bluuebunny/crossref_metadata_2025_split huggingface dataset:
Safety and pharmacodynamics of rontalizumab in patients with systemic lupus erythematosus: Results of a phase I, placebo‐controlled, double‐blind, dose‐escalation study
Authors: McBride Jacqueline M. , Jiang Jenny , Abbas Alexander R. , Morimoto Alyssa , Li Jing , Maciuca Romeo , Townsend Michael , Wallace Daniel J. , Kennedy William P. , Drappa Jorn 
Published: July 2012

AbstractObjectiveSystemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by the presence of autoantibodies and inflammation in multiple organ systems. Elevation of messenger RNA levels of interferon (IFN)–regulated genes (IRGs) has been described in the peripheral blood of SLE patients and has been associated with disease activity. The safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of rontalizumab, a humanized IgG1 monoclonal antibody that neutralizes IFNα, were assessed in a phase I dose‐escalation study of single and repeat doses of rontalizumab in adults with mildly active SLE. The present report describes the safety results and the impact of rontalizumab on expression of IRGs, IFN‐inducible proteins, and autoantibodies.MethodsPatients were enrolled into dose groups ranging from 0.3 to 10 mg/kg, administered via intravenous (IV) or subcutaneous routes. Expression levels of 7 IRGs and IFN‐inducible serum proteins were monitored as potential biomarkers for the PD activity of rontalizumab.ResultsAn acceptable safety profile was demonstrated for rontalizumab in patients with SLE. Prespecified criteria for dose‐limiting toxicity were not met. The incidence of serious adverse events was comparable across cohorts. The PK properties were as expected for an IgG1 monoclonal antibody and were proportional to dose. Following administration of rontalizumab, a rapid decline in the expression of IRGs was observed in the 3 mg/kg and 10 mg/kg IV cohorts, and this effect could be sustained with repeat dosing. There was no apparent decline in the levels of IFN‐inducible proteins or levels of anti–double‐stranded DNA and anti–extractable nuclear antigen autoantibodies following treatment with rontalizumab.ConclusionThe preliminary safety, PK profile, and observed PD effects of rontalizumab support further evaluation of its safety and efficacy in SLE.
Association of two independent functional risk haplotypes in TNIP1 with systemic lupus erythematosus
Authors: Adrianto Indra , Wang Shaofeng , Wiley Graham B. , Lessard Christopher J. , Kelly Jennifer A. , Adler Adam J. , Glenn Stuart B. , Williams Adrienne H. , Ziegler Julie T. , Comeau Mary E. , Marion Miranda C. , Wakeland Benjamin E. , Liang Chaoying , Kaufman Kenneth M. , Guthridge Joel M. , Alarcón‐Riquelme Marta E. ,   BIOLUPUS and GENLES Networks, Alarcón Graciela S. , Anaya Juan‐Manuel , Bae Sang‐Cheol , Kim Jae‐Hoon , Joo Young Bin , Boackle Susan A. , Brown Elizabeth E. , Petri Michelle A. , Ramsey‐Goldman Rosalind , Reveille John D. , Vilá Luis M. , Criswell Lindsey A. , Edberg Jeffrey C. , Freedman Barry I. , Gilkeson Gary S. , Jacob Chaim O. , James Judith A. , Kamen Diane L. , Kimberly Robert P. , Martín Javier , Merrill Joan T. , Niewold Timothy B. , Pons‐Estel Bernardo A. , Scofield R. Hal , Stevens Anne M. , Tsao Betty P. , Vyse Timothy J. , Langefeld Carl D. , Harley John B. , Wakeland Edward K. , Moser Kathy L. , Montgomery Courtney G. , Gaffney Patrick M. 
Published: July 2012

