Deepa Balachandran , Tucker David , Hughes Rhian , Greenacre Judith , Morgan Margery
Published: June 2015

Background

Trisomy 13 is one of the three autosomal trisomies compatible with viability. It is associated with structural anomalies, learning disability and poor survival. Advanced maternal age is the most frequently suggested risk factor. This is a population based register study to investigate the temporal trends of trisomy 13.

Methods

Chromosomal trisomies were reviewed by the Welsh Congenital Anomaly Register using data from 1998‐2012. All pregnancy outcomes were included. Prevalence rates and trends for all cases and for cases with mothers aged below 35 years and those aged 35 years and older were plotted for trisomy 13, 18 and 21. Possible risk factors contributing to the trend in older mothers were compared in the early and late period of the study.

Results

There were 124 cases of trisomy 13 over the 15 year period with 55 mothers aged 35 years and older. Overall prevalence was 2.5 per 10,000 total births. A significant declining trend in the prevalence of trisomy 13 in mothers aged 35 and older (χ2trend = 4.98, p=0.026) was noted. Rates for younger mothers were lower and remained stable. Prevalence of trisomy 18 and 21 in older mothers remained stable.

Conclusion

The unexpected declining trend in trisomy 13 in older mothers could not be explained by the risk factors examined in this study. There have been no other reports of trends in the prevalence of trisomy 13 in older mothers in recent years. There is further need for surveillance of trends in future and in other populations. Birth Defects Research (Part A) 103:610–616, 2015. © 2015 Wiley Periodicals, Inc.
Reflections on the etiology of structural birth defects: Established teratogens and risk factors
Authors: Feldkamp Marcia L. , Botto Lorenzo D. , Carey John C.
Published: June 2015

Background

Various experts in clinical teratology have proposed what they consider to be well‐established teratogens. With the recent growth in the number of resources and investigations, there has been a notable proliferation of proposed risk factors as potential causes of human congenital structural defects. The purpose of this Commentary is to provide a concise summary of the current state of knowledge regarding known causes and environmental risk factors of structural defects.

Methods

We performed a comprehensive search of PubMed for papers in English and in humans only, 2010 to 2014, that included birth defects, risk factors, and teratogens as key terms.

Results

Our search led to over 9000 papers dealing with these categories. From this, we were able to construct a timetable documenting the recognition of human teratogens and list several proposed environmental risk factors. Three relevant current trends were noticed: An increase of prescription and nonprescription medication use by women during pregnancy; the rise in obesity and its association with structural defects; and a growing body of work regarding outcomes associated with assisted reproductive technology.

Conclusion

There are numerous risk factors, some modifiable, that have been proposed in recent years. These factors (associations) are only at the preliminary level in the causal chain and require replication. There is a need for more work on protective factors. The phenotypic characterization of cases with congenital defects has improved remarkably in recent years. However, there remains considerable concern with the precise characterization of exposures and the documentation of timing during embryologic development. Birth Defects Research (Part A) 103:652–655, 2015. © 2015 Wiley Periodicals, Inc.
Microwave‐assisted extraction in combination with HPLC‐UV for quantitative analysis of six bioactive oxoisoaporphine alkaloids in Menispermum dauricum DC
Authors: Wei Jinxia , Chen Jing , Liang Xinlei , Guo Xingjie
Published: June 2015

A novel and reliable method based on microwave‐assisted extraction (MAE) followed by HPLC‐UV was developed and validated for the simultaneous quantification of six pharmacologically important oxoisoaporphine alkaloids in the total plants of Menispermum dauricum DC. The optimal MAE extraction condition was performed at 60°C for 11 min with ethanol–water (70:30, v/v) as the extracting solvent, and the solvent to solid ratio was 20:1. Chromatographic separation was achieved on a reversed‐phase YMC C18 column (250 × 4.6 mm, i.d., 5 µm) with a gradient mobile phase consisting of A (1% aqueous formic acid) and B (acetonitrile containing 1% formic acid) at a flow rate of 1.5 mL/min. The detection wavelength was set at 422 nm. Excellent linearity over the investigated concentration ranges was observed with values of r >0.999 for all analytes. The method developed was validated with acceptable sensitivity, intra‐ and inter‐day precision and extraction recoveries. It was successfully applied to the determination of six alkaloids in Menispermum dauricum DC from different sources and different parts of Menispermum dauricum DC. The results obtained indicated that the method is suitable for the quality control of Menispermum dauricum DC. Copyright © 2015 John Wiley & Sons, Ltd.
Novel LC‐ ESI‐MS/MS method for desvenlafaxine estimation human plasma: application to pharmacokinetic study
Authors: Kancharla Pushpa Kumari , Kondru Venu Gopal Raju , Dannana Gowri Sankar
Published: June 2015

