bluuebunny/crossref_metadata_2025 huggingface dataset:
On the Properties of Nanoporous SiO2 Films for Single Layer Antireflection Coating
Authors: Ghazaryan Lilit , Sekman Yusuf , Schröder Sven , Mühlig Christian , Stevanovic Igor , Botha Roelene , Aghaee Morteza , Creatore Mariadriana , Tünnermann Andreas , Szeghalmi Adriana
Published: March 2019

Single layer antireflection coatings (SLAR) consisting of nanoporous silica (NP SiO2) films are developed by selective chemical etching of atomic layer deposited (ALD) Al2O3:SiO2 composite films. The reflective index of the final NP SiO2 film is finely adjusted from 1.132 to 1.400 at 600 nm wavelength by applying an appropriate ratio in the composite. To meet the requirements of the SLAR coatings from the deep UV (DUV) to the near IR (NIR) spectral range, the film thickness is controlled with nanometer precision by the ALD process. The SLAR are simultaneously applied on both sides of flat or highly curved substrates. Transmittance values above 99.4% are achieved even at a wavelength of 193 nm on fused silica substrates. Various characterization methods demonstrate the advantages of these SLAR with regard to impurities, optical losses, laser induced damage threshold (LIDT) properties, and surface super‐hydrophilicity. The absorption losses at 193 nm wavelength as determined by laser induced deflection measurements amount to approximately 200 ppm, and to approximately 2 ppm at a wavelength of 1064 nm, while the scattering losses are around 30 ppm at 532 nm wavelength for quarter‐wave layers. The LIDT values at 1064 nm are in the range of 93 J cm−2 being close to the values measured on the uncoated substrate.
Observation of Twin Transmission Process in Mg Alloys by In Situ EBSD
Authors: Guo Changfa , Xin Renlong , Wu Guilin , Liu Feiya , Hu Guangshan , Liu Qing
Published: March 2019

Twin pairs are frequently observed at the common grain boundaries of Mg alloys. The formation of twin pairs is associated with a twin transmission (TT) process. Investigating the TT process is important for understanding the deformation mechanism of Mg alloys. Here, the authors report an in situ electron backscatter diffraction (EBSD) examination on the TT process in AZ31 Mg alloys subjected to tensile deformation. TT process is clearly observed by band contrast images resulting in the formation of twin chains as strain increases. Interestingly, transmitted twins are developed in advance in form of non‐indexing dislocations or twins in neighboring grain. The TT direction is roughly along the shear plane normal or shear direction of the paired twins. In addition, multiple twin variants are activated by TT mechanism and nucleation of new twins at pre‐existing twin boundaries.
On the Process Variables and Weld Quality of a Linear Friction Welded Dissimilar Joint between S31042 and S34700 Austenitic Steels
Authors: Su Yu , Li Wenya , Wang Xinyu , Ma Tiejun , Li Yanmo , Liu Yongchang , Vairis Achilles
Published: March 2019

In this study, the dissimilar S31042 and S34700 austenitic stainless steels joints are welded with linear friction welding (LFW). The history of shear stress at the interface and axial shortening during LFW, the microstructure evolution and mechanical properties of the joint are studied. Results show that axial shortening develops during the equilibrium and deceleration phases. The shear stress reaches a maximum during deceleration as a metallurgical bond forms in sections of the interface. The weld center zone is a narrow layer with a thickness of about 380 µm, where there are fine equiaxed grains with a strong {112}<110> texture. Elongated grains are present in the thermo‐mechanically affected zone due to the shear stress. The average tensile strength and elongation of the joints are measured to be 577 MPa and 33.3%, respectively. All tensile test samples fail at the base material of S34700, as the tensile strength of the joint is equal to or better than that of the base S34700.
Synthesis of 3,4‐Dihydrobenzo[f]phthalazines via Iodine/tert‐Butyl Hydroperoxide‐Mediated Annulation Cascade of Yne‐Allenones
Authors: Fu Rong , Li Meng‐Fan , Zhou Peng , Hao Wen‐Juan , Tu Shu‐Jiang , Jiang Bo
Published: March 2019

An iodine (I2)/tert‐butyl hydroperoxide (TBHP)‐mediated annulation cascade between yne‐allenones and sulfonyl hydrazides has been established, in which a wide set of dihydrobenzo[f]phthalazines were synthesized through one‐pot, two‐step strategy under metal‐free conditions. The synthetic utility of these transformations leads to subsequent C−C and C−N bond‐forming reactions to effectively build up functional aza‐heterocycle with potential significance.

magnified image
Molecular Dynamics of Open Systems: Construction of a Mean‐Field Particle Reservoir
Authors: Delle Site Luigi , Krekeler Christian , Whittaker John , Agarwal Animesh , Klein Rupert , Höfling Felix
Published: March 2019

The simulation of open molecular systems requires explicit or implicit reservoirs of energy and particles. Whereas full atomistic resolution is desired in the region of interest, there is some freedom in the implementation of the reservoirs. Here, a combined, explicit reservoir is constructed by interfacing the atomistic region with regions of point‐like, non‐interacting particles (tracers) embedded in a thermodynamic mean field. The tracer molecules acquire atomistic resolution upon entering the atomistic region and equilibrate with this environment, while atomistic molecules become tracers governed by an effective mean‐field potential after crossing the atomistic boundary. The approach is extensively tested on thermodynamic, structural, and dynamic properties of liquid water. Conceptual and numerical advantages of the procedure as well as new perspectives are highlighted and discussed.
Extensive allopolyploidy in the neotropical genus Lachemilla (Rosaceae) revealed by PCR‐based target enrichment of the nuclear ribosomal DNA cistron and plastid phylogenomics
Authors: Morales‐Briones Diego F. , Tank David C.
Published: March 2019

Premise of the Study

Polyploidy has been long recognized as an important force in plant evolution. Previous studies had suggested widespread occurrence of polyploidy and the allopolyploid origin of several species in the diverse neotropical genus Lachemilla (Rosaceae). Nonetheless, this evidence has relied mostly on patterns of cytonuclear discordance, and direct evidence from nuclear allelic markers is still needed.

