bluuebunny/crossref_metadata_2025_split huggingface dataset:
Syntheses of Atypically Fluorinated Peptidyl Macrocycles through Sequential Vinylic Substitutions
Authors: Tsunemi Tomoyuki , Bernardino Salvador J. , Mendoza Angel , Jones Christopher G. , Harran Patrick G. 
Published: November 2019

AbstractSmall peptides containing combinations of cysteine, tyrosine, histidine, and serine residues react with octafluorocyclopentene (OFCP) to afford atypically structured macrocycles through successive vinylic substitutions. The reactions proceed rapidly in air at 0 °C and are tolerant of spectating tryptophan, asparagine, glutamine, and threonine residues. Hexapeptides of consensus sequence YXCXXC displace four fluorine atoms from OFCP to generate fluorinated macrobicyclic compounds that display dual‐turn surfaces. The method provides facile access to a wide range of previously unknown heterocyclic structures.
Rapid Syntheses of (−)‐FR901483 and (+)‐TAN1251C Enabled by Complexity‐Generating Photocatalytic Olefin Hydroaminoalkylation
Authors: Reich Dominik , Trowbridge Aaron , Gaunt Matthew J. 
Published: November 2019

AbstractWe report a common strategy to facilitate the syntheses of the polycyclic alkaloids (−)‐FR901483 (1) and (+)‐TAN1251C (2). A divergent synthetic strategy provides access to both natural products through a pivotal spirolactam intermediate (3), which can be accessed on a gram‐scale. A photocatalytic olefin hydroaminoalkylation brings together three readily available building blocks and forges the majority of the carbon framework present in 1 and 2 in a single operation, leading to concise total syntheses. The complexity‐generating photocatalytic process also provides direct access to novel non‐racemic spirolactam scaffolds that are likely to be of interest to early‐stage drug discovery programs.
Total Synthesis and Structural Revision of a Harziane Diterpenoid
Authors: Hönig Moritz , Carreira Erick M. 
Published: November 2019

AbstractThe first total synthesis of nominal harziane diterpenoid 1 is disclosed, whose spectral characteristics did not match those of the reported natural product. Stereochemical analysis and subsequent synthesis of the epimeric tertiary alcohol led to reassignment of configuration of the natural product as shown for 2. At the heart of the synthesis is an enyne cycloisomerization that sets a key quaternary stereocenter within a cyclobutane with high diastereocontrol. The route features strategies for the synthesis of the highly congested 6‐5‐7‐4 carbon skeleton characteristic of the caged harziane diterpenoids.
Isatin–azole hybrids and their anticancer activities
Authors: Hou Yani , Shang Congshan , Wang Hui , Yun Jie 
Published: November 2019

AbstractIsatin and azole moieties, which have the ability to form various noncovalent interactions with different therapeutic targets, are common pharmacophores in drug development. Isatin and azole derivatives possess promising in vitro and in vivo anticancer activity, and many of them, such as semaxanib, sunitinib, and carboxyamidotriazole, could be used to treat various cancers. Thus, it is conceivable that hybridization of the isatin moiety with azole may provide a valuable therapeutic intervention for the treatment of cancer. Substantial efforts have been made to develop isatin–azole hybrids as novel anticancer agents, and some of the isatin–azole hybrids exhibited considerable activity. This review emphasizes isatin–azole hybrids with potential anticancer activity, covering articles published between 2010 and 2019. The structure–activity relationships as well as the mechanisms of action are also discussed to provide insights for the rational design of more effective candidates.
WB‐PBPK approach in predicting zidovudine pharmacokinetics in preterm neonates
Authors: Wei Liuya , Mansoor Najia , Khan Rafeeq Alam , Czejka Martin , Ahmad Tasneem , Ahmed Mansoor , Ali Mohsin , Yang Dong‐Hua 
Published: November 2019