A simple, sensitive and specific liquid chromatography tandem mass spectrometry (LC‐ESI‐MS/MS) method was developed for the quantification of desvenlafaxine in human plasma using desvenlafaxine d6 as an internal standard (IS). Chromatographic separation was performed using a Thermo‐BDS hypersil C8 column (50 × 4.6 mm, 3 µm) with an isocratic mobile phase composed of 5 mM ammonium acetate buffer: methanol (20:80, v/v), at a flow rate of 0.80 mL/min. Desvenlafaxine and desvenlafaxine d6 were detected with proton adducts at m/z 264.2/58.1 and 270.2/ 64.1 in multiple reaction monitoring positive mode, respectively. Liquid–liquid extraction was used to extract the drug and the IS. The method was linear over the concentration range 1.001–400.352 ng/mL with a correlation coefficient of ≥0.9994. This method demonstrated intra and inter‐day precision within 0.7–5.5 and 1.9–6.8%, and accuracy within 95.3–107.4 and 93.4–99.5%. Desvenlafaxine was found to be stable throughout the freeze–thaw cycles, bench‐top and long‐term matrix stability studies. The developed and validated method can be successfully applied for the bioequivalence/pharmacokinetic studies of desvenlafaxine in pharmaceutical dosage forms. Copyright © 2015 John Wiley & Sons, Ltd.
Computer‐based experiments for learning seismic signal processing concepts
Authors: Khan Khalid Amin , Akhter Gulraiz
Published: June 2015

A good understanding of digital signal processing concepts is essential for students of geophysical engineering, electrical engineering, and image processing. This paper presents a computer‐based training software, which uses signal processing libraries to perform a number of interesting seismic experiments. Each experiment is focused towards a specific concept and presents a parameters input interface. The results are instantly generated in the form of a graphical display. This facilitates the student to play with parameters and observe their effects on the output. Some selected experiments have been discussed along with their parameters input interfaces and sample outputs. Such experiments provide a better understand and visualization of various seismic concepts. Studies on student groups indicate that these experiments motivate students and expedite self‐learning, thus reducing the teaching load. © 2015 Wiley Periodicals, Inc. Comput Appl Eng Educ 23:959–966, 2015; View this article online at wileyonlinelibrary.com/journal/cae; DOI 10.1002/cae.21669
Graph‐cut based interactive image segmentation with randomized texton searching
Authors: Ma Wei , Zhang Yu , Yang Luwei , Duan Lijuan
Published: June 2015

In the paper, we present an interactive image‐segmentation method in the framework of graph cut, which incorporates not only traditional color and gradient constraints, but also a new type of texture constraint. Given an image with user‐input strokes, we first establish the color and texture prior models of the foreground/background. The texture prior model, which is key to establish the texture constraints, is represented by local binary patterns (LBP) histograms. Then, an energy function composed of color, gradient, and texture terms is formulated. At last, by using graph cut, we minimize the energy function to obtain the foreground. In the energy function, the color and gradient terms have similar forms with traditional methods. The texture term in the function is generated using a proposed randomized texton‐searching algorithm. First, the algorithm locates an approximately best representative texton for every unknown pixel as foreground and an approximately best one as background, through randomized searching. Second, it computes the LBP histograms of the two textons as the pixel's foreground/background texture descriptors, respectively. Finally, the distances between the descriptors and the foreground/background prior models are used to formulate the texture term. Experimental results demonstrate that our method outperforms traditional ones. Copyright © 2015 John Wiley & Sons, Ltd.
Circulating miR‐145 is associated with plasma high‐sensitivity C‐reactive protein in acute ischemic stroke patients
Authors: Jia Lihua , Hao Fang , Wang Weihua , Qu Yang
Published: June 2015