Methods

Here we used PCR target enrichment in combination with high throughput sequencing to obtain multiple copies of the nuclear ribosomal (nr) DNA cistron and 45 regions of the plastid genome (cpDNA) from 219 accessions representing 48 species of Lachemilla and to explore the allopolyploid origin of species in this group.

Key Results

We were able to identify multiple nrDNA ribotypes and establish clear evidence of allopolyploidy in 33 species of Lachemilla, showing that this condition is common and widespread in the genus. Additionally, we found evidence for three autopolyploid species. We also established multiple, independent origins of several allopolyploid species. Finally, based solely on the cpDNA phylogeny, we identified that the monotypic genus Farinopsis is the sister group of Lachemilla and allied genera within subtribe Fragariinae.

Conclusions

Our study demonstrates the utility of the nuclear ribosomal DNA cistron to detect allopolyploidy when concerted evolution of this region is not complete. Additionally, with a robust chloroplast phylogeny in place, the direction of hybridization events can be established, and multiple, independent origins of allopolyploid species can be identified.
A Ten‐Step Total Synthesis of Speradine C
Authors: Liu Haichao , Chen Lijun , Yuan Kuo , Jia Yanxing
Published: March 2019

The first total synthesis of speradine C has been achieved in only ten steps from a commercially available 4‐bromoindole. Salient features of the work are the formation of four rings through three cyclizations, namely a bioinspired [3+2] annulation to form the C/D rings, an NCS‐mediated oxidation to construct the E ring, and a Ru‐catalyzed ketohydroxylation to assemble the F ring. This work highlights how strategic ring constructions can streamline the synthesis of polycyclic compounds.
N‐heterocyclic carbene–palladium(II) complex supported on magnetic mesoporous silica for Heck cross‐coupling reaction
Authors: Nuri Ayat , Mansoori Yagoub , Bezaatpour Abolfazl
Published: March 2019

Magnetic mesoporous silica was prepared via embedding magnetite nanoparticles between channels of mesoporous silica (SBA‐15). The prepared composite (Fe3O4@SiO2‐SBA) was then reacted with 3‐chloropropyltriethoxysilane, sodium imidazolide and 2‐bromopyridine to give 3‐(pyridin‐2‐yl)‐1H‐imidazol‐3‐iumpropyl‐functionalized Fe3O4@SiO2‐SBA as a supported pincer ligand for Pd(II). The functionalized magnetic mesoporous silica was further reacted with [PdCl2(SMe2)2] to produce a supported N‐heterocyclic carbene–Pd(II) complex. The obtained catalyst was characterized using Fourier transform infrared spectroscopy, scanning electron microscopy, energy‐dispersive X‐ray analysis, vibrating sample magnetometry, Brunauer–Emmett–Teller surface area measurement and X‐ray diffraction. The amount of the loaded complex was 80.3 mg g−1, as calculated through thermogravimetric analysis. The formation of the ordered mesoporous structure of SBA‐15 was confirmed using low‐angle X‐ray diffraction and transmission electron microscopy. Also, X‐ray photoelectron spectroscopy confirmed the presence of the Pd(II) complex on the magnetic support. The prepared magnetic catalyst was then effectively used in the coupling reaction of olefins with aryl halides, i.e. the Heck reaction, in the presence of a base. The reaction parameters, such as solvent, base, temperature, amount of catalyst and reactant ratio, were optimized by choosing the coupling reaction of 1‐bromonaphthalene and styrene as a model Heck reaction. N‐Methylpyrrolidone as solvent, 0.25 mol% catalyst, K2CO3 as base, reaction temperature of 120°C and ultrasonication of the catalyst for 10 min before use provided the best conditions for the Heck cross‐coupling reaction. The best results were observed for aryl bromides and iodides while aryl chlorides were found to be less reactive. The catalyst exhibited noticeable stability and reusability.
Preparation of a superparamagnetic nanocomposite hydrogel for adsorptive performance in the wastewater treatment
Authors: Maciel Diana J. , da Silva Manoel R. , Ferreira Ivana L. M.
Published: March 2019

Magnetic nanocomposite hydrogels based on carrageenan (kappa:iota = 1:1) and maghemite (γ‐Fe2O3) are prepared. Scanning electron microscopyimages show that the γ‐Fe2O3 is dispersed on the surface of the hydrogels and transmission electron microscopy images show that maghemite particles are in nanometric size. The hydrogels present superparamagnetic behavior and respond to the stimulus of a magnet. The samples crosslinked with KCl are classified as superabsorbent materials (swelling degree >700%) and they show a higher saturation magnetization value than those crosslinked with CaCl2. Vibrating sample magnetometry curves show that the hydrogels do not present a hysteresis cycle and the remanent magnetization in all the samples is near zero. The performance of the hydrogels is evaluated for adsorption of heavy metals from aqueous solutions. The samples are immersed in aqueous solutions containing Cd(II) and Pb(II) ions. After 150 min of immersion, the hydrogels remove about 40% and 30% of each heavy metal contaminant, respectively. © 2019 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2019, 136, 47705.
Exploring the Lipid Paradox Theory in Rheumatoid Arthritis: Associations of Low Circulating Low‐Density Lipoprotein Concentration With Subclinical Coronary Atherosclerosis
Authors: Giles Jon T. , Wasko Mary Chester M. , Chung Cecilia P. , Szklo Moyses , Blumenthal Roger S. , Kao Amy , Bokhari Sabahat , Zartoshti Afshin , Stein C. Michael , Bathon Joan M.
Published: March 2019

Objective

Rheumatoid arthritis (RA) patients with the lowest circulating low‐density lipoprotein (LDL) concentrations are at heightened risk of cardiovascular events. However, the atherosclerosis burden within this subgroup is unknown.

Methods

RA patients pooled from 4 cohort studies of cardiovascular disease (CVD; n = 546) were compared with non‐RA controls from the Multi‐Ethnic Study of Atherosclerosis (n = 5,279). Those taking lipid‐lowering medications were excluded. Differences in cardiac computed tomography–derived Agatston coronary artery calcium (CAC) scores between the RA and control groups were compared across strata of LDL concentration.

Results

Among those with low LDL concentrations (<70 mg/dl), mean adjusted CAC scores were >4‐fold higher for RA patients than for controls (18.6 versus 4.6 Agatston units, respectively; P < 0.001), a difference significantly greater than that in any other LDL concentration stratum except LDL concentration ≥160 mg/dl. Similarly, 32% of the RA patients with low LDL concentration had a CAC score of ≥100 Agatston units compared with only 7% of controls in the same LDL concentration stratum (odds ratio 5.97; P < 0.001), a difference significantly greater than that in all of the other LDL concentration strata. Low LDL concentration was most strongly associated with higher CAC score among RA patients who were white, had ever smoked, or were not obese. Other than a higher frequency of current smokers, RA patients with low LDL concentrations did not have more CVD risk factors or higher measures of RA disease activity or severity than RA patients with higher LDL concentrations.

Conclusion

RA patients with low LDL concentration may represent a group for whom heightened screening and prevention of atherosclerotic CVD is appropriate.
Granular activated carbon adsorption of carcinogenic volatile organic compounds at low influent concentrations
Authors: Kempisty David M. , Summers R. Scott , Abulikemu Gulizhaer , Deshpande Niranjan V. , Rebholz Jacob A. , Roberts Kelsey , Pressman Jonathan G.
Published: March 2019

The effectiveness of granular activated carbon (GAC) for carcinogenic volatile organic compounds (cVOCs) has not been evaluated in the low‐ to submicrogram per liter range. Rapid small‐scale column tests were used to determine the GAC performance at empty bed contact times (EBCTs) of 7.5 and 15 min for 13 cVOCs at a target influent concentration of 5 μg/L in a typical groundwater matrix. Breakthrough was assessed for vinyl chloride, dichloromethane, 1,1‐dichloroethane (1,1 DCA), 1,2‐dichloroethane (1,2 DCA), 1,2‐dichloropropane, carbon tetrachloride, 1,3‐butadiene, 1,1,1,2‐tetrachloroethane, 1,2,3‐trichloropropane, trichloroethylene, and tetrachloroethylene. The throughput to breakthrough was found to be linearly correlated to capacities calculated with single‐solute equilibrium isotherm parameters. Modest decreases, 9–13% on average, in throughput to 50 and 75% breakthrough were found when the EBCT was increased from 7.5 to 15 min. The carbon use rate (CUR), when scaled to simulate full‐scale adsorption, indicated that GAC would be a viable technology for seven of the cVOCs evaluated, with a CUR threshold of less than 0.2 lb/1,000 gal. It may be possible to use 1,1 DCA and 1,2 DCA as surrogates for assessing chemicals near the feasibility limit.
Modell zur Beschreibung der zeitabhängigen Rissbreitenentwicklung in Stahlbetonbauteilen
Authors: Empelmann Martin , Cramer Jonas
Published: March 2019

Die Begrenzung der Rissbreite ist eine wesentliche Bemessungsaufgabe bei Stahlbetonkonstruktionen, um Gebrauchstauglichkeit und Dauerhaftigkeit zu gewährleisten. Unter Langzeitbeanspruchungen vergrößern sich die Rissbreiten durch das zeitabhängige Materialverhalten von Beton. Aufgrund der Überlagerung der unterschiedlichen Effekte (Verbundkriechen, Betonkriechen und Betonschwinden) sind konsistente und mechanisch basierte Untersuchungen für eine zuverlässige Vorhersage der Rissbreiten unerlässlich. Zu diesem Zweck wurde ein rheologisches Modell entwickelt. Das Modell wurde anhand von Versuchsergebnissen unter Langzeitbelastung validiert und zeigt eine sehr gute Übereinstimmung zwischen den zeitabhängigen rechnerischen und experimentellen Rissbreiten.
Investigation of cathepsin D–mAb interactions using a combined experimental and computational tool set
Authors: Ranjan Swarnim , Chung Wai Keen , Hofele Romina , Heidbrink Thompson Jenny , Bee Jared , Zhang Limin , Robbins David , Cramer Steven M.
Published: March 2019

