bluuebunny/crossref_metadata_2025 huggingface dataset:
Rh‐Catalyzed Direct Carboxylation of Alkenyl C−H Bonds of Alkenylpyrazoles
Authors: Saitou Takanobu , Jin Yushu , Isobe Kotaro , Suga Takuya , Takaya Jun , Iwasawa Nobuharu
Published: May 2020

The Rh‐catalyzed direct carboxylation of alkenyl C−H bonds was achieved by using pyrazole as a removable directing group. In the presence of 5 mol% RhCl3 ⋅ 3H2O, 6 mol% P(Mes)3, and 2 equiv. of AlMe2(OMe), the alkenyl C−H bond of various alkenylpyrazoles was directly carboxylated in good yields under CO2 atmosphere. Furthermore, several useful transformations of the pyrazole moiety of the product were achieved to afford synthetically useful carboxylic acid derivatives in good yields.
Synthesis of substituted 2H‐chromenes catalyzed by lipase immobilized on magnetic multiwalled carbon nanotubes
Authors: Liu Jiaxu , Zhao Wenxin , Zhang Liu , Zhang Min , Chen Yanqiang , Xu You , Li Yinghua , Wang Lei
Published: May 2020

Porcine pancreas lipase (PPL) was immobilized on magnetic multiwalled carbon nanotubes successfully for the synthesis of substituted 2H‐chromenes. The catalytic activity of immobilized PPL was much higher than that of free PPL. Effects of reaction medium, temperature, and enzyme dosage were also investigated. Under optimum reaction conditions (acetylacetone (1 mmol), salicylaldehyde (1 equivalent), methanol (10 equivalent), and immobilized PPL (protein content: 30 mg; 65 °C; DMF 5 mL; 5 H), the immobilized PPL showed an excellent catalytic performance on the synthesis of substituted 2H‐chromenes. Moreover, the immobilized PPL exhibited satisfactory thermostability, operational simplicity, and reusability in this reaction.
Male‐to‐female ratios among NTDs and women's periconceptional intake of folic acid
Authors: Shaw Gary M. , Yang Wei , Finnell Richard H.
Published: May 2020

Background

About a decade ago, a hypothesis was put forward to explain the preponderance of females among neural tube defect (NTD) fetuses. That hypothesis predicts that a woman's higher levels of early gestational intake of methyl groups, such as folic acid, will be associated with lesser male‐to‐female ratio differences in NTD‐affected births, specifically less preponderance of females. We explored this hypothesis in four distinct studies that investigated human NTDs, obtained information on folic acid, and capitalized on timing of folic acid fortification by investigating data that were collected both prior to and after the 1998 initiation of U.S. mandatory folic acid fortification of grains.

Methods

We analyzed data from four population‐based case control studies conducted in California for birth years spanning 1987–2011. Two studies were conducted before folic acid fortification of the U.S. food supply. Each of the four studies included interviews of women who either had NTD‐affected pregnancies (cases) or who did not have a pregnancy affected by a birth defect (controls). In each study, information on periconceptional supplement use was elicited. We explored male‐to‐female ratios and 95% binomial confidence limits in each data set.

Results

Our analyses of two case–control studies performed prior to and two performed post mandatory folate fortification in the United States showed that more NTD‐affected fetuses were female in the first two studies. In the studies done before fortification, the frequency of females was even greater among those pregnancies without folic acid supplementation.

Conclusion

Our findings suggest folic acid may differentially reduce risk of NTDs among female fetuses.
Perspectives on challenges and opportunities for birth defects surveillance programs during and after the COVID‐19 era
Authors: Ludorf Katherine L. , Salemi Jason L. , Kirby Russell S. , Tanner Jean Paul , Agopian A. J.
Published: May 2020

In recent months, various public health measures have been implemented throughout the world in response to the coronavirus disease 2019 (COVID‐19) pandemic. This outbreak, and the subsequent containment policies, may have a range of potential short‐ and long‐term impacts on the monitoring and surveillance of other conditions, such as birth defects. In this commentary, we provide a perspective on these potential impacts on birth defects surveillance and analysis. We discuss possible effects on clinical birth defect diagnoses, routine birth defects surveillance system activities, and epidemiologic considerations, as well as opportunities for mitigating the impact of COVID‐19. Like many other sectors of public health and medicine, birth defects surveillance programs may be faced with organizational and methodological obstacles in the wake of a changing landscape. A better understanding of these potential challenges faced by birth defects surveillance programs could facilitate better planning and collaboration across programs to overcome barriers to core activities and to prepare for novel opportunities for research and prevention.
The experience of school in Scotland, 1970s to 1990s
Authors: Paterson Lindsay
Published: May 2020

Reforms to secondary schooling in the 20th century are most commonly discussed in relation to structures—the extension of secondary education to all students in the first half of the century, and the ending of selection into different kinds of school after the 1960s. Yet reformers also sought to give students a more satisfactory experience of school. Understanding statistically the changing experience which students had of secondary school following the reforms of the 1960s requires a lengthy time series of survey data collected contemporaneously and the capacity to link that information to evidence on attainment and on demographic factors such as sex and socio‐economic status. Data from a unique series of such surveys in Scotland is used to investigate whether secondary schools became more humane in this period, whether students were more engaged with their schooling, and whether they thought that schools prepared them for life after they left. The conclusions are that the long‐term aspirations of reformers to make schooling more satisfactory for students were broadly achieved. There were indeed improvements of experience and sentiment of these kinds, and they extended to students at all levels of attainment, to both sexes, and to all levels of socio‐economic status.
Tiering in the GCSE: A children’s rights perspective
Authors: Barrance Rhian
Published: May 2020

