bluuebunny/crossref_metadata_2025 huggingface dataset:
Comunicación y engagement en Instagram de las plataformas de televisión a la carta: Netflix, HBO y Movistar+
Authors: Ortega Fernández Eglée , Santos Herrero Noemí
Published: October 2020

Purpose: The main objective is to determine how the television a la carte platforms connect with their followers through the social network Instagram and if they succeed, based on the hypothesis that the three platforms have defined their digital strategies and have a great interaction with users, as part of their communication and engagement actions.

Design / Methodology / Approach: Quantitative methodology is used through a review on Instagram, in which different variables are established for the joint and comparative analysis of the three platforms.

Results: The results highlight that each platform has a differentiated strategy on Instagram. Likewise, it is concluded that there is no key strategy for the success of a social network, but each of the profiles must bet on building their own particular style and strategy.

Limitations / Implications: Social networks are a whole world and without a doubt they coexist with us forming part of our lives, and, probably, over the years, the different technological evolutions, the appearance of new social networks or changes in current ones, digital strategies that exist now, will vary and very likely there will be an expansion of the present possibilities.

Originality / Contribution: It is a contribution that deepens the use of one of the most used social networks and details the strategies that successful platforms apply as part of their actions for communication and engagement.
Riding elevators into and out of cells
Authors: Duster Adam W , Lin Hai
Published: October 2020

The mechanisms responsible for the trafficking of carboxylate ions across cell membranes are becoming clearer.
The challenges of vaccine strain selection
Authors: Perofsky Amanda C , Nelson Martha I
Published: October 2020

New measures of influenza virus fitness could improve vaccine strain selection through more accurate forecasts of the evolution of the virus.
On the (non-)expletive uses of the preverbal negative ne/en in the history of (Low) German and Dutch
Authors: Witzenhausen Elisabeth
Published: October 2020

This article presents novel data from Middle High German, Middle Low German and Middle Dutch showing that two phenomena which often have been treated as one, namely the single former negativemarker ne/en appearing in adverbial and complement clauses, have to be treated as distinct phenomena. I argue that only in complement clauses, ne/en is a paratactic negation marker, while in adverbial clausesit functions as an exceptive and adversative discourse marker. In these contexts, I refer to ne/en as post-cyclical Furthermore, I propose a scenario as to how the reanalysis from negation to exceptive markerproceeded.
The dangers of controlling memes through copyright law
Authors: Capelotti Joao Paulo
Published: October 2020

Intertextuality plays a great role in the production and comprehension of various forms of humorous expressions, such as parodies and memes. The latter often rely on previous facts, images, videos, statements etc., to express a certain comic idea. Nowadays, memes and parodic videos are not just made by comedians, but also by ordinary people on social networks, mostly using images, videos and gifs found in search engines like Google. However, attempts at regulating the use of such materials, particularly from the point of view of copyright, threaten the freedom of this sort of humorous expression. The article discusses a case from Brazil in 2017, when the then President Michel Temer tried to stop the unauthorised use of his image in the creation of memes, stating that the pictures in the Presidency’s website were available for journalistic purposes only, and any other use needed the government’s consent. This strange situation, that could give the president the power of approving the satire made at his expense, was itself the subject of various memes, which ultimately forced the government to step back. The article then discusses similar risks of a directive recently approved by the European Parliament, which, under the flag of protecting copyright, may have a controversial chilling effect in the creation of memes and satiric videos.
Revisiting intertextuality and humour: fresh perspectives on a classic topic
Authors: Tsakona Villy , Chovanec Jan
Published: October 2020

In humour research, intertextuality has been extensively studied with the aim of understanding how humorous texts are constructed on the basis of previous texts. In this paper, we elaborate on the sociopragmatic functions of intertextuality, pointing out not only how humorous texts rely on previous texts and background knowledge, but also what sociopragmatic functions intertextuality serves in actual communicative situations, e.g. the effect the recognition (or not) of intertextual references has on the segmentation of recipients into various groups. To this end, the paper discusses intertextuality in relation to such traditional concepts as textuality and genre, and adds a focus on the speaker’s intention and the recipient’s interpretation. The paper serves as a framing introduction to six other papers in the special issue on the topic of “Intertextuality and humour”, articulating a common research position and arguing for the extension of scholarly attention to such applied domains as critical literacy education, marketing communication, and the legal framework regulating the creation and reception of humorous texts and artefacts.
Plasma miRNA profiles associated with stable warfarin dosage in Chinese patients
Authors: Zhao Li , Wang Jin , Shi Shaoxin , Wu Yuan , Liu Jumei , He Shiwei , Zou Yue , Xie Huabin , Ge Shengxiang , Ye Huiming
Published: October 2020

Background

We used bioinformatic analysis and quantitative reverse transcription polymerase chain reaction (RT-qPCR) assays to investigate the association between plasma microRNAs (miRNAs) and stable warfarin dosage in a Chinese Han population.

Methods

Bioinformatics analysis was used to screen out potential warfarin dose-associated miRNAs. Three plasma miRNAs were validated in 99 samples by RT-qPCR. Kruskal–Wallis test and multivariate logistic regression were used to compare differences in plasma miRNAs expression levels between three warfarin dosage groups.

Results

There were significant between-group differences among the three dose groups for hsa-miR-133b expression (p = 0.005), but we observed an “n-shaped” dose-dependent curve rather than a linear relationship. Expression levels of hsa-miR-24-3p (p = 0.475) and hsa-miR-1276 (p = 0.558) were not significantly different in the multivariate logistic regression.

