bluuebunny/crossref_metadata_2025 huggingface dataset:
Mass Activated Droplet Sorting (MADS) Enables High‐Throughput Screening of Enzymatic Reactions at Nanoliter Scale
Authors: Holland‐Moritz Daniel A. , Wismer Michael K. , Mann Benjamin F. , Farasat Iman , Devine Paul , Guetschow Erik D. , Mangion Ian , Welch Christopher J. , Moore Jeffrey C. , Sun Shuwen , Kennedy Robert T.
Published: December 2019

Microfluidic droplet sorting enables the high‐throughput screening and selection of water‐in‐oil microreactors at speeds and volumes unparalleled by traditional well‐plate approaches. Most such systems sort using fluorescent reporters on modified substrates or reactions that are rarely industrially relevant. We describe a microfluidic system for high‐throughput sorting of nanoliter droplets based on direct detection using electrospray ionization mass spectrometry (ESI‐MS). Droplets are split, one portion is analyzed by ESI‐MS, and the second portion is sorted based on the MS result. Throughput of 0.7 samples s−1 is achieved with 98 % accuracy using a self‐correcting and adaptive sorting algorithm. We use the system to screen ≈15 000 samples in 6 h and demonstrate its utility by sorting 25 nL droplets containing transaminase expressed in vitro. Label‐free ESI‐MS droplet screening expands the toolbox for droplet detection and recovery, improving the applicability of droplet sorting to protein engineering, drug discovery, and diagnostic workflows.
Bioorthogonal Ligation and Cleavage by Reactions of Chloroquinoxalines with ortho‐Dithiophenols
Authors: Li Youshan , Lou Zhenbang , Li Hongyun , Yang Haijun , Zhao Yufen , Fu Hua
Published: December 2019

A bioorthogonal ligation and cleavage method via reactions of chloroquinoxalines (CQ) and ortho‐dithiophenols (DT) is presented. Double nucleophilic substitutions of ortho‐dithiophenols to chloroquinoxalines provide conjugates containing tetracyclic benzo[5,6][1,4]dithiino[2,3‐b]quinoxaline with strong built‐in fluorescence together with release of the other functional molecules. Three cleavable linkers were designed and successfully used in release of the molecules containing biotin from the protein conjugates. The CQ‐DT bioorthogonal reactions can be applied for the bioorthogonal ligations, bioorthogonal cleavages, and trans‐tagging of proteins, and show advantages of readily accessible unnatural orthogonal groups, appealing reaction kinetics (k2≈1.3 m−1 s−1), excellent biocompatibility of orthogonal groups, and high stability of conjugates. This complements previous bioorthogonal reactions and is a new route for protein‐fishing applications and in‐gel fluorescence analysis.
Fragmentverknüpfungen in der Totalsynthese – Bildung von C‐C‐Bindungen über intermediäre Carbanionen oder freie Radikale
Authors: Tomanik Martin , Hsu Ian Tingyung , Herzon Seth B.
Published: December 2019

Fragmentverknüpfungen unter Bildung von C‐C‐Bindungen sind nützlich für die Syntheseplanung. Die Fortschritte auf dem Gebiet der metallkatalysierten Kreuzkupplungen Anfang der 2000er Jahre sorgten für eine hohe Planbarkeit und Zuverlässigkeit bei C‐C‐Verknüpfungen zwischen ungesättigten Synthesebausteinen. In den vergangenen Jahren stieg hingegen das Interesse an Fragmentverknüpfungen, die über carbanionische oder offenschalige (radikalische) Zwischenstufen verlaufen. Radikalische Fragmentverknüpfungen wurden vor allem durch die Weiterentwickelung von Methoden zur Herstellung und Verwendung von Kohlenstoffradikalen unter milden Bedingungen vorangebracht. In diesem Aufsatz geben wir einen Überblick über ausgewählte neue Synthesen, in denen auf Carbanionen oder Radikalen basierende Fragmentverknüpfungen zur Bildung von C‐C‐Bindungen genutzt wurden. Unser Ziel ist, den strategischen Nutzen dieser Bindungsbrüche in ihren jeweiligen Anordnungen hervorzuheben und aus jedem Beispiel breiter anwendbare Lehren zu ziehen, die für Studierende aufschlussreich sein könnten.
Ruthenium(II)‐Catalyzed Asymmetric Inert C−H Bond Activation Assisted by a Chiral Transient Directing Group
Authors: Li Guozhu , Liu Qinzhe , Vasamsetty Laxmaiah , Guo Weicong , Wang Jun
Published: December 2019

A ruthenium(II)‐catalyzed asymmetric intramolecular hydroarylation assisted by a chiral transient directing group has been developed. A series of 2,3‐dihydrobenzofurans bearing chiral all‐carbon quaternary stereocenters have been prepared in remarkably high yields (up to 98 %) and enantioselectivities (up to >99 % ee). By this methodology, a novel asymmetric total synthesis of CB2 receptor agonist MDA7 has been successfully developed.
EGF‐artige und andere disulfidreiche Mikrodomänen als therapeutische Molekülgerüste
Authors: Tombling Benjamin J. , Wang Conan K. , Craik David J.
Published: December 2019

In Peptiden und Proteinen führen Disulfidbrücken typischerweise zu konformativer Einschränkung, welche die biopharmazeutischen Eigenschaften verbessert und das therapeutische Potenzial vergrößert. Unserer Meinung nach stellen disulfidreiche Mikrodomänen von Proteinen möglicherweise eine reichhaltige und unerschlossene Quelle an Wirkstoff‐Leitsubstanzen dar. Eine Untersuchung der Proteindatenbank UniProt zeigt, dass solche Domänen im Pflanzen‐ und Tierreich weit verbreitet sind, und EGF‐artige Domänen am häufigsten vorkommen. EGF‐artige Domänen zeigen eine hohe Vielfalt an Disulfidbrückenstrukturen sowie Arten der Calciumbindung, welche wir hier im Detail klassifizieren. Viele EGF‐artige Domänen sind mit Krankheitsphänotypen assoziiert, und die von ihnen gesteuerten Wechselwirkungen sind potenzielle therapeutische Angriffspunkte. Tatsächlich wurden auf EGF basierende therapeutische Leitsubstanzen identifiziert, und wir schlagen vor, dass diese Domänen mithilfe von chemischen Designstrategien optimiert werden können, um ihr therapeutisches Potenzial zu erweitern. Dieser Aufsatz streicht das Potenzial solcher disulfidreicher Mikrodomänen als zukünftige Peptidtherapeutika heraus.
PIII/PV=O Catalyzed Cascade Synthesis of N‐Functionalized Azaheterocycles
Authors: Nykaza Trevor V. , Li Gen , Yang Junyu , Luzung Michael R. , Radosevich Alexander T.
Published: December 2019