This article presents findings on students’ views and experiences of tiering in Northern Ireland and Wales from a children’s rights perspective. It considers the extent to which tiering fulfils the rights to education, best interests, non‐discrimination, and participation under the Convention on the Rights of the Child. It emphasises that while the majority of students were supportive of tiering, their responses highlighted a range of negative effects of tiering on students taking foundation tier. Students described the impact of being placed in the foundation tier on their self‐esteem and relationship with their peers, indicating that being allocated to foundation tier can have a labelling effect. Students who were taking foundation papers, or a mixture of foundation and higher‐tier papers, were more likely than those taking higher‐tier papers to report that they wanted to change tier and to raise issues overall regarding tiering. Furthermore, students who were faced with these difficult choices often had a poor understanding of several aspects of tiers. The article argues that alternative forms of differentiation should be considered, and presents students’ perspectives on some of these. It argues that we must ensure that young people have a good understanding of tiering and that their views and experiences of tiering are taken into account when considering further reforms to GCSEs.
Alterations of white matter integrity associated with cognitive deficits in patients with glioma
Authors: Liu Dongming , Liu Yong , Hu Xinhua , Hu Guanjie , Yang Kun , Xiao Chaoyong , Hu Jun , Li Zonghong , Zou Yuanjie , Chen Jiu , Liu Hongyi
Published: May 2020

Objective

This study aimed to investigate the characteristic of brain structural connections in glioma patients and further evaluate the relationship between changes in the white matter tracts and cognitive decline.

Methods

This retrospective study included a total of 35 subjects with glioma and 14 demographically matched healthy controls, who underwent diffusion tensor imaging scans and formal neuropsychological assessment tests. Fractional anisotropy (FA) values of white matter tracts were derived from atlas‐based analysis to compare group differences. Furthermore, subgroup‐level analysis was performed to differentiate the effects of tumor location on white matter tracts. Partial correlation analysis was used to examine the associations between neurocognitive assessments and the integrity of tracts. Region of interest‐based network analysis was performed to validate the alteration of structural brain network in subjects with glioma.

Results

Compared with controls, subjects with glioma exhibited reduced FA values in the right uncinate fasciculus. Besides, subjects with glioma exhibited worse performance in several cognitive assessments. Partial correlation analysis indicated that the FA value in the right superior longitudinal fasciculus temporal part was significantly positively correlated with scores of visual–spatial abilities in subjects with glioma in the right temporal lobe (r = .932, p = .002). Region of interest‐based network analysis revealed that subjects with glioma exhibited reduced FA, fiber length (FL), and fiber number (FN) between specific brain regions compared with controls.

Conclusion

The present study demonstrated the reduced integrity of white matter tracts and altered structural connectivity in brain networks in patients with glioma. Notably, white matter tracts in the right hemisphere might be vulnerable to the effects of a frontal or temporal lesion and might be associated with deficient cognitive function.
Reduction of medium consumption in perfusion mammalian cell cultures using a perfusion rate equivalent concentrated nutrient feed
Authors: Bielser Jean‐Marc , Kraus Leon , Burgos‐Morales Orlando , Broly Hervé , Souquet Jonathan
Published: May 2020

Media preparation for perfusion cell culture processes contributes significantly to operational costs and the footprint of continuous operations for therapeutic protein manufacturing. In this study, definitions are given for the use of a perfusion equivalent nutrient feed stream which, when used in combination with basal perfusion medium, supplements the culture with targeted compounds and increases the medium depth. Definitions to compare medium and feed depth are given in this article. Using a concentrated nutrient feed, a 1.8‐fold medium consumption (MC) decrease and a 1.67‐fold increase in volumetric productivity (PR) were achieved compared to the initial condition. Later, this strategy was used to push cell densities above 100 × 106 cells/ml while using a perfusion rate below 2 RV/day. In this example, MC was also decreased 1.8‐fold compared to the initial condition, but due to the higher cell density, PR was increased 3.1‐fold and to an average PR value of 1.36 g L−1 day−1 during a short stable phase, and versus 0.46 g L−1 day−1 in the initial condition. Overall, the performance improvements were aligned with the given definitions. This multiple feeding strategy can be applied to gain some flexibility during process development and also in a manufacturing set‐up to enable better control on nutrient addition.
Neoadjuvant‐modified FOLFIRINOX vs nab‐paclitaxel plus gemcitabine for borderline resectable or locally advanced pancreatic cancer patients who achieved surgical resection
Authors: Wolfe Adam R. , Prabhakar Dhivya , Yildiz Vedat O. , Cloyd Jordan M. , Dillhoff Mary , Abushahin Laith , Alexandra Diaz Dayssy , Miller Eric D. , Chen Wei , Frankel Wendy L. , Noonan Anne , Williams Terence M.
Published: May 2020