AbstractAntiretroviral therapy has been the mainstay of treatment for neonates born to HIV infected mothers. Neonates born prematurely to HIV positive mothers are underdeveloped not only in anatomical terms but also in their physiological systems. Zidovudine, the first antiretroviral drug in clinical therapy for the treatment of HIV has been approved for use in preterm neonates both prophylactically and therapeutically. The present work describes the whole body physiologically based pharmacokinetic (WB‐PBPK) model development for zidovudine in preterm neonates of varying gestational ages, to observe the pharmacokinetic behavior of the drug in this vulnerable group of the population. Along with the height, weight, post‐natal, and gestational ages of the preterm neonates, metabolic enzymes CYP2A6, CYP2C8, etc. were incorporated for each neonate. The composition of the different organs in terms of water and lipid components, blood flow rates, etc. were specified during simulations according to the gestational ages of these neonates. The following PK parameters were estimated for preterm neonates using simulated plasma profiles: AUC 2686.41 ± 123.49 μmol min/L, Cmax 6.46 ± 0.74 μmol/L, half‐life 8.98 ± 2.36 hr, mean residence time 12.23 ± 3.43 hr, and total plasma clearance 1.48 ± 0.19 ml/min/kg in comparison with the observed PK parameters of a clinical study by Mirochknic et al. in preterm neonates with AUC 2020.04 μmol/min/L, Cmax 6.10 μmol/L, and total plasma clearance 1.62 ml/min/kg. PBPK simulations provide an opportunity to visualize the possible impact of physiological maturity levels at varying gestational ages on the pharmacokinetic behavior of zidovudine in preterm neonates.
Pharmacokinetic profile analyses for inhaled drugs in humans using the lung delivery and disposition model
Authors: Raut Anuja , Dhapare Sneha , Venitz Jürgen , Sakagami Masahiro 
Published: November 2019

AbstractThe kinetic clarification of lung disposition for inhaled drugs in humans via pharmacokinetic (PK) modeling aids in their development and regulation for systemic and local delivery, but remains challenging due to its multiplex nature. This study exercised our lung delivery and disposition kinetic model to derive the kinetic descriptors for the lung disposition of four drugs [calcitonin, tobramycin, ciprofloxacin and fluticasone propionate (FP)] inhaled via different inhalers from the published PK profile data. With the drug dose delivered to the lung (DTL) estimated from the corresponding γ‐scintigraphy or in vivo predictive cascade impactor data, the model‐based curve‐fitting and statistical moment analyses derived the rate constants of lung absorption (ka) and non‐absorptive disposition (knad). The ka values differed substantially between the drugs (0.05–1.00 h−1), but conformed to the lung partition‐based membrane diffusion except for FP, and were inhaler/delivery/deposition‐independent. The knad values also varied widely (0.03–2.32 h−1), yet appeared to be explained by the presence or absence of non‐absorptive disposition in the lung via mucociliary clearance, local tissue degradation, binding/sequestration and/or phagocytosis, and to be sensitive to differences in lung deposition. For FP, its ka value of 0.2 h−1 was unusually low, suggesting solubility/dissolution‐limited slow lung absorption, but was comparable between two inhaler products. Thus, the difference in the PK profile was attributed to differences in the DTL and the knad value, the latter likely originating from different aerosol sizes and regional deposition in the lung. Overall, this empirical, rather simpler model‐based analysis provided a quantitative kinetic understanding of lung absorption and non‐absorptive disposition for four inhaled drugs from PK profiles in humans.
A visual application for teaching pipe flow optimization in engineering curricula
Authors: Türkkan Yusuf Alptekin , Eryılmaz Türkkan Gökçen  , Yılmaz Hamid 
Published: November 2019

AbstractThe main purpose of this study is to investigate the importance of programming in the learning and understanding of water distribution networks. This paper presents the implementation of a programming language C# for applications for teaching water distribution networks calculations at both undergraduate and graduate levels. A user's guide is also prepared for the software which includes the theory of hydraulic and optimization calculations. There are many ways to design water distribution networks. Hardy Cross method is very often used for optimization of networks. Thus, Hardy Cross optimization method was preferred in this study. It is a perfect study to implement as an educational tool at undergraduate and graduate levels of education.
Serial ultra‐deep sequencing of circulating tumor DNA reveals the clonal evolution in non‐small cell lung cancer patients treated with anti‐PD1 immunotherapy
Authors: Li Li , Wang Yubo , Shi Weiwei , Zhu Mengxiao , