bluuebunny/crossref_metadata_2025 huggingface dataset:
Reactivity of C1‐Symmetric Heteroarylamido Hafnium Complexes towards Unsaturated Electrophilic Molecules: Development of New Families of Olefin Polymerization Catalysts
Authors: Kulyabin Pavel S. , Goryunov Georgy P. , Mladentsev Dmitry Y. , Uborsky Dmitry V. , Voskoboynikov Alexander Z. , Canich Jo Ann M. , Hagadorn John R.
Published: May 2019

Heteroarylamido hafnium post‐metallocenes with [C,N,N] ligands were functionalized by the insertion of small electrophilic unsaturated molecules into the CAr−Hf bond of the ligand, which gave rise to various 1,1‐ and 1,2‐insertion complexes with the modified ligands of previously unknown [O,N,N], [N,N,N], [O,N,N,N], and [N,N,N,N] types. It was found that C1 symmetry of the starting complexes, in some cases, results in the formation of two diastereoisomers after 1,1‐ or 1,2‐insertion. Most of the obtained novel complexes were shown to form active catalysts for olefin polymerization in the presence of MAO (methylaluminoxane). Thus, a new approach to the feasible and easy “late stage” modification of the precatalyst structure has been suggested; it can be performed immediately prior to the polymerization tests without isolation and even in a high‐throughput manner.
Impact of C=C/B−N Replacement on the Diels–Alder Reactivity of Curved Polycyclic Aromatic Hydrocarbons
Authors: García‐Rodeja Yago , Fernández Israel
Published: May 2019

The influence of the replacement of C=C bonds by isoelectronic B−N moieties on the reactivity of π‐curved polycyclic aromatic hydrocarbons has been computationally explored by means of density functional theory calculations. To this end, we selected the Diels–Alder cycloaddition reactions of the parent corannulene and its BN‐doped counterparts with either cyclopentadiene or maleic anhydride. In addition, the analogous reactions involving larger buckybowls, such as BN‐hemifullerene, BN‐circumtrindene, and BN‐fullerene, have been also considered. It has been found that whereas corannulene behaves as a dienophile, its BN counterpart better acts as a diene. In contrast, the larger BN‐curved systems cannot be used as dienes in Diels–Alder reactions, but undergo facile (i.e., low barrier) cycloaddition reactions with cyclopentadiene. The observed trends in reactivity, which cannot be directly explained by using typical frontier molecular orbital arguments, are quantitatively described in detail by means of state‐of‐the‐art computational methods, namely the activation strain model of reactivity combined with the energy decomposition analysis method. The results of our calculations highlight the crucial role of the curvature of the system on the reactivity and its influence on the strength of the orbital interactions between the deformed reactants during their transformations.
Optimal distribution function determination for plus fraction splitting
Authors: Foroughi Sajjad , Khoozan Davood , Jamshidi Saeid
Published: May 2019

Reservoir fluid modelling is one of the most important steps in reservoir simulation and modelling of flow lines as well as surface facilities. One of the most uncertain parameters of the reservoir fluids is the plus fraction. An accurate and consistent splitting scheme can reduce this uncertainty and as a result, enhance the modelling of reservoir fluids. The existing schemes for splitting plus fractions are all based on assuming a specific mole fraction‐molecular weight distribution with predefined constant values that may yield inaccurate and inconsistent results. In this study, an optimization‐based algorithm was developed to determine the aforementioned controlling parameters of the plus fraction distribution function, enforcing the relationship between specific gravity and molecular weight of the single carbon numbers (SCNs). The introduced optimization‐based splitting technique was applied to different samples, covering a wide range of reservoir fluids, including gas condensates, volatile oils, black oils, and heavy oils. The results showed that the proposed technique yielded a more consistent molecular weight‐mole fraction distribution concerning the experimental extended analysis of plus fractions, yielding an average relative error of 25.8 % compared to 76, 33.6, and 45.9 % for the Katz, Ahmed, and Whitson methods, respectively. It was also shown that the proposed method results in more accurate and more consistent phase behaviour predictions than the existing methods concerning the experimental data. Furthermore, the results showed that the introduced optimization‐based method yields monotonic split samples regarding specific gravity and molecular weight, while the conventional techniques do not guarantee to preserve the monotonicity.
Optimization of zinc‐nickel film electrodeposition for better corrosion resistant characteristics
Authors: Anwar Shams , Khan Faisal , Zhang Yahui , Caines Susan
Published: May 2019

Corrosion is one of the main causes of structural deterioration in offshore and marine structures. One way to mitigate the effect of corrosion is with Zn‐Ni electroplated coatings. An experimental design and optimization procedures for Zn‐Ni alloy electroplating was an explored. This study analyzed a five‐variable experimental plan comprised of four steps: (1) a two‐level fractional factorial design (FFD); (2) a response surface design the steepest ascent analysis; (3) a central composite design (CCD); and (4) a corrosion behaviour test to optimize the factors in Zn‐Ni deposition. The critical plating variables in step 1 were zinc/nickel molar concentration ratio, current density, citrate concentrations, plating temperature, and plating time, used to determine their influence on the polarization resistance and corrosion resistance. In steps 2 and 3 the significant variables were studied using the steepest ascent method and the central composite design (CCD) to find the most optimal conditions for zinc‐nickel electroplating. These conditions were found to be a Zn/Ni molar concentration ratio of 0.66, a plating temperature of 28 °C, an electroplating current density of 60 mA/cm2, an electroplating time of 13 min, and a citrate concentration of 0.062 mol/L. The corrosion behaviour test of step 4 showed that the films with a higher intensity of the γ‐NiZn3, γ‐Ni2Zn11, and γ‐Ni3Zn22 phases exhibited better corrosion resistance.
Temperature Inferential Control of Heat‐Integrated Distillation Column Based on Variable Sensitive Stage Temperature Set‐point
Authors: Cong Lin , Liu Xinggao
Published: May 2019