We conducted an institutional study to compare the clinical and pathological efficacy between the neoadjuvant therapy (NAT)‐modified FOLFIRINOX (mFOLF) vs nanoparticle albumin–bound paclitaxel plus gemcitabine (nab‐P/G) for borderline resectable pancreatic cancer (BRPC) and locally advanced pancreatic cancer (LAPC) patients who completed resection. The study retrospectively enrolled patients with pathologically confirmed BRPC or LAPC from 2010 to 2018 at our institution. The survival rates were determined by the Kaplan‐Meier method and log‐rank test was used to test differences. Cox's proportional hazard model was used to assess survival with respect to covariates. Seventy‐two patients who completed at least two cycles of neoadjuvant chemotherapy and surgical resection were included, with 52 (72.2%) patients receiving mFOLF and 20 (27.8%) receiving nab‐P/G. Patients treated with mFOLF had statistically higher rates of RECIST 1.1 partial or complete response (16/52 vs 1/20, P = .028). Additionally, mFOLF patients had greater pathological tumor size reduction, fewer positive lymph nodes, and higher treatment response grade compared to the nab‐P/G patients (all P < .05). The median overall survival was 33.3 months vs 27.1 months (P = .105), and distant metastasis‒free survival (DMFS) was 21.3 months vs 14.6 months (P = .042) in the mFOLF vs nab‐P/G groups, respectively. On multivariate analysis, mFOLF (hazard ratio, 0.428; 95% confidence interval [CI], 0.186‐0.987) and abnormal postoperative CA 19‐9 (hazard ratio, 2.47; 95% CI, 1.06‐5.76) were associated with DMFS. Among patients with BRPC and LAPC who complete surgical resection, neoadjuvant mFOLF was associated with improved pathological and clinical outcomes compared with nab‐P/G.
Duration of nivolumab for pretreated, advanced non–small‐cell lung cancer
Authors: Geier Margaux , Descourt Renaud , Corre Romain , Léveiller Guillaume , Lamy Régine , Goarant Éric , Bizec Jean‐Louis , Bernier Cyril , Quéré Gilles , Amrane Karim , Gaye Elisabeth , Lucia François , Burte Emilie , Chouaid Christos , Robinet Gilles
Published: May 2020

Background

A standard of care for pretreated, advanced non–small‐cell lung cancers (NSCLCs), nivolumab has demonstrated long‐term benefit when administered for 2 years. We aimed to better discern an optimized administration duration by retrospectively analyzing real‐life long‐term efficacy in a prospective cohort.

Methods

All nivolumab‐treated adults with advanced NSCLCs (01/09/2015 to 30/09/2016) from nine French centers were eligible. On 31/12/2018, patients who are alive ≥ 2 years after starting nivolumab were defined as long‐term survivors (LTSs) and were divided into three nivolumab treatment groups: <2, 2, or > 2 years. Co‐primary endpoints were LTSs’ progression‐free survival (PFS) and overall survival (OS).

Results

The median follow‐up was 32 months (95% CI, 31.0 to 34.0). The 3‐year OS rate for the 259 cohort patients was 16.6%. Among them, 65 were LTSs: 47 treated < 2 years, 7 for 2 years, and 11 > 2 years. Their respective characteristics were: median age: 59, 52, and 58 years; smoking history: 92.9, 100, and 100%; adenocarcinomas: 66, 57.1, and 54.5%. LTSs’ median (m)PFS was 28.4 months; mOS was not reached. LTSs’ objective response rate was 61.6%. mOS was 32.7 months for those treated < 2 years and not reached for the others. The > 2‐year group's 3‐year OS was longer. Twenty‐eight LTSs experienced no disease progression; 7 had durable complete responses. However, LTSs had more frequent and more severe adverse events.

Conclusion

In real‐life, prolonged nivolumab use provided long‐term benefit with 16.6% 3‐year OS and 25% LTSs. Survival tended to be prolonged with nivolumab continued beyond 2 years. Prospective randomized trials with adequate design are needed.
Lipophilic Metabolites from Five‐Needle Pines, Pinus armandii and Pinus kwangtungensis, Exhibiting Antibacterial Activity
Authors: Shpatov Alexander V. , Frolova Tatyana S. , Popov Sergey A. , Sinitsyna Olga I. , Salnikova Olga I. , Zheng Guangyao , Yan Linlin , Sinelnikova Nadezhda V. , Pshennikova Lyudmila M. , Kochetov Alexey V.
Published: May 2020

Lipophilic extractive metabolites from needles and defoliated twigs of Pinus armandii and P. kwangtungensis were studied by GC/MS. Needles of P. armandii contained predominantly 15‐O‐functionalized labdane type acids (anticopalic acid), fatty acids, nonacosan‐10‐ol, sterols, nonacosan‐10‐ol and sterol saponifiable esters, and acylglycerols, while P. kwangtungensis needles contained no anticopalic acid, but more trinorlabdane (14,15,16‐trinor‐8(17)‐labdene‐13,19‐dioic acid) and other labdane type acids, nonacosan‐10‐ol and its saponifiable esters. The major compounds in the P. armandii defoliated twig extract were abietane and isopimarane type acids, fatty acids, sterols, labdanoids (cis‐abienol), cembranoids (isocembrol and 4‐epi‐isocembrol), saponifiable sterol esters, and acylglycerols. The same extract of P. kwangtungensis contained larger quantities of fatty acids, caryophyllene oxide, serratanoids, sterols, saponifiable sterol esters, and acylglycerols, but lesser amounts of abietane and isopimarane type acids, cis‐abienol, and lacked cembranoids. Both twig and needle extracts of P. armandii and P. kwangtungensis, as well as the extracts’ fractions, significantly inhibited the growth of Gram‐negative bacteria Serratia marcescens with MIC of 0.1 mg ml−1, while in most cases they slightly stimulated the growth of Gram‐positive bacteria Bacillus subtilis at the same concentrations. Thus, lipophilic extractive compounds from the needles and defoliated twigs of both pines are prospective for the development of antiseptics against Gram‐negative bacteria.
Reversal of Regioselectivity in Zinc‐Dependent Medium‐Chain Alcohol Dehydrogenase from Rhodococcus erythropolis toward Octanone Derivatives
Authors: Dhoke Gaurao V. , Ensari Yunus , Hacibaloglu Dinc Yasat , Gärtner Anna , Ruff Anna Joëlle , Bocola Marco , Davari Mehdi D.
Published: May 2020