An organocatalytic method for the modular synthesis of diverse N‐aryl and N‐alkyl azaheterocycles (indoles, oxindoles, benzimidazoles, and quinoxalinediones) is reported. The method employs a small‐ring organophosphorus‐based catalyst (1,2,2,3,4,4‐hexamethylphosphetane P‐oxide) and a hydrosilane reductant to drive the conversion of ortho‐functionalized nitroarenes into azaheterocycles through sequential intermolecular reductive C−N cross coupling with boronic acids, followed by intramolecular cyclization. This method enables the rapid construction of azaheterocycles from readily available building blocks, including a regiospecific approach to N‐substituted benzimidazoles and quinoxalinediones.
Complex Carbocyclic Skeletons from Aryl Ketones through a Three‐Photon Cascade Reaction
Authors: Næsborg Line , Jandl Christian , Zech Andreas , Bach Thorsten
Published: December 2019

Starting from readily available 7‐substituted 1‐indanones, products with a tetracyclo[5.3.1.01,704,11]undec‐2‐ene skeleton were obtained upon irradiation at λ=350 nm (eight examples, 49–67 % yield). The assembly of the structurally complex carbon framework proceeds in a three‐photon process comprising an ortho photocycloaddition, a disrotatory [4π] photocyclization, and a di‐π‐methane rearrangement. The flat aromatic core of the starting material is converted into a functionalized polycyclic hydrocarbon with exit vectors in three dimensions. Ring opening reactions at the central cyclopropane ring were explored, which enable the preparation of tricyclo[5.3.1.04,11]undec‐2‐enes and of tricyclo[6.2.1.01,5]undecanes.
Radical Transfer Dissociation for De Novo Characterization of Modified Ribonucleic Acids by Mass Spectrometry
Authors: Calderisi Giovanni , Glasner Heidelinde , Breuker Kathrin
Published: December 2019

Mass spectrometry (MS) can reliably detect and localize all mass‐altering modifications of ribonucleic acids (RNA), but current MS approaches that allow for simultaneous de novo sequencing and modification analysis generally require specialized instrumentation. Here we report a novel RNA dissociation technique, radical transfer dissociation (RTD), that can be used for the comprehensive de novo characterization of ribonucleic acids and their posttranscriptional or synthetic modifications. We demonstrate full sequence coverage for RNA consisting of up to 39 nucleotides and show that RTD is especially useful for RNA with highly labile modifications such as 5‐hydroxymethylcytidine and 5‐formylcytidine.
Deconstructive Oxygenation of Unstrained Cycloalkanamines
Authors: Zhang Jian‐Wu , Wang Yuan‐Rui , Pan Jia‐Hao , He Yi‐Heng , Yu Wei , Han Bing
Published: December 2019

A deconstructive oxygenation of unstrained primary cycloalkanamines has been developed for the first time using an auto‐oxidative aromatization promoted C(sp3)−C(sp3) bond cleavage strategy. This metal‐free method involves the substitution reaction of cycloalkanamines with hydrazonyl chlorides and subsequent auto‐oxidative annulation to in situ generate pre‐aromatics, followed by N‐radical‐promoted ring‐opening and further oxygenation by 2,2,6,6‐tetramethylpiperidine‐1‐oxyl (TEMPO) and m‐cholorperoxybenzoic acid (mCPBA). Consequently, a series of 1,2,4‐triazole‐containing acyclic carbonyl compounds were efficiently produced. This protocol features a one‐pot operation, mild reaction conditions, high regioselectivity and ring‐opening efficiency, broad substrate scope, and is compatible with alkaloids, osamines, and peptides, as well as steroids.
Water Soluble Nickel – metformin ternary complexes: Thermal, DNA binding and molecular docking studies
Authors: Rajeshwari K. , Vasantha P. , Kumar B.S. , Shekhar B. , Lakshmi P.V.A.
Published: December 2019

The Nickel (II) complexes [Ni(Cl)2(metf)(o‐phen)] (1), [Ni(Cl)2(metf)(opda)] (2), [Ni(Cl)2(metf)(en)](3), [Ni(Cl)2(metf)(2,2'‐bipy)](4), (metf = metformin, o‐phen = ortho‐phenanthroline, opda = ortho‐phenylenediamine, en = ethylenediamine, 2–2′ bipy = 2–2′ bipyridyl) were synthesized and characterized using LC–MS, elemental analysis, molar conductance measurements, TGA‐DTA, IR spectroscopy, magnetic moment measurements and electronic spectroscopy. The central Ni2+ was found to be in octahedral geometry. The DNA interaction of these complexes have been studied by UV–visible absorption studies, fluorescence emission technique and viscosity measurement. The complexes showed absorption hyperchromism in UV–visible spectra with calf thymus DNA. The binding constants from UV–visible absorption studies were 7.42 × 104, 0.74 × 104, 3.19 × 104, 5.9 × 104 M−1 for 1, 2, 3 and 4, respectively and Stern‐Volmer quenching constants from fluorescence studies were 0.16, 0.41, 0.23, 0.18, respectively. Viscosity measurements revealed that the binding of the complexes with DNA could be surface binding, mainly due to groove binding. The highest DNA cleavage activity of the complexes is recorded for complex 1. The complexes were docked in to B‐DNA sequence, 5′(D*AP*CP*CP*GP*AP*CP* GP*TP*CP*GP*GP*T)‐3′ retrieved from protein data bank (PDB ID: 423D), using Discovery Studio 2.1 software. C Docker Intectraction energy of 1, 2, 3 and 4 complexes is 32.027, 31.427, 35.393 and 30.521 respectively. The highest docking score is seen for complex 3.
Green synthesis and antifungal mechanism of silver nanoparticles derived from chitin‐ induced exometabolites of Trichoderma interfusant
Authors: Hirpara Darshna G. , Gajera H.P.
Published: December 2019