AbstractObjectiveSystemic lupus erythematosus (SLE) is an autoimmune disease characterized by autoantibody production and altered type I interferon expression. Genetic surveys and genome‐wide association studies have identified >30 SLE susceptibility genes. One of these genes, TNIP1, encodes the ABIN1 protein. ABIN1 functions in the immune system by restricting NF‐κB signaling. The present study was undertaken to investigate the genetic factors that influence association with SLE in genes that regulate the NF‐κB pathway.MethodsWe analyzed a dense set of genetic markers spanning TNIP1 and TAX1BP1, as well as the TNIP1 homolog TNIP2, in case–control populations of diverse ethnic origins. TNIP1, TNIP2, and TAX1BP1 were fine‐mapped in a total of 8,372 SLE cases and 7,492 healthy controls from European‐ancestry, African American, Hispanic, East Asian, and African American Gullah populations. Levels of TNIP1 messenger RNA (mRNA) and ABIN1 protein in Epstein‐Barr virus–transformed human B cell lines were analyzed by quantitative reverse transcription–polymerase chain reaction and Western blotting, respectively.ResultsWe found significant associations between SLE and genetic variants within TNIP1, but not in TNIP2 or TAX1BP1. After resequencing and imputation, we identified 2 independent risk haplotypes within TNIP1 in individuals of European ancestry that were also present in African American and Hispanic populations. Levels of TNIP1 mRNA and ABIN1 protein were reduced among subjects with these haplotypes, suggesting that they harbor hypomorphic functional variants that influence susceptibility to SLE by restricting ABIN1 expression.ConclusionOur results confirm the association signals between SLE and TNIP1 variants in multiple populations and provide new insight into the mechanism by which TNIP1 variants may contribute to SLE pathogenesis.
Potential roles of interleukin‐17A in the development of skin fibrosis in mice
Authors: Okamoto Yoshinobu , Hasegawa Minoru , Matsushita Takashi , Hamaguchi Yasuhito , Huu Doanh Le , Iwakura Yoichiro , Fujimoto Manabu , Takehara Kazuhiko 
Published: July 2012

AbstractObjectiveAlthough transforming growth factor β (TGFβ) and connective tissue growth factor (CTGF) have been considered to play central roles in the pathogenesis of systemic sclerosis (SSc), other cytokines may also be crucial for the development of SSc. The aim of this study was to examine the roles of T helper cytokines in the development of skin fibrosis.MethodsTo compare the roles of Th1, Th2, and Th17 cytokines, we examined bleomycin‐induced SSc in mice deficient for interferon‐γ (IFNγ), interleukin‐4 (IL‐4), and IL‐17A. The mechanism by which IL‐17A contributes to bleomycin‐induced fibrosis was investigated in vivo and in vitro. The outcome of mice lacking IL‐17A was also investigated in TSK‐1 mice.ResultsThe loss of IL‐17A significantly attenuated bleomycin‐induced skin fibrosis, whereas a deficiency of IFNγ or IL‐4 did not. Leukocyte infiltration and the expression of TGFβ and CTGF messenger RNA in bleomycin‐injected skin were significantly reduced in IL‐17A–deficient mice compared with wild‐type (WT) mice. Daily bleomycin injections induced the expression of IL‐17A in the skin and potent IL‐17A producers in splenic CD4+ T cells from WT mice. Furthermore, a skin fibroblast cell line expressed increased TGFβ, CTGF, and collagen after the addition of recombinant IL‐17A. IL‐17A deficiency also attenuated skin thickness in TSK‐1 mice.ConclusionThis study demonstrates that IL‐17A contributes to skin fibrosis in 2 mouse models of SSc. These findings suggest that inhibition of IL‐17A represents a therapeutic target for antagonizing fibrotic skin disorders such as SSc.
Effect of nonsteroidal antiinflammatory drugs on the C‐reactive protein level in rheumatoid arthritis: A meta‐analysis of randomized controlled trials
Authors: Tarp Simon , Bartels Else M. , Bliddal Henning , Furst Daniel E. , Boers Maarten , Danneskiold‐Samsøe Bente , Rasmussen Mette , Christensen Robin 
Published: July 2012

AbstractObjectiveTo evaluate the effects of oral nonsteroidal antiinflammatory drugs (NSAIDs) on C‐reactive protein (CRP) levels in rheumatoid arthritis (RA) patients, with a prespecified focus on the different NSAIDs.MethodsWe performed a systematic search in Medline via PubMed, the Cochrane Central Register of Controlled Trials, EMBase via OVID, the Institute for Scientific Information Web of Science, and other sources. Eligible trials were parallel‐group, randomized, placebo‐controlled trials of oral NSAID therapy in RA patients for which there were extractable CRP data. Standardized mean differences (SMDs) with 95% confidence intervals (95% CIs) were calculated from the differences in means of CRP levels between groups (active treatment minus placebo) divided by the pooled SDs. For the meta‐analysis, a random‐effects model was used to estimate the overall change in CRP level, and stratified analysis was used to examine differences among NSAIDs.ResultsWe included 19 trials of 10 different NSAIDs. Overall, NSAIDs showed no effect on the CRP level (SMD 0.01 [95% CI −0.03, 0.06], P = 0.62). However, the prespecified stratified analysis indicated varying effects on the CRP level according to the different NSAIDs; lumiracoxib caused a statistically significant and consistent (I2 = 0%) increase in the CRP level (SMD 0.13 [95% CI 0.01, 0.25], P = 0.037), whereas naproxen caused a statistically significant and consistent (I2 = 0%) decrease in the CRP level (SMD −0.11 [95% CI −0.20, −0.02], P = 0.022).ConclusionOverall, NSAIDs have no effect on the CRP level. However, the nonselective NSAID naproxen was associated with a significant decrease in the CRP level, whereas the cyclooxygenase 2–selective NSAID lumiracoxib was associated with a significant increase in the CRP level. This finding is interesting considering the suspected influence of NSAIDs on cardiovascular complications.
Th1 and Th17 lymphocytes expressing CD161 are implicated in giant cell arteritis and polymyalgia rheumatica pathogenesis
Authors: Samson Maxime , Audia Sylvain , Fraszczak Jennifer , Trad Malika , Ornetti Paul , Lakomy Daniela , Ciudad Marion , Leguy Vanessa , Berthier Sabine , Vinit Julien , Manckoundia Patrick , Maillefert Jean‐Francis , Besancenot Jean‐François , Aho‐Glele Serge , Olsson Nils Olivier , Lorcerie Bernard , Guillevin Loïc , Mouthon Luc , Saas Philippe , Bateman Andrew , Martin Laurent , Janikashvili Nona , Larmonier Nicolas , Bonnotte Bernard 
Published: July 2012

AbstractObjectiveGiant cell arteritis (GCA) is the most frequently occurring vasculitis in elderly individuals, and its pathogenesis is not fully understood. The objective of this study was to decipher the role of the major CD4+ T cell subsets in GCA and its rheumatologic form, polymyalgia rheumatica (PMR).MethodsA prospective study of the phenotype and the function of major CD4+ T cell subsets (Th1, Th17, and Treg cells) was performed in 34 untreated patients with GCA or PMR, in comparison with 31 healthy control subjects and with the 27 treated patients who remained after the 7 others withdrew.ResultsCompared with control subjects, patients with GCA and patients with PMR had a decreased frequency of Treg cells and Th1 cells, whereas the percentage of Th17 cells was significantly increased. Furthermore, an analysis of temporal artery biopsy specimens obtained from patients affected by GCA for whom biopsy results were positive demonstrated massive infiltration by Th17 and Th1 lymphocytes without any Treg cells. After glucocorticoid treatment, the percentages of circulating Th1 and Th17 cells decreased, whereas no change in the Treg cell frequency was observed. The frequency of CD161+CD4+ T cells, which are considered to be Th17 cell precursors, was similar in patients and control subjects. However, these cells highly infiltrated GCA temporal artery biopsy specimens, and their ability to produce interleukin‐17 in vitro was significantly enhanced in patients with GCA and patients with PMR and was correlated with a decrease in the phosphorylated form of STAT‐1.ConclusionThis study is the first to demonstrate that the frequency of Treg cells is decreased in patients with GCA and patients with PMR, and that CD161+CD4+ T lymphocytes, differentiated into Th1 cells and Th17 cells, are involved in the pathogenesis of GCA and PMR.
α,α′‐Diarylacenaphtho[1,2‐c]phosphole P‐Oxides: Divergent Synthesis and Application to Cathode Buffer Layers in Organic Photovoltaics
Authors: Matano Yoshihiro , Saito Arihiro , Suzuki Yuto , Miyajima Tooru , Akiyama Seiji , Otsubo Saika , Nakamoto Emi , Aramaki Shinji , Imahori Hiroshi 
Published: July 2012