The zinc‐dependent medium‐chain alcohol dehydrogenase from Rhodococcus erythropolis (ReADH) is one of the most versatile biocatalysts for the stereoselective reduction of ketones to chiral alcohols. Despite its known broad substrate scope, ReADH only accepts carbonyl substrates with either a methyl or an ethyl group adjacent to the carbonyl moiety; this limits its use in the synthesis of the chiral alcohols that serve as a building blocks for pharmaceuticals. Protein engineering to expand the substrate scope of ReADH toward bulky substitutions next to carbonyl group (ethyl 2‐oxo‐4‐phenylbutyrate) opens up new routes in the synthesis of ethyl‐2‐hydroxy‐4‐phenylbutanoate, an important intermediate for anti‐hypertension drugs like enalaprilat and lisinopril. We have performed computer‐aided engineering of ReADH toward ethyl 2‐oxo‐4‐phenylbutyrate and octanone derivatives. W296, which is located in the small binding pocket of ReADH, sterically restricts the access of ethyl 2‐oxo‐4‐phenylbutyrate, octan‐3‐one or octan‐4‐one toward the catalytic zinc ion and thereby limits ReADH activity. Computational analysis was used to identify position W296 and site‐saturation mutagenesis (SSM) yielded an improved variant W296A with a 3.6‐fold improved activity toward ethyl 2‐oxo‐4‐phenylbutyrate when compared to WT ReADH (ReADH W296A: 17.10 U/mg and ReADH WT: 4.7 U/mg). In addition, the regioselectivity of ReADH W296A is shifted toward octanone substrates. ReADH W296A has a more than 16‐fold increased activity toward octan‐4‐one (ReADH W296A: 0.97 U/mg and ReADH WT: 0.06 U/mg) and a more than 30‐fold decreased activity toward octan‐2‐one (ReADH W296A: 0.23 U/mg and ReADH WT: 7.69 U/mg). Computational and experimental results revealed the role of position W296 in controlling the substrate scope and regiopreference of ReADH for a variety of carbonyl substrates.
A Biocatalytic Cascade Reaction to Access a Valuable Long‐Chain ω‐Hydroxy Fatty Acid
Authors: Becker Aileen , Böttcher Dominique , Katzer Werner , Siems Karsten , Müller‐Kuhrt Lutz , Bornscheuer Uwe T.
Published: May 2020

Environmentally‐friendly processes for the manufacturing of valuable industrial compounds like ω‐hydroxy fatty acids (ω‐OHFAs) are highly desirable. Herein, we present such an approach by establishing a two‐step enzymatic cascade reaction for the production of 2,15,16‐trihydroxy hexadecanoic acid (THA). Starting with the easily accessible natural compound ustilagic acid (UA) that is secreted by the corn smut fungus Ustilago maydis, the recombinantly expressed esterase BS2 from Bacillus subtilis and the commercial β‐glucosidase from almonds were applied yielding 86 % product. Both hydrolases do not require expensive cofactors, making the process economically attractive. Additionally, no harmful solvents are required, so that the product THA can be labelled natural to be used in food and cosmetic products.
Scalable In Situ Reactive Assembly of Polypyrrole‐Coated MnO2 Nanowire and Carbon Nanotube Composite as Freestanding Cathodes for High Performance Aqueous Zn‐Ion Batteries
Authors: Zhang Yong , Xu Guobao , Liu Xiong , Wei Xiaolin , Cao Juexian , Yang Liwen
Published: May 2020

Flexible aqueous zinc‐ion batteries are attracting increasing interest owing to high theoretical capacity, low cost and high safety, however, it is highly challenging to design and fabricate suitable cathodes with superior Zn2+ storage as well as high flexibility. Herein, a free‐standing flexible film composed of carbon nanotubes and polypyrrole (PPy)‐coated MnO2 nanowires is prepared via a facile in situ reactive self‐assembly and following vacuum filtration. The unique hierarchically porous 3D architecture of uniformly dispersed MnO2 nanowires with PPy coating in highly electrically conductive and interconnected CNTs networks not only improve the reaction kinetics and structural stability of the electrodes during repeated cycling, but also provides abundant sites for Zn2+ and H+ adsorption, giving rise to additional pseudocapacitive charge storage. When the free‐standing flexible film is used as a freestanding cathode for an aqueous zinc ion battery, the electrode shows a good storage capacity of H+ and Zn2+ ions and a superior durability with a good capacity retention rate of 87.4 % after 1000 times at 1 A/g. And the energy density of the flexible device is about 341.6 Wh/kg (based on the mass of MnO2).The results provide a feasible strategy of constructing high‐performance cathodes for flexible aqueous zinc‐ion batteries.
False discovery rates, power and related concepts
Authors: Brereton Richard G.
Published: May 2020

Following on from the definitions of Null and Alternative hypothesis, and number of definitions are described including the concept of False Discovery Rates, Power, Sensitivity, Selectivity and Likelihood Ratios, among others.
Direct growth of ordered N‐doped carbon nanotube arrays on carbon fiber cloth as a free‐standing and binder‐free air electrode for flexible quasi‐solid‐state rechargeable Zn‐Air batteries
Authors: Lu Qian , Zou Xiaohong , Liao Kaiming , Ran Ran , Zhou Wei , Ni Meng , Shao Zongping
Published: May 2020