Cathepsin D has been identified as a challenge to remove in downstream bioprocessing of monoclonal antibodies (mAbs) due to interactions with some mAbs. This study focused on investigating the mechanisms of interaction between cathepsin D and two industrial mAbs using a combined experimental and computational approach. Surface plasmon resonance was used to study the impact of pH and salt concentration on these protein–protein interactions. While salt had a moderate effect on the interactions with one of the mAbs, the other mAb demonstrated highly salt‐dependent association behavior. Cathepsin D binding to the mAbs was also seen to be highly pH dependent, with operation at pH 9 resulting in a significant decrease in the binding affinity. Protein–protein docking simulations identified three interaction sites on both mAbs; near the complementarity determining region (CDR), in the hinge, and in the CH3 domain. In contrast, only one face of cathepsin D was identified to interact with all the three sites on the mAbs. Surface property analysis revealed that the binding regions on the mAbs contained strong hydrophobic clusters and were predominantly negatively charged. In contrast, the binding site on cathepsin D was determined to be highly positively charged and hydrophobic, indicating that these protein–protein interactions were likely due to a combination of hydrophobic and electrostatic interactions. Finally, covalent crosslinking coupled with mass spectrometry was used to validate the docking predictions and to further investigate the regions of interaction involved in mAb–cathepsin D binding. A strong agreement was observed between the two approaches, and the CDR loops were identified to be important for cathepsin D interactions. This study establishes a combined experimental and computational platform that can be used to probe mAb–host cell protein (HCP) interactions of importance in biomanufacturing.
Changes in gut hormones, glycaemic response and symptoms after oesophagectomy
Authors: Elliott J A , Docherty N G , Murphy C F , Eckhardt H-G , Doyle S L , Guinan E M , Ravi N , Reynolds J V , le Roux C W
Published: March 2019

Background

Oesophagectomy is associated with reduced appetite, weight loss and postprandial hypoglycaemia, the pathophysiological basis of which remains largely unexplored. This study aimed to investigate changes in enteroendocrine function after oesophagectomy.

Methods

In this prospective study, 12 consecutive patients undergoing oesophagectomy were studied before and 10 days, 6, 12 and 52 weeks after surgery. Serial plasma total fasting ghrelin, and glucagon-like peptide 1 (GLP-1), insulin and glucose release following a standard 400-kcal mixed-meal stimulus were determined. CT body composition and anthropometry were assessed, and symptom scores calculated using European Organisation for Research and Treatment of Cancer (EORTC) questionnaires.

Results

At 1 year, two of the 12 patients exhibited postprandial hypoglycaemia, with reductions in bodyweight (mean(s.e.m.) 17·1(3·2) per cent, P < 0·001), fat mass (21.5(2.5) kg versus 25.5(2.4) kg before surgery; P = 0·014), lean body mass (51.5(2.2) versus 54.0(1.8) kg respectively; P = 0·003) and insulin resistance (HOMA-IR: 0.84(0.17) versus 1.16(0.20); P = 0·022). Mean(s.e.m.) fasting ghrelin levels decreased from postoperative day 10, but had recovered by 1 year (preoperative: 621·5(71·7) pg/ml; 10 days: 415·1(59·80) pg/ml; 6 weeks: 309·0(42·0) pg/ml; 12 weeks: 415·8(52·1) pg/ml; 52 weeks: 547·4(83·2) pg/ml; P < 0·001) and did not predict weight loss (P = 0·198). Postprandial insulin increased progressively at 10 days, 6, 12 and 52 weeks (mean(s.e.m.) insulin AUC0–30 min: fold change 1·7(0·4), 2·0(0·4), 3·5(0·7) and 4·0(0·8) respectively; P = 0·001). Postprandial GLP-1 concentration increased from day 10 after surgery (P < 0·001), with a 3·3(1·8)-fold increase at 1 year (P < 0·001). Peak GLP-1 level was inversely associated with the postprandial glucose nadir (P = 0·041) and symptomatic neuroglycopenia (Sigstad score, P = 0·017, R2 = 0·45). GLP-1 AUC predicted loss of weight (P = 0·008, R2 = 0·52) and fat mass (P = 0·010, R2 = 0·64) at 1 year.

Conclusion

Altered enteroendocrine physiology is associated with early satiety, weight loss and postprandial hypoglycaemia after oesophagectomy.
Metabolomics analysis of the therapeutic mechanism of Semen Descurainiae Oil on hyperlipidemia rats using 1H‐NMR and LC–MS
Authors: Cai Yi , Zhao Min , Guan Zhibo , Han Xue , Wang Miao , Zhao Chunjie
Published: March 2019

Semen descurainiae oil (SDO) is an important traditional Chinese medicine that was recently discovered to have the function of reducing blood lipids. Metabolomics analyses of plasma, liver and kidney in rats were performed using 1H‐NMR and LC–MS to illuminate the lower blood lipid concentration effect of SDO, and niacin was considered as the active control. The measure of total cholesterol (TC) and low‐density‐lipoprotein cholesterol (LDL‐C) in plasma showed that SDO treatment decreased significantly the content of TC and LDL‐C. An orthogonal partial least squares–discriminant analysis approach was applied to identify the different metabolic profiles of plasma, liver and kidney in rats and to detect related potential biomarkers. The results suggested that the metabolic profiles of the control group and hyperlipidemia group showed significant difference and the SDO and niacin group had effective anti‐hyperlipidemia function. The biomarkers primarily concern lipid metabolism, amino acid metabolism and glycometabolism, and the change in biomarkers indicated that hyperlipidemia could cause the unbalance of these metabolic pathways in vivo. SDO reduced blood lipids by repairing amino acid and lipid metabolism.
Transfer Hydrogenation of Carbonyl Groups, Imines andN‐Heterocycles Catalyzed by Simple, Bipyridine‐Based MnIComplexes
Authors: Dubey Abhishek , Rahaman S. M. Wahidur , Fayzullin Robert R. , Khusnutdinova Julia R.
Published: March 2019