The potent biocontrol agent Trichoderma interfusant (Fu21) derived by protoplast fusion of mycoparasitic T.virens NBAII Tvs12 and multistress (fungicides and abiotic stress) tolerant T. koningii MTCC796. The chitin‐induced exometabolites harvested by culturing the diverse and stress tolerant Trichoderma fusant (Fu21) and utilized for synthesis of green silver nanoparticles (Ag‐NPs). Green Ag‐NPs characterized for size (62.6 nm in PSA), shape (spherical with 59.66 ± 4.18 nm under SEM), stability (51.2 mv as ZETA) and purity (3.40 ke V peak corresponded to the binding energy of silver under EDAX). A Fourier transform infrared spectroscopy exhibited electromagnetic spectra of various functional groups of exometabolites conforming the synthesis of green Ag‐NPs. We investigated novel route and mechanism of mycelial degradation at minimum inhibitory concentration (MIC) of green nanoformulation (20 μg Ag.ml−1) to restrain phytopathogen Sclerotium rolfsii. The antifungal action of green Ag‐NPs on MIC at 3 DAI elevated the mycelial cell membrane leakages (sugars and proteins), lipid peroxidation, depressed the respiratory chain dehydrogenase activity and destroyed the structure of S. rolfsii mycelia (SEM morphology) which cause phytopathogen to die. The use of green Ag‐NPs as antifungal agent is considered to be eco‐friendly resource, alternate to fungicides and cost‐effective means to diminish phytopathogen S. rolfsii causing stem rot in groundnut. Further, bioefficacy of green Ag‐NPs against S. rolfsii may be tested under field condition in groundnut rhizosphere which proved sustainability and it's advancement towards greener chemistry.
Green‐synthesized Zinc oxide nanoparticle, an efficient safe anticancer compound for human breast MCF7 cancer cells
Authors: Salari Sahar , Neamati Ali , Tabrizi Masoud Homayouni , Seyedi Seyed Mohammad Reza
Published: December 2019

There are many types of researches investigating anticancer therapeutics for breast cancer therapy. Zinc oxide nanoparticles (ZnONPs) as an efficient drug delivery system, has been widely being used in various biomedical applications. In the current study, we synthesized ZnONP applying Rheum rhaponticum Waste (RRW) as a novel bio‐platform to investigate its anticancer impacts on MCF7 breast cancer cells compared with normal Human HFF and HDF cells. In this regard, RRW was triggered to synthesize the ZnONPs. Then, they were characterized by XRD, FTIR, TEM, and SEM analysis. Next, the MCF‐7, HFF, and HDF cell lines were cultured and treated as the following plane: Incubation of all cell lines for 72, 48, and 24 hours at the presence of different ZnONPs doses. Finally, the cell morphology, BCL2‐ BAX genes expression profile and AO/PI‐fluorescent cell staining on the 48‐hour incubated cells were analyzed to check the ZnONP apoptotic activity. Moreover, the ZnONP antioxidant activity was analyzed by a DPPH antioxidant test. We produced the 30 nm ZnONPs which significantly increased the BAX and decreased the BCL‐2 gene expression. According to the results including the Sub G1 enhancement peaks, apoptotic hallmarks, MTT assay, and the AO/PI‐fluorescent stained cells, ZnONPs can specifically induce apoptotic death in MCF7 breast cancer cells compared with normal HFF and HDF cells. The IC50 values of MCF‐7 in 72, 48, and 24 hr were measured at 8, 11, and 12 μg/ml in 72, 48, and 24 hr, respectively. This is while the mentioned values in the normal cells (HFF, HDF) were estimated at higher treatment doses. In conclusion, we suggest that the ZnONPs have the potential to be applied as a safe cell‐specific apoptosis inducer in breast cancer treatment. However, there are many challenges that need to be clarified for applying them as an efficient anticancer agent.
Effectively promoted catalytic activity by adjusting calcination temperature of Ce‐Fe‐Ox catalyst for NH3‐SCR
Authors: Song Zhongxian , Xing Yun , Zhang Tingji , Zhao Jinggang , Wang Junkai , Mao Yanli , Zhao Baolin , Zhang Xuejun , Zhao Min , Ma Ziang
Published: December 2019

A series of Ce‐Fe‐Ox catalysts prepared by the different calcination temperatures (marked as CF‐X, where X represented calcination temperature) were used to the selectivity catalytic reduction of NOx by NH3. The results explained the relationship between calcination temperature and the sulfate species over Ce‐Fe‐Ox, and then investigated the surface acidity and catalytic performance. The large amounts of sulfate species were formed over CF‐450 and CF‐550 while it was decomposed with further the increasing of calcination temperature, which resulted in the loss of surface acidity, causing a decrease in the catalytic activity over Ce‐Fe‐Ox. Thereby, the CF‐450 catalyst showed the best catalytic activity and over 90% NOx conversion was obtained at 244–450 °C. Besides, the favored pore structure, more Fe3+ active species, higher Ce3+ concentration and the abundance of chemical adsorbed oxygen species, as well as the surface acid sites, would together contribute to the excellent catalytic activity of CF‐450 catalyst.
Multiscale techniques for 3D imaging of magnetic data for archaeo‐geophysical investigations in the Middle East: the case of Tell Barri (Syria)
Authors: Florio Giovanni , Cella Federico , Speranza Luca , Castaldo Raffaele , Pierobon Benoit Raffaella , Palermo Rocco
Published: December 2019