Heat‐integrated distillation is an improved distillation technique with remarkable energy‐saving potential. A control scheme with a variable sensitive stage temperature set‐point is proposed to solve the control problem of a heat‐integrated distillation column (HIDiC). An online estimator is designed to support the variation of the set‐point. The locations of the stage temperature measurements are carefully selected based on a combination strategy with three steps. First, the sensitive stages are selected. Then, the following stages are determined by a PCA‐based method. Finally, a maximum differentiation method provides the remaining measurement selections. According to the profile parameters estimated by the proposed estimator, the set‐point of the sensitive stage temperature is adjusted adaptively to reduce the influence of the disturbances. Two commonly‐used PID controllers, the sensitive temperature control and the temperature differential control, are developed as the comparative study. The simulation results show that the proposed control scheme has a distinct advantage in restraining different disturbances.
Tumor downstaging as an intermediate endpoint to assess the activity of neoadjuvant systemic therapy in patients with muscle‐invasive bladder cancer
Authors: Martini Alberto , Jia Rachel , Ferket Bart S. , Waingankar Nikhil , Plimack Elizabeth R. , Crabb Simon J. , Harshman Lauren C. , Yu Evan Y. , Powles Thomas , Rosenberg Jonathan E. , Pal Sumanta K. , Vaishampayan Ulka N. , Necchi Andrea , Wiklund N. Peter , Mehrazin Reza , Mazumdar Madhu , Sfakianos John P. , Galsky Matthew D.
Published: May 2019

Background

Achieving a pathologic complete response (pCR) with neoadjuvant chemotherapy (NAC) in patients with muscle‐invasive bladder cancer (MIBC) has been associated with improved overall survival (OS). This study was aimed at evaluating the impact of pathologic downstaging (pDS; ie, a pT stage at least 1 stage lower than the pre‐NAC cT stage) on the OS of patients with MIBC treated with NAC.

Methods

The Retrospective International Study of Cancers of the Urothelial Tract (RISC) and the National Cancer Database (NCDB) were queried for cT2‐4N0M0 patients treated with NAC. A multivariable Cox model including either pDS or pCR was generated. A nested model was built to evaluate the added value of pDS (excluding patients achieving a pCR) to a model including pCR alone. C indices were computed to assess discrimination. NCDB was used for validation. The treatment effect of NAC versus cystectomy alone in achieving pDS was estimated through an inverse probability–weighted regression adjustment.

Results

Overall, 189 and 2010 patients from the RISC and NCDB cohorts, respectively, were included; pDS and pCR were achieved by 33% and 35% and by 20% and 15% in RISC and NCDB, respectively. In both data sets, pDS and pCR were associated with better OS and C indices. Adding pDS excluding pCR to the model with pCR fit the data better (likelihood ratio, P = .019 for RISC and P < .001 for NCDB), and it yielded better discrimination (incremental C index, 4.2 for RISC and 1.6 for NCDB). The treatment effect of NAC in achieving pDS was 2.07‐fold (P < .001) in comparison with cystectomy alone.

Conclusions

A decrease of at least 1 stage from the cT stage to the pT stage is associated with improved OS in patients with MIBC treated with NAC.
Use and early mortality outcomes of active surveillance in patients with intermediate‐risk prostate cancer
Authors: Butler Santino S. , Mahal Brandon A. , Lamba Nayan , Mossanen Matthew , Martin Neil E. , Mouw Kent W. , Nguyen Paul L. , Muralidhar Vinayak
Published: May 2019

Background

Certain patients with intermediate‐risk prostate cancer (PCa) may be appropriate candidates for active surveillance (AS). In the current study, the authors sought to characterize AS use and early mortality outcomes for patients with intermediate‐risk PCa in the United States.

Methods

The novel Surveillance, Epidemiology, and End Results Active Surveillance/Watchful Waiting database identified 52,940 men diagnosed with National Comprehensive Cancer Network intermediate‐risk PCa (cT2b‐c, Gleason score of 7, or a prostate‐specific antigen level of 10‐20 ng/mL) and actively managed (AS, radiotherapy, or radical prostatectomy) from 2010 through 2015. The Cuzick test assessed AS time trends, and logistic multivariable regression characterized features associated with AS. Fine‐Gray and Cox modeling determined PCa‐specific mortality (PCSM) and overall survival, respectively.

Results

The rate of AS increased from 3.7% in 2010 to 7.3% in 2015, and from 7.2% to 11.7% among men aged ≥70 years. Among men with favorable and unfavorable intermediate‐risk disease, the use of AS increased from 7.2% to 14.9% and from 2.2% to 3.8%, respectively (all P value for trend, <.001). The mean age of those patients managed with AS decreased from 69.9 years to 67.9 years (P = .0004). Factors found to be associated with AS included favorable risk disease; black race; higher socioeconomic status; older age; and diagnosis in the West, Northwest, or Midwest regions of the United States. The 5‐year PCSM rate was comparable to AS versus treatment among patients with low‐risk and favorable intermediate‐risk disease, but was worse with AS among those with unfavorable intermediate‐risk disease (PCSM, 1.3% vs 0.5%; adjusted hazard ratio, 2.48 [95% CI, 1.11‐5.50; P = .026]) and intermediate‐risk disease overall (PCSM, 1.1% vs 0.4%; adjusted hazard ratio, 2.34 [95% CI, 1.25‐4.37; P = .008]).

Conclusions

The use of AS for patients with intermediate‐risk PCa is increasing across the United States, particularly for older men and those with favorable intermediate‐risk disease. Early estimates of cancer‐specific and overall mortality rates are low with AS, although significantly higher compared with treatment.
Effects of Food and Gender on Pharmacokinetics of Rosuvastatin in a Chinese Population Based on 4 Bioequivalence Studies
Authors: Chen Jinliang , Lou Honggang , Jiang Bo , Shao Rong , Yang Dandan , Hu Yin , Xu Yichao , Ruan Zourong
Published: May 2019

The effects of food and gender on the pharmacokinetics of rosuvastatin in healthy Chinese subjects were investigated from 4 bioequivalence studies. These studies were designed as randomized, open‐label, and 2‐period crossover in both fasting and fed states. A total of 204 subjects were enrolled, 134 men and 70 women. These subjects received a single oral 10‐mg dose of rosuvastatin with a 7‐day washout between 2 periods. The plasma concentrations were determined using a validated liquid chromatography tandem mass spectrometry method, and pharmacokinetic parameters were calculated by noncompartmental methods. Compared with the fasting condition, administration after a high‐fat and high‐calorie meal resulted in an approximately 40% reduction of rosuvastatin exposure and a near 50% decrease in absorption rate. Moreover, the apparent clearance was significantly greater in the fed state than that in the fasting state. It was noted that the adverse events incidence is increased by approximately 30% in the fasting state; however, no serious adverse events were observed. Additionally, small differences in pharmacokinetic characteristics were found between male and female subjects. Food effect might be considered for optimal effectiveness and safety of rosuvastatin therapy.
Development of a lateral flow dipstick for simultaneous and semi‐quantitative analysis of dihydroartemisinin and piperaquine in an artemisinin combination therapy
Authors: Ning Xiangxue , Tan Guiyu , Chen Xiaojiao , Wang Mian , Wang Baomin , Cui Liwang
Published: May 2019

Dihydroartemisinin (DHA) and piperaquine (PPQ) are two drugs used in an artemisinin‐based combination therapy (ACT). The circulation of counterfeit antimalarial drugs demands the development of simple, point‐of‐care (POC) tests for monitoring drug quality. Here we aimed to design an antibody‐based lateral flow dipstick assay for simultaneous quality control of DHA and PPQ. To obtain a monoclonal antibody (mAb) for PPQ, one structural unit of the symmetric PPQ molecule was used to derive a carboxylic acid for linkage to a carrier protein as immunogen. Screening of hybridoma cells identified an mAb 4D112B2 that reacted with the PPQ‐based immunogen. A highly‐sensitive icELISA was designed based on this mAb, which showed 50% inhibition concentration of PPQ at 1.66 ng/mL and a working range of 0.35 – 7.40 ng/mL. The mAb showed 10.2, 15.9 and 30.4% cross reactivity to hydroxychloroquine sulfate, chloroquine and amodiaquine, respectively. No cross reactivity was observed to lumefantrine, mefloquine artemisinin and its derivatives. Using our previous DHA dipstick design, a lateral flow dipstick for simultaneous analysis of PPQ and DHA was developed. The indicator ranges for PPQ and DHA were 2 – 5 μg/mL and 250 – 500 ng/mL, respectively. The dipstick was used to semi‐quantitatively analyze PPQ and DHA content in commercial ACT drugs, which produced agreeable results to those determined by high‐performance liquid chromatography. This combination dipstick makes it a potential POC device for quality control of the two active ingredients in a commonly used ACT.
Detection of cocaine and its metabolites in whole blood and plasma following a single dose, controlled administration of intranasal cocaine
Authors: Menzies Eleanor L. , Archer John R.H. , Dargan Paul I. , Parkin Mark C. , Yamamoto Takahiro , Wood David M. , Braithwaite Robin A. , Elliott Simon P. , Kicman Andrew T.
Published: May 2019

The disposition of drugs and their metabolites have been extensively described in the literature, based primarily on the analysis of plasma and urine. However, there are more limited data on their disposition in whole blood, which is often the only specimen available in forensic investigations and cases of driving under the influence of drugs. In this study, we have, for the first time, established pharmacokinetic properties of cocaine (COC) and its metabolites from concurrently collected whole blood and plasma samples, following a single 100 mg dose of cocaine hydrochloride administered via nasal insufflation to seven healthy volunteers. The median Cmax of COC and its major metabolites, benzoylecgonine (BZE) and ecgonine methyl ester (EME), were closely related in whole blood and plasma. The median Cmax for COC in plasma was 379.7 ng/mL (347.5–517.7) and 344.24 ng/mL (271.6–583.2) in whole blood. The median Cmax for BZE in plasma was 441.2 ng/mL (393.6–475. and 371.18 ng/mL (371.1–477.3) in whole blood, EME was 105.5 ng/mL (93.6–151.8) in plasma and 135.5 ng/mL (87.8–183) in whole blood. Calculated medians of the whole blood to plasma ratio of COC (0.76), BZE (0.98) and EME (1.02) of approximately 1, strongly suggesting that the erythrocyte cell wall presents no barrier to COC and its metabolites. Furthermore, whole blood and plasma concentrations of COC were strongly correlated (R2 = 0.0914 R = 0.956, p < 0.0001), as was BZE (R2 = 0.0932 R = 0.965, p < 0.0001) and EME (R2 = 0.0964R = 0.928, p < 0.0001). The minor oxidative metabolite norcocaine (NCOC) was detected in both whole blood and plasma at concentrations between 1 and 5 ng/mL within 60–180 minutes, suggesting that NCOC could be indicator of recent COC administration. Data from this study have shown for the first time that COC and its metabolites BZE and EME are evenly distributed between plasma and whole blood following controlled single‐dose intranasal COC administration.
An alternative approach to reduce algorithm‐derived biases in monitoring soil organic carbon changes
Authors: Zhang Weixin , Chen Yuanqi , Shi Leilei , Wang Xiaoli , Liu Yongwen , Mao Rong , Rao Xingquan , Lin Yongbiao , Shao Yuanhu , Li Xiaobo , Zhao Cancan , Liu Shengjie , Piao Shilong , Zhu Weixing , Zou Xiaoming , Fu Shenglei
Published: May 2019

Quantifying soil organic carbon (SOC) changes is a fundamental issue in ecology and sustainable agriculture. However, the algorithm‐derived biases in comparing SOC status have not been fully addressed. Although the methods based on equivalent soil mass (ESM) and mineral‐matter mass (EMMM) reduced biases of the conventional methods based on equivalent soil volume (ESV), they face challenges in ensuring both data comparability and accuracy of SOC estimation due to unequal basis for comparison and using unconserved reference systems. We introduce the basal mineral‐matter reference systems (soils at time zero with natural porosity but no organic matter) and develop an approach based on equivalent mineral‐matter volume (EMMV). To show the temporal bias, SOC change rates were recalculated with the ESV method and modified methods that referenced to soils at time t1 (ESM, EMMM, and EMMV‐t1) or referenced to soils at time zero (EMMV‐t0) using two datasets with contrasting SOC status. To show the spatial bias, the ESV‐ and EMMV‐t0‐derived SOC stocks were compared using datasets from six sites across biomes. We found that, in the relatively C‐rich forests, SOC accumulation rates derived from the modified methods that referenced to t1 soils and from the EMMV‐t0 method were 5.7%–13.6% and 20.6% higher than that calculated by the ESV method, respectively. Nevertheless, in the C‐poor lands, no significant algorithmic biases of SOC estimation were observed. Finally, both the SOC stock discrepancies (ESV vs. EMMV‐t0) and the proportions of this unaccounted SOC were large and site‐dependent. These results suggest that although the modified methods that referenced to t1 soils could reduce the biases derived from soil volume changes, they may not properly quantify SOC changes due to using unconserved reference systems. The EMMV‐t0 method provides an approach to address the two problems and is potentially useful since it enables SOC comparability and integrating SOC datasets.
Development of data‐based controller synthesis by convex optimization
Authors: Yubai Kazuhiro
Published: May 2019

Recently, many researches extracting an essence from a huge number of data receive much attention in the various field of engineering. In the field of control engineering, the controller syntheses from time‐domain and/or frequency domain data are energetically studied based on numerical optimization techniques. This paper presents a recent development of data‐based controller synthesis by convex optimization, and shows that a special case of nonconvex optimization problems, which is often encountered in the control field, is reformulated as a convex optimization problem by introducing the concave‐convex procedure or the Iterated LMI constraints. As an application, the H∞ loop shaping design procedure reformulated using frequency response data of a controlled plant is presented.
Suppression of Aiolos and Ikaros expression by lenalidomide reduces human ILC3−ILC1/NK cell transdifferentiation
Authors: Mazzurana Luca , Forkel Marianne , Rao Anna , Van Acker Aline , Kokkinou Efthymia , Ichiya Tamaki , Almer Sven , Höög Charlotte , Friberg Danielle , Mjösberg Jenny
Published: May 2019

The Ikaros family of transcription factors (TFs) are important regulators of lymphocyte function. However, their roles in human innate lymphoid cell (ILC) function remain unclear. Here, we found that Ikaros (IKZF1) is expressed by all ILC subsets, including NK cells, in blood, tonsil, and gut, while Helios (IKZF2) is preferentially expressed by ILC3 in tonsil and gut. Aiolos (IKZF3) followed the expression pattern of T‐bet and Eomes, being predominantly expressed by ILC1 and NK cells. Differentiation of IFN‐γ‐producing ILC1 and NK cells from ILC3 by IL‐1β plus IL‐12‐stimulation was associated with upregulation of T‐bet and Aiolos. Selective degradation of Aiolos and Ikaros by lenalidomide suppressed ILC1 and NK cell differentiation and expression of ILC1 and NK cell‐related transcripts (LEF1, PRF1, GRZB, CD244, NCR3, and IRF8). In line with reduced ILC1/NK cell differentiation, we observed an increase in the expression of the ILC3‐related TF Helios, as well as ILC3 transcripts (TNFSF13B, IL22, NRP1, and RORC) and in the frequency of IL‐22 producing ILC3 in cultures with IL‐1β and IL‐23. These data suggest that suppression of Aiolos and Ikaros expression inhibits ILC1 and NK cell differentiation while ILC3 function is maintained. Hence, our results open up for new possibilities in targeting Ikaros family TFs for modulation of type 1/3 immunity in inflammation and cancer.
Preservative Effect of Algae Extracts on Lipid Composition and Rancidity Development in Brine‐Canned Atlantic Chub Mackerel (Scomber colias)
Authors: Barbosa Roberta G. , Trigo Marcos , Campos Carmen A. , Aubourg Santiago P.
Published: May 2019

This research focuses on the lipid fraction and the rancidity stability of commercial canned Atlantic Chub mackerel (Scomber colias). For it, two different concentrations of aqueous extracts of two abundant algae (Fucus spiralis and Ulva lactuca) are included in the brine‐packing (aq. 2% NaCl) medium during mackerel canning. Quality analyses are carried out after a 3‐month canned storage (20 °C). Phospholipids, sterols, and α‐tocopherol contents show a marked loss as a result of canning, this loss being mostly inhibited when considering the canned fish packed in the presence of the most concentrated algae extracts. Breakdown of free fatty acids and peroxides produced during the thermal treatment is inhibited by the presence of the algae extracts, a higher retention of such molecules being observed by increasing the algae extract concentration. Analysis of fluorescent compounds formation (tertiary lipid oxidation) shows a marked increase after canning, this increase being partly inhibited by the presence of antioxidant compounds present in the algae extracts; interestingly, oxidation inhibition is found more important in canned fish corresponding to F. spiralis batches than U. lactuca. A preservative effect on lipid constituents and rancidity development is concluded by the presence of algae extracts in the packing medium.