AbstractA divergent method for the synthesis of α,α′‐diarylacenaphtho[1,2‐c]phosphole P‐oxides has been established; α,α′‐dibromoacenaphtho[c]phosphole P‐oxide, which was prepared through a TiII‐mediated cyclization of 1,8‐bis(trimethylsilylethynyl)naphthalene, underwent a Stille coupling with three different kinds of aryltributylstannanes to afford the α,α′‐diarylacenaphtho[c]phosphole P‐oxides in moderate to good yields. X‐ray crystallographic analyses and UV/Vis absorption/fluorescence measurements have revealed that the degree of π‐conjugation, the packing motif, the electron‐accepting ability, and the thermal stability of the acenaphtho[c]phosphole π‐systems are finely tunable with the α‐aryl substituents. All the PO and PS derivatives exhibited high stability in their electrochemically reduced state. To use this class of arene‐fused phosphole π‐systems as n‐type semiconducting materials, we evaluated device performances of the bulk heterojunction organic photovoltaics (OPV) that consist of poly(3‐hexylthiophene), an indene‐C70 bisadduct, and a cathode buffer layer. The insertion of the diarylacenaphtho[c]phosphole P‐oxides as the buffer layer was found to improve the power conversion efficiency of the polymer‐based OPV devices.
An Active Disturbance Rejection Based Approach to Vibration Suppression in Two‐Inertia Systems
Authors: Zhao Shen , Gao Zhiqiang 
Published: July 2012

AbstractThis study concerns the resonance problems found in motion control, typically described in a two‐inertia system model as compliance between the motor and the load. We reformulate the problem in the framework of active disturbance rejection control (ADRC), where the resonance is assumed to be unknown and treated as disturbance, estimated and mitigated. This allows the closed‐loop bandwidth to go well beyond the resonant frequency, which is quite difficult using existing methods. In addition, such level of performance is achieved with minimum complexity in the controller design and tuning: no parameter estimation or adaptive algorithm is needed, and the controller is tuned by adjusting one parameter, namely, the bandwidth of the control loop. It is also shown that the proposed solution applies to both the velocity and position control problems, and the fact that ADRC offers an effective and practical motion control solution, in the presence of unknown resonant frequency within the bandwidth of the control system. Finally, frequency response analysis is performed where stability margin is obtained before the simulation results are verified in the hardware experiments.
The use of pH‐sensitive nitroxide spin probe to study diffusion of acids diffusion of HCl and CCl3COOH in Glassy Glycerol/Water Mixture
Authors: Paschenko S. V. , Dzuba S. A. , Khramtsov V. V. , Tsvetkov Yu. D. 
Published: July 2012

AbstractProton transfer from surrounding matrix to imidazolidine‐based nitroxide spin probe in viscous solution is shown to affect noticeably the nitroxide solid‐like EPR spectrum. The use of this property is suggested for studying diffusion of guest acid molecules. Diffusion of hydrochloric and trichloroacetic acid in glassy 85%/ 15% wt:wt glycerol/water mixture has been studied. Values of diffusion coefficient obtained in the range 3·−9 − 5·−8cm2/s show a remarkable breakdown of the Stokes‐Einstein law. The data may be fitted by the empirical law D ∝︁ η−b, with b ≈ 0.6.
A. coherent vs. incoherent hydrogen dynamics across or through a barrier: Infrared laser pulse controlled ultrafast H‐atom switching in two‐dimensional asymmetric double well potentials
Authors: Došlić N. , Kühn O. , Manz J. 
Published: July 2012