The development of an air electrode that is flexible in physical property and highly active and durable at different geometric status for both oxygen reduction reaction (ORR) and oxygen evolution reaction (OER) is of crucial importance for the rational design of flexible rechargeable Zn‐air batteries (ZABs). Considering their good elasticity, high conductivity, and superior thermal and chemical stability, carbon nanotubes have been widely used as a catalyst support in various electrocatalysts, while oxide or metal nanoparticles have been frequently deposited on the carbon nanotube substrate to perform as the active materials. Considering the poor contact between active materials and carbon nanotubes may introduce a challenge for long‐term operating stability, in particular in flexible devices, pure carbon electrocatalyst is highly appreciated. Herein, a free‐standing air electrode with cobalt nanoparticles encapsulated N‐codoped carbon nanotube arrays uniformly grown on the surface of carbon fiber cloth is developed by a two‐step in situ growth method. Such a carbon‐based electrode shows outstanding activity for both ORR and OER. The flexible ZAB with such air electrode shows superior flexibility and stability working under extreme bending conditions. Moreover, the polarization and round‐trip efficiency for the flexible battery is 0.67 V and 64.4% at 2 mA/cm2, respectively, even after being operated for 30 hours. This study provides a feasible way to design all carbon‐based free‐standing and flexible electrode and enlightens the electrode design for flexible energy conversion/storage devices.
Statistical Data Analysis in the Era of Big Data
Authors: Lengauer Thomas
Published: May 2020

Big data is on everyone's lips and often raises emotions. On the one hand, the notion is a basis for much technological optimism, mostly directed towards new business models, or simplifications and optimizations in professional and private life. On the other hand, it is a basis for dystopic perspectives, which are targeted, e.g., at profiling of the individual and their privacy space, overarching optimization in daily life and intransparency of decision making. In this article, after a short historical prolog, it is discussed what distinguishes big data from traditional data analysis. The underlying mathematical methods are introduced and scientific successes are reported. Additionally, the risks and limits – especially regarding the derivation of causal relationships – of data analysis are discussed.
Experimental methods in chemical engineering: Electron paramagnetic resonance spectroscopy‐EPR/ESR
Authors: Bakker Martin G. , Fowler Benjamin , Bowman Michael K. , Patience Gregory S.
Published: May 2020

Electron paramagnetic resonance (EPR) spectroscopy, also known as electron spin resonance spectroscopy (ESR), utilizes absorption of microwave radiation by unpaired electrons in a magnetic field. The interaction between the unpaired electron(s) and nearby magnetic nuclei helps identify paramagnetic species and can provide information about the motion of the molecule and the local polarity, pH, viscosity, concentration, and accessibility to other paramagnetic species. This mini‐review discusses the fundamental underpinnings of EPR needed to correctly interpret EPR spectra. We describe various types of EPR spectra encountered by chemical engineers, and use application examples drawn from the chemical engineering literature to illustrate the information available from the technique. Few chemical engineering departments or even chemistry departments have EPR instruments, which contributes to the significant barrier that prevents this being adopted as a routine measurement technique. However, in 2016 and 2017, Web of Science indexed 7000 articles that applied EPR spectroscopy. A bibliometric map categorized the keywords in four categories based on co‐occurrences: magnetic properties, films, and luminescence; crystal structure, complexes, and ligands; nanoparticles, oxidation, and degradation; and, systems, radicals, and H2O2.
Hemovasculogenic origin of blood vessels in the developing mouse brain
Authors: Gama Sosa Miguel A. , De Gasperi Rita , Perez Gissel M. , Hof Patrick R. , Elder Gregory A.
Published: May 2020

Vascular structures in the developing brain are thought to form via angiogenesis from preformed blood vessels in the cephalic mesenchyme. Immunohistochemical studies of developing mouse brain from E10.5 to E13.5 revealed the presence of avascular blood islands of primitive erythroid cells expressing hemangioblast markers (Flk1, Tal1/Scl1, platelet endothelial cell adhesion molecule 1, vascular endothelial‐cadherin, and CD34) and an endothelial marker recognized by Griffonia simplicifolia isolectin B4 (IB4) in the cephalic mesenchyme. These cells formed a perineural vascular plexus from which angiogenic sprouts originated and penetrated the neuroepithelium. In addition, avascular isolated cells expressing primitive erythroid, hemangioblast and endothelial makers were visible in the neuroepithelium where they generated vasculogenic and hemogenic foci. From E10.5 to E13.5, these vasculogenic foci were a source of new blood vessel formation in the developing brain. In vitro, cultured E13.5 brain endothelial cells contained hemogenic endothelial cells capable of generating erythroid cells. Similar cells were present in primary cultures of dissociated cells from E10.5 embryonic head. Our results provide new evidence that the brain vasculature, like that of the yolk sac and the eye choriocapillaris and hyaloid vascular systems, develops at least in part via hemovasculogenesis, a process in which vasculogenesis and hematopoiesis occur simultaneously.
Pharmacokinetics and Bioequivalence of 2 Olanzapine Orally Disintegrating Tablet Products in Healthy Chinese Subjects Under Fed and Fasting Conditions
Authors: Fan Lin , Zhang Lizhi , Zheng Hongquan , Cheng Junlin , Hu Yunfang , Liu Jianghui , Fan Hongwei
Published: May 2020

To assess the bioequivalence of two 5‐mg olanzapine orally disintegrating tablet (ODT) products, 2 randomized, open‐label, single‐dose, 2‐way crossover studies were carried out under fasting or fed conditions. Blood samples were collected at scheduled times according to the study protocol. Statistical analysis of area under the concentration‐time curve from time 0 to 168 hours (AUC0‐t), area under the curve from time zero to infinity (AUC0‐∞), and peak plasma concentration (Cmax) was conducted. Two formulations were considered bioequivalent if the 90% confidence intervals (CIs) of the geometric mean ratios for AUC0‐t, AUC0‐∞, and Cmax were within the range of 0.80‐1.25. Adverse events were recorded and evaluated throughout the studies. A total of 48 subjects with 24 in each study completed the 2 studies. In fasted subjects, the 90%CIs for the test product versus the reference product were 97.28%‐105.13% for AUC0‐t, 97.57%‐105.54% for AUC0‐∞, and 90.94%‐103.97% for Cmax. In fed subjects, the 90%CIs for AUC0‐t, AUC0‐∞ and Cmax were 99.73%‐122.63%, 99.56%‐121.75%, and 99.46%‐120.46%, respectively. No serious adverse events were reported in the studies. The reference and the test product of 5‐mg olanzapine ODT show comparable pharmacokinetic profiles under both fed and fasted conditions and were considered bioequivalent.
Effect of Opicapone Tablets on Levodopa and 3‐O‐Methyldopa Pharmacokinetics in Healthy Japanese Subjects: Phase 1 Study
Authors: Nomoto Masahiro , Takeda Atsushi , Iwai Katsuaki , Nishimura Akihisa , Hattori Nobutaka
Published: May 2020