Utilization of hydroxy‐substituted bipyridine ligands in transition metal catalysis mimicking [Fe]‐hydrogenase has been shown to be a promising approach in developing new catalysts for hydrogenation. For example, MnIcomplexes with 6,6′‐dihydroxy‐2,2′‐bipyridine ligand have been previously shown to be active catalysts for CO2hydrogenation. In this work, simple bipyridine‐based Mn catalysts were developed that act as active catalysts for transfer hydrogenation of ketones, aldehydes and imines. For the first time, Mn‐catalyzed transfer hydrogenation ofN‐heterocycles was reported. The highest catalytic activity among complexes with variously substituted ligands was observed for the complex bearing two OH groups in bipyridine. Deuterium labeling experiments suggest a monohydride pathway.
First experiences with concrete screw anchors as postinstalled shear reinforcement in concrete bridges
Authors: Lechner Johannes , Feix Jürgen
Published: March 2019

Due to growing traffic volume and more restrictive design standards, structural engineers require new strengthening systems for concrete structures. Especially the level of calculated shear reinforcement has increased with the introduction of the Eurocode standards. Therefore, new methods to improve the shear strength of existing structures are needed. Concrete screws are used as a fastening system in concrete. Due to the mechanical connection, a very robust bond between the reinforcement element and the concrete is given. The new idea is to use these anchoring elements as postinstalled shear reinforcement. To show the usability and enhancements of the new method, several test series with concrete girders have been performed at the University of Innsbruck. Using concrete screws in several different configurations all test beams showed a remarkable increase in shear‐load capacity. With a new design approach derived from the test results it was possible to apply the new system to several pilot‐projects. One slab bridge built in the 1970s was strengthened to the load level according to Eurocode. Another pilot‐project was realized at a railway bridge with a two span concrete box girder. This bridge was built with tendons vulnerable to stress corrosion cracking. To ensure a ductile failure, strengthening was necessary which was realized with concrete screws under ongoing traffic on and underneath the bridge. Currently a shear strengthening of a city tunnel in the central area of Munich is planned. In the roof slab about 7000 concrete screws are projected to be installed as shear and bending strengthening system.
A Bait‐and‐Switch Method for the Construction of Artificial Esterases for Substrate‐Selective Hydrolysis
Authors: Hu Lan , Zhao Yan
Published: March 2019

Outcomes of chemical reactions are generally dominated by the intrinsic reactivities of reaction partners, but enzymes frequently override such constraints to transform less reactive molecules in the presence of more reactive ones. Despite the attractiveness of such catalysis, it is difficult to build synthetic catalysts with these features. Micellar imprinting is a powerful method to create template‐complementary binding sites inside protein‐sized water‐soluble nanoparticles. When a photocleavable functional monomer was used to bind two phosphonate/phosphate templates as transition‐state analogues, active sites with predetermined size and shape were formed inside doubly cross‐linked micelles through molecular imprinting. Postmodification replaced the binding group with a catalytic pyridyl group, forming highly selective artificial esterases. The catalysts displayed enzyme‐like kinetics and turnover numbers that were in the hundreds. The selectivity of the catalysts, derived from the substrate‐complementary imprinted active sites, enabled transformation of less reactive esters in the presence of more reactive ones.
Multiple Luminescence Responses towards Mechanical Stimulus and Photo‐Induction: The Key Role of the Stuck Packing Mode and Tunable Intermolecular Interactions
Authors: Dang Qianxi , Hu Lanzhen , Wang Jiaqiang , Zhang Qunhua , Han Mengmeng , Luo Simeng , Gong Yanbin , Wang Can , Li Qianqian , Li Zhen
Published: March 2019

Organic luminescence with different forms continues to be one of the most active research fields in science and technology. Herein, an ultra‐simple organic molecule (TPA‐B), which exhibits both mechanoluminescence (ML) and photo‐induced room‐temperature phosphorescence (RTP) in the crystalline state, provides an opportunity to reveal the internal mechanism of ML and the dynamic process of photo‐induced RTP in the same molecule. Through the detailed investigation of photophysical properties together with crystal structures, the key role of molecular packing and intermolecular interactions was highlighted in the luminescence response by mechanical and light stimulus, affording efficient strategies to design potential smart functional materials with multiple luminescence properties.
Alkoxide‐Promoted Selective Hydroboration of N‐Heteroarenes: Pivotal Roles of in situ Generated BH3 in the Dearomatization Process
Authors: Jeong Eunchan , Heo Joon , Park Sehoon , Chang Sukbok
Published: March 2019

While numerous organo(metallic)catalyst systems were documented for dearomative hydroboration of N‐aromatics, alkoxide base catalysts have not been disclosed thus far. Described herein is the first example of alkoxide‐catalyzed hydroboration of N‐heteroaromatics including pyridines, providing a broad range of reduced N‐heterocycles with high efficiency and selectivity. Mechanistic studies revealed an unprecedented counterintuitive dearomatization pathway, in which 1) pyridine‐BH3 adducts undergo a hydride attack by alkoxyborohydrides, 2) in situ generated BH3 serves as a catalytic promoter, and 3) 1,4‐dihydropyridyl borohydride is in a predominant resting state.
Use of 19F Differential Labelling for the Simultaneous Detection and Monitoring of Three Individual Proteins in a Serum Environment
Authors: Edwards John M. , Harris Pernille , Bukrinski Jens T. , Golovanov Alexander P.
Published: March 2019