AbstractThe laser induced isomerisation of malonaldehyde derivatives is studied using a two‐dimensional model Hamiltonian. The two selected coordinates describe the H‐atom motion coupled to a heavy atom mode which modulates the reaction barrier. On the basis of the solutions of the time‐dependent Schrödinger equation pulse characteristics are determined which yield an efficient switching of the H‐atom wavepacket between the two isomers within a pump‐dump scheme. The influence of various system parameters such as the heavy‐light atom coupling and the direction of the dipole moment is investigated.
The quantum dynamics of proton transfer in the hydrogen bond
Authors: Horsewill A. J. , Brougham D. F. , Jenkinson R. I. , Mcgloin C. J. , Trommsdorff H. P. , Johnson M. R. 
Published: July 2012

AbstractDouble proton transfer in the hydrogen bonds of carboxylic acid dimers has been investigated via measurements of the dispersion of the proton spin‐lattice relaxation time, T1, using magnetic field‐cycling NMR. A plot of the spin‐lattice relaxation rate, T1−1, as a function of magnetic field, provides a direct measurement of the motional spectrum and hence of the proton transfer rate. In the materials studied, these NMR experiments are optimised for the low temperature region where the dynamics are dominated by incoherent quantum tunnelling. Measurements of the proton transfer rate at higher temperatures have been made using quasi‐elastic neutron scattering (QENS) and these facilitate the characterisation of the transition between quantum and classical dynamics in the intermediate temperature region. The role of tunnelling in the excited vibrational states of the double minimum potential (DMP) which characterises the system is revealed in these measurements and has been analysed according to the behaviour of a particle in a DMP which is coupled to a bath of phonons. The complementarity between the NMR and QENS techniques is emphasised and discussed, and the dynamic range accessible to the field‐cycling NMR technique is explored through studying a range of related materials.
Proton transfer and hydrogen bonding with transition metal atoms and hydride hydrogen by IR and NMR studies
Authors: Epstein L. M. , Shubina E. S. 
Published: July 2012

AbstractThe present review considers the results of investigations of novel types of hydrogen bonds inherent in transition metal complexes, namely H‐bonds with the metal atom (XH…M) and with hydrogen atom of transition metal hydrides and boron hydrides (XH…HM), (XH…HB). The spectral (IR, NMR) evidence of the hydrogen bond formation due to interaction of proton donors with metal and hydride hydrogen as proton acceptors is presented. The thermodynamic and spectral characteristics of these hydrogen bonds are determined. An analysis of similarity between spectral and thermodynamic properties of the novel and classical H‐bonding with organic bases is carried out. The participation of these hydrogen bonds in proton transfer is analyzed.
Proton transfer reaction in N‐methyl‐2‐hydroxy‐Schiff bases
Authors: Filarowski Aleksander , Koll Aleksander , Glowiak Tadeusz , Majewski Eugeniusz , Dziembowska Teresa 
Published: July 2012

AbstractThe structure of two ortho‐hydroxy N‐methyl Schiff bases as well as the selfcondensation product of 2‐(N‐methyliminomethyl)‐phenol are determined by X‐Ray crystallography and by ab initio DFT, on B3LYP/6‐31G** level, calculations. Electronic coupling between acidic and basic centres of the molecules, especially effective in the proton transfer structure, is discussed on the basis of detailed analysis of differentiation of bond lengths both in aromatic and chelate rings. Consequences of this coupling on the intramolecular hydrogen bonding and proton transfer process are discussed.
Compared 13C NMR spectra of acetanilide and N‐methylacetamide
Authors: Barthes Mariette , Ribet Michèle 
Published: July 2012