This study evaluated the effect of a small‐tablet formulation of opicapone for use in clinical trials in Japan on the pharmacokinetics of levodopa (l‐dopa) and 3‐O‐methyldopa (3‐OMD). In an open‐label, 3‐period, single‐sequence crossover phase 1 study in 80 healthy Japanese males (aged 20‐45 years; body mass index, 18.5 to <30.0 kg/m2), 10 mg of l‐dopa/carbidopa 100 was administered 3 times daily on day 0 (period 1) and day 12 (period 3), and opicapone tablets (5, 10, 25, or 50 mg; n = 20 each group) were administered once daily for 11 days (period 2). During periods 1 and 3, plasma concentrations of l‐dopa and 3‐OMD were measured and pharmacokinetic parameters (maximum observed plasma concentration, time at which maximum concentration was observed, area under the plasma concentration–time curve from time 0 to 5 hours [AUC5h] and from time 0 to 24 hours [AUC24h] following each dose, terminal half‐life) of plasma l‐dopa and 3‐OMD were determined along with the geometric mean ratio (period 3/period 1) of AUC24h for l‐dopa and 3‐OMD. Maximum concentration of l‐dopa for the first, second, or third doses of l‐dopa/carbidopa did not significantly increase with increasing opicapone dose. The AUC of l‐dopa increased with increasing opicapone dose but tended toward a peak plateau with opicapone doses of 25 mg and higher. Geometric mean ratios (90% confidence intervals) of AUC24h were 5 mg, 1.16 (1.10‐1.21); 10 mg, 1.26 (1.23‐1.30); 25 mg, 1.51 (1.44‐1.57); 50 mg, 1.60 (1.54‐1.66). Opicapone tablets were well tolerated. In Japanese healthy subjects, increases in plasma exposure to l‐dopa appear to level off with opicapone doses of 25 mg and higher, which may be relevant for optimal dosing among Japanese patients with Parkinson disease.
Mesostructured Electroactive Thin Films Through Layer‐by‐Layer Assembly of Redox Surfactants and Polyelectrolytes
Authors: Piccinini Esteban , Ceolín Marcelo , Battaglini Fernando , Azzaroni Omar
Published: May 2020

Electroactive thin films are an important element in the devices devoted to energy conversion, actuators, and molecular electronics, among others. Their build‐up by the layer‐by‐layer technique is an attractive choice since a fine control over the thickness and composition can be achieved. However, most of the assemblies described in the literature show a lack of internal order, and their thicknesses change upon oxidation‐state alterations. In this work, we describe the formation of layer‐by‐layer assemblies of redox surfactants and polyelectrolytes that leads to the construction of mesoscale organized electroactive films. In contrast to thin films prepared with traditional redox polymers, here, the redox surfactant does not only allow the control of the film meso‐organization (from 2D hexagonal to circular hexagonal phases) but it also allows the control of the number and position of the redox centers. Finally, these films show high stability and a negligible structural deformation under redox‐state changes.
Posttraumatic stress symptoms of health care workers during the corona virus disease 2019
Authors: Yin Qianlan , Sun Zhuoer , Liu Tuanjie , Ni Xiong , Deng Xuanfeng , Jia Yanpu , Shang Zhilei , Zhou Yaoguang , Liu Weizhi
Published: May 2020

Corona virus disease 2019 (COVID‐19) outbreak has attracted worldwide attention. The COVID‐19 outbreak is unique in its rapid transmission and results in heavy stress for the front‐line health care workers (HCWs). The current study aimed to exam posttraumatic stress symptoms (PTSSs) of HCWs fighting for the COVID‐19 and to evaluate their sleep quality after 1‐month stressful suffering. Three hundred seventy‐seven HCWs working in different provinces of China participated in the survey between February 1 and 5. The demographic information was collected first. Posttraumatic Stress Disorder Checklist for DSM‐5 (PCL‐5) and the Pittsburgh Sleep Quality Index (PSQI) were selected to measure PTSSs and sleep quality. Results showed that 1 month after the outbreak, the prevalence of PTSSs was 3.8% in HCWs. Female HCWs were more vulnerable to PTSSs with hazard ratio of 2.136 (95% CI = 1.388–3.286). HCWs with higher exposure level also significantly rated more hyperarousal symptoms (hazard ratio = 4.026, 95% CI = 1.233–13.140). There was a significant difference of sleep quality between participants with and without PTSSs (z value = 6.014, p < .001) and among different groups with various contact frequencies (chi‐square = 7.307, p = .026). Path analysis showed that there was a significant indirect effect from exposure level to PTSSs through sleep quality (coefficient = 1.750, 95% CI of Boostroop test = 0.543–2.998). In summary, targeted interventions on sleep contribute to the mental recovery during the outbreak of COVID‐19. Understanding the mental health response after a public health emergency might help HCWs and communities prepare for a population's response to disaster.
Population Pharmacokinetics and Pharmacodynamics of Chloroquine in a Plasmodium vivax Volunteer Infection Study
Authors: Abd‐Rahman Azrin N. , Marquart Louise , Gobeau Nathalie , Kümmel Anne , Simpson Julie A. , Chalon Stephan , Möhrle Jörg J. , McCarthy James S.
Published: May 2020