Stroke is a major cerebrovascular disease threatening human health and life with high morbidity, disability and mortality. We aimed to find effective biomarkers for the early diagnosis on stroke. Nine previously reported stroke‐associated miRNAs (miR‐21, miR‐23a, miR‐29b, miR‐124, miR‐145, miR‐210, miR‐221, miR‐223 and miR‐483‐5p) were measured by quantitative real time‐PCR, and plasma high‐sensitivity C‐reactive protein (hs‐CRP) and serum interleukin 6 (IL‐6), the pro‐inflammation markers in brain injury, were examined by enzyme‐linked immunosorbent assay in 146 acute ischemic stroke patients and 96 healthy blood donors. We found that serum miR‐145 was significantly increased within 24 h after stroke onset and serum miR‐23a and miR‐221 were decreased in patients. Moreover, serum miR‐145 was strong positively correlated with plasma hs‐CRP and moderate positively correlated with serum IL‐6. Meanwhile, serum miR‐23a and miR‐221 were moderate negatively correlated with plasma hs‐CRP but not serum IL‐6. Importantly, the combination of hs‐CRP and serum miR‐145 gained a better sensitivity/spectivity for prediction of acute ischemia stroke (area under receiver operating characteristic curve from 0.794 to 0.896). Conclusively, our preliminary findings indicate that serum miR‐145 upregulated in acute ischemic stroke might be a new biomarker for acute ischemia stroke evaluation. Copyright © 2015 John Wiley & Sons, Ltd.
Hsa‐miR‐132 inhibits proliferation of hepatic carcinoma cells by targeting YAP
Authors: Lei Chang‐Jiang , Li Lei , Gao Xia , Zhang Jun , Pan Qing‐Yun , Long Hao‐Cheng , Chen Chun‐Zhou , Ren De‐Fa , Zheng Gang
Published: June 2015

MicroRNAs and Yes‐associated protein (YAP) play an important role in the occurrence and development of hepatic carcinomas. However, the interaction between microRNAs and YAP was seldom elucidated. In this study, we showed that miR‐132 could target YAP gene by using dual‐luciferase reporter system. Further quantitative polymerase chain reaction analysis and western blotting showed that miR‐132 could significantly reduce the expression of YAP at mRNA and protein levels. Results of annexin V‐fluorescein isothiocyanate, 5‐ethynyl‐2′‐deoxyuridine staining and transwell assays showed that miR‐132 significantly promoted the cell apoptosis and effectively inhibited the proliferation and invasion of hepatoma cells. These results indicated that miR‐132 could inhibit the growth of hepatoma cells by targeting YAP gene and reducing its expression level. Taken together, results from this study would help us to understand the mechanisms for occurrence and development of hepatic carcinoma and provide new targets for diagnosis and treatment of liver cancer. Copyright © 2015 John Wiley & Sons, Ltd.
Preparation, Characterization, and Oxygenase Activity of a Photocatalytic Artificial Enzyme
Authors: Gu Yifan , Ellis‐Guardiola Ken , Srivastava Poonam , Lewis Jared C.
Published: June 2015

A bicyclo[6,1,0]nonyne‐substituted 9‐mesityl‐10‐methyl‐acridinium cofactor was prepared and covalently linked to a prolyl oligopeptidase scaffold containing a genetically encoded 4‐azido‐L‐phenylalanine residue in its active site. The resulting artificial enzyme catalyzed sulfoxidation when irradiated with visible light in the presence of air. This reaction proceeds by initial electron abstraction from the sulfide within the enzyme active site, and the protein scaffold extended the fluorescence lifetime of the acridium cofactor. The mode of sulfide activation and placement of the acridinium cofactor (5) in POP‐ZA4‐5 make this artificial enzyme a promising platform for developing selective photocatalytic transformations.
Detection of Human α‐L‐Fucosidases by a Quinone Methide‐Generating Probe: Enhanced Activities in Response to Helicobacter pylori Infection
Authors: Nandakumar Manjula , Hsu Yu‐Ling , Lin Jason C.‐Y , Lo Chun , Lo Lee‐Chiang , Lin Chun‐Hung
Published: June 2015

α‐L‐Fucosidase activity is associated with several diseases. To study the enzymatic activity change under pathological conditions, we developed a quinone methide‐generating activity‐based probe useful for examining the presence, activity, and localization of human α‐L‐fucosidase in vivo in the context of Helicobacter pylori infection. In particular, an increase in intracellular fucosidase (Fuca1) activity was found in gastric epithelial cells upon bacterial infection. We further studied the effect of several bacterial stimulants on this enhanced Fuca1 activity and identified lipopolysaccharides to be a major contributing factor.
Handicap‐Recover Evolution Leads to a Chemically Versatile, Nucleophile‐Permissive Protease
Authors: Shafee Thomas , Gatti‐Lafranconi Pietro , Minter Ralph , Hollfelder Florian
Published: June 2015