Protein behavior in complex mixtures, such as biological fluids, is often modeled by simplified buffer systems in solution. Here we have used the recently described differential 19F labelling approach (with NMR detection) to monitor and compare the solution behaviour of three proteins at once: human serum albumin (HSA), transferrin (TrF), and immunoglobulin G (IgG), both in serum and in buffer. We demonstrate that monitoring three proteins simultaneously and independently in biological fluid is possible, and that the presence of other endogenous components greatly changes the association characteristics of these proteins. For example, in the simplified model buffer system, all three proteins diffuse at a similar rate, while in serum HSA diffuses around three times faster than TrF, and four times faster than IgG. This 19F NMR approach allows characterization of the behaviour of complex multiprotein systems in their native environment, e. g., in biological fluids.
An Efficient Synthesis of 5‐Aminopropargyl‐Pyrimidine‐5′‐O‐Triphosphates Through Palladium‐Catalyzed Sonogashira Coupling
Authors: Shanmugasundaram Muthian , Senthilvelan Annamalai , Kore Anilkumar R.
Published: March 2019

The utilization of 5‐aminopropargyl nucleotide serves as a versatile molecular biology tool for the introduction of functional groups into a nucleic acid target of interest by using in‐vitro enzymatic incorporation method. This article describes a simple, reliable, general, and efficient two‐step chemical method for the synthesis of 5‐(3‐aminopropargyl)‐2′‐deoxycytidine‐5′‐O‐triphosphate, 5‐(3‐aminopropargyl)‐cytidine‐5′‐O‐triphosphate, 5‐(3‐aminopropargyl)‐2′‐deoxyuridine‐5′‐O‐triphosphate, and 5‐(3‐aminopropargyl)‐uridine‐5′‐O‐triphosphate, starting from the corresponding pyrimidine triphosphate. The first step involves regioselective C‐5 iodination of pyrimidine triphosphate using N‐iodosuccinimide and sodium azide. In the second step, propargylamine is coupled to the iodo‐pyrimidine using the palladium‐catalyzed Sonogashira reaction, producing good yields of highly pure (>99.5% HPLC) 5‐aminopropargyl‐pyrimidine‐5′‐O‐triphosphate. In this approach, the palladium‐catalyzed Sonogashira coupling reaction is highly chemoselective and does not involve protection and deprotection. © 2019 by John Wiley & Sons, Inc.
Regulation and Innovation: Role of Regulatory Science in Facilitating Pharmaceutical Innovation
Authors: Honig Peter , Zhang Lei
Published: March 2019

Regulatory science is defined as science and research intended to inform decision making in a regulatory framework. This issue of Clinical Pharmacology & Therapeutics and the papers herein deal with the expansive topic of regulatory science and its role in fostering innovation and accelerating access to medicines. Regulatory health authorities, industry, and multiple stakeholders have a shared objective in advancing regulatory science to keep up with the ever‐increasing pace of biomedical science.
Mahi‐mahi (Coryphaena hippurus) life development: morphological, physiological, behavioral and molecular phenotypes
Authors: Perrichon Prescilla , Stieglitz John D. , Xu Elvis Genbo , Magnuson Jason T. , Pasparakis Christina , Mager Edward M. , Wang Yadong , Schlenk Daniel , Benetti Daniel D. , Roberts Aaron P. , Grosell Martin , Burggren Warren W.
Published: March 2019

Background

Mahi‐mahi (Coryphaena hippurus) is a commercially and ecologically important fish species that is widely distributed in tropical and subtropical waters. Biological attributes and reproductive capacities of mahi‐mahi make it a tractable model for experimental studies. In this study, life development of cultured mahi‐mahi from the zygote stage to adult has been described.

Results

A comprehensive developmental table has been created reporting development as primarily detailed observations of morphology. Additionally, physiological, behavioral, and molecular landmarks have been described to significantly contribute in the understanding of mahi life development.

Conclusion

Remarkably, despite the vast difference in adult size, many developmental landmarks of mahi map quite closely onto the development and growth of Zebrafish and other warm‐water, active Teleost fishes.
Joule heating effects in optimized insulator‐based dielectrophoretic devices: An interplay between post geometry and temperature rise
Authors: Gallo‐Villanueva Roberto C. , Perez‐Gonzalez Victor H. , Cardenas‐Benitez Braulio , Jind Binny , Martinez‐Chapa Sergio O. , Lapizco‐Encinas Blanca H.
Published: March 2019

Insulator‐based dielectrophoresis (iDEP) is the electrokinetic migration of polarized particles when subjected to a non‐uniform electric field generated by the inclusion of insulating structures between two remote electrodes. Electrode spacing is considerable in iDEP systems when compared to electrode‐based DEP systems, therefore, iDEP systems require high voltages to achieve efficient particle manipulation. A consequence of this is the temperature increase within the channel due to Joule heating effects, which, in some cases, can be detrimental when manipulating biological samples. This work presents an experimental and modeling study on the increase in temperature inside iDEP devices. For this, we studied seven distinct channel designs that mainly differ from each other in their post array characteristics: post shape, post size and spacing between posts. Experimental results obtained using a custom‐built copper Resistance Temperature Detector, based on resistance changes, show that the influence of the insulators produces a difference in temperature rise of approximately 4°C between the designs studied. Furthermore, a 3D COMSOL model is also introduced to evaluate heat generation and dissipation, which is in good agreement with the experiments. The model allowed relating the difference in average temperature for the geometries under study to the electric resistance posed by the post array in each design.
Characteristics and content of intrusive images in patients with eating disorders
Authors: Kadriu Fortesa , Claes Laurence , Witteman Cilia , Norré Jan , Vrieze Elske , Krans Julie
Published: March 2019