Conclusion

miRNAs have received extensive attention as ideal biomarkers and possible therapeutic targets for various diseases. However, they are not yet widely used in precision medicine. Our results indicate that hsa-miR-133b may be a possible reference factor for the warfarin dosage algorithm. These findings emphasize the importance of a comprehensive evaluation of complex relationships in warfarin dose prediction models and provide new avenues for future pharmacogenomics studies.
Novel Association between Gemfibrozil and Dyslipidemia: A Case Report
Authors: Barrouq Deena M. S. , Irshaidat Tareq
Published: October 2020

Dyslipidemia is a risk factor in many health complications, among them is hypertension.

Case: This report presents a case of a poorly controlled dyslipidemia that could not be managed by medications. A surprisingly and an unexpected factor interfered; the triglyceride-lowering medication caused a significant increase in the appetite toward fat-rich food items which opposed its intended purpose.

Methodology: A dietary intervention and an uncommon drug dose modification were necessary. Results: The personally designed protocol led to a significant overall improvement and was successful in adjusting the biochemical parameters especially the plasma triglycerides and the total cholesterol and was effective in reversing hypertension and a pre-diabetic state to safer values. Conclusion: This is the first characterized case in the literature on the involvement of gemfibrozil in poor management of dyslipidemia.
Regulation of human sphingomyelin synthase 1 translation through its 5′‐untranslated region
Authors: Daian Foysal , Esper Brecken Shenandoah , Ashrafi Navid , Yu Gui‐Qin , Luciano Gabriella , Moorthi Sitapriya , Luberto Chiara
Published: October 2020

Bcr‐abl1 oncogene causes a shift in the transcription start site of the SMS1 gene (SGMS1) encoding the sphingomyelin (SM) synthesizing enzyme, sphingomyelin synthase 1 (SMS1). This results in an mRNA with a significantly shorter 5′‐UTR, called 7‐SGMS1, which is translated more efficiently than another transcript (IIb‐SGMS1) with a longer 5′UTR in Bcr‐abl1‐positive cells. Here, we determine the effects of these alternative 5′UTRs on SMS1 translation and investigate the key features underlying such regulation. First, the presence of the longer IIb 5′UTR is sufficient to greatly impair translation of a reporter gene. Deletion of the upstream open reading frame (−164 nt) or of the predicted stem‐loops in the 5′UTR of IIb‐SGMS1 has minimal effects on SGMS1 translation. Conversely, deletion of nucleotides −310 to −132 enhanced transcription of IIb‐SGMS1 to reach that of 7‐SGMS1. We thus suggest that regulatory features within nucleotides −310 and −132 modulate IIb‐SGMS1 translation efficiency.
Tumors driven by RAS signaling harbor a natural vulnerability to oncolytic virus M1
Authors: Cai Jing , Lin Kaiying , Cai Wei , Lin Yuan , Liu Xincheng , Guo Li , Zhang Jifu , Xu Wencang , Lin Ziqing , Wong Chun Wa , Sander Max , Hu Jun , Yan Guangmei , Zhu Wenbo , Liang Jiankai
Published: October 2020

Oncolytic viruses are potent anticancer agents that replicate within and kill cancer cells rather than normal cells, and their selectivity is largely determined by oncogenic mutations. M1, a novel oncolytic virus strain, has been shown to target cancer cells, but the relationship between its cancer selectivity and oncogenic signaling pathways is poorly understood. Here, we report that RAS mutation promotes the replication and oncolytic effect of M1 in cancer, and we further provide evidence that the inhibition of the RAS/RAF/MEK signaling axis suppresses M1 infection and the subsequent cytopathic effects. Transcriptome analysis revealed that the inhibition of RAS signaling upregulates the type I interferon antiviral response, and further RNA interference screen identified CDKN1A as a key downstream factor that inhibits viral infection. Gain‐ and loss‐of‐function experiments confirmed that CDKN1A inhibited the replication and oncolytic effect of M1 virus. Subsequent TCGA data mining and tissue microarray (TMA) analysis revealed that CDKN1A is commonly deficient in human cancers, suggesting extensive clinical application prospects for M1. Our report indicates that virotherapy is feasible for treating undruggable RAS‐driven cancers and provides reliable biomarkers for personalized cancer therapy.
Saturated observer‐based adaptive neural network leader‐following control of N tractors with n‐trailers with a guaranteed performance
Authors: Shojaei Khoshnam , Abdolmaleki Mohammad
Published: October 2020

This article addresses the leader‐following neural network adaptive observer‐based control of N tractors connected to n trailers with the prescribed performance specifications. To propose the controller, a change of coordinates and a nonlinear error transformation are used to transform the constrained error dynamics to a new second‐order Euler‐Lagrange unconstrained error dynamics which inherits all structural properties of ith vehicle dynamic model. By combining a projection‐type neural network and an adaptive robust technique, a novel leader‐following saturated output‐feedback controller is proposed to force that ith vehicle tracks a virtual leader trajectory with the prescribed transient and steady‐state characteristics while reducing the actuator saturation risk and compensating all unknown dynamic model parameters, external disturbances, unmolded dynamics, and NN approximation errors. A saturated velocity observer is heuristically proposed to obviate the requirement for the velocity measurements of ith vehicle without any unwanted peaking. A Lyapunov‐based stability analysis is utilized to prove that all the tracking and state observation errors are semi‐globally uniformly ultimately bounded (SGUUB) and they converge to small bounds including the origin with a prescribed performance. At the end, computer simulations will be shown to validate the efficacy of the proposed controller in practice.
SUD facilities billed $845 million fraudulently, says DOJ
Authors: Knopf Alison
Published: October 2020

More than 100 doctors, nurses and other licensed medical professionals were charged last month by the federal Department of Justice (DOJ) for submitting more than $6 billion in false and fraudulent claims to Medicare, Medicaid and private insurance companies. This included more than $845 million connected to “sober homes.” The enforcement action, announced Sept. 30, involved 345 defendants across 51 federal districts, and was led by the DOJ's Criminal Division. Prosecution will be by U.S. attorneys and the DOJ's Criminal Division's Fraud Section. The cases are connected to telemedicine, which has taken off since the COVID‐19 pandemic. “Telemedicine can foster efficient, high‐quality care when practiced appropriately and lawfully,” said Acting Assistant Attorney General Brian C. Rabbitt. “Unfortunately, bad actors attempt to abuse telemedicine services and leverage aggressive marketing techniques to mislead beneficiaries about their health care needs and bill the government for illegitimate services,” said Department of Health and Human Services Deputy Inspector General Gary Cantrell. “Unfortunately, audacious schemes such as these are prevalent and often harmful. Therefore, collaboration is critical in our fight against health care fraud.” Rabbitt said the enforcement action will “send a clear deterrent message and should leave no doubt about the department's ongoing commitment to ensuring the safety of patients and the integrity of health care benefit programs, even amid a national health emergency.”
Adaptive Wettability of a Programmable Metasurface
Authors: Specht Marius , Berwind Matthew , Eberl Chris
Published: October 2020

Metasurfaces with specific wettability have recently been gaining relevance in numerous areas of science and industry. This hasled to the technical requirements of these functional metasurfaces increasing in cost and complexity. Examples can be found in adjustable filters and membranes, as well as in lab‐on‐chip systems. For a large number of these applications, surfaces with adaptive properties offer unique advantages compared with traditionally engineered systems. Such surfaces with adaptable surface energies, and thus wetting properties, can be realized by either a change in the surface chemistry or structure. Due to novel additive manufacturing methods such as two‐photon lithography, high‐resolution 3D microstructures can be prototypically fabricated and highly specific adjustments of the surface structure can be realized. These advances have enabled a field with particularly broad development possibilities in the area of metamaterials. Herein, a novel mechanoadaptive surface with strain‐dependent wettability states is detailed. The surface was designed, fabricated, and experimentally characterized with a custom test setup that combines the capabilities of contact angle measurements and mechanical straining in one. The results demonstrate a mechanically induced, topologically driven modification of the surface's wetting properties from the hydrophobic to the super‐hydrophobic regime.
Umpolung Strategy with 2‐Aminothiophenols: Access to 2‐Arylbenzothiazine Derivatives from Alkyl Aryl Ketones
Authors: Nguyen Thanh Binh , Retailleau Pascal
Published: October 2020

Strong Brønsted acids were found to catalyze the oxidative condensation of 2‐aminothiophenols with aryl alkyl ketones in DMSO to provide a wide range of complex 2‐arylbenzothiazines. With acetophenones, dimeric 2‐arylbenzothiazines were formed. On the other hand, the reaction with propiophenones resulted in 2:1 adducts whereas 1:1 adducts were produced with isobutyrophenones, benzoylacetonitrile and ethyl benzoylacetate.

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Enantioselective Synthesis of Chromanones through Organocatalytic Tandem Reactions
Authors: Lu Mengxue , Wang Xin , Xiong Zongli , Duan Jingxiang , Ren Wen , Yao Weijun , Xia Yi , Wang Zhen
Published: October 2020

An enantioselective approach to lactone‐fused chromanone derivatives from 1‐(2‐hydroxyaryl)‐1,3‐diketones and α,β‐unsaturated aldehydes under mild conditions has been developed, which included organocatalytic stepwise Michael addition/ cycloketalization/hemiacetalization and followed by oxidation reaction. In the presence of chiral amine organocatalyst and an additional salicylic acid, a wide range of 1‐(2‐hydroxyaryl)‐1,3‐diketones and α,β‐unsaturated aldehydes were tolerated, furnishing a spectrum of lactone‐fused tricyclic chromanones bearing three contiguous stereocenters in high yields with good to excellent selectivities (90‐>99% ee, >19:1 d.r.).

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Light‐Responsive, Reversible Emulsification and Demulsification of Oil‐in‐Water Pickering Emulsions for Catalysis
Authors: Li Zhiyong , Shi Yunlei , Zhu Anlian , Zhao Yuling , Wang Huiyong , Binks Bernard P. , Wang Jianji
Published: October 2020

Pickering emulsions are an excellent platform for interfacial catalysis. However, developing simple and efficient strategies to achieve product separation and catalyst and emulsifier recovery is still a challenge. Herein, we report the reversible transition between emulsification and demulsification of a light‐responsive Pickering emulsion, triggered by alternating between UV and visible light irradiation. The Pickering emulsion is fabricated from Pd‐supported silica nanoparticles, azobenzene ionic liquid surfactant, n‐octane, and water. This phase behavior is attributed to the adsorption of azobenzene ionic liquid surfactant on the surface of the nanoparticles and the light‐responsive activity of ionic liquid surfactant. The Pickering emulsion can be used as a microreactor that enables catalytic reaction, product separation as well as emulsifier and catalyst recycling. Catalytic hydrogenation of unsaturated hydrocarbons at room temperature and atmospheric pressure has been performed in this system to demonstrate product separation and emulsifier and catalyst re‐use.
Enzymatic Kinetic Resolution by Addition of Oxygen
Authors: Harwood Lucy A. , Wong Luet L. , Robertson Jeremy
Published: October 2020

Kinetic resolution using biocatalysis has proven to be an excellent complementary technique to traditional asymmetric catalysis for the production of enantioenriched compounds. Resolution using oxidative enzymes produces valuable oxygenated structures for use in synthetic route development. This Minireview focuses on enzymes which catalyse the insertion of an oxygen atom into the substrate and, in so doing, can achieve oxidative kinetic resolution. The Baeyer–Villiger rearrangement, epoxidation, and hydroxylation are included, and biological advancements in enzyme development, and applications of these key enantioenriched intermediates in natural product synthesis are discussed.
Putting Single Session Thinking to Work: Conceptual, Practical, Training, and Implementation Ideas
Authors: Young Jeff
Published: October 2020

There is growing pressure on health and welfare services to provide more efficient and effective services. For one thing, the world’s ageing population is resulting in increased pressure on healthcare costs and the availability of government funding. At the same time, community expectations of quick and easy access to high‐quality client‐centred services is growing. Single session ideas can make a valuable contribution to responding to these somewhat competing factors, by providing a basis for effective, efficient, client‐centred, accessible services. This article begins with a functional definition and description of single session therapy (SST), which is used to inform article sections on the attitudinal, clinical, and organisational implications, and ends with ideas for implementing the approach into services, thus, putting SST to work.
Synthesis, characterization, antimicrobial activity, 3D‐QSAR, DFT, and molecular docking of some ciprofloxacin derivatives and their copper(II) complexes
Authors: Khalil Tarek E. , El‐Dissouky Ali , Al‐Wahaib Dhuha , Abrar Nada M. , El‐Sayed Doaa S.
Published: October 2020

Six new derivatives of ciprofloxacin compounds and their copper(II) complexes were synthesized, characterized by spectroscopic methods (ultraviolet–visible [UV–vis], Fourier transform infrared [FTIR], nuclear magnetic resonance [NMR], mass spectrometry [MS], and electron paramagnetic resonance [EPR]), and tested for antibacterial activities against gram‐negative and gram‐positive bacteria. The data showed that ciprofloxacin derivatives act as bidentate ligands and the metal ions coordinate through the pyridone carbonyl and the carboxylate oxygen atoms. Tetragonally distorted octahedral ligand fields were assumed for all complexes based on their spectral studies. Copper(II) complexes of the synthesized ciprofloxacin derivatives revealed higher antibacterial activities against gram‐positive and gram‐negative bacterial species than the parent ciprofloxacin antibiotic. Furthermore, three‐dimensional quantitative structure–activity relationship (3D‐QSAR) models were evaluated by studying 30 antibiotic compounds of the quinolone class. Density function theory (DFT) calculations were applied to evaluate the optimized geometrical structures using the B3LYP method and 6‐311G(d,p) basis set. The 3D‐QSAR study revealed that there are eight optimum parameters that give the best predictive modulation with good reliability (R2 = 0.996, F = 12.004, sigma = 0.426). In silico molecular docking was also performed on the derivatives, and the results revealed the presence of two types of interactions between the Escherichia coli and the derivatives, H‐bonding and Van der Waals interactions, and an effective inhibition at the docked site.
Development of internal structure of polymer‐modified asphalts via transformations of the reduced frequency
Authors: Jasso Martin , Stastna Jiri , Polacco Giovanni , Cuciniello Giacomo
Published: October 2020

The independent variable of dynamic material functions and corresponding master curves, the reduced angular frequency , was transformed into the apparent molecular weight MW*. As a function of MW*, the normalized master phase angle represented an apparent cumulative molecular weight. This function's numerical differentiation yielded the probability density function of the apparent molecular weight, f(MW*). While this procedure is unproblematic in conventional (straight run) asphalts, it is yielding peaks of negative MW* in polymer modified asphalts. Thus reduced frequency was also transformed to the temperature, which allowed us to determine that the apparent glass transition temperature as the maximum on the master curve of loss modulus G"(T). The master curve of the normalized phase angle as a function of temperature helped to explain the phenomenon associated with the probability density function in modified asphalts. The results presented in this article were obtained numerically, without the use of rheological models.
An ovary‐specific mucin is associated with choriogenesis mediated by prostaglandin signaling in Spodoptera exigua
Authors: Ahmed Shabbir , Seo Kiwon , Kim Yonggyun
Published: October 2020

