bluuebunny/crossref_metadata_2025 huggingface dataset:
Sensitivity analyses for scenario reduction in flexible flow sheet design with a large number of uncertain parameters
Authors: Pintarič Zorka Novak , Kasaš Mihael , Kravanja Zdravko
Published: February 2013

A solution strategy for designing flexible process flow sheets with a large number of uncertain parameters is presented. The basic mathematical formulation is a two‐stage stochastic program transformed into its multi‐scenario deterministic equivalent. The main feature of the proposed approach is a tremendous reduction in scenarios to a smaller number of those critical ones. This reduction is achieved through simple sensitivity analyses that identify those uncertain parameters that are critical for feasibility and those that are involved in a stochastic approximation of the objective value. Through the application of this strategy, it is possible to solve the problems with several tens or even hundred uncertain parameters, assuming weak interactions between them. Feasible designs are obtained for a fixed degree of flexibility, while the expected objective function is approximated fairly well. The strategy is applied to two flow sheet examples. © 2013 American Institute of Chemical Engineers AIChE J, 59: 2862–2871, 2013
Application of Tertiary Amines Synthesized by Catalytic Dehydrogenation of Enamines as Nucleophilic C2 Synthons for 1,4‐Conjugate Addition with Fluoroalkylated Olefins
Authors: Morigaki Atsunori , Kawamura Mio , Arimitsu Satoru , Ishihara Takashi , Konno Tsutomu
Published: February 2013

A catalytic amount of Pd(OAc)2 was successfully applied for the generation of enamines from various tertiary amines under oxidative conditions. As a synthetic application, the generated enamines were used for 1,4‐conjugate addition reactions with fluoroalkylated olefins. Thus, a catalytic amount of Pd(OAc)2 was added to a mixture of tertiary amines and fluoroalkylated olefins in N,N,‐dimethylacetamide in air, and the corresponding 1,4‐adducts were obtained in moderate to good yields for a variety of substrates. This unique reaction can allow readily available tertiary amines to be used as nucleophilic C2 synthons and is an alternative synthetic protocol for the hydroformylmethylation of olefins.
Invasive dynamics of the crayfish Procambarus clarkii (Girard, 1852) in the international section of the River Minho (NW of the Iberian Peninsula)
Authors: Sousa Ronaldo , Freitas Fabiana E. P. , Mota Micaela , Nogueira António J. A. , Antunes Carlos
Published: February 2013

Procambarus clarkii (Girard, 1852) is a well‐established invasive species in many worldwide aquatic ecosystems and is responsible for several ecological and economic impacts. This study examines the major factors responsible for its invasive dynamics in the international section of the River Minho (north‐west Iberian Peninsula).

Data collected from June 2007 to May 2011 showed that abundance and biomass increased in the first 3 years of sampling, but suffered a decrease in the fourth year. Higher abundance and biomass were always found from May to October. These higher values have a clear relationship with water temperature and probably reflect higher activity and mobility.

The sex‐ratio was 1.08:1 in favour of females; eggs start to appear in May/June and the majority of juveniles in August/September.

Information collected in this study is extremely important for future management actions that could be applied to this invasive species. Accordingly, we propose that control actions to minimize P. clarkii impacts in this system, such as intensive trapping, should be applied during late spring/early summer, when the catches are higher, the females are dominant, and before juvenile recruitment.

Copyright © 2013 John Wiley & Sons, Ltd.
Proteomic Analysis of Synovial Fluid From the Osteoarthritic Knee: Comparison With Transcriptome Analyses of Joint Tissues
Authors: Ritter Susan Y. , Subbaiah Roopashree , Bebek Gurkan , Crish James , Scanzello Carla R. , Krastins Bryan , Sarracino David , Lopez Mary F. , Crow Mary K. , Aigner Thomas , Goldring Mary B. , Goldring Steven R. , Lee David M. , Gobezie Reuben , Aliprantis Antonios O.
Published: February 2013

Objective

The pathophysiology of the most common joint disease, osteoarthritis (OA), remains poorly understood. Since synovial fluid (SF) bathes joint cartilage and synovium, we reasoned that a comparative analysis of its protein constituents in health and OA could identify pathways involved in joint damage. We undertook this study to perform a proteomic analysis of knee SF from OA patients and control subjects and to compare the results to microarray expression data from cartilage and synovium.

Methods

Age‐matched knee SF samples from 10 control subjects, 10 patients with early‐stage OA, and 10 patients with late‐stage OA were compared using 2‐dimensional difference‐in‐gel electrophoresis and mass spectrometry (MS). MS with a multiplexed peptide selected reaction monitoring assay was used to confirm differential expression of a subset of proteins in an independent OA patient cohort. Proteomic results were analyzed by Ingenuity Pathways Analysis and compared to published synovial tissue and cartilage messenger RNA profiles.

Results

Sixty‐six proteins were differentially present in healthy and OA SF. Three major pathways were identified among these proteins: the acute‐phase response signaling pathway, the complement pathway, and the coagulation pathway. Differential expression of 5 proteins was confirmed by selected reaction monitoring assay. A focused analysis of transcripts corresponding to the differentially present proteins indicated that both synovial and cartilage tissues may contribute to the OA SF proteome.

Conclusion

Proteins involved in the acute‐phase response signaling pathway, the complement pathway, and the coagulation pathway are differentially regulated in SF from OA patients, suggesting that they contribute to joint damage. Validation of these pathways and their utility as biomarkers or therapeutic targets in OA is warranted.
Identification of Citrullinated Hsp90 Isoforms as Novel Autoantigens in Rheumatoid Arthritis–Associated Interstitial Lung Disease
Authors: Harlow Lisa , Rosas Ivan O. , Gochuico Bernadette R. , Mikuls Ted R. , Dellaripa Paul F. , Oddis Chester V. , Ascherman Dana P.
Published: February 2013

Objective

Subsets of patients with rheumatoid arthritis (RA) develop extraarticular complications that include interstitial lung disease (ILD). Because standardized algorithms for identification of RA patients at risk of developing clinically significant ILD are lacking, the purpose of this study was to elucidate unique serologic markers of RA‐associated ILD (RA‐ILD).