Practical Applications: The extensive heat treatment involved during fish canning has been reported to produce breakdown of constituents, lipid damage (oxidation and hydrolysis) development showing a marked effect on nutritional and sensory properties; furthermore, this effect has shown to be greater when a brine medium is applied as packing system. Marine algae have been described as being a relevant source of chemical constituents including an antioxidant and antibacterial behavior. In the current work, employment of a commercial brine‐packing including aqueous algae extracts shows a preservative effect on the lipid fraction (composition and rancidity stability) during the canning process of Atlantic Chub mackerel. The proposed strategy may open the way to the development of a natural biopreservation for commercial canned fish due to the simple methodology employed and the abundancy of the two algae chosen for the study. Further research should envisage optimization of the preservative compounds extraction by advanced technologies.

Aqueous extracts of algae Fucus spiralis and Ulva lactuca are included in the packing medium during Atlantic Chub mackerel (Scomber colias) canning. As a result, an inhibitory effect on lipid composition changes and rancidity development is obtained. Better results are observed by employing alga F. spiralis.
The dynamic effect of macroeconomic news on the euro/US dollar exchange rate
Authors: Ben Omrane Walid , Welch Robert , Zhou Xinyao
Published: May 2019

This study investigates the impact of 70 US and EU macroeconomic news announcements on euro/dollar returns and volatility from November 2004 to April 2014. We use regime smooth transition regression to endogenously define recession and expansion. Our sample period includes the US mortgage crisis and EU sovereign debt crisis. Most news is unstable as its effect varies between these economic states. There are asymmetrical effects between recession and expansion states for both US and EU news, with most US news having a larger impact and nearly double the number of significant EU announcements. Volatility increases for over 85% of news coefficients, with more than half still being significantly different between states.
Experimental design modulates variance in BOLD activation: The variance design general linear model
Authors: Gaut Garren , Li Xiangrui , Lu Zhong‐Lin , Steyvers Mark
Published: May 2019

Typical fMRI studies have focused on either the mean trend in the blood‐oxygen‐level‐dependent (BOLD) time course or functional connectivity (FC). However, other statistics of the neuroimaging data may contain important information. Despite studies showing links between the variance in the BOLD time series (BV) and age and cognitive performance, a formal framework for testing these effects has not yet been developed. We introduce the variance design general linear model (VDGLM), a novel framework that facilitates the detection of variance effects. We designed the framework for general use in any fMRI study by modeling both mean and variance in BOLD activation as a function of experimental design. The flexibility of this approach allows the VDGLM to (a) simultaneously make inferences about a mean or variance effect while controlling for the other and (b) test for variance effects that could be associated with multiple conditions and/or noise regressors. We demonstrate the use of the VDGLM in a working memory application and show that engagement in a working memory task is associated with whole‐brain decreases in BOLD variance.
Evaluation of the Potential of Cobalamin Derivatives Bearing Ru(II) Polypyridyl Complexes as Photosensitizers for Photodynamic Therapy
Authors: Jakubaszek Marta , Rossier Jeremie , Karges Johannes , Delasoie Joachim , Goud Bruno , Gasser Gilles , Zobi Fabio
Published: May 2019

The current photosensitizers (PSs) for photodynamic therapy (PDT) lack selectivity for cancer cells. To tackle this drawback, in view of selective cancer delivery, we envisioned conjugating two ruthenium polypyridyl complexes to vitamin B12(Cobalamin, Cbl) to take advantage of the solubility and active uptake of the latter. Ultimately, our results showed that the transcobalamin pathway is unlikely involved for the delivery of these ruthenium‐based PDT PSs, emphasizing the difficulty in successfully delivering metal complexes to cancer cells.
The relationship between intercultural abilities and cultural identity styles: A longitudinal cross‐lagged analysis
Authors: Szabó Ágnes , Ward Colleen
Published: May 2019

Hybrid and alternating identity styles are dynamic strategies that members of immigrant and ethnic minority groups use to maintain multiple cultural identities. Although research shows that the two strategies predict different outcomes for cultural identity development and psychological well‐being, less is known about their antecedents. The present study investigated the temporal relationship between intercultural abilities (i.e. intercultural effectiveness) and the activation of hybrid and alternating identity styles in a community sample of Filipino and Indian New Zealanders. Cross‐lagged analysis indicated that intercultural abilities positively predicted the hybrid identity style and negatively predicted the alternating identity style. Cultural identity styles were not predictive of intercultural abilities over time. Multigroup analysis indicated equivalence of regression paths across ethnic groups. Findings suggest that intercultural abilities function as an antecedent of cultural identity styles.
Rs531564 polymorphism in microRNA‐214 regulates interleukin‐6R expression in anal fissure patients to affect the risk of anal abscess formation
Authors: Liu Jiangang , Li Changlu , Yin Peiwei , Guo Xiuli , Liu Zhichao
Published: May 2019

Background

Anal abscess is an important complication of anal fissure (AF), whereas interleukin‐6R (IL‐6R) has been implicated in the development of abscess. In this study, we aimed to explore the possible molecular mechanisms underlying the regulatory effects of miRNAs on IL‐6R and other inflammatory factors related to the induction of anal abscess in AF.

Methods

Bioinformatics analysis, luciferase assay, real‐time polymerase chain reaction, and Western blot analysis were performed to identify the possible regulatory relationships between IL‐6R and miR‐124/miR‐125a by comparing the differentiated expression of miR‐125a, miR‐124, tumor necrosis factor‐α (TNF‐α), interferon‐γ (IFN‐γ), and IL‐4 among different groups of AF patients.