Recent techniques of three‐dimensional (3D) imaging of potential field anomalies are effective in estimating the source position in the subsurface by exploiting both the differentiation of the field and the stability of the method. Such a processing is fast and especially suitable for detecting isolated and compact sources, as usually are those of archaeological interest. Among these methods we employed techniques that take advantage from innovative concepts like the multiscale transformation and the scaling function, going well beyond the standard procedures usually employed for data processing with archaeological purposes. We interpreted magnetic data acquired during two geophysical surveys carried out in 2008 and 2010 at Tell Barri, in north‐eastern Syria. Tell Barri is a relevant site for the history of North Mesopotamia. The earliest settlement dates back to the end of the fourth millennium bce whereas the site has been occupied – with no major breaks – until the fourteenth century ce. Based on the magnetic data interpretation, we have selected a test area as a target for an archeological excavation. The excavation found ancient structures closely matching the magnetic source revealed by the geophysical imaging. Since both the ground soil and the material of buried archaeological structures are representative of several ancient settlements in a much larger area (Upper Mesopotamia), we believe that such a geophysical approach could be successful in many archaeological sites scattered through this broad region.
Improved lignocellulolytic enzyme production and antioxidant extraction using solid‐state fermentation of olive pomace mixed with winery waste
Authors: Filipe Diogo , Fernandes Helena , Castro Carolina , Peres Helena , Oliva‐Teles Aires , Belo Isabel , Salgado José M.
Published: December 2019

Olive pomace is characterized by its low nutritional value and high phenolic content, which hinders its direct use as animal feed, fertilizer, or as a substrate in bioprocesses such as solid‐state fermentation (SSF). A possible strategy for bioprocessing olive pomace by SSF is the mixture of olive mill wastes with other wastes produced in the same region, such as winery wastes. This may improve the production of bioactive compounds like enzymes and antioxidant phenolics. A simplex‐centroid design was used to evaluate the use of olive mill and winery wastes alone or in combination as a substrate for SSF with Aspergillus niger and Aspergillus ibericus. Synergistic effects of combinations of crude olive pomace (COP), exhausted olive pomace (EOP), vine trimming shoots (VTS), and exhausted grape marc (EGM) were observed in the production of xylanases, cellulases, β‐glucosidases, and in the variation in total phenolics and antioxidant activity of SFF extracts. A multiple response optimization was carried out, leading to the following optimal mixture of substrates: for A. niger, 23% (w/w) COP, 30% EGM, 33% VTS, 14% EOP; for A. ibericus, 30% EGM, 36% VTS, 34% EOP. The scale‐up to tray bioreactor with optimal substrate made it possible to achieve the maximum xylanase, cellulase, and β‐glucosidase production of 189.1 ± 26.7, 56.3 ± 2.1 and 10.9 ± 0.8 U/g, respectively. The antioxidant activity of fermented wastes was also improved 2.2‐fold as compared with unfermented wastes. Thus, a combination of olive mill and winery wastes in SSF is a potential strategy to increase their value and to develop a circular strategy in these industries. © 2019 Society of Chemical Industry and John Wiley & Sons, Ltd.
Micellar‐based spectrofluorimetric method for the selective determination of ledipasvir in the presence of sofosbuvir: application to dosage forms and human plasma
Authors: Abdel‐Lateef Mohamed A. , Ali Ramadan , Omar Mahmoud A. , Derayea Sayed M.
Published: December 2019

A fast, low‐cost, sensitive, and selective spectrofluorimetric method for the determination of ledipasvir was developed and validated. The method is based on an enhancement in the native fluorescence intensity of ledipasvir by 500% of its original value by the formation of hydrogen bonds between the cited drug and Tween‐20 in the micellar system (pH = 5.0). All fluorescence measurements were carried out at 425 nm and 340 nm for emission and excitation wavelengths, respectively. A linear relationship between the concentration of ledipasvir and the observed fluorescence intensity was achieved in the range of 0.1–2.0 μg ml−1 with 0.028, 0.084 μg ml−1, for detection and quantitation limits, respectively. The acquired selectivity and sensitivity using the proposed method facilitate the analysis of ledipasvir in spiked human plasma with sufficient percentage recovery (95.36–99.30%). The proposed method was developed and validated according to International Council for Harmonisation (ICH) guidelines. Moreover, the cited drug was successfully determined in its pharmaceutical dosage form using the proposed method. In addition, the validity of the proposed results was statistically confirmed using Student's t‐test, variance ratio F‐test, and interval hypothesis test.
Improved succinate production from galactose‐rich feedstocks by engineered Escherichia coli under anaerobic conditions
Authors: Zhu Fayin , San Ka‐Yiu , Bennett George N.
Published: December 2019

It is of great economic interest to produce succinate from low‐grade carbon sources, which can make it more economically competitive against petrochemical‐based succinate. Galactose sugars constitute a significant fraction of the soluble carbohydrate in a meal from agricultural sources which is considered a low value or waste byproduct of oilseed processing. To improve the galactose utilization, the effect of galR and glk on sugars uptake was investigated by deactivation of each gene in three previously engineered host strains. As expected, glk plays an important role in glucose uptake, while, the effect of deactivation of galR is highly dependent on the strength of the downstream module (succinate production module). A new succinate producer FZ661T was constructed by enhancement of the succinate producing module and manipulation of the gal operon. The succinate productivity reached 4.57 g/L/hr when a mixed sugar feedstock was used as a carbon source in shake‐flask fermentation, up to 812 mM succinate was accumulated in 80 hr in fed‐batch fermentation. When SoyMolaGal hydrolysate was used as a carbon source, 628 mM (74 g/L) succinate was produced within 72 hr. In this study, we demonstrate that FZ661T can produce succinate quickly with relatively high yield, giving it the potential for industrial application.
What do clinical supervision research reviews tell us? Surveying the last 25 years
Authors: Watkins C. Edward
Published: December 2019

What do clinical supervision research reviews across the last 25 years tell us? That question is subsequently examined. Based on database and literature searches, 20 reviews appearing from 1995 through 2019 were identified for survey examination; consistencies, inconsistencies and other defining features were determined across reviews; and the survey findings and their implications are considered. Primary findings are as follows: (a) ‘proof’ for supervision appears to be more ‘proof by association’ than otherwise, being primarily a product of ex post facto, cross‐sectional, correlational study; (b) evidence supporting supervision impact of any type is weak at best, especially so for worker and client outcomes; (c) supervision models generally lack empirical foundation; (d) evidence‐based supervision appears to be more a hope and dream than supervision‐based reality at present; and (e) the primary methodological problems that plagued supervision research in the 1990s are still all too frequent in modern research. Some questions to entertain about supervision going forward, and some remedies for improving its research, are proposed.
Mechanophysical Cues in Extracellular Matrix Regulation of Cell Behavior
Authors: Wang Tuntun , Nanda Sitansu Sekhar , Papaefthymiou Georgia C. , Yi Dong Kee
Published: December 2019

The extracellular matrix (ECM) is a macromolecular network that can provide biochemical and structural support for cell adhesion and formation. It regulates cell behavior by influencing biochemical and physical cues. It is a dynamic structure whose components are modified, degraded, or deposited during connective tissue development, giving tissues strength and structural integrity. The physical properties of the natural ECM environment control the design of naturally or synthetically derived biomaterials to guide cell function in tissue engineering. Tissue engineering is an important field that explores physical cues of the ECM to produce new viable tissue for medical applications, such as in organ transplant and organ recovery. Understanding how the ECM exerts physical effects on cell behavior, when cells are seeded in synthetic ECM scaffolds, is of utmost importance. Herein we review recent findings in this area that report on cell behaviors in a variety of ECMs with different physical properties, i.e., topology, geometry, dimensionality, stiffness, and tension.
Heparan sulfate maintains adult midgut homeostasis in Drosophila
Authors: Wei Min , Shi Lin , Kong Ruiyan , Zhao Hang , Li Zhouhua
Published: December 2019

Tissue homeostasis is controlled by the differentiated progeny of residential progenitors (stem cells). Adult stem cells constantly adjust their proliferation/differentiation rates to respond to tissue damage and stresses. However, how differentiated cells maintain tissue homeostasis remains unclear. Here, we find that heparan sulfate (HS), a class of glycosaminoglycan (GAG) chains, protects differentiated cells from loss to maintain intestinal homeostasis. HS depletion in enterocytes (ECs) leads to intestinal homeostasis disruption, with accumulation of intestinal stem cell (ISC)‐like cells and mis‐differentiated progeny. HS‐deficient ECs are prone to cell death/stress and induced cytokine and epidermal growth factor (EGF) expression, which, in turn, promote ISC proliferation and differentiation. Interestingly, HS depletion in ECs results in the inactivation of decapentaplegic (Dpp) signaling. Moreover, ectopic Dpp signaling completely rescued the defects caused by HS depletion. Together, our data demonstrate that HS is required for Dpp signal activation in ECs, thereby protecting ECs from ablation to maintain midgut homeostasis. Our data shed light into the regulatory mechanisms of how differentiated cells contribute to tissue homeostasis maintenance.
DJ‐1 inhibits autophagy activity of prostate cancer cells by repressing JNK–Bcl2–Beclin1 signaling
Authors: Qin Xiangcheng , Lu Aimei , Ke Meilin , Zhu Weizhi , Ye Xiaolei , Wang Gang , Weng Guobin
Published: December 2019

The regulation of DJ‐1 on AR signaling plays an important role in the pathogenesis of prostate cancer (PCa). DJ‐1 could alter autophagy and regulate Beclin1‐involved autophagy response through JNK‐dependent pathway. JNK is known to mediate autophagy through Bcl2–Beclin1 complex. Therefore, this study aimed to investigate the significance of autophagy in DJ‐1‐modulated PCa cells. The current studies showed that DJ‐1 overexpression in LNCaP decreased LC3 transformation and autophagosome formation. However, DJ‐1 knockdown exerted the opposite effect. Moreover, DJ‐1 silencing inhibited survival and promoted death in LNCaP, which was recovered by autophagy inhibition with 3‐MA. In addition, DJ‐1 overexpression inhibited the phosphorylation of JNK and Bcl2, and the dissociation of Beclin1 and Bcl2; while the effect of silencing DJ‐1 was completely opposite. More important, JNK activated by anisimycin inhibited the proliferation and promoted death of DJ‐1‐overexpressed LNCaP while increasing LC3 transformation and LC3‐puncta formation, but these results were reversed by the decrease of Beclin1 (by spautin‐1). In contrast, when DJ‐1 was silenced, the death of LNCaP, LC3 transformation, and LC3‐puncta formation were inhibited by JNK inhibitor SP600125, which promoted cell proliferation. However, Bcl2 inhibition (by ABT737) reversed all the effects of SP600125. Our results suggested that DJ‐1 in PCa cells could promote the growth of PCa through autophagy inhibition, and JNK–Bcl2–Beclin1 signaling played an important role in it. The study provided new insights into the role of DJ‐1 in the development of PCa.
Molecular Chirality in Classical Spacetime: Solving the Controversy about the Spinning Cone Model of Rotating Molecules
Authors: Petitjean Michel
Published: December 2019

The spinning cone is a model of rotating molecules used by Barron in 1986 in relation to asymmetric synthesis and to parity violation. He considered that the non‐translating cone spinning about its symmetry axis has false chirality (i.e., it is not chiral), whereas Mislow concluded in 1999 that it is indeed chiral and severely criticized the true versus false chirality nomenclature introduced by Barron, who still disagreed in 2013 with the conclusion of Mislow. Here, it is shown that this controversy comes from an ambiguity in the spinning cone model and that in fact both authors were right. Light is thrown on the true chirality versus false chirality controversy with a very recently published result, which was thus unavailable to both authors: this is a new definition of chirality that encompasses the one introduced by Lord Kelvin at the end of the 19th century.
Copper Bis(oxazoline)‐Catalyzed Enantioselective Alkynylation of Benzopyrylium Ions
Authors: Guan Yong , Attard Jonathan W. , Mattson Anita E.
Published: December 2019