Methods

Sera from RA patients with ILD and from RA patients without ILD were used to immunoprecipitate citrullinated and uncitrullinated proteins derived from K562 cell extracts. Mass spectrometry was performed to facilitate identification of citrullinated proteins differentially immunoprecipitated by RA‐ILD patient sera. These candidate proteins were then used as substrate antigens in custom enzyme‐linked immunosorbent assays (ELISAs) for high‐throughput screening of sera obtained from cohorts of patients with RA, RA‐ILD mixed connective tissue disease (MCTD), or idiopathic pulmonary fibrosis (IPF).

Results

Differential immunoprecipitation and subsequent mass spectrometric sequencing identified citrullinated Hsp90α and citrullinated Hsp90β as candidate autoantigens in patients with RA‐ILD. ELISAs incorporating uncitrullinated and citrullinated isoforms of Hsp90 as substrate antigens demonstrated that sera from patients with RA‐ILD preferentially recognized citrullinated versions of Hsp90 with moderate sensitivity (range 20–30%) and great specificity (>95%) relative to sera derived from patients with RA alone (without ILD), patients with MCTD, or patients with IPF.

Conclusion

These studies demonstrate the utility of a novel autoantigen discovery method based on differential immunoprecipitation of citrullinated protein extracts. Application of these techniques identified citrullinated versions of Hsp90α and Hsp90β as autoantibody targets distinguishing RA‐ILD from RA without ILD, MCTD, and IPF, suggesting that anti–citrullinated Hsp90α/β autoantibodies may serve as effective biomarkers for the potentially devastating pulmonary manifestations of RA‐ILD.
Normalization of Widespread Pressure Pain Hypersensitivity After Total Hip Replacement in Patients With Hip Osteoarthritis Is Associated With Clinical and Functional Improvements
Authors: Aranda‐Villalobos Pilar , Fernández‐de‐las‐Peñas César , Navarro‐Espigares Jose L. , Hernández‐Torres Elisa , Villalobos Mercedes , Arendt‐Nielsen Lars , Arroyo‐Morales Manuel
Published: February 2013

Objective

To evaluate the relevance of ongoing nociceptive joint inputs to the maintenance of widespread pain hypersensitivity in patients with hip osteoarthritis (OA) and to determine whether a reversal in the widespread pressure hypersensitivity together with an improvement in pain and function occurs after total hip replacement in these patients.

Methods

Forty patients with hip OA participated. Twenty patients underwent total hip replacement, and the other 20 patients were assigned to a waiting list. Pressure–pain thresholds (PPTs) over the second metacarpal bone and the gluteus medius, vastus medialis, vastus lateralis, and tibialis anterior muscles were assessed bilaterally with a pressure algometer before and 3 months after total hip replacement surgery. Assessments of pain intensity (by visual analog scale [VAS]), physical function (by the Western Ontario and McMaster Universities Osteoarthritis Index), and health status (by the Short Form 12 health survey and the EuroQol 5‐domain index) were also performed.

Results

Patients who underwent total hip arthroplasty exhibited a reduction in widespread pressure pain hyperalgesia (increases in PPTs) over local and distant pain‐free areas, as compared with before surgery and as compared with the patients assigned to the waiting list. PPTs were related to hip pain intensity, and significant correlations were found between higher VAS scores and lower average PPTs over all points assessed (−0.409 < r < −0.306, P < 0.05). Patients who underwent total hip arthroplasty exhibited a greater decrease in pain intensity and greater increases in function and health status than did those who were on the waiting list. Changes in the intensity of hip pain were moderately associated with changes in pressure pain sensitivity in the hip arthroplasty group.

Conclusion

Normalization of widespread pressure pain hyperalgesia was found after successful hip joint replacement in patients with hip OA. Altered pain processing seems to be driven by ongoing peripheral joint pathology, which stresses the importance of reducing pain in OA.
Variants in RUNX3 Contribute to Susceptibility to Psoriatic Arthritis, Exhibiting Further Common Ground With Ankylosing Spondylitis
Authors: Apel Maria , Uebe Steffen , Bowes John , Giardina Emiliano , Korendowych Eleanor , Juneblad Kristina , Pasutto Francesca , Ekici Arif B. , McManus Ross , Ho Pauline , Bruce Ian N. , Ryan Anthony W. , Behrens Frank , Böhm Beate , Traupe Heiko , Lohmann Jörg , Gieger Christian , Wichmann Heinz‐Erich , Padyukov Leonid , FitzGerald Oliver , Alenius Gerd‐Marie , McHugh Neil J. , Novelli Giuseppe , Burkhardt Harald , Barton Anne , Reis André , Hüffmeier Ulrike
Published: February 2013

Objective

Psoriatic arthritis (PsA) is a common inflammatory joint disease distinct from other chronic arthritides and frequently accompanied by psoriasis vulgaris. In a first genome‐wide association study (GWAS), we were able to identify several genetic risk factors. However, even combined with previously identified factors, the genetic contribution to disease was not fully explained. Therefore, we undertook this study to investigate further 17 loci from our GWAS that did not reach genome‐wide significance levels of association in the initial analysis.

Methods

Twenty‐one of 22 single‐nucleotide polymorphisms were successfully genotyped in independent cohorts of 1,398 PsA patients and 6,389 controls and in a group of 964 German patients with psoriasis vulgaris.

Results

Association with a RUNX3 variant, rs4649038, was replicated in independent patients and controls and resulted in a combined P value of 1.40 × 10−8 by Cochran‐Mantel‐Haenszel test and an odds ratio (OR) of 1.24 (95% confidence interval [95% CI] 1.15–1.33). Further analyses based on linkage disequilibrium (LD) at RUNX3 refined the most significant association to an LD block located in the first intron of one isoform. Weaker evidence for association was detected in German patients with psoriasis vulgaris (P = 5.89 × 10−2; OR 1.13 [95% CI 1.00–1.28]), indicating a role in the skin manifestations of psoriasis.