The aim of this study was to examine the characteristics and content of intrusive images in patients with different subtypes of eating disorders (EDs). Data were collected from 74 ED patients, 22 dieting, and 29 nondieting controls. Participants completed a set of self‐report questionnaires. Intrusive images of ED patients were significantly more repetitive, detailed, vivid, and distressing than intrusive images of dieting and/or nondieting controls. Most of the intrusive images were the same for the ED subtypes; however, patients with anorexia nervosa were more likely to report an observer vantage perspective than patients with bulimia nervosa, who were more likely to report a field vantage perspective. As expected, intrusive images' content was related to body checking (weight and shape) or negative self (evaluated by themselves or others). Finally, there were significant associations between intrusive images' vividness and weight and shape concerns. These findings indicate that intrusive images may be a core element of EDs and targeting intrusive images in therapy may be helpful.
A Modified a‐Stratified Method for Computerized Adaptive Testing
Authors: Gu Lixiong , Ling Guangming , Qu Yanxuan
Published: March 2019

Research has found that the a‐stratified item selection strategy (STR) for computerized adaptive tests (CATs) may lead to insufficient use of high a items at later stages of the tests and thus to reduced measurement precision. A refined approach, unequal item selection across strata (USTR), effectively improves test precision over the STR by allowing more items to be selected from the strata with higher a‐parameter values. However, both approaches ignore the contribution of items' c‐parameters to the information. This study proposes another procedure—maximum information STR (MISTR)—that groups items based on the maximum amount of Fisher information an item can provide. This information is a function of its a‐ and c‐parameters. MISTR can be further modified to select more items from strata with high a‐parameter values (unequal MISTR [UMISTR]). This study evaluated and compared MISTR, UMISTR, STR, and USTR on two aspects of the CAT performance: (a) quality of θ estimation and (b) effectiveness in item pool usage. The results showed that both the MISTR and UMISTR approaches produced more precise ability estimation than the STR approach when the test length was longer and when an item‐exposure‐control procedure was used. The UMISTR produced slightly less precise ability estimation than USTR but led to fewer underused items, indicating a more balanced use of the item pool. These findings suggest that MISTR and UMISTR can be viable alternatives to STR and USTR.
The combined impact of cold smoking and natural antioxidants on quality and shelf life of dolphinfish (Coryphaena hippurus) fillets
Authors: Messina Concetta Maria , Bono Gioacchino , Arena Rosaria , Randazzo Mariano , Morghese Maria , Manuguerra Simona , La Barbera Laura , Ozogul Fatih , Sadok Saloua , Santulli Andrea
Published: March 2019

This study aimed to produce new value‐added products from dolphinfish (Coryphaena hippurus) as fillets when using cold smoking combined with natural antioxidants, obtained from Halocnemum strobilaceum a plant belonging to halophytes. The fillet treatments were controlled (untreated), immersed in standard brine (STD), treated with NaCI and antioxidant before freezing (Aox‐pre) and treated with NaCl and antioxidant after thawing (Aox‐post). The quality of dolphinfish fillets was assessed using sensory, biochemical, microbiological, and technological parameters. Treating fillets with antioxidants before freezing and cold smoking (Aox‐pre) enhanced significantly the shelf life, as well as improved the biochemical, microbiological, and sensory aspects of the product. Aox‐pre fillets had the lowest peroxide values (PV) and malondialdehyde (MDA) content, demonstrating that the immediate treatment of fillets with the polyphenols protected lipids from peroxidation. The smoking process, together with antioxidant treatment, significantly reduced microbial counts after 15 days of storage, compared to the control. Overall, combining antioxidant treatments with cold smoking has a positive effect on the quality of Aox‐pre fillets with respect to both sensory components and biochemical parameters associated with shelf life. Consequently, Aox‐pre treatment enhances the marketability of this species, promoting local and seasonal products, contributing to costal fisheries sustainability.
Knockdown of circulating C1 inhibitor induces neurovascular impairment, glial cell activation, neuroinflammation, and behavioral deficits
Authors: Farfara Dorit , Feierman Emily , Richards Allison , Revenko Alexey S. , MacLeod Robert A. , Norris Erin H. , Strickland Sidney
Published: March 2019

The cross‐talk between blood proteins, immune cells, and brain function involves complex mechanisms. Plasma protein C1 inhibitor (C1INH) is an inhibitor of vascular inflammation that is induced by activation of the kallikrein‐kinin system (KKS) and the complement system. Knockout of C1INH was previously correlated with peripheral vascular permeability via the bradykinin pathway, yet there was no evidence of its correlation with blood–brain barrier (BBB) integrity and brain function. In order to understand the effect of plasma C1INH on brain pathology via the vascular system, we knocked down circulating C1INH in wild‐type (WT) mice using an antisense oligonucleotide (ASO), without affecting C1INH expression in peripheral immune cells or the brain, and examined brain pathology. Long‐term elimination of endogenous C1INH in the plasma induced the activation of the KKS and peritoneal macrophages but did not activate the complement system. Bradykinin pathway proteins were elevated in the periphery and the brain, resulting in hypotension. BBB permeability, extravasation of plasma proteins into the brain parenchyma, activation of glial cells, and elevation of pro‐inflammatory response mediators were detected. Furthermore, infiltrating innate immune cells were observed entering the brain through the lateral ventricle walls and the neurovascular unit. Mice showed normal locomotion function, yet cognition was impaired and depressive‐like behavior was evident. In conclusion, our results highlight the important role of regulated plasma C1INH as it acts as a gatekeeper to the brain via the neurovascular system. Thus, manipulation of C1INH in neurovascular disorders might be therapeutically beneficial.
Panglial gap junctions between astrocytes and olfactory ensheathing cells mediate transmission of Ca2+ transients and neurovascular coupling
Authors: Beiersdorfer Antonia , Scheller Anja , Kirchhoff Frank , Lohr Christian
Published: March 2019