Mutation of the tobacco etch virus (TEV) protease nucleophile from cysteine to serine causes an approximately ∼104‐fold loss in activity. Ten rounds of directed evolution of the mutant, TEVSer, overcame the detrimental effects of nucleophile exchange to recover near‐wild‐type activity in the mutant TEVSerX. Rather than respecialising TEV to the new nucleophile, all the enzymes along the evolutionary trajectory also retained the ability to use the original cysteine nucleophile. Therefore the adaptive evolution of TEVSer is paralleled by a neutral trajectory for TEVCys, in which mutations that increase serine nucleophile reactivity hardly affect the reactivity of cysteine. This apparent nucleophile permissiveness explains how nucleophile switches can occur in the phylogeny of the chymotrypsin‐like protease PA superfamily. Despite the changed key component of their chemical mechanisms, the evolved variants TEVSerX and TEVCysX have similar activities; this could potentially facilitate escape from adaptive conflict to enable active‐site evolution.
Sphere‐forming cells from peripheral cornea demonstrate a wound‐healing response to injury
Authors: Huang Stephanie U. , Yoon Jinny J. , Ismail Salim , McGhee Jennifer J. , Sherwin Trevor
Published: June 2015

The cornea is the initial refractive interface of the eye. Its transparency is critical for clear vision and is maintained by stem cells which also act to repair injury inflicted by external insults, such as chemical and thermal burns. Damage to the epithelium compromises its clarity and can reduce or eliminate the stem cell population, diminishing the ability for self‐repair. This condition has been termed “limbal stem cell deficiency”; severe cases can lead to corneal blindness. Sphere‐forming cells isolated from peripheral cornea are a potential source of stem and progenitor cells for corneal repair. When provided with appropriate substrate, these spheres have the ability to adhere and for cells to migrate outwards akin to that of their natural environment. Direct compression injury and remote scratch injury experiments were conducted on the sphere cells to gauge their wound healing capacity. Measures of proliferation, differentiation, and migration were assessed by immunohistochemical detection of EdU incorporation, α‐smooth muscle actin expression and confocal image analysis, respectively. Both modes of injury were observed to draw responses from the spheres indicating wound healing processes. Direct wounding induced a rapid, but transient increase in expression of α‐SMA, a marker of corneal myofibroblasts, followed by a proliferative and increasing migratory response. The spheres were observed to respond to remote injury as entire units, with no directional response seen for targeted repair over the scratch injury area. These results give strength to the future use of these peripheral corneal spheres as transplantable units for the regeneration of corneal tissue.
Plant microRNAs: master regulator of gene expression mechanism
Authors: Datta Riddhi , Paul Soumitra
Published: June 2015

Several signaling molecules critically regulate the physiological responses in plants. Among them, miRNAs, generally 21–24 nucleotides long, are widely distributed in different plant species and play as key signaling intermediates in diverse physiological responses. The mature miRNAs are synthesized from MIR genes by RNA polymerase II and processed by Dicer‐like (DCL) protein family members associated with some accessory protein molecules. The processed miRNAs are transported to the cytoplasm from the nucleus by specific group of transporters and incorporated into RNA‐induced silencing complex (RISC) for specific mRNA cleavage. MicroRNAs can suppress the diverse gene expression, depending on the sequence complementarity of the target transcript except of its own gene. Besides, miRNAs can modulate the gene expression by DNA methylation and translational inhibition of the target transcript. Different classes of DCLs and Argonaute proteins (AGOs) help the miRNAs‐mediated gene silencing mechanism in plants.
Adipose progenitor cells reside among the mature adipocytes: morphological research using an organotypic culture system
Authors: Anayama Hisashi , Fukuda Ryo , Yamate Jyoji
Published: June 2015

The precise localization and biological characteristics of the adipose progenitor cells are still a focus of debate. In this study, the localization of the adipose progenitor cells was determined using an organotypic culture system of adipose tissue slices. The tissue slices of subcutaneous white adipose tissue from rats were placed on a porous membrane and cultured at the interface between air and the culture medium for up to 5 days with or without adipogenic stimulation. The structure of adipose tissue components was sufficiently preserved during the culture and, following adipogenic stimulation with insulin, dexamethasone, and 3‐isobutyl‐1‐methylxanthine, numerous multilocular adipocytes appeared in the interstitium among the mature adipocytes. Histomorphological 3‐D observation using confocal laser microscopy revealed the presence of small mesenchymal cells containing little or no fat residing in the perivascular region and on the mature adipocytes and differentiation from the pre‐existing mesenchymal cells to multilocular adipocytes. Immunohistochemistry demonstrated that these cells were initially present within the fibronectin‐positive extracellular matrix (ECM). The adipose differentiation of the mesenchymal cells was confirmed by the enhanced expression of C/EBP‐β suggesting adipose differentiation and the concurrent advent of CD105‐expressing mesenchymal cells within the interstitium of the mature adipocytes. Based on the above, the mesenchymal cells embedded in the ECM around the mature adipocytes were confirmed to be responsible for adipogenesis because the transition of the mesenchymal cells to the stem state contributed to the increase in the number of adipocytes in rat adipose tissue.