Conclusion

Our analyses identified variants in RUNX3 as susceptibility factors for PsA. RUNX3 has already been implicated in susceptibility to ankylosing spondylitis, another spondyloarthritis, although its risk allele is independent from the one for PsA. RUNX‐3 is involved in CD8+ T lymphocyte differentiation and is therefore a good candidate for involvement in PsA and psoriasis vulgaris as T cell–mediated diseases.
Increased Expression of Endoplasmic Reticulum Stress and Unfolded Protein Response Genes in Peripheral Blood Mononuclear Cells From Patients With Limited Cutaneous Systemic Sclerosis and Pulmonary Arterial Hypertension
Authors: Lenna Stefania , Farina Alessandra G. , Martyanov Viktor , Christmann Romy B. , Wood Tammara A. , Farber Harrison W. , Scorza Raffaella , Whitfield Michael L. , Lafyatis Robert , Trojanowska Maria
Published: February 2013

Objective

Pulmonary arterial hypertension (PAH), a common complication of limited cutaneous systemic sclerosis (lcSSc), is associated with alterations of markers of inflammation and vascular damage in peripheral blood mononuclear cells (PBMCs). Endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) have been implicated in autoimmune and inflammatory diseases. The goal of this study was to assess whether markers of ER stress and the UPR are present in PBMCs from lcSSc patients with PAH.

Methods

PBMCs were purified from 36 healthy controls, 32 lcSSc patients with PAH, and 34 lcSSc patients without PAH. Gene expression in healthy control PBMCs stimulated with thapsigargin was analyzed by DNA microarray. Genes were validated by quantitative real‐time reverse transcription–polymerase chain reaction in PBMCs from healthy controls and lcSSc patients.

Results

Several ER stress/UPR genes, including BiP, activating transcription factor 4 (ATF‐4), ATF‐6, and a spliced form of X‐box binding protein 1, were up‐regulated in PBMCs from lcSSc patients, with the highest levels in patients with PAH. Thapsigargin up‐regulated heat‐shock proteins (HSPs) and interferon (IFN)–regulated genes in PBMCs from healthy controls. Selected HSP genes (particularly DnaJB1) and IFN‐related genes were also found at significantly elevated levels in PBMCs from lcSSc patients, while IFN regulatory factor 4 expression was significantly decreased. There was a positive correlation between DnaJB1 and severity of PAH (measured by pulmonary artery pressure) (r = 0.56, P < 0.05) and between ER stress markers and interleukin‐6 levels (r = 0.53, P < 0.0001) in PBMCs from lcSSc patients.

Conclusion

This study demonstrates an association between select ER stress/UPR markers and lcSSc with PAH, suggesting that ER stress and the UPR may contribute to the altered function of circulating immune cells in lcSSc.
Fluorescence spectroscopic analysis on interaction of fleroxacin with pepsin
Authors: Lian Shuqin , Wang Guirong , Zhou Liping , Yang Dongzhi
Published: February 2013

The interaction between fleroxacin (FLX) and pepsin was investigated by spectrofluorimetry. The effects of FLX on pepsin showed that the microenvironment of tryptophan residues and molecular conformation of pepsin were changed based on fluorescence quenching and synchronous fluorescence spectroscopy in combination with three‐dimensional fluorescence spectroscopy. Static quenching was suggested and it was proved that the fluorescence quenching of pepsin by FLX was related to the formation of a new complex and a non‐radiation energy transfer. The quenching constants KSV, binding constants K and binding sites n were calculated at different temperatures. The molecular interaction distance (r = 6.71) and energy transfer efficiency (E = 0.216) between pepsin and FLX were obtained according to the Forster mechanism of non‐radiation energy transfer. Hydrophobic and electrostatic interaction played a major role in FLX–pepsin association. In addition, the hydrophobic interaction and binding free energy were further tested by molecular modeling study. Copyright © 2013 John Wiley & Sons, Ltd.
Development of a stable isotope dilution UPLC‐MS/MS method for quantification of dexmedetomidine in a small amount of human plasma
Authors: Inoue Koichi , Sakamoto Tasuku , Fujita Yoshihito , Yoshizawa Saya , Tomita Maiko , Min Jun Zhe , Todoroki Kenichiro , Sobue Kazuya , Toyo'oka Toshimasa
Published: February 2013

Dexmedetomidine (Dex) is a selective central α2‐agonist with anesthetic properties and has been used in clinical practice for sedation in the intensive care unit (ICU) after operations. In this study, an analytical assay for the determination of Dex in a small amount of plasma was developed for the application to pediatric ICU trials. The quantification of Dex was constructed using the original stable isotope Dex‐d3 for electrospray ionization‐tandem mass spectrometry (ESI‐MS/MS) in the selected reaction monitoring mode. A rapid ultra‐performance liquid chromatography technique was adopted using ESI‐MS/MS with a runtime of 3 min. Efficacious concentration levels (50 pg/mL to 5 ng/mL) could be evaluated using a very small amount of plasma (10 μL) from patients. The lower limit of the quantification was 5 pg/mL in the plasma (100 µL). For sample preparation, a solid‐phase extraction was used along with the OASIS‐HLB cartridge type. Recovery values ranged from 98.8 to 100.3% for the intra‐ [relative standard deviation (RSD), 0.9–1.3%] and inter‐ (RSD, 0.9–1.5%) day assays. A stable test had recovery values that ranged from 97.8 to 99.7% with an RSD of 1.0–1.9% for the process/wet extract, bench‐top, freeze–thaw and long‐term tests. This method was used to measure the Dex levels in plasma from pediatric ICU patients. In the clinical ICU trial, the small amount of blood (approximate plasma volume, 200 μL) remaining from blood gas analysis was reused and targeted for the clinical analysis of Dex in plasma. Copyright © 2013 John Wiley & Sons, Ltd.
Osteopontin gene polymorphisms as predictors for the efficacy of interferon therapy in chronic hepatitis C Egyptian patients with genotype 4
Authors: Shaker Olfat , El‐Shehaby Amal , Fayez Salwa , Zahra Amr , Marzouk Samar , El Raziky Maissa
Published: February 2013