Polytrophic ovarioles of Spodoptera exigua, a lepidopteran insect, begins with the development of oocytes and differentiation of nurse cells followed by vitellogenesis and choriogenesis. Compared with previtellogenic and vitellogenic developments, choriogenesis has not been clearly understood yet in endocrine control. This study investigated the expression and function of a mucin‐like structural protein of S. exigua called Se‐Mucin1 in choriogenesis. It was highly expressed in ovarioles containing chorionated oocytes. The expression level of Se‐Mucin1 was increased during adult stage as early as 18 h after adult emergence, reaching the maximal level at 24 h and later. Interestingly, DNA amount of Se‐Mucin1 was increased by almost four folds during early adult stage while other genes (hexokinase and glyceraldehyde‐3‐phosphate dehydrogenase) not directly associated with chorion formation did not show genomic DNA increase, suggesting specific gene amplification of Se‐Mucin1. RNA interference (RNAi) suppressed Se‐Mucin1 expression by injecting 1 μg of double‐strand RNA to teneral females (<5 h after emergence), which exhibited significantly impaired fecundity and egg hatching rate. Eggs laid by RNAi‐treated females were malformed in eggshell structures with loss of mesh‐like fibers. Treatment with aspirin, a prostaglandin (PG) biosynthesis inhibitor, suppressed the induction of Se‐Mucin1 expression during early adult stage and impaired egg development. An addition of PGE2 significantly rescued such impairment in Se‐Mucin1 expression and subsequent egg development. These results suggest that PGs mediate choriogenesis of S. exigua by activating the expression of chorion‐associated genes including Se‐Mucin1.
Distinct Expression of Coinhibitory Molecules on Alveolar T Cells in Patients With Rheumatoid Arthritis–Associated and Idiopathic Inflammatory Myopathy–Associated Interstitial Lung Disease
Authors: Nakazawa Maho , Suzuki Katsuya , Takeshita Masaru , Inamo Jun , Kamata Hirofumi , Ishii Makoto , Oyamada Yoshitaka , Oshima Hisaji , Takeuchi Tsutomu
Published: October 2020

Objective

To identify immunologic factors in the lungs of patients with rheumatoid arthritis–associated interstitial lung disease (RA‐ILD) and patients with idiopathic inflammatory myopathy–associated ILD (IIM‐ILD) and to examine their pathologic mechanisms.

Methods

Eleven patients with RA‐ILD, 16 with IIM‐ILD, 6 with drug‐induced ILD (DI‐ILD), and 8 healthy controls were enrolled. Peripheral blood (PB) and bronchoalveolar lavage (BAL) fluid were immunophenotyped by flow cytometry. Alveolar macrophages (AMs) were analyzed by coculture assay with PB naive CD4+ T cells from healthy individuals and RNA sequencing.

Results

Several coinhibitory molecules were coexpressed on BAL fluid T cells (CTLA‐4, programmed death 1 [PD‐1], T cell immunoglobulin and mucin domain–containing protein 3 [TIM‐3], and lymphocyte activation gene 3 protein, from most to least), whereas only PD‐1 was expressed on PB T cells. CTLA‐4+PD‐1+CD4+ T cells were characteristic of RA‐ILD, whereas CTLA‐4+PD‐1+TIM‐3+CD8+ T cells were characteristic of IIM‐ILD. BAL fluid PD‐1+CD4+ T cells rarely expressed CXCR5, but their levels correlated with levels of plasmablasts and plasma cells (ρ = 0.57, P = 0.006), indicating that most of them would be considered peripheral helper T cells. In coculture experiments, AMs from patients with RA‐ILD and IIM‐ILD induced more PD‐1 and TIM‐3 on T cells (P < 0.05), suggesting that coinhibitory molecule expression on BAL fluid T cells was partly due to AMs. RNA sequencing showed significant down‐regulation of PD ligand 1/2 genes in AMs from patients with RA‐ILD compared to those with DI‐ILD.

Conclusion

We have identified differences in coinhibitory molecule expression between patients with RA‐ILD and those with IIM‐ILD. PD‐1 on T cells in RA‐ILD and TIM‐3 on CD8+ T cells in IIM‐ILD might be key factors in the disease process. Evaluation of coinhibitory molecules on BAL fluid T cells could be clinically useful.
Efficacy and Safety of E6011, an Anti‐Fractalkine Monoclonal Antibody, in Patients With Active Rheumatoid Arthritis With Inadequate Response to Methotrexate: Results of a Randomized, Double‐Blind, Placebo‐Controlled Phase II Study
Authors: Tanaka Yoshiya , Takeuchi Tsutomu , Yamanaka Hisashi , Nanki Toshihiro , Umehara Hisanori , Yasuda Nobuyuki , Tago Fumitoshi , Kitahara Yasumi , Kawakubo Makoto , Torii Kentaro , Hojo Seiichiro , Kawano Tetsu , Imai Toshio
Published: October 2020

Objective

To evaluate the efficacy and safety of E6011, a humanized IgG2 monoclonal antibody against human fractalkine (FKN), in a phase II, double‐blind, placebo‐controlled study in rheumatoid arthritis (RA) patients.

Methods

Patients with moderate‐to‐severe RA who had an inadequate response to methotrexate were randomly assigned to a placebo group or to E6011 100‐mg, 200‐mg, or 400/200‐mg groups at a 2:1:2:2 ratio. During the 24‐week period, patients received the study drug subcutaneously at weeks 0, 1, and 2 and then once every 2 weeks. The primary end point was the American College of Rheumatology 20% improvement criteria (ACR20) response rate at week 12.

Results

Study drugs were administered to 190 patients (placebo, n = 54; E6011 100 mg, n = 28; E6011 200 mg, n = 54; E6011 400/200 mg, n = 54), and 169 patients completed treatment. A significant difference from placebo was not found in ACR20 response rates at week 12 (37.0% [placebo], 39.3% [100 mg], 48.1% [200 mg], and 46.3% [400/200 mg], using nonresponder imputation). As a secondary end point, ACR20 response rate in the 200‐mg and 400/200‐mg groups attained statistical significance at week 24 (35.2% [placebo], 39.3% [100 mg], 53.7% [200 mg], and 57.4% [400/200 mg]). Subsequent exploratory subgroup analysis revealed greater efficacy of E6011, particularly in patients with a higher baseline proportion of CD16+ monocytes; ACR20 response rates in this patient subgroup at week 24 were 30.0% (placebo), 46.7% (100 mg), 57.7% (200 mg), and 69.6% (400/200 mg). E6011 administered for 24 weeks was well tolerated.