AbstractAcetanilide and N‐methylacetamide are both crystals in which the existence of non linear excitations (self‐trapped excitons or acoustic polarons) have been postulated as an explanation of the unconventional amide spectroscopy. This theory is debated and a dynamic proton transfer along the hydrogen bond could be an alternative explanation for the unexpected sidebands and temperature dependences.Our compared 13C NMR study demonstrates a similar behaviour for the EFG at the 14N atom in these both compounds, indicating a very close electronic density around the nitrogen in both cases, and thus does not confirm the hypothesis of a proton transfer in N‐methylacetamide.
Diversity of excited state deactivation paths in heteroazaaromatics with multiple intermolecular hydrogen bonds
Authors: Dobkowski Jacek , Herbich Jerzy , Galievsky Victor , Thummel Randolph P. , Wu Feiyue , Waluk Jacek 
Published: July 2012

AbstractTransient absorption and luminescence studies were performed for several heteroazaaromatic molecules which possess both hydrogen bonding donor and acceptor groups, and which are capable of forming cyclic, double intermolecular hydrogen bonds. In protic solvents, these systems exhibit complex photophysics, manifested by a strong quenching of the fluorescence. In dipyrido[2,3‐a:3′,2′‐i]carbazole and 7,8,9,10‐tetrahydropyri‐do[2,3‐a]carbazole, photoinduced double proton transfer is observed in the first excited singlet state, leading to tautomeric species which emit strongly Stokes‐shifted fluorescence. The large and temperature‐independent rate of this reaction is observed for the case in which a cyclic complex with an alcohol molecule is formed already in the ground state. Another excited state depopulation channel, internal conversion caused by proton movement in the cyclic complex, is observed in alcohol solutions of 2‐(2′‐pyridyl)‐indoles and pyrido[2,3‐a]carbazole. In these cases, formation of cyclic, doubly hydrogen‐bonded structures occurs in the excited state and involves solvent rearrangement. The rate of this process changes with solvent viscosity and becomes negligible at low temperatures, when the viscosity is high. Fast internal conversion has also been observed in hydrogen‐bonded complexes with azaaromatic bases. Its mechanism can be explained by intermolecular charge transfer interactions. In alcohol solutions of 2‐(2′‐pyridyl)indoles, transient absorption results point to yet another channel of excited state deactivation – photoionization, occurring faster than S1 decay.
Discrimination between hydrogen atom and proton abstraction in the quenching of n, π* singlet‐excited states by protic solvents
Authors: Nau Werner M. , Greiner Gerhard , Rau Hermann , Olivucci Massimo , Robb Michael A. 
Published: July 2012

AbstractThe fluorescence quenching of the azoalkane 2,3‐diazabicyclo[2.2.2]oct‐2‐ene by protic solvents (methanol, methanol‐OD, water, deuterium oxide, acetic acid) has been examined. The pseudo‐unimolecular quenching rate constants (kq) vary from 0.30‐44×106s−1 and decrease upon deuteration of the solvent OH bonds, e.g., the isotope effect for methanol/methanol‐OD is ca. 8.5. This demonstrates that the hydroxylic hydrogens are predominantly responsible for the fluorescence quenching. The activation parameters were determined for methanol and methanol‐OD. The activation enthalpies are unexpectedly low (ΔH‡ = 1.8 kcal mol−1 for methanol) and increase upon deuteration (ΔH‡ = 3.0 kcal mol−1 for methanol‐OD), while the activation entropies remain the same (ΔS‡ ca. 17.5 cal K−1 mol−1. This provides evidence for a fully classical isotope effect related to differences in zero‐point vibrational energies. Tunneling appears to play no significant role. The quenching rate constants display no trend with the acidity of the solvent (pKa values) but with the homolytic bond dissociation energies of the OH bonds. This suggests the involvement of a hydrogen atom rather than a proton transfer. All important aspects (activation enthalpies, isotope effects, etc.) of this novel quenching mechanism of protic solvents are reproduced by MCSCF quantum‐chemical calculations with a complete active space of CAS (12,10) or CAS (8,7). Most importantly, the computed data indicate the occurrence of a conical intersection, i.e., a real surface crossing, which follows the transition state and provides an efficient trigger for radiationless return to the ground‐state energy surface (fluorescence quenching).