The stereocontrolled construction of biologically relevant chromanones and tetrahydroxanthones has been achieved through the addition of alkynes to benzopyrylium trilfates under the influence of copper bis(oxazoline) catalysis. Excellent levels of enantiocontrol (63–98 % ee) are achieved in the addition of a variety of alkynes to an array of chromenones with a hydrogen in the 2‐position. Promising levels of enantiocontrol (54–67 % ee) are achieved in the alkynylation of chromenones with esters in the 2‐position, generating tertiary ether stereocenters resembling those frequently found in naturally occurring metabolites.
Bimodal Heterogeneous Functionality in Redox‐Active Conjugated Microporous Polymer toward Electrocatalytic Oxygen Reduction and Photocatalytic Hydrogen Evolution
Authors: Singh Ashish , Verma Parul , Samanta Debabrata , Singh Tarandeep , Maji Tapas Kumar
Published: December 2019

The designing and development of heterogeneous catalysts for conversion of renewable energy to chemical energies by electrochemical as well as photochemical processes is at the forefront of energy research. In this work, two new donor–acceptor‐based redox‐active conjugated microporous polymers (CMPs) (TAPA‐OPE‐mix and TAPA‐OPE‐gly) are synthesized through Schiff base condensation reaction using a microwave synthesizer. Notably, the asymmetric and symmetric bola‐amphiphilic nature of the OPE struts results in distinct nanostructuring and morphologies in the CMPs. Interestingly, both CMPs show impressive heterogeneous catalytic activity toward electrochemical O2 reduction and photocatalytic H2 evolution reactions, and therefore, act as bimodal electro‐ and photocatalytic porous organic materials. Furthermore, the redox‐active property of the CMPs is exploited for in situ generation and stabilization of platinum nanoparticles (Pt), and these Pt@CMPs exhibit significantly enhanced photocatalytic activity.
Monofluoroalkene‐Isostere as a 19F NMR Label for the Peptide Backbone: Synthesis and Evaluation in Membrane‐Bound PGLa and (KIGAKI)3
Authors: Drouin Myriam , Wadhwani Parvesh , Grage Stephan L. , Bürck Jochen , Reichert Johannes , Tremblay Sébastien , Mayer Marie Sabine , Diel Christian , Staub Alexander , Paquin Jean‐François , Ulrich Anne S.
Published: December 2019

Solid‐state 19F NMR is a powerful method to study the interactions of biologically active peptides with membranes. So far, in labelled peptides, the 19F‐reporter group has always been installed on the side chain of an amino acid. Given the fact that monofluoroalkenes are non‐hydrolyzable peptide bond mimics, we have synthesized a monofluoroalkene‐based dipeptide isostere, Val‐Ψ[(Z)‐CF=CH]‐Gly, and inserted it in the sequence of two well‐studied antimicrobial peptides: PGLa and (KIGAKI)3 are representatives of an α‐helix and a β‐sheet. The conformations and biological activities of these labeled peptides were studied to assess the suitability of monofluoroalkenes for 19F NMR structure analysis.
Conversion/Alloying Pseudocapacitance‐Dominated Perovskite KZnF3 Anode for Advanced Lithium‐Based Dual‐Ion Batteries
Authors: Ying Danfeng , Ding Rui , Huang Yongfa , Yan Tong , Huang Yuxi , Tan Caini , Sun Xiujuan , Gao Ping , Liu Enhui
Published: December 2019

Cost‐competitive perovskite fluoride KZnF3 has been introduced for the first time as an advanced anode for high‐performance lithium‐based dual‐ion batteries, exhibiting conversion/alloying hybrid mechanisms and dominated pseudocapacitive kinetics for Li‐ion storage.
Boron‐Doped PdCuAu Nanospine Assembly as an Efficient Electrocatalyst toward Formic Acid Oxidation
Authors: Wang Hongjing , Qian Xiaoqian , Liu Songliang , Yin Shuli , Xu You , Li Xiaonian , Wang Ziqiang , Wang Liang
Published: December 2019

Control of the composition and morphology of Pd‐based electrocatalysts is a promising strategy for the development of efficient direct formic acid fuel cells. Herein, a two‐step method is presented for the design of B‐doped PdCuAu nanospine assemblies (B‐PdCuAu NAs) using NaBH4 as the boron dopant. The boron content can be tailored easily by tuning the reaction time, and an optimal boron content is beneficial to promote the formic acid oxidation reaction. Such B‐PdCuAu NAs exhibit superior mass and specific activities to commercial Pd black and PdCuAu NAs in alkaline solution. The excellent catalytic performance of B‐PdCuAu NAs may arise from the increase in surface active sites and the electronic effect of boron modification. This work provides a facile synthesis of the B‐doped metallic catalysts and highlights the boron modification in improving their performance as anode electrocatalysts for fuel cells.
Chiral Phosphoric Acid Creates Promising Opportunities for Enantioselective Photoredox Catalysis
Authors: Li Shaoyu , Xiang Shao‐Hua , Tan Bin
Published: December 2019

In recent years, visible light driven enantioselective chemical transformations have emerged as new additions to the toolkit of synthetic chemists to accomplish more efficient assembly of chiral molecules. Nonetheless, implementing precise stereocontrol on photoinduced intermolecular radical coupling process remains arduous. Recent studies unveil the underexplored competence of chiral phosphoric acid for this class of asymmetric photoredox reactions, endowed by its capability as a bifunctional H‐bonding catalyst for synchronous interaction with radical intermediate and substrate while channeling the cross‐coupling in a highly enantioselective manner. This paper highlights the recent advances, future outlook as well as the prospective challenges in this research area.
A single‐institution, randomized, pilot study evaluating the efficacy of gabapentin and methadone for patients undergoing chemoradiation for head and neck squamous cell cancer
Authors: Hermann Gregory M. , Iovoli Austin J. , Platek Alexis J. , Wang Chong , Miller Austin , Attwood Kristopher , Bourgeois Daniel J. , Singh Anurag K.
Published: December 2019

Background

The objective of the current study was to compare the safety and efficacy between 2 analgesic regimens for patients with head and neck cancer (HNC) undergoing definitive chemoradiation (CRT).