Conclusion

This is the first evidence that E6011, a novel cell trafficking inhibitor targeting the FKN–CX3CR1 interaction, is modestly effective with 24 weeks of treatment in RA patients, although the primary end point was not met.
Cognitive Predictors of Self‐Reported Camouflaging in Autistic Adolescents
Authors: Hull Laura , Petrides K. V. , Mandy William
Published: October 2020

Camouflaging involves masking and/or compensating for autistic characteristics and has been identified in autistic individuals through a variety of different methods. Individual variation in the extent, processes and outcomes of camouflaging has been reported in autistic adults, and there has been some investigation of camouflaging by autistic adolescents. This study was conducted to better understand how some of these individual differences emerge, by examining potential mechanisms (theory of mind, executive function, intelligence quotient and age) involved in camouflaging by 58 autistic adolescents aged 13–18 years (29 females, 29 males). Fewer executive function difficulties predicted greater use of total camouflaging strategies and the compensation subscale, but not the masking or assimilation subscales; no other predictors reached statistical significance. These findings suggest that individual differences in executive function ability may underlie variation in the use of camouflaging by adolescents. The total variance explained in the model was small, suggesting the need to examine other factors which may underpin camouflaging. The implications of this finding for the relationship between camouflaging and well‐being are discussed, along with the distinction between attempts to camouflage and the efficacy of those attempts.

Lay Summary

Camouflaging involves hiding your autism or finding ways around difficulties in order to fit in during social situations. This study found that autistic teenagers with good executive function abilities camouflage their autism more than those who struggle with executive function (which includes planning, goal‐direction and memory). This may have implications for teenagers' mental health and their social functioning.
An electrogenerated chemiluminescence aptasensor for lysozyme based on the interaction between Ru(bpy)32+ and cucurbit[8]uril
Authors: Hu LiQiao , Yin Hao , Dong YongPing , Liu JingXin , Chu XiangFeng
Published: October 2020

Strong anodic Ru(bpy)32+ electrogenerated chemiluminescence (ECL) was obtained at a cucurbil[8]uril (CB[8]) modified electrode in neutral conditions without the need of an additional coreactant. An ECL aptasensor was fabricated based on the strong ECL emission as well as the host–guest interaction between DNA and CB[8]. Firstly, amino group‐terminated complementary DNA (DNA‐NH2) was firmly immobilized on CB[8]/glass carbon electrode, which could further increase ECL intensity. Then, a ferrocene group‐terminated lysozyme aptamer (Fc‐DNA) was hybridized with complementary DNA. The inhibiting effect of ferrocene on Ru(bpy)32+ ECL resulted in the apparent decrease in ECL signal. When the modified electrode was incubated in lysozyme, specific binding between lysozyme and its aptamer could release the ferrocene group from the electrode surface, and the ECL emission was recovered. As a result, an ‘on–off–on’ mode ECL aptasensor for lysozyme was fabricated. In the range 0.14–140 pg ml−1, the increased ECL intensities exhibited excellent linearity with the logarithm of lysozyme concentrations, and the detection limit was calculated as 0.093 pg ml−1 (3σ). The proposed ECL aptasensor exhibited satisfactory analytical performance, revealing the potential application of CB[n]s in an ECL sensing field.
Analytical method development and determination of hydrocortisone acetate and fusidic acid simultaneously in cream formulation, by reversed‐phase HPLC
Authors: Rasool Nawaz , Kanwal Qudsia , Waseem Muhammad , Mehrunnisa  , Khan Muhammad Irfan
Published: October 2020

In this study, an accurate, simple, economical, precise and reproducible reversed‐phase HPLC method was developed for the estimation of fusidic acid and hydrocortisone acetate, according to the International Conference on Harmonization guidelines, in a cream formulation. Chromatographic separation was achieved by isocratic elution, on a Shimadzu reversed‐phased high‐pressure liquid chromatography instrument, equipped with a C18 column (150 × 4.6 mm, 5 μm) and UV detector at 225 nm wavelength, using acetonitrile and 0.05% trifluoroacetic acid (60:40), as a mobile phase and diluent, at flow rate 2 ml/min and an injection volume of 20 μl. The calibration curves were acquired with concentration range 80–120% and mean percentage recoveries for hydrocortisone acetate and fusidic acid were 100.14 and 100.81%, respectively. The limits of detection was obtained as 6.0667 and 6.807 μm ml−1 and the limits of quantification were 20.204 and 20.628 μm ml−1 for hydrocortisone acetate and fusidic acid, respectively. All of the validation parameters were within the acceptance criteria, as per International Conference on Harmonization requirements, for hydrocortisone acetate and fusidic acid. This method was found to be validated, simple, rapid and applicable for the simultaneous estimation of hydrocortisone acetate and fusidic acid by reversed‐phased high‐pressure liquid chromatography, for routine analytical testing in quality control, with a run time of 8 min.
Digital proportional‐derivative controller implemented in low‐resource microcontrollers
Authors: Jiménez‐Ramírez Omar , Cárdenas‐Valderrama José A. , Ordoñez‐Sánchez Alejandro A. , Quiroz‐Juárez Mario A. , Vázquez‐Medina Rubén
Published: October 2020