This study aimed to determine the relationship between osteopontin gene polymorphisms and its protein level and the efficacy of interferon‐based therapies in Hepatitis C virus (HCV) patients. Hundreds HCV patients genotype 4, treated with pegylated interferon alfa‐2b plus ribavirin and 60 healthy subjects were enrolled. All individuals were subjected to clinical and laboratory parameters, including hepatitis markers and HCV quantitation by real‐time polymerase chain reaction. Single nucleotide polymorphisms (SNPs) of osteopontin (OPN) gene (nucleotide −155, −443 and −1748) were analysed by direct sequencing in addition to estimation of serum level of OPN. SNP at −443 (C/C versus C/T, T/T) was found to represent predictors for treatment response by univariate logistic regression analysis. OPN serum level was independent predictors for treatment response by both univariate and multivariate logistic regression analysis. SNP at nucleotide −443 and serum OPN protein levels could be used as useful markers to predict the efficacy of treatment. Copyright © 2013 John Wiley & Sons, Ltd.
Caffeic acid phenethyl ester modulates aflatoxin B1‐induced hepatotoxicity in rats
Authors: Akçam Mustafa , Artan Reha , Yilmaz Aygen , Ozdem Sebahat , Gelen Tekinalp , Nazıroğlu Mustafa
Published: February 2013

Aflatoxin B1 (AFB1) is the most potent of the mycotoxins and is widely observed in nutrition abnormalities. There are some studies suggesting oxidative stress‐induced toxic changes on liver related to AFB1 toxicity. The aim of the present study was to evaluate whether antioxidant caffeic acid phenethyl ester (CAPE) relieves oxidative stress in AFB1‐induced liver injury in rat. Twenty‐four male rats were equally divided into three groups. The first group was used as a control. The second group received three doses of AFB1. The three doses of CAPE were given to constitute the third group with doses of AFB1. After 10 days of experiment, liver and serum samples were taken from all animals. Serum gamma glutamyl transferase (GGT), alkaline phosphatase (ALP), glutathione s‐transferase (GST), nitric oxide (NO) and sulfhydryl values were higher in the AFB1 group than in control, whereas serum GGT, ALP, GST and NO values were decreased by in the AFB1 + CAPE group than in AFB1 group. Liver GST, total oxidant capacity, sulfhydryl, apoptosis index and ischemia‐modified albumin values were higher in the AFB1 group than in control, whereas the GST activity and apoptosis index were lower in the AFB1 + CAPE group than in the AFB1 group. There were histopathological degeneration and apoptosis in hepatocytes of AFB1 group. The findings were totally recovered by CAPE administration. In conclusion, we observed that AFB1 caused oxidative and nitrosative hepatoxicity to hepatocytes in the rat. However, CAPE induced protective effects on the AFB1‐induced hepatoxicity by modulating free radical production, biochemical values and histopathological alterations. Copyright © 2013 John Wiley & Sons, Ltd.
Induction of apoptosis in osteosarcoma s180 cells by polysaccharide from dictyophora indusiata
Authors: Zhong Biao , Ma Yushui , Fu Da , Zhang Chi
Published: February 2013

Polysaccharides have shown great importance in cancer therapy. The current study showed that a polysaccharide from Dictyophora indusiata (PDI) also possessed anti‐cancer properties. Methyl thiazolyl tetrazolium assay revealed a dose‐dependent reduction of osteosarcoma S180 growth in response to PDI treatment. Apoptosis was observed following treatments with PDI, as reflected by the appearance of the subdiploid fraction and DNA fragmentations. We then investigated effects of PDI on expression of apoptosis‐associated genes and the results revealed an increase of expression of bcl‐2 and decreases of cdk4 and p53 protein levels. Finally, PDI treatment significantly increased the activation of caspase‐3, a key executioner of apoptosis. These findings indicate that PDI may act as a chemopreventive and/or chemotherapeutic agent in osteosarcoma cells by reducing cell viability and inducing apoptosis. Copyright © 2013 John Wiley & Sons, Ltd.
QSAR, docking and ADMET studies of camptothecin derivatives as inhibitors of DNA topoisomerase‐I
Authors: Yadav Dharmendra K. , Khan Feroz
Published: February 2013

In the present work, quantitative structure–activity relationship (QSAR) models of camptothecin derivatives against DNA Topoisomerase‐I (DNA Topo‐I) were developed by multiple linear regression method using leave‐one‐out validation approach. The r2 and rCV2 of the model were 0.89 and 0.86, respectively. The QSAR study indicates that chemical descriptors, namely Connectivity Index (order 1, standard), Electron Affinity (eV), Molecular Weight, Group Count (ether) are correlated well with activity. Further, screening for drug likeness, ADME and toxicity showed that compound CPT9, CPT14, CPT20, CPT21 and CPT22 exhibits marked anticancer activity and possesses two times more potent than standard drug camptothecin. The docking study showed a high binding affinity of predicted active derivatives and showed H‐bond formation with GLY363, ARG364, LYS374, GLN421, ARG488, and ASP‐533 residues, therefore considered as more stable and potent anticancer compounds. The obtained results can be used for the design of novel potent and selective inhibitors of DNA Topo‐I. Copyright © 2013 John Wiley & Sons, Ltd.
Binary Compounds of Boron and Beryllium: A Rich Structural Arena with Space for Predictions
Authors: Hermann Andreas , Ashcroft N. W. , Hoffmann Roald
Published: February 2013

We explore ground‐state structures and stoichiometries of the BeB system in the static limit, with Be atom concentrations of 20 % or greater, and from P=1 atm up to 320 GPa. At P=1 atm, predictions are offered for several known compounds, the structures of which have not yet been determined experimentally. Specifically, at 1 atm, we predict a structure of R$\bar 3$m symmetry for the compound Be2B3, seen experimentally at high temperatures, which contains interesting BeBBBBe rods; and for the compound BeB4 we calculate metastability with respect to the elements with a structure similar to MgB4, which is quickly replaced as the pressure is elevated by a Cmcm structure that features 6‐ and 4‐membered rings in B cages, with Be interstitials. For another high‐temperature compound, Be2B, we confirm the CaF2 structure, but find a competitive and actually slightly more stable ground‐state structure of C2/m symmetry that features B2 pairs. In the case of BeB2, a material for which the stoichiometry has been the subject of debate, we have a clear prediction of a stable F$\bar 4$3m structure at P=1 atm. It has a diamondoid structure that is based on cubic (lower P) or hexagonal (higher P) diamond networks of B, but with Be in the interstices. This Zintl structure is a semiconductor at low and intermediate pressures. At higher pressures, BeB2 dominates the phase diagram. In general, the Zintl–Klemm concept of effective electron transfer from the more electropositive ion and bond formation among the resulting anions has proven useful in analyzing the structural preferences of many compositions in the BeB system at P=1 atm and at elevated pressures. An unusual feature of this binary system is that the 1:1 BeB stoichiometry never appears to reach stability in the static limit, although it comes close, as does Be17B12. Also stable at high pressures are stoichiometries BeB3, BeB4, and Be5B2.
Synthesis, Bonding and Reactivity of a Terminal Titanium Alkylidene Hydrazido Compound
Authors: Tiong Pei Jen , Groom Laura R. , Clot Eric , Mountford Philip
Published: February 2013

We report a detailed study of the reactions of the TiNNCPh2 alkylidene hydrazide functional group in [Cp*Ti{MeC(NiPr)2}(NNCPh2)] (8) with a variety of unsaturated and saturated substrates. Compound 8 was prepared from [Cp*Ti{MeC(NiPr)2}(NtBu)] and Ph2CNNH2. DFT calculations were used to determine the nature of the bonding for the TiNNCPh2 moiety in 8 and in the previously reported [Cp2Ti(NNCPh2)(PMe3)]. Reaction of 8 with CO2 gave dimeric [(Cp*Ti{MeC(NiPr)2}{μ‐OC(NNCPh2)O})2] and the “double‐insertion” dicarboxylate species [Cp*Ti‐{MeC(NiPr)2}{OC(O)N(NCPh2)C(O)O}] through an initial [2+2] cycloaddition product [Cp*Ti{MeC(NiPr)2}{N(NCPh2)C(O)O}], the congener of which could be isolated in the corresponding reaction with CS2. The reaction with isocyanates or isothiocyanates tBuNCO or ArNCE (Ar=Tol or 2,6‐C6H3iPr2; E=O, S) gave either complete NNCPh2 transfer, [2+2] cycloaddition to TiNα or single‐ or double‐substrate insertion into the TiNα bond. The treatment of 8 with isonitriles RNC (R=tBu or Xyl) formed σ‐adducts [Cp*Ti{MeC(NiPr)2}(NNCPh2)(CNR)]. With ArF5CCH (ArF5=C6F5) the [2+2] cycloaddition product [Cp*Ti{MeC(NiPr)2}{N(NCPh2)C(ArF5)C(H)}] was formed, whereas with benzonitriles ArCN (Ar=Ph or ArF5) two equivalents of substrate were coupled in a head‐to‐tail manner across the TiNα bond to form [Cp*Ti{MeC(NiPr)2}{N(NCPh2)C(Ar)NC(Ar)N}]. Treatment of 8 with RSiH3 (R=aryl or Bu) or Ph2SiH2 gave [Cp*Ti{MeC(NiPr)2}{N(SiHRR′)N(CHPh2)}] (R′=H or Ph) through net 1,3‐addition of SiH to the NNCPh2 linkage of 8, whereas reaction with PhSiH2X (X=Cl, Br) led to the TiNα 1,2‐addition products [Cp*Ti{MeC(NiPr)2}(X){N(NCPh2)SiH2Ph}].
Magnetic Anisotropy of the CC Single Bond
Authors: Baranac‐Stojanović Marija , Stojanović Milovan
Published: February 2013

Anisotropic effects are broadly used in NMR spectroscopy for structure elucidation. With the development of computational methods it has become possible to quantify the effects and obtain further insight into their origin. Some classical interpretations have been questioned. Herein, we show that the classical “anisotropy cone” representing the anisotropic effect of the CC single bond should be revised: deshielding at its side and shielding along its end are observed. Consequently, methyl, methylene, and methyne hydrogen atoms are not deshielded by CC bonds as is conventionally explained in NMR spectroscopy textbooks. They are just less shielded than by the CH bonds attached at the same carbon. In addition, this anisotropic effect is dependent on the environment and care should be taken when drawing conclusions based on it. For example, it differs for the staggered and eclipsed conformations of ethane in HCCH planes, as well as for cyclohexane. In fact, it is not the anisotropy of the C2C3/C5C6 bonds that determines the chemical shift difference of axial and equatorial protons of a rigid cyclohexane ring, but magnetic contributions from all bonds.
Synthesis of gem‐Diaurated Species from Alkynols
Authors: Zhdanko Alexander , Maier Martin E.
Published: February 2013

A number of enol ether‐derived diaurated species were synthesized directly from different alkynols and cationic gold complexes in the presence of a non‐nucleophilic base (proton sponge). The reaction can be easily applied for in situ generation of diaurated species from all common types of hydroalkoxylation substrates: 5‐endo, 5‐exo/6‐endo, 6‐exo/7‐endo and intermolecular types. Six examples were also synthesized in individual state as stable hexafluoroantimonate salts. Whereas diaurated species are obtained reliably from all conventional mononuclear gold catalysts, application of binuclear ones often gave diaurated species with unusual properties. The preliminary results point to complexities of behavior of binuclear gold catalysts and would require more research in future for this subclass. The formation of diaurated species from various gold‐oxo compounds (LAu)2OH+, (LAu)3O+, and LAuOH (L=phosphine ligand) was also studied. Of these three types, only (LAu)2OH+ is reactive, whereas (LAu)3O+ and LAuOH are not reactive alone but require acidic promoters to enable the reaction. These differences in reactivity were explained by ability of these compounds to generate the necessary acetylene π‐complex intermediate.
Self‐Assembly of Anionic Porphyrins and Alkaline or Alkaline Earth Metal Ions Mediated by Cucurbit[7,8]uril
Authors: Lei Wanhua , Jiang Guoyu , Zhou Qianxiong , Hou Yuanjun , Zhang Baowen , Cheng Xuexin , Wang Xuesong
Published: February 2013