Chloroquine has been used for the treatment of malaria for > 70 years; however, chloroquine pharmacokinetic (PK) and pharmacodynamic (PD) profile in Plasmodium vivax malaria is poorly understood. The objective of this study was to describe the PK/PD relationship of chloroquine and its major metabolite, desethylchloroquine, in a P. vivax volunteer infection study. We analyzed data from 24 healthy subjects who were inoculated with blood‐stage P. vivax malaria and administered a standard treatment course of chloroquine. The PK of chloroquine and desethylchloroquine was described by a two‐compartment model with first‐order absorption and elimination. The relationship between plasma and whole blood concentrations of chloroquine and P. vivax parasitemia was characterized by a PK/PD delayed response model, where the equilibration half‐lives were 32.7 hours (95% confidence interval (CI) 27.4–40.5) for plasma data and 24.1 hours (95% CI 19.0–32.7) for whole blood data. The estimated parasite multiplication rate was 17 folds per 48 hours (95% CI 14–20) and maximum parasite killing rate by chloroquine was 0.213 hour−1 (95% CI 0.196–0.230), translating to a parasite clearance half‐life of 4.5 hours (95% CI 4.1–5.0) and a parasite reduction ratio of 400 every 48 hours (95% CI 320–500). This is the first study that characterized the PK/PD relationship between chloroquine plasma and whole blood concentrations and P. vivax clearance using a semimechanistic population PK/PD modeling. This PK/PD model can be used to optimize dosing scenarios and to identify optimal dosing regimens for chloroquine where resistance to chloroquine is increasing.
FinFET‐based power‐efficient, low leakage, and area‐efficient DWT lifting architecture using power gating and reversible logic
Authors: Subannan Palanisamy Kesavan , Ramachandran Rajeswari
Published: May 2020

For ultra‐low‐power applications, the computing components are smaller in size and consume less energy. In nonstationary signal analysis, the transformation plays an important role. Out of different transformation techniques, the most famous and dominant architecture is the discrete wavelet transform. The building block of the architecture should be optimized by all parameters. In this paper, the optimization was done on the power reduction and leakage current reduction. A new FinFET‐based lifting‐based wavelet architecture was proposed. Power gating and reversible logic methodology are proposed for the FinFET‐based transform to reduce the dynamic power by about 30%. The proposed FinFET‐based processing elements were utilized in the various blocks of the lifting‐based DWT architecture. The implementation was done in 32‐nm CMOS and FinFET technology. From the results, it has been investigated that the FinFET‐based circuits are efficient when compared with CMOS technology. This is due to the second‐order effects happening in CMOS circuits below 45 nm. The proposed design consumes less area and low leakage current and power when compared with the CMOS technology. Future trends of using multigate devices below 14 nm technology are presented finally.
OMIP‐064: A 27‐Color Flow Cytometry Panel to Detect and Characterize Human NK Cells and Other Innate Lymphoid Cell Subsets, MAIT Cells, and γδ T Cells
Authors: Hertoghs Nina , Schwedhelm Katharine V. , Stuart Kenneth D. , McElrath Margaret Juliana , De Rosa Stephen C.
Published: May 2020

This 27‐color flow cytometry panel was developed in order to assess immunological changes over the course of an immunization and challenge regimen in two experimental malaria vaccine trials. The aim of the study was to find correlates of vaccine‐induced protection. Several studies have indicated that protection against malaria appears to involve immune responses at various immunological sites, with liver‐resident responses playing an essential role. As it is not feasible to monitor the immune responses within the liver in humans, this panel is developed with the aim to thoroughly characterize the immune responses over time in blood in addition to detecting changes that might reflect what happens in other immunological sites like the liver. The focus of this panel is to detect several innate lymphoid cell populations, including NK cells and their activation status. Moreover, unconventional T cells like mucosal associated invariant T cells and γδ T cells are assessed in the panel. © 2020 International Society for Advancement of Cytometry
Androgen sensitivity gateway to COVID‐19 disease severity
Authors: Wambier Carlos Gustavo , Goren Andy , Vaño‐Galván Sergio , Ramos Paulo Müller , Ossimetha Angelina , Nau Gerard , Herrera Sabina , McCoy John
Published: May 2020

In this communication, we present arguments for androgen sensitivity as a likely determinant of COVID‐19 disease severity. The androgen sensitivity model explains why males are more likely to develop severe symptoms while children are ostensibly resistant to infection. Further, the model explains the difference in COVID‐19 mortality rates among different ethnicities. Androgen sensitivity is determined by genetic variants of the androgen receptor. The androgen receptor regulates transcription of the transmembrane protease, serine 2 (TMPRSS2), which is required for SARS‐CoV‐2 infectivity. TMPRSS2 primes the Spike protein of the virus, which has two consequences: diminishing viral recognition by neutralizing antibodies and activating SARS‐CoV‐2 for virus‐cell fusion. Genetic variants that have been associated with androgenetic alopecia, prostate cancer, benign prostatic hyperplasia and polycystic ovary syndrome could be associated with host susceptibility. In addition to theoretical epidemiological and molecular mechanisms, there are reports of high rates of androgenetic alopecia of from hospitalized COVID‐19 patients due to severe symptoms. Androgen sensitivity is a likely determinant of COVID‐19 disease severity. We believe that the evidence presented in this communication warrants the initiation of trials using anti‐androgen agents.
Therapeutic application of nutraceuticals in diabetic nephropathy: Current evidence and future implications
Authors: Dehdashtian Ehsan , Pourhanifeh Mohammad Hossein , Hemati Karim , Mehrzadi Saeed , Hosseinzadeh Azam
Published: May 2020