Results

IL‐6R messenger RNA (mRNA) was identified as a target gene of miR‐124 because the luciferase activity in cells cotransfected with wild‐type IL‐6R and miR‐124 mimics was significantly reduced. In addition, the expression of IL‐6R mRNA and protein was significantly inhibited in the presence of miR‐124 or an IL‐6R inhibitor, confirming the presence of a negative regulatory relationship between miR‐124 and IL‐6R. Moreover, miR‐124 and inflammatory factors were differentially expressed in AF patients carrying different genotypes of rs531564 polymorphism.

Conclusions

miR‐124 and inflammatory factors TNF‐α, IFN‐γ, and IL‐4 may be used as indicators of anal abscess development in AF patients. In addition, miR‐124 polymorphism rs531564 is involved with the pathogenesis of anal abscess in AF patients, and the presence of rs531564 may increase the incidence of anal abscess via upregulating the expression of IL‐6R, TNF‐α, IFN‐γ, and IL‐4.
miR‐4319 inhibited the development of thyroid cancer by modulating FUS‐stabilized SMURF1
Authors: Bian Shuquan
Published: May 2019

Thyroid cancer, a common type of endocrine system cancer, has witnessed rising incidence and deaths over the past few years. The role of microRNAs is being increasingly discovered in a variety of cancers, including thyroid cancer. miR‐4319 has been elucidated in several studies to exert an antitumor function in multiple cancers but has never been explored in thyroid cancer. Our study proposed to explore the function and modulatory mechanism of miR‐4319 in thyroid cancer. First, we confirmed the downregulation of miR‐4319 in thyroid cancer tissues and cells, and revealed the correlation of miR‐4319 expression and clinical features in thyroid cancer. Functional assays illustrated that miR‐4319 attenuated proliferation, migration, and epithelial‐to‐mesenchymal transition (EMT) in thyroid cancer. Mechanistically, we identified through the miRDB database and proved that miR‐4319 targeted SMAD specific E3 ubiquitin protein ligase 1 (SMURF1). Furthermore, we discovered that miR‐4319 competed with fused in sarcoma (FUS) to bind to SMURF1, inhibiting the stabilization of SMURF1 messenger RNA. Rescue assays suggested that miR‐4319 retarded proliferation, migration, and EMT through SMURF1. Collectively, the results of this study showed that miR‐4319 inhibited the development of thyroid cancer by modulating FUS‐stabilized SMURF1, indicating miR‐4319 as a potent biological target for thyroid cancer.
Quantum effects on the stability of the He5I2 van der Waals conformers
Authors: Valdés Álvaro , Prosmiti Rita
Published: May 2019

We present 15‐dimensional quantum multiconfiguration time‐dependent Hartree calculations of the vibrational levels of the He5I2 van der Waals (vdW) complex employing an ab initio‐based potential energy surface (PES). The energies and spatial features of such bound structures are analyzed, providing predictions on the structures and relative stabilities of its three lowest isomers. We found that the most stable isomer corresponds to all five He atoms encircling the I2 molecule, indicating that in this case the anharmonic quantum effects do not stabilize the isomers involving a He atom in a linear configuration as reported previously for the smaller HeNI2 systems. Such finding provides information on the overall structuring of the finite‐size‐solvent systems, highlighting the intriguing interplay between weak intermolecular interactions and quantum effects. © 2019 Wiley Periodicals, Inc.
Clinical diagnostic performance of light‐initiated chemiluminescent assay compared with the Architect chemiluminescence immunoassay for detection of HCV antibody
Authors: Yang Shuo , Yang Ruifeng , Zhang Siyu , Liu Di , Zhou Jiansuo , Wang Tiancheng , Cui Liyan
Published: May 2019

Background

Hepatitis C virus antibody (anti‐HCV) test had been approved as a preliminary screening test for HCV infection. Light‐initiated chemiluminescent assay (LiCA) was a homogenous method. We aimed to assess the clinical diagnostic performance of LiCA and compare it with that of chemiluminescence immunoassay (CLIA) which was widely used in clinical laboratories.

Methods

A total of 10 772 patients from the Peking University Third Hospital were enrolled. The serum samples were detected on the ChIVD LiCA500 and Abbott Architect i2000SR platforms. Recombinant immunoblot assay (RIBA) and HCV RNA assay were used for confirmation.

Results

The negative agreement rate between ChIVD LiCA anti‐HCV assay and Abbott Architect anti‐HCV assay was 99.91%, the positive agreement rate was 37.31%, the total agreement rate was 98.74%, and the kappa coefficient (κ) was 0.519. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of ChIVD LiCA anti‐HCV assay were 96.39%, 99.95%, 89.58%, and 99.97%, respectively, which were superior to those of Abbott Architect anti‐HCV assay (93.98%, 99.25%, 51.90%, and 99.95%, respectively).

Conclusion

ChIVD LiCA anti‐HCV assay was a highly sensitive, specific homogenous method with good diagnostic performance, and was applicable for the routine screening of HCV infection in clinical laboratories.
GNAS knockdown suppresses osteogenic differentiation of mesenchymal stem cells via activation of Hippo signaling pathway
Authors: An Jiangdong , Li Guangjie , Zhang Jin , Zhou Haiyu , Jiang Jin , Wang Xingwen , Feng Xiaofei , Wang Shuanke
Published: May 2019