Nanoscaled coordination polymers based on biologically prevalent ions have potential applications in drug delivery and biomedical imaging. Herein, coordination polymer nanoparticles of anionic porphyrins, including meso‐tetra(4‐carboxyphenyl)‐porphyrin (H2TCPP4−) and meso‐tetra(4‐sulfonatophenyl)‐porphyrin (H2TPPS4−), and alkaline or alkaline earth metal cations, such as K+ and Ca2+, were constructed in aqueous solution in the presence of cucurbit[7]uril (CB7) or cucurbit[8]uril (CB8). UV/Vis absorption and fluorescence spectroscopy, dynamic light scattering (DLS), scanning electron spectroscopy (SEM), and atomic force microscopy (AFM) were applied to explore the assembly and particle formation of porphyrin anions and metal cations mediated by CBn. The particle size depends on the kinds of CBn and metal cations and their concentrations. The uptake of H2TPPS4− particles by tumor cells (A549 cells) was found to be more efficient than H2TPPS4− at 37 °C, showing the application potential of such assembled particles in biology and medicine.
Anti‐Oligomannose Antibodies as Potential Serum Biomarkers of Aggressive Prostate Cancer
Authors: Wang Denong , Dafik Laila , Nolley Rosalie , Huang Wei , Wolfinger Russell D. , Wang Lai‐Xi , Peehl Donna M.
Published: February 2013

Preclinical Research

This study bridges a carbohydrate microarray discovery and a large‐scale serological validation of anti‐oligomannose antibodies as novel serum biomarkers of aggressive prostate cancer (PCa). Experimentally, a Man9‐cluster‐specific enzyme‐linked immunosorbent assay was established to enable sensitive detection of anti‐Man9 antibodies in human sera. A large‐cohort of men with PCa or benign prostatic hyperplasia (BPH) whose sera were banked at Stanford University was characterized using this assay. Subjects included patients with 100% Gleason grade 3 cancer (n = 84), with Gleason grades 4 and/or 5 cancer (n = 204), and BPH controls (n = 135). Radical prostatectomy Gleason grades and biochemical (PSA) recurrence served as key parameters for serum biomarker evaluation. It was found that IgGMan9 and IgMMan9 were widely present in the sera of men with BPH, as well as those with cancer. However, these antibody reactivities were significantly increased in the subjects with the largest volumes of high grade cancer. Detection of serum IgGMan9 and IgMMan9 significantly predicted the clinical outcome of PCa post‐radical prostatectomy. Given these results, we suggest that IgGMan9 and IgMMan9 are novel serum biomarkers for monitoring aggressive progression of PCa. The potential of oligomannosyl antigens as targets for PCa subtyping and targeted immunotherapy is yet to be explored.
At diagnosis, diffuse large B‐cell lymphoma patients show impaired rituximab‐mediated NK‐cell cytotoxicity
Authors: Danielou‐Lazareth Anne , Henry Guylaine , Geromin Daniela , Khaznadar Zena , Briere Josette , Tamouza Ryad , Cayuela Jean‐Michel , Thieblemont Catherine , Toubert Antoine , Dulphy Nicolas
Published: February 2013

Diffuse large B‐cell lymphoma (DLBCL) is the most common subtype of non‐Hodgkin's lymphoma in adults. It is generally treated by a combination of chemotherapy and CD20‐specific mAbs, such as rituximab, which act, at least partially, by activating antibody‐dependent cell‐mediated cytotoxicity (ADCC). ADCC involves NK cells, particularly the CD56dim NK‐cell subset expressing CD16, the low affinity Fcγ receptor. Here, we show that CD16 expression levels are decreased in a cohort of 36 newly diagnosed DLBCL patients compared with those in 20 healthy controls (HCs). CD137, a co‐stimulatory molecule expressed on activated NK cells, was also expressed at lower levels in patients compared with controls. Cells sampled from our cohort also showed severely reduced degranulation activity when challenged with rituximab‐coated tumor cells, which could not be corrected by stimulation with high doses of IL‐2. These results suggest that rituximab‐induced NK‐cell ADCC could be defective in some DLBCL patients at diagnosis. These patients should be closely monitored and attempts made to improve their NK‐cell function.
Increased thymic development of regulatory T cells in NOD mice is functionally dissociated from type I diabetes susceptibility
Authors: Tellier Julie , Andrianjaka Andry , Vicente Rita , Thiault Nicolas , Enault Geneviève , Garchon Henri‐Jean , van Meerwijk Joost P. M. , Romagnoli Paola
Published: February 2013

Regulatory T (Treg) lymphocytes play a central role in the control of autoimmune pathology. Any alteration in Treg‐cell biology in mouse strains used for the study of these disorders therefore raises the question of its direct link with disease susceptibility. Paradoxically, in non‐obese diabetic (NOD) mice increased numbers of Treg cells develop in the thymus. In this report we identify a locus of <7 Mbp that quantitatively controls Treg‐cell development in the thymus of the NOD mouse. This ‘Trd1' region is located centromeric to the H2 complex on chromosome 17 and does not include genes encoding classical MHC molecules. The genomic region identified here contains the Idd16 diabetes susceptibility locus and the use of congenic mouse strains allowed us to investigate the potential link between quantitatively altered thymic Treg cells and diabetes susceptibility. Hybrid mice present similar levels of thymic Treg cells as B6 animals but they developed diabetes with the same kinetics as NOD mice. Therefore, the increased Treg‐cell development in NOD mice controlled by Trd1 is functionally dissociated from the susceptibility of NOD to diabetes.
Rational Synthesis and Mutual Conversion of Bis‐N‐heterocyclic Diphosphanes and Secondary N‐Heterocyclic Phosphanes
Authors: Puntigam Oliver , Förster Daniela , Giffin Nick A. , Burck Sebastian , Bender Johannes , Ehret Fabian , Hendsbee Arthur D. , Nieger Martin , Masuda Jason D. , Gudat Dietrich
Published: February 2013