The use of software and microcontrollers helps engineering students to gain a better understanding of the different concepts and algorithms of digital control theory, which they can apply in their professional work in industrial environments. Typically, these digital control concepts and algorithms are implemented in high‐resources microcontrollers; nevertheless, we show that they can also be implemented in low‐resource devices, helping students to acquire fundamental knowledge and develop long‐term skills to solve real problems from the learning they achieve in their undergraduate educational programs in control or computer engineering. For this purpose, we provide an algorithm to synthesize a digital proportional‐derivative controller oriented to low‐resource microcontrollers (microcontrollers without floating‐point unit). This algorithm allows implementing solutions for classic controllers in low‐resource microcontrollers applied to academic and technological fields. This algorithm reduces the excessive amount of execution time in a low‐resource microcontroller, it works with integer numbers and it is designed to implement fast classical controllers, which typically are performed with floating‐point operations. Furthermore, we present a brief description of the implemented electronic circuit, serving as a guide for students to develop their own circuits. The experimental results show that the proposed algorithm can be successfully applied to an electromagnetic levitation system, which is commonly used in the academic training of electronics and control engineers, mainly due to its unstable nature. In this case, although the levitation system has a small time constant, the proposed algorithm appropriately leads the system to a stable regime.
Eco‐Friendly Methodology for the Formation of Aromatic Carbon–Heteroatom Bonds by Using Green Ionic Liquids
Authors: Richards Kenza , Petit Eddy , Legrand Yves‐Marie , Grison Claude
Published: October 2020

A new sustainable method is reported for the formation of aromatic carbon–heteroatom bonds under solvent‐free and mild conditions (no co‐oxidant, no strong acid and no toxic reagents) by using a new type of green ionic liquid. The bromination of methoxy arenes was chosen as a model reaction. The reaction methodology is based on only using natural sodium bromine, which is transformed into an electrophilic brominating reagent within an ionic liquid, easily prepared from the melted salt FeCl3 hexahydrate. Bromination reactions with this in‐situ‐generated reagent gave good yields and excellent regioselectivity under simple and environmentally friendly conditions. To understand the unusual bromine polarity reversal of sodium bromine without any strong oxidant, the molecular structure of the reaction medium was characterised by Raman and direct infusion electrospray ionisation mass spectroscopy (ESI‐MS). An extensive computational investigation using density functional theory methods was performed to describe a mechanism that suggests indirect oxidation of Br− through new iron adducts. The versatility of the methodology was successively applied to nitration and thiocyanation of methoxy arenes using KNO3 and KSCN in melted hexahydrated FeCl3.
The Tri(imidazole)‐Derivative Moiety: A New Category of Electron Acceptors for the Design of Crystalline Hybrid Photochromic Materials
Authors: Jiang Xiao‐Fan , Han Song‐De , Wang A‐Ni , Pan Jie , Wang Guo‐Ming
Published: October 2020

The intermarriage of neutral and tripodal imidazole ligand, tris(4‐(1H‐imidazol‐1‐yl)phenyl)amine (TIPA), with zinc phosphite yields two hybrid phosphites, [Zn2(HPO3)2(TIPA)]⋅2 H2O (1) and [Zn3(HPO3)3(TIPA)]⋅6 H2O (2). Compound 1 has a hybrid sheet with neutral zinc‐phosphite chains as supramolecular building blocks (SBBs), whereas 2 exhibits a 3D hybrid architecture with other neutral zincophosphite chains as supramolecular building blocks. The structural discrepancy between 1 and 2 is mainly due to the distinct linkage modes between organic TIPA ligands and inorganic zincophosphite chains. Interestingly, compounds 1 and 2 feature fast photochromism in response to UV light irradiation under ambient conditions. The discrepancy of photochromic performance between 1 and 2 is mainly due to the different geometrical configuration of the TIPA ligand. Different to majority of reported hybrid photochromic compounds driven by photochromic active units, the photochromism in 1 and 2 is derived from the electron transfer (ET) between phosphite and non‐photochromic triimidazole‐derivative ligand TIPA. Compared with the widely explored nonphotochromic polypyridine‐derivative as electron acceptors (EAs), our work provides a new EA model for the design of hybrid photochromic materials based on the ligand‐to‐ligand ET mechanism. A multiple anti‐counterfeiting application based on 1 and 2 was investigated.
A Comprehensive Overview of Structure‐Activity Relationships of Small‐Molecule Splicing Modulators Targeting SF3B1 as Anticancer Agents
Authors: Zhang Datong , Meng Fancui
Published: October 2020

The pre‐mRNA splicing factor SF3B1 shows recurrent mutations among hematologic malignancies and some solid tumors. In 2007, the identification of two cytotoxic natural products, which showed splicing inhibition by binding to SF3b, prompted the development of small‐molecule splicing modulators of SF3B1 as therapeutics for cancer. Recent studies suggested that spliceosome‐mutant cells are preferentially sensitive to pharmacologic splicing modulation; therefore, exploring the clinical utility of splicing modulator therapies in patients with spliceosome‐mutant hematologic malignancies who have failed current therapies is greatly needed, as these patients have few treatment options. H3B‐8800 had unique pharmacological activity and exhibited favorable data in phase I clinical trials to treat patients with advanced myeloid malignancies, indicating that further clinical trials are promising. The most established small‐molecule modulators of SF3B1 can be categorized into three classes: the bicycles, the monopyranes, and the 12‐membered macrolides. This review provides a comprehensive overview of the structure‐activity relationships of small‐molecule SF3B1 modulators, with a detailed analysis of interactions between modulators and protein binding pocket. The future strategy for splicing modulators development is also discussed.
Sex‐specific behavioral and neurogenic responses to cocaine in mice lacking and blocking dopamine D1 or dopamine D2 receptors
Authors: Rivera Patricia , Aranda Jesús , Alén Francisco , Vargas Antonio , Serrano Antonia , Pavón Francisco Javier , Orio Laura , Rubio Leticia , Moratalla Rosario , de Fonseca Fernando Rodríguez , Suárez Juan
Published: October 2020