Methods

The current study was a prospective, single‐institution, 2‐arm, randomized pilot study. Patients with American Joint Committee on Cancer seventh edition stage II to stage IV squamous cell carcinoma of the head and neck who were undergoing CRT were randomized to either arm 1, which entailed high‐dose gabapentin (2700 mg daily) with the institutional standard of care (hydrocodone and/or acetaminophen progressing to fentanyl as needed), or arm 2, which comprised low‐dose gabapentin (900 mg daily) with methadone. The primary endpoints were safety and toxicity. Secondary endpoints were pain, opioid requirement, and quality of life (QOL). Differences between the treatment arms at multiple time points were compared using a generalized linear mixed regression model with Sidak correction.

Results

A total of 60 patients (31 in arm 1 and 29 in arm 2) were enrolled from April 2015 to August 2017. There was no difference between the treatment arms with regard to adverse events or serious adverse events. Pain was not found to be different between the treatment arms. More patients in arm 1 did not require an opioid during treatment (42% vs 7%; P = .002). Patients in arm 2 experienced significantly better QOL outcomes across multiple domains, including overall health (P = .05), physical functioning (P = .04), role functioning (P = .01), and social functioning (P = .01).

Conclusions

High‐dose prophylactic gabapentin increased the percentage of patients who required no opioid during treatment. Methadone may improve QOL compared with a regimen of short‐acting opioids and fentanyl. However, pain was found to significantly worsen throughout treatment regardless of treatment arm, necessitating further studies to identify a more optimal regimen.
All‐Metallic Zn=Zn Double‐π Bonded Octahedral Zn2M4 (M=Li, Na) Clusters with Negative Oxidation State of Zinc
Authors: Liu Xingman , Zhang Min , Wu Shuixing , Zhong Ronglin , Liu Yingying , Arif Ali Muhammad , Geng Yun , Su Zhongmin
Published: December 2019

Zn=Zn double bonded‐especially double‐π bonded‐systems are scarce due to strong Coulomb repulsion caused by the Zn atom's internally crowded d electrons and very high energy of the virtual π orbitals in Zn2 fragments. It is also rare for Zn atoms to exhibit negative oxidation states within reported Zn−Zn bonded complexes. Herein, we report Zn=Zn double‐π bonded octahedral clusters Zn2M4 (M=Li, Na) bridged by four alkali metal ligands, in which the central Zn atom is in a negative oxidation state. Especially in D4h−Zn2Na4, the natural population analysis shows that the charge of the Zn atom reaches up to −0.89 |e| (−1.11 |e| for AIM charge). Although this cooperation inevitably increases the repulsion between two Zn atoms, the introduction of the s1‐type ligands results in occupation of degenerated π orbitals and the electrons being delocalized over the whole octahedral framework as well, in turn stabilizing the octahedral molecular structure. This study demonstrates that maintaining the degeneracy of the π orbitals and introducing electrons from equatorial plane are effective means to construct double‐π bonds between transitional metals.
Localizing Binding Sites on Bioconjugated Hydrogen‐Bonded Organic Semiconductors at the Nanoscale
Authors: Koehler Melanie , Farka Dominik , Yumusak Cigdem , Serdar Sariciftci Niyazi , Hinterdorfer Peter
Published: December 2019

Hydrogen‐bonded organic semiconductors are extraordinarily stable organic solids forming stable, large crystallites with the ability to preserve favorable electrical properties upon bioconjugation. Lately, tremendous efforts have been made to use these bioconjugated semiconductors as platforms for stable multifunctional bioelectronics devices, yet the detailed characterization of bio‐active binding sites (orientation, density, etc.) at the nanoscale has not been achieved yet. The presented work investigates the bioconjugation of epindolidione and quinacridone, two representative semiconductors, with respect to their exposed amine‐functionalities. Relying on the biotin‐avidin lock‐and‐key system and applying the atomic force microscopy (AFM) derivative topography and recognition (TREC) imaging, we used activated biotin to flag crystal‐faces with exposed amine functional groups. Contrary to previous studies, biotin bonds were found to be stable towards removal by autolysis. The resolution strength and clear recognition capability makes TREC‐AFM a valuable tool in the investigation of bio‐conjugated, hydrogen‐bonded semiconductors.
Body‐related cognitive distortions (thought–shape fusion body) associated with thin‐ideal exposure in female students—An ecological momentary assessment study
Authors: Wyssen Andrea , Leins Judith , Reichenberger Julia , Blechert Jens , Munsch Simone , Steins‐Loeber Sabine
Published: December 2019

Etiological models of eating disorders (EDs) describe body dissatisfaction (BD)as one of the major influences fostering dysfunctional body‐related behaviour and disordered eating behaviour. BD is influenced by repeated exposure to thin ideals that evoke high self‐ideal discrepancy and result in body‐related cognitive distortions such as thought–shape fusion body (TSF‐B). The aim of this study was to investigate the covariation of daily media exposure and the experience of TSF‐B in a naturalistic setting. It was further analysed whether TSF‐B is associated with self‐ideal discrepancy, dysfunctional body‐related behaviour, and disordered eating behaviour. Moreover, person‐related predictors of TSF‐B were explored. Altogether, 51healthy female students (mean age 21.06years, SD = 1.76) participated in an ecological momentary assessment study with four daily surveys during 10consecutive days. Exposure with thin ideals in contrast to exposure to unspecific media contents went along with the experience of TSF‐B. TSF‐B was associated with higher self‐ideal discrepancy and dysfunctional body‐related behaviour as well as more pronounced disordered eating behaviour, suggesting that TSF‐B is a common phenomenon in young healthy females' everyday life. A main effect of trait measures (e.g., pre‐existing BD) on TSF‐B was observable but has no moderating effect. Thus, a specific vulnerability has not been detected.
Fine‐Needle Aspiration for the Evaluation of Hepatic Pharmacokinetics of Vaniprevir: A Randomized Trial in Patients With Hepatitis C Virus Infection
Authors: Gao Wei , Webber Andrea L. , Maxwell Jill , Anderson Melanie , Caro Luzelena , Chung Chris , Miltenburg André M.M. , Popa Serghei , Van Dyck Kristien , Wenning Larissa , Mangin Eric , Fandozzi Christine , Railkar Radha , Shire Norah J. , Fraser Iain , Howell Bonnie , Talal Andrew H. , Stoch S. Aubrey
Published: December 2019