Symmetrical N‐heterocyclic 1,1′,3,3′‐tetrahydro‐2,2′‐bi‐1,3,2‐diazaphospholes and 2,2′‐bi‐1,3,2‐diazaphospholidines are prepared by time‐saving, sequential “one‐pot” syntheses starting from 1,4‐diazabutadienes or N‐alkyl or N‐aryl‐substituted ethane‐1,2‐diamines. This method offers high selectivity and minimizes the loss of products owing to unwanted hydrolysis, and thus grants high product yields. In some cases, secondary phosphanes were formed together with or instead of diphosphanes. This reaction is explained by a follow‐up process involving homolytic fission of diphosphanes to give phosphanyl radicals, which then react with ammonium salts to give a mixture of secondary phosphanes and chlorophosphanes. Even if its synthetic scope is as yet limited, this approach seems promising in offering superior selectivity and higher yields than common synthetic protocols that rely on the use of complex hydrides as reducing agents. In addition to the reductive conversion of diphosphanes into secondary phosphanes, a reverse reaction under exposure of the reactants to light is also reported.
A Divergent and Stereoselective Approach for the Syntheses of Some Polyhydroxylated Indolizidine and Pyrrolizidine Iminosugars
Authors: Rajender Anugula , Rao Jalagam Prasada , Rao Batchu Venkateswara
Published: February 2013

A common, divergent, and efficient approach to the syntheses of (+)‐steviamine (9), (–)‐1‐deoxy‐8a‐epi‐castanospermine (10), (+)‐trihydroxyindolizidine (11), (+)‐3,7a‐di‐epi‐hyacinthacine A1 (12), and (–)‐2‐epi‐lentiginosine (4) was achieved by starting from D‐ribose‐derived intermediate 13. The key steps involved in these syntheses are a highly diasteroselective Grignard addition to a ribosylimine, a one‐pot stereoselective intramolecular reductive amination, a selectve deprotection of a silyl ether, and a ring‐closing metathesis (RCM) reaction.
Enantioselective Friedel–Crafts Alkylation of Indoles with (E)‐1‐Aryl‐4‐benzyloxybut‐2‐en‐1‐ones Catalyzed by an (R)‐3,3′‐Br2BINOLate–Hafnium(IV) Complex
Authors: Blay Gonzalo , Fernández Isabel , Muñoz M. Carmen , Pedro José R. , Vila Carlos
Published: February 2013

A highly enantioselective Friedel–Crafts reaction of unprotected indoles with (E)‐1‐aryl‐4‐benzyloxybut‐2‐en‐1‐ones catalyzed by a new chiral [Hf{(R)‐3,3′‐Br2‐BINOL}(OtBu)2]2 complex has been developed to functionalize the C‐3 position of the indole nucleus with a side chain bearing a 1,4‐difunctionalized moiety and a benzylic stereogenic center. The reaction proceeds in good to excellent yields and excellent enantioselectivities (up to 97 % ee). The usefulness of this approach was illustrated with the synthesis of a tryptophol derivative.
Glutathione modified CdTe quantum dots as a label for studying DNA interactions with platinum based cytostatics
Authors: Ryvolova Marketa , Smerkova Kristyna , Chomoucka Jana , Hubalek Jaromir , Adam Vojtech , Kizek Rene
Published: February 2013

Cisplatin, carboplatin, and oxaliplatin represent three generations of platinum based drugs applied successfully for cancer treatment. As a consequence of the employment of platinum based cytostatics in the cancer treatment, it became necessary to study the mechanism of their action. Current accepted opinion is the formation of Pt‐DNA adducts, but the mechanism of their formation is still unclear. Nanomaterials, as a progressively developing branch, can offer a tool for studying the interactions of these drugs with DNA. In this study, fluorescent CdTe quantum dots (QDs, λem = 525 nm) were employed to investigate the interactions of platinum cytostatics (cisplatin, carboplatin, and oxaliplatin) with DNA fragment (500 bp, c = 25 μg/mL). Primarily, the fluorescent behavior of QDs in the presence of platinum cytostatics was monitored and major differences in the interaction of QDs with tested drugs were observed. It was found that the presence of carboplatin (c = 0.25 mg/mL) had no significant influence on QDs fluorescence; however cisplatin and oxaliplatin quenched the fluorescence significantly (average decrease of 20%) at the same concentration. Subsequently, the amount of platinum incorporated in DNA was determined by QDs fluorescence quenching. Best results were reached using oxaliplatin (9.4% quenching). Linear trend (R2 = 0.9811) was observed for DNA platinated by three different concentrations of oxaliplatin (0.250, 0.125, and 0.063 mg/mL). Correlation with differential pulse voltammetric measurements provided linear trend (R2 = 0.9511). As a conclusion, especially in the case of oxaliplatin‐DNA adducts, the quenching was the most significant compared to cisplatin and nonquenching carboplatin.
Bayesian nonstationary spatial modeling for very large datasets
Authors: Katzfuss Matthias
Published: February 2013