Adult neurogenesis in rodents is modulated by dopaminergic signaling and inhibited by cocaine. However, the sex‐specific role of dopamine D1 and D2 receptors (D1R, D2R) in the deleterious effect of cocaine on adult neurogenesis has not been described yet. Here, we explored sex differences in (a) cell proliferation (5′‐bromo‐2′‐deoxyuridine [BrdU]), (b) neural precursor (nestin), (c) neuronal phenotype (BrdU/β3‐tubulin), and (d) neuronal maturity (NeuN) in the subventricular zone (SVZ) of the lateral ventricles and striatum of mice with genetic deletion (D1−/−, D2−/−) or pharmacological blockage (SCH23390: 0.1 mg/kg/day/5 days; Raclopride: 0.3 mg/kg/day/5 days) of D1R and D2R, and treated (10 mg/kg/day/5 days) and then challenged (5 mg/kg, 48 hr later) with cocaine. Results indicated that hyperactivity responses to cocaine were absent in D1−/− mice and reduced in SCH23390‐treated mice. Activity responses to cocaine were reduced in D2−/− males, but absent in D2−/− females and increased in Raclopride‐treated females. D1R deletion blocked the deleterious effect of cocaine on SVZ cell proliferation in males. Cocaine‐exposed D1−/− males also had reduced neuronal phenotype of SVZ newborn cells and increased striatal neuronal maturity. D2−/− mice had lower proliferative and neural precursor responses. Cocaine in D2−/− females or coadministered with Raclopride in wild‐type females improved SVZ cell proliferation, an effect that positively correlated with plasma brain‐derived neurotrophic factor (BDNF) concentrations. In conclusion, the sex‐specific D1R and D2R signaling on SVZ cell proliferation, neural progenitor and neuronal maturity is differentially perturbed by cocaine, and BDNF may be required to link D2R to neuroplasticity in cocaine addiction in females.
Optimal structural pattern for maximal compliance using topology optimization based on phasefields: Application to improve skin graft meshing efficiency
Authors: Sutula Danas , Henyš Petr , Čapek Lukáš
Published: October 2020

This article focuses on the problem of maximal compliance design of a hyper‐elastic solid with the optimal design of human skin grafts as the application in mind. The solution method is a phasefield‐based topology optimization method that supposes multiple local phasefields and a minimum distance constraint in order to prevent the phasefields from merging. Consequently, structurally disintegrating solutions such as by the coalescence of voids can be prevented. The method is used to find an optimal graft meshing pattern for a sample that is subjected to a biaxial extension of up to 150%, which corresponds to an expansion ratio of 1 : 2.25. Three prospective unitcell solutions that exhibit meta‐material behavior are proposed for a periodic graft pattern. The results are a step toward improving the skin graft meshing efficiency. This work does not cover experimental validation.
Model‐Based Quantification of Impact of Genetic Polymorphisms and Co‐Medications on Pharmacokinetics of Tamoxifen and Six Metabolites in Breast Cancer
Authors: Puszkiel Alicja , Arellano Cécile , Vachoux Christelle , Evrard Alexandre , Le Morvan Valérie , Boyer Jean‐Christophe , Robert Jacques , Delmas Caroline , Dalenc Florence , Debled Marc , Venat‐Bouvet Laurence , Jacot William , Dohollou Nadine , Bernard‐Marty Chantal , Laharie‐Mineur Hortense , Filleron Thomas , Roché Henri , Chatelut Etienne , Thomas Fabienne , White‐Koning Melanie
Published: October 2020

Variations in clinical response to tamoxifen (TAM) may be related to polymorphic cytochromes P450 (CYPs) involved in forming its active metabolite endoxifen (ENDO). We developed a population pharmacokinetic (PopPK) model for tamoxifen and six metabolites to determine clinically relevant factors of ENDO exposure. Concentration‐time data for TAM and 6 metabolites come from a prospective, multicenter, 3‐year follow‐up study of adjuvant TAM (20 mg/day) in patients with breast cancer, with plasma samples drawn every 6 months, and genotypes for 63 genetic polymorphisms (PHACS study, NCT01127295). Concentration data for TAM and 6 metabolites from 928 patients (n = 27,433 concentrations) were analyzed simultaneously with a 7‐compartment PopPK model. CYP2D6 phenotype (poor metabolizer (PM), intermediate metabolizer (IM), normal metabolizer (NM), and ultra‐rapid metabolizer (UM)), CYP3A4*22, CYP2C19*2, and CYP2B6*6 genotypes, concomitant CYP2D6 inhibitors, age, and body weight had a significant impact on TAM metabolism. Formation of ENDO from N‐desmethyltamoxifen was decreased by 84% (relative standard error (RSE) = 14%) in PM patients and by 47% (RSE = 9%) in IM patients and increased in UM patients by 27% (RSE = 12%) compared with NM patients. Dose‐adjustment simulations support an increase from 20 mg/day to 40 and 80 mg/day in IM patients and PM patients, respectively, to reach ENDO levels similar to those in NM patients. However, when considering Antiestrogenic Activity Score (AAS), a dose increase to 60 mg/day in PM patients seems sufficient. This PopPK model can be used as a tool to predict ENDO levels or AAS according to the patient’s CYP2D6 phenotype for TAM dose adaptation.