Astrocytes are arranged in highly organized gap junction‐coupled networks, communicating via the propagation of Ca2+ waves. Astrocytes are gap junction‐coupled not only to neighboring astrocytes, but also to oligodendrocytes, forming so‐called panglial syncytia. It is not known, however, whether glial cells in panglial syncytia transmit information using Ca2+ signaling. We used confocal Ca2+ imaging to study intercellular communication between astrocytes and olfactory ensheathing glial cells (OECs) in in‐toto preparations of the mouse olfactory bulb. Our results demonstrate that Ca2+ transients in juxtaglomerular astrocytes, evoked by local photolysis of “caged” ATP and “caged” tACPD, led to subsequent Ca2+ responses in OECs. This transmission of Ca2+ responses from astrocytes to OECs persisted in the presence of neuronal inhibition, but was absent when gap junctional coupling was suppressed with carbenoxolone. When Ca2+ transients were directly evoked in OECs by puff application of DHPG, they resulted in delayed Ca2+ responses in juxtaglomerular astrocytes, indicating that panglial transmission of Ca2+ signals occurred in a bidirectional manner. In addition, panglial transmission of Ca2+ signals from astrocytes to OECs resulted in vasoconstriction of OEC‐associated blood vessels in the olfactory nerve layer. Our results demonstrate functional transmission of Ca2+ signals between different classes of glial cells within gap junction‐coupled panglial networks and the resulting regulation of blood vessel diameter in the olfactory bulb.
An auristatin‐based antibody‐drug conjugate targeting HER3 enhances the radiation response in pancreatic cancer
Authors: Bourillon Laura , Bourgier Céline , Gaborit Nadège , Garambois Véronique , Llès Eva , Zampieri Alexandre , Ogier Charline , Jarlier Marta , Radosevic‐Robin Nina , Orsetti Béatrice , Delpech Hélène , Theillet Charles , Colombo Pierre‐Emmanuel , Azria David , Pèlegrin André , Larbouret Christel , Chardès Thierry
Published: March 2019

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer characterized by poor response to chemotherapy and radiotherapy due to the lack of efficient therapeutic tools and early diagnostic markers. We previously generated the nonligand competing anti‐HER3 antibody 9F7–F11 that binds to pancreatic tumor cells and induces tumor regression in vivo in experimental models. Here, we asked whether coupling 9F7–F11 with a radiosensitizer, such as monomethylauristatin E (MMAE), by using the antibody‐drug conjugate (ADC) technology could improve radiation therapy efficacy in PDAC. We found that the MMAE‐based HER3 antibody‐drug conjugate (HER3‐ADC) was efficiently internalized in tumor cells, increased the fraction of cells arrested in G2/M, which is the most radiosensitive phase of the cell cycle, and promoted programmed cell death of irradiated HER3‐positive pancreatic cancer cells (BxPC3 and HPAC cell lines). HER3‐ADC decreased the clonogenic survival of irradiated cells by increasing DNA double‐strand break formation (based on γH2AX level), and by modulating DNA damage repair. Tumor radiosensitization with HER3‐ADC favored the inhibition of the AKT‐induced survival pathway, together with more efficient caspase 3/PARP‐mediated apoptosis. Incubation with HER3‐ADC before irradiation synergistically reduced the phosphorylation of STAT3, which is involved in chemoradiation resistance. In vivo, the combination of HER3‐ADC with radiation therapy increased the overall survival of mice harboring BxPC3, HPAC cell xenografts or patient‐derived xenografts, and reduced proliferation (KI67‐positive cells). Combining auristatin radiosensitizer delivery via an HER3‐ADC with radiotherapy is a new promising therapeutic strategy in PDAC.
Circulating cKIT and PDGFRA DNA indicates disease activity in Gastrointestinal Stromal Tumor (GIST)
Authors: Jilg Stefanie , Rassner Michael , Maier Jacqueline , Waldeck Silvia , Kehl Victoria , Follo Marie , Philipp Ulrike , Sauter Andreas , Specht Katja , Mitschke Jan , Lange Thoralf , Bauer Sebastian , Jost Philipp J. , Peschel Christian , Duyster Justus , Gaiser Timo , Hohenberger Peter , von Bubnoff Nikolas
Published: March 2019

This prospective trial aimed to investigate whether tumor‐specific cKIT and PDGFRA mutations can be detected and quantified in circulating tumor (ct)DNA in patients with active GIST, and whether detection indicates disease activity. We included 25 patients with active disease and cKIT or PDGFRA mutations detected in tissue. Mutant ctDNA was detected in the peripheral blood plasma using allele‐specific ligation (L‐)PCR and droplet digital (d)PCR. CtDNA harboring tumor‐specific cKIT or PDGFRA mutations was detected at least once in 16 out of 25 patients using L‐PCR (64%) and in 20 out of 25 patients with dPCR (80%). Using dPCR, the absolute numbers of ctDNA fragments (DNA copies/ml) and the mutant allele frequency (MAF; in percent of wild‐type control) strongly correlated with tumor size expressed as RECIST1.1 sum of diameter (SOD) in mm (ρ = 0.3719 and 0.408, respectively, p < 0.0001) and response status (ρ = 0.3939 and 0.392, respectively, p < 0.0001 and p < 0.001). Specificity of dPCR for detection of progression was 79.2% with a sensitivity of 55.2% and dPCR discriminated CR from active disease with a specificity of 96% and s sensitivity of 44.7%. With L‐PCR, correlations of MAF with tumor size and response status were less prominent. Serial ctDNA measurement reflected individual disease courses over time. Targeted panel sequencing of four patients detected additional driver mutations in all cases and secondary resistance mutations in two cases. Thus, ctDNA indicates disease activity in patients with GIST and should be incorporated as companion biomarker in future prospective trials.