With the proliferation of modern high‐resolution measuring instruments mounted on satellites, planes, ground‐based vehicles, and monitoring stations, a need has arisen for statistical methods suitable for the analysis of large spatial datasets observed on large spatial domains. Statistical analyses of such datasets provide two main challenges: first, traditional spatial‐statistical techniques are often unable to handle large numbers of observations in a computationally feasible way; second, for large and heterogeneous spatial domains, it is often not appropriate to assume that a process of interest is stationary over the entire domain. We address the first challenge by using a model combining a low‐rank component, which allows for flexible modeling of medium‐to‐long‐range dependence via a set of spatial basis functions, with a tapered remainder component, which allows for modeling of local dependence using a compactly supported covariance function. Addressing the second challenge, we propose two extensions to this model that result in increased flexibility: first, the model is parameterized on the basis of a nonstationary Matérn covariance, where the parameters vary smoothly across space; second, in our fully Bayesian model, all components and parameters are considered random, including the number, locations, and shapes of the basis functions used in the low‐rank component. Using simulated data and a real‐world dataset of high‐resolution soil measurements, we show that both extensions can result in substantial improvements over the current state‐of‐the‐art. Copyright © 2013 John Wiley & Sons, Ltd.
ENVIRONMENTAL FATE OF THREE NOVEL BROMINATED FLAME RETARDANTS IN AQUATIC MESOCOSMS
Authors: de Jourdan Benjamin P. , Hanson Mark L. , Muir Derek C.G. , Solomon Keith R.
Published: February 2013

Currently, little is known about the environmental fate and persistence of novel brominated flame retardants (NBFRs). The recent detection of NBFRs in sediment cores and air samples provides insight into their persistence and potential for transport. Limited numbers of laboratory studies have examined the fate and behavior of these compounds, but field-based fate studies have been especially lacking. The authors conducted an aquatic mesocosm experiment to assess the behavior of three NBFRs: bis(tribromophenoxy)ethane (BTBPE), tetrabromobisphenol A bis(2,3-dibromopropyl ether; TBBPA-DBPE), and Firemaster BZ-54, a commercial mixture containing bis(2-ethylhexyl)tetrabromophthalate (BEHTBP) and 2-ethylhexyl-2,3,4,5-tetrabromobenzoate (EHTeBB) in a ratio of 1:4. Analysis by gas chromatography–mass spectrometry, operated in the electron capture negative ionization mode, revealed partitioning between the particulate and sediment phases, with BTBPE, TBBPA-DBPE, and BEHTBP identified as being environmentally persistent in both the particulate and the sediment compartments. The median dissipation times (DT50) differed in each compartment, with more rapid disappearance in the particulate (9–30 d) compared with the sediment compartment (>100 d) for each compound. The degradation products were more concentrated in the particulate compartment and corresponded to known photodegradation products. The ratio of EHTeBB to BEHTBP differed in the mesocosm compartments compared with the technical product used for treatment, indicating increased degradation of EHTeBB relative to BETHBP. Environ. Toxicol. Chem. 2013;32:1060–1068. © 2013 SETAC
Acute exposure to DE-71 causes alterations in visual behavior in zebrafish larvae
Authors: Chen Lianguo , Huang Yubin , Huang Changjiang , Hu Bing , Hu Chenyan , Zhou Bingsheng
Published: February 2013

Polybrominated diphenyl ethers (PBDEs) cause neurobehavioral toxicity, but their effects on visual behavior remain unknown. In the present study, the impact of PBDEs on visual behavior was examined using optokinetic responses and phototaxis in zebrafish larvae. Zebrafish embryos were exposed to pentabrominated diphenyl ethers mixture (DE-71) at concentrations of 0, 0.32, 3.58, and 31.0 µg/L until 15 d postfertilization. The authors then assessed photoreceptor opsin expression, retinal histology, and visual behavior of the larvae. The results showed that the transcriptions of the opsin genes, zfrho and zfgr1, were significantly upregulated. Western blotting further demonstrated a significant increase in rhodopsin protein expression after exposure of the larvae to DE-71. Histological examination revealed the following morphological alterations in the retina: increased area of inner nuclear layer, decreased area of inner plexiform layer, and decreased density of ganglion cells. Tests of optokinetic and phototactic behavior showed hyperactive responses on exposure to DE-71, including increased saccadic eye movements and phototactic response. The present study is the first to demonstrate that the acute exposure of zebrafish larvae to DE-71 causes biochemical and structural changes in the eye that lead to behavioral alterations. Analysis of these visual behavioral paradigms may be useful in predicting the adverse effects of toxicants on visual function in fish. Environ Toxicol Chem 2013;32:1370–1375. © 2013 SETAC
BIOACCUMULATION AND BIOMAGNIFICATION OF MERCURY AND SELENIUM IN THE SARASOTA BAY ECOSYSTEM
Authors: Hong Yong-Seok , Hull Peter , Rifkin Erik , Bouwer Edward J.
Published: February 2013

The bioaccumulation and biomagnification of Hg and Se were investigated in Sarasota Bay, Florida, USA, to characterize the Hg exposure risks to wild bottlenose dolphins in the bay. Concentrations of total mercury (THg), monomethylmercury (MMHg), and total selenium (TSe) were monitored in the bay, the latter of which might reduce Hg toxicity. The food web structure and dolphins' trophic level–specific consumption rates were evaluated using stable isotope ratios of carbon (δ13C) and nitrogen (δ15N). Regressions developed for Hg biomagnification in the food chain were log10CTHg (nanograms per gram) = 0.27 × δ15N (‰) – 0.42, R2 = 0.87, for THg and log10CMMHg = 0.33 × δ15N (‰) – 1.0, R2 = 0.93, for MMHg. Unlike Hg, nearly constant TSe concentrations were observed at 248 ± 179 ng g−1 in the food web, and the TSe-to-THg molar ratio was predicted by log10(CTSe/CTHg) = −0.10 × δ15N (‰) + 2.8, R2 = 0.60. The THg-uptake rates of Sarasota bottlenose dolphins are estimated to vary between 2.1 and 4.9 µg kg−1 d−1; however, the estimated TSe-uptake rates (15.1 µg kg−1 d−1) were higher than those for THg, and the Hg-exposure risks of the Sarasota Bay resident bottlenose dolphins are considered to be low. Approaches employed in the present study can be extended to other environments to characterize Hg contamination in aquatic systems and Hg exposure risks in top predators. Environ. Toxicol. Chem. 2013;32:1143–1152. © 2013 SETAC