Diabetes mellitus (DM) is a common metabolic disease which may cause several complications, such as diabetic nephropathy (DN). The routine medical treatments used for DM are not effective enough and have many undesirable side effects. Moreover, the global increased prevalence of DM makes researchers try to explore potential complementary or alternative treatments. Nutraceuticals, as natural products with pharmaceutical agents, have a wide range of therapeutic properties in various pathologic conditions such as DN. However, the exact underlying mechanisms have not been fully understood. The purpose of this review is to summarize recent findings on the effect of nutraceuticals on DN.
Phase I metabolites (organic acids) of gamma‐hydroxybutyric acid–validated quantification using GC–MS and description of endogenous concentration ranges
Authors: Jarsiah Pouria , Roehrich Joerg , Wyczynski Marek , Hess Cornelius
Published: May 2020

Gamma‐hydroxybutyric acid (GHB) is a sedative drug used in drug‐facilitated crimes. Its detection window is very short. GHB undergoes intensive phase I metabolism to organic acids (glycolic acid, succinic acid, dihydroxybutyric acids). These could be potential analytical targets to broaden the detection window. The aim of the present study was to enable the detection of endogenous levels of these metabolites in biological samples (blood and urine). A gas chromatographic–mass spectrometric method using liquid–liquid extraction and derivatization with N‐methyl‐N‐tri‐methylsilyltrifluoracetamide was developed for the quantification. Validation results were consistent with international guidelines, and the method was able to quantify endogenous levels of the substances in both urine and blood. Endogenous concentrations were shown to be <0.03–4.92 mg/L for glycolic acid, <0.03–1.28 mg/L for GHB, <0.28–18.1 mg/L for succinic acid, <0.12–1.38 mg/L for 2,4‐dihydroxybutyric acid, and <0.13–2.59 mg/L for 3,4‐dihydroxybutyric acid in serum samples of 101 volunteers. Urinary endogenous concentrations were shown to be 1.30–400 mg/L for glycolic acid, <0.03–1.94 mg/L for GHB, 1.17–2.73 mg/L for succinic acid, 0.72–26.2 mg/L for 2,4‐dihydroxybutyric acid, and 1.88–122 mg/L for 3,4‐dihydroxybutyric acid in urine samples of 132 volunteers. These endogenous concentrations represent a basis to which concentrations after the intake of GHB can be compared to in order to prove the intake of this substance.
Zooplankton invasion on a grand scale: insights from a 20‐yr time series across 38 Northeast Pacific estuaries
Authors: Dexter Eric , Bollens Stephen M. , Cordell Jeffery , Rollwagen‐Bollens Gretchen
Published: May 2020

We present the first comprehensive analysis of the Pacific Northwest estuaries (PNWE) zooplankton time series, which encompasses 38 estuaries distributed across more than 1000 km of the North American Pacific Coast. With observations spanning more than 20 yr, we here examine biogeographic trends among zooplankton communities, patterns of biological invasion across the region, and environmental correlates with dominant native and invasive taxa. Our results show that some estuaries across the region are invaded by multiple zooplankton species and that the geographic extent of invasion is far greater than previously reported for at least five species of copepods: Pseudodiaptomus inopinus, Pseudodiaptomus forbesi, Oithona davisae, Limnoithona sinensis, Sinocalanus doerrii, and the cladoceran Bosmina coregoni. Some of these species appear to be rapidly spreading across the region, while others have occupied a relatively static geographic range for decades. The copepod, P. inopinus, is by far the most abundant and geographically widespread of these invaders, comprising more than 90% of all zooplankton abundance at some sites. We propose that the geographic distribution of these invaders is strongly constrained by geomorphic characteristics that define the salinity and mixing regimes in these estuaries, reflecting the strong role that physical forces play in structuring estuarine zooplankton communities.
The affordable laboratory of climate change: devices to estimate ectotherm vital rates under projected global warming
Authors: Garcia‐Robledo Carlos , Kuprewicz Erin K. , Dierick Diego , Hurley Sarah , Langevin Abigail
Published: May 2020

Determining organisms’ responses to novel temperatures is relevant from ecological, evolutionary, and conservation perspectives. Here, we have validated designs and included biological examples for three affordable devices to estimate thermal responses of ectotherms: (1) a water bath that can be programmed to increase temperatures to estimate an organismal critical thermal maximum (CTmax), (2) a miniature portable refrigerator to estimate an organism's critical thermal minimum (CTmin), and (3) inexpensive growth chambers that maintain constant temperatures or simulate dynamic environmental temperature patterns. We tested the reliability of the CTmax device at temperature increase rates of 1° and 2°C/min. Observed temperatures deviated 0.01°C and 0.02°C from target temperatures, respectively. The CTmin device easily attained target temperatures via manipulation of the input voltage. The maximum deviation from target temperatures in environmental chambers programmed to maintain constant temperatures between 10°C and 30°C was 0.8°C. Environmental chambers programmed to simulate temperature profiles of tropical rain and montane forests deviated from target temperatures by a maximum of −0.5°C to 0.9°C. Examples of applications show that (1) tropical insects at high elevations are less tolerant to high temperatures than insects in lowland forests, (2) nocturnal ants display lower CTmax and CTmin than diurnal ant species, and (3) experiments in growth chambers show high mortality of high‐elevation insect species when exposed to temperatures that typify lowland forests, and high mortality of lowland insect species when exposed to temperatures that typify high elevations. The devices described in this study can be mass‐produced inexpensively and are currently being used in laboratories in the United States, Mexico, and Costa Rica. The main goal of this project is to encourage the construction of affordable devices and the use of standardized methodologies to create a global network of researchers studying thermal responses in diverse taxa and geographic locations.