Fine‐needle aspiration (FNA) for serial hepatic sampling may be an efficient and less invasive alternative to core needle biopsy (CNB), the current standard for liver tissue sampling. In this randomized, open‐label trial in 31 participants with hepatitis C virus genotype 1 infection (NCT01678131/Merck protocol PN048), we evaluated the feasibility of using FNA to obtain human liver tissue samples appropriate for measuring hepatic pharmacokinetics (PK), using vaniprevir as a tool compound. The primary end point was successful retrieval of liver tissue specimens with measurable vaniprevir concentrations at two of three specified FNA time points. Twenty‐nine patients met the primary end point and, therefore, were included in the PK analyses. Hepatic vaniprevir concentrations obtained with FNA were consistent with known vaniprevir PK properties. The shape of liver FNA and CNB concentration‐time profiles were comparable. In conclusion, FNA may be effective for serial tissue sampling to assess hepatic drug exposure in patients with liver disease.
Assessment of Maternal and Fetal Dolutegravir Exposure by Integrating Ex Vivo Placental Perfusion Data and Physiologically‐Based Pharmacokinetic Modeling
Authors: Freriksen Jolien J.M. , Schalkwijk Stein , Colbers Angela P. , Abduljalil Khaled , Russel Frans G.M. , Burger David M. , Greupink Rick
Published: December 2019

Antiretroviral therapy during pregnancy reduces the risk of vertical HIV‐1 transmission. However, drug dosing is challenging as pharmacokinetics (PK) may be altered during pregnancy. We combined a pregnancy physiologically‐based pharmacokinetic (PBPK) modeling approach with data on placental drug transfer to simulate maternal and fetal exposure to dolutegravir (DTG). First, a PBPK model for DTG exposure in healthy volunteers was established based on physiological and DTG PK data. Next, the model was extended with a fetoplacental unit using transplacental kinetics obtained by performing ex vivo dual‐side human cotyledon perfusion experiments. Simulations of fetal exposure after maternal dosing in the third trimester were in accordance with clinically observed DTG cord blood data. Furthermore, the predicted fetal trough plasma concentration (Ctrough) following 50 mg q.d. dosing remained above the concentration that results in 90% of viral inhibition. Our integrated approach enables simulation of maternal and fetal DTG exposure, illustrating this to be a promising way to assess DTG PK during pregnancy.
Pharmacodynamics of Glyburide, Metformin, and Glyburide/Metformin Combination Therapy in the Treatment of Gestational Diabetes Mellitus
Authors: Shuster Diana L. , Shireman Laura M. , Ma Xiaosu , Shen Danny D. , Flood Nichols Shannon K. , Ahmed Mahmoud S. , Clark Shannon , Caritis Steve , Venkataramanan Raman , Haas David M. , Quinney Sara K. , Haneline Laura S. , Tita Alan T. , Manuck Tracy A. , Thummel Kenneth E. , Brown Linda Morris , Ren Zhaoxia , Brown Zane , Easterling Thomas R. , Hebert Mary F.
Published: December 2019

In gestational diabetes mellitus (GDM), women are unable to compensate for the increased insulin resistance during pregnancy. Data are limited regarding the pharmacodynamic effects of metformin and glyburide during pregnancy. This study characterized insulin sensitivity (SI), β‐cell responsivity, and disposition index (DI) in women with GDM utilizing a mixed‐meal tolerance test (MMTT) before and during treatment with glyburide monotherapy (GLY, n = 38), metformin monotherapy (MET, n = 34), or GLY and MET combination therapy (COMBO; n = 36). GLY significantly decreased dynamic β‐cell responsivity (31%). MET and COMBO significantly increased SI (121% and 83%, respectively). Whereas GLY, MET, and COMBO improved DI, metformin (MET and COMBO) demonstrated a larger increase in DI (P = 0.05) and a larger decrease in MMTT peak glucose concentrations (P = 0.03) than subjects taking only GLY. Maximizing SI with MET followed by increasing β‐cell responsivity with GLY or supplementing with insulin might be a more optimal strategy for GDM management than monotherapy.
Broad‐Spectrum Profiling of Drug Safety via Learning Complex Network
Authors: Liu Ke , Ding Ruo‐Fan , Xu Han , Qin Yang‐Mei , He Qiu‐Shun , Du Fei , Zhang Yun , Yao Li‐Xia , You Pan , Xiang Yan‐Ping , Ji Zhi‐Liang
Published: December 2019

Drug safety is a severe clinical pharmacology and toxicology problem that has caused immense medical and social burdens every year. Regretfully, a reproducible method to assess drug safety systematically and quantitatively is still missing. In this study, we developed an advanced machine learning model for de novo drug safety assessment by solving the multilayer drug‐gene‐adverse drug reaction (ADR) interaction network. For the first time, the drug safety was assessed in a broad landscape of 1,156 distinct ADRs. We also designed a parameter ToxicityScore to quantify the overall drug safety. Moreover, we determined association strength for every 3,807,631 gene‐ADR interactions, which clues mechanistic exploration of ADRs. For convenience, we deployed the model as a web service ADRAlert‐gene at http://www.bio-add.org/ADRAlert/. In summary, this study offers insights into prioritizing safe drug therapy. It helps reduce the attrition rate of new drug discovery by providing a reliable ADR profile in the early preclinical stage.