Bone marrow‐derived mesenchymal stem cells (BMSCs) are a suitable option for cell‐based tissue engineering therapies due to their ability to renew and differentiate into multiple different tissue types, such as bone. Over the last decade, the effect of GNAS on the regulation of osteoblast differentiation has attracted great attention. Herein, this study aimed to explore the role of GNAS in osteogenic differentiation of MSCs. A total of 85 GNASf/f male mice were selected for animal experiments and 10 GNASf/f male mice for BMSC isolation to conduct cell experiments. The mice and BMSCs were treated with Verteporfin (a Hippo signaling pathway inhibitor) to inhibit the Hippo signaling pathway or recombinant adenovirus‐expressing Cre to knockout the GNAS expression. Next, computed tomography scan, Von Kossa staining, and alizarin red staining were performed to detect osteogenic differentiation ability. Moreover, immunohistochemistry and alkaline phosphatase (ALP) staining were used to assess the expression of Oc and Osx in femur tissues and ALP activity. At last, the expression of GNAS, osteogenic markers, and factors related to the Hippo signaling pathway was evaluated. Initially, the results displayed successful knockout of the GNAS gene from mice and BMSCs. Moreover, the data indicated that GNAS knockout inhibits expression of Oc, Osx, ALP, BMP‐2, and Runx2, and ALP activity. Additionally, GNAS knockout promotes activation of the Hippo signaling pathway, so as to repress osteogenic differentiation. Collectively, depleted GNAS exerts an inhibitory role in osteogenic differentiation of MSCs by activating Hippo signaling pathway, providing a candidate mediator for osteoporosis.
KPC1 alleviates hypoxia/reoxygenation‐induced apoptosis in rat cardiomyocyte cells though BAX degradation
Authors: Yuan Ye , Wang Yong‐yi , Liu Xin , Luo Bin , Zhang Lei , Zheng Fei , Li Xing‐Yuan , Guo Ling‐Yun , Wang Lu , Jiang Miao , Pan Ya‐mu , Yan Yu‐wen , Yang Jian‐ye , Chen Shi‐You , Wang Jia‐Ning , Tang Jun‐Ming
Published: May 2019

Bax triggers cell apoptosis by permeabilizing the outer mitochondrial membrane, leading to membrane potential loss and cytochrome c release. However, it is unclear if proteasomal degradation of Bax is involved in the apoptotic process, especially in heart ischemia‐reperfusion (I/R)‐induced injury. In the present study, KPC1 expression was heightened in left ventricular cardiomyocytes of patients with coronary heart disease (CHD), in I/R‐myocardium in vivo and in hypoxia and reoxygenation (H/R)‐induced cardiomyocytes in vitro. Overexpression of KPC1 reduced infarction size and cell apoptosis in I/R rat hearts. Similarly, the forced expression of KPC1 restored mitochondrial membrane potential (MMP) and cytochrome c release driven by H/R in H9c2 cells, whereas reducing cell apoptosis, and knockdown of KPC1 by short‐hairpin RNA (shRNA) deteriorated cell apoptosis induced by H/R. Mechanistically, forced expression of KPC1 promoted Bax protein degradation, which was abolished by proteasome inhibitor MG132, suggesting that KPC1 promoted proteasomal degradation of Bax. Furthermore, KPC1 prevented basal and apoptotic stress‐induced Bax translocation to mitochondria. Bax can be a novel target for the antiapoptotic effects of KPC1 on I/R‐induced cardiomyocyte apoptosis and render mechanistic penetration into at least a subset of the mitochondrial effects of KPC1.
Immunomodulatory activity of Ganoderma lucidum immunomodulatory protein via PI3K/Akt and MAPK signaling pathways in RAW264.7 cells
Authors: Li Qi‐Zhang , Chang Yu‐Zhou , He Zhu‐Mei , Chen Lei , Zhou Xuan‐Wei
Published: May 2019

Ganoderma lucidum immunomodulatory protein (FIP‐glu) is an active ingredient with potential immunoregulatory functions. The study was conducted to explore the immunomodulatory activities of recombinant FIP‐glu (rFIP‐glu) and its possible mechanism in macrophage RAW264.7 cells. In vitro assays of biological activity indicated that rFIP‐glu significantly activated RAW264.7 cells and possessed proinflammatory and anti‐inflammatory abilities. RNA sequencing analysis and Western blot analysis showed that macrophage activation involved PI3K/Akt and MAPK pathways. Furthermore, real‐time quantitative polymerase chain reaction indicated that the PI3K inhibitor LY294002 blocked the messenger RNA (mRNA) levels of MCP‐1 (CCL‐2), the MEK1/2 inhibitor U0126 reduced the mRNA levels of TNF‐α and MCP‐1 (CCL‐2), and the JNK1/2/3 inhibitor SP600125 prevented the upregulation of inducible nitric oxide synthase mRNA in rFIP‐glu‐induced cells. rFIP‐glu did not mediate these inflammatory effects through a general pathway but rather through a different pathway for a different inflammatory mediator. These data imply that rFIP‐glu possessed immunomodulatory activity in macrophages, which was mediated through PI3K/Akt and MAPK pathways.
Validation of a self‐report adherence measurement tool among a multinational cohort of children living with HIV in Kenya, South Africa and Thailand
Authors: Vreeman Rachel C , Scanlon Michael L , Tu Wanzhu , Slaven James E , McAteer Carole I , Kerr Stephen J , Bunupuradah Torsak , Chanthaburanum Sararut , Technau Karl‐Günter , Nyandiko Winstone M
Published: May 2019

Introduction

There are few data on adherence and low‐cost measurement tools for children living with HIV. We collected prospective data on adherence to antiretroviral therapy (ART) among a multinational cohort of children to evaluate an adherence questionnaire.

Methods

We enrolled 319 children ages 0 to 16 years on ART in Kenya (n = 110), South Africa (n = 109) or Thailand (n = 100). Children were followed up for six months of adherence monitoring between March 2015 and August 2016 using Medication Event Monitoring Systems (MEMS®) with at least one viral load measure. At month 3 and 6, children or their caregivers were administered a 10‐item adherence questionnaire. Repeated measures analyses were used to compare responses on questionnaire items to external adherence criteria: MEMS® dichotomized adherence (≥90% of doses taken vs. <90%), 48‐hour MEMS® treatment interruptions and viral suppression (<1000 copies/mL). Items associated with outcomes (p < 0.10) were coefficient‐weighted to calculate a total adherence score, which was tested in multivariate regression against MEMS® and viral suppression outcomes. Odds ratios (OR) and 95% confidence intervals (95% CI) were calculated.

Results

Mean child age was 11 years and 54% were female. Children from Thailand (median age 14 years) were significantly older compared to Kenya (10 years) and South Africa (10 years). Prevalence of viral suppression was 97% in Thailand, 81% in South Africa and 69% in Kenya, while the prevalence of MEMS® adherence ≥90% was 57% in Thailand, 58% in South Africa and 40% in Kenya. Across sites, child‐reported adherence using the questionnaire was significantly associated with dichotomized MEMS® adherence (OR 1.8, 95% CI 1.4 to 2.4), 48‐hour treatment interruptions (OR 0.41, 95% CI 0.3 to 0.6), and viral suppression (OR 3.4, 95% CI 1.7 to 6.7). We did find, however, that different cut‐points for the adherence score may be context‐specific. For example, MEMS® non‐adherent children in Kenya had a lower adherence score (0.98) compared to South Africa (1.77) or Thailand (1.58).

Conclusions

We found suboptimal adherence to ART was common by multiple measures in this multi‐country cohort of children. The short‐form questionnaire demonstrated reasonable validity to screen for non‐adherence in these diverse settings.
Evaluation of the serum metabolome of patients with alkaptonuria before and after two years of treatment with nitisinone using LC‐QTOF‐MS
Authors: Davison Andrew S. , Norman Brendan P. , Ross Gordon A. , Hughes Andrew T. , Khedr Milad , Milan Anna M. , Gallagher James A. , Ranganath Lakshminarayan R.
Published: May 2019

Background

The homogentisic acid‐lowering therapy nitisinone is being evaluated for the treatment of alkaptonuria (AKU) at the National Centre for AKU. Beyond hypertyrosinemia, the wider metabolic consequences of its use are largely unknown. The aim of this work was to evaluate the impact of nitisinone on the serum metabolome of patients with AKU after 12 and 24 months of treatment.

Methods

Deproteinized serum from 25 patients with AKU (mean age[±SD] 51.1 ± 14.9 years, 12 male) was analyzed using the 1290 Infinity II liquid chromatography system coupled to a 6550 quadrupole time‐of‐flight mass spectrometry (Agilent, UK). Raw data were processed using a batch targeted feature extraction algorithm and an accurate mass retention time database containing 469 intermediary metabolites (MW 72‐785). Matched entities (±10 ppm theoretical accurate mass and ±0.3 minutes retention time window) were filtered based on their frequency and variability (<25% CV) in group quality control samples, and repeated measures statistical significance analysis with Benjamini‐Hochberg false discovery rate adjustment was used to assess changes in metabolite abundance.

Results

Eight metabolites increased in abundance (log2 fold change [FC] 2.1‐15.2, P < .05); 7 of 8 entities were related to tyrosine metabolism, and 13 decreased in abundance (log2 FC 1.5‐15.5, P < .05); including entities related to tyrosine (n = 2), tryptophan (n = 3), xanthine (n = 2), and citric acid cycle metabolism (n = 2).

Conclusions

Evaluation of the serum metabolome of patients with AKU showed a significant difference in the abundance of several metabolites following treatment with nitisinone, including a number that have not been previously reported; several of these were not related to the tyrosine metabolic pathway.

Synopsis

Nitisinone therapy has a significant impact on several metabolites beyond the tyrosine metabolic pathway, several of which appear to be related to the redox state of the cell.
Increasing body mass index in an elderly cohort: Effects on the quantitative MR parameters of the brain
Authors: Schall Melissa , Iordanishvili Elene , Mauler Jörg , Oros‐Peusquens Ana‐Maria , Shah N. Jon
Published: May 2019

Background

Body mass index (BMI) is increasing in a large number of elderly persons. This increase in BMI is known to put one at risk for many "diseases of aging," although less is known about how a change in BMI may affect the brains of the elderly.

Purpose

To investigate the relationship between BMI and quantitative water content, T1, T2*, and the semi‐quantitative magnetization transfer ratio (MTR) of various structures in elderly brains.

Study Type

Cross‐sectional.

Subjects

Forty‐two adults (BMI range: 19.1–33.5 kg/m2, age range: 58–80 years).

Field Strength

3T MRI (two multi‐echo gradient echoes, actual flip angle imaging, magnetization prepared rapid gradient echo, fluid attenuated inversion recovery).

Assessment

The 3D two‐point method was used to derive (semi‐)quantitative parameters in global white (WM) and gray matter (GM) and their regions as defined by the Johns Hopkins University and the Montreal Neurological Institute atlases.

Statistical Tests

Multivariate linear regression with BMI as principal regressor, corrected for the additional regressors age, gender, and glycated hemoglobin. Spearman correlation between quantitative parameters of the regions showing significant changes and the lipid spectra / C‐reactive protein (CRP). Voxel‐based morphometry and analysis of covariance (ANCOVA) to explore changes in the GM volume.

Results

T1increased significantly (P < 0.05) in the frontal, temporal, and parietal cortices, while the bilateral corona radiata, right superior longitudinal fasciculus, as well as the corpus callosum showed significant changes in the WM regions. T2* increased significantly in the global WM and left corona radiata. Changes in MTR and the free water content did not reach significance. No significant correlation between any quantitative parameter and the lipid spectra or CRP could be identified.

Data Conclusion

These results suggest that an elevated BMI predominantly affects T1in WM as well as GM structures in the elderly human brain.

Level of Evidence:3

Technical Efficacy:Stage 3

J. Magn. Reson. Imaging 2020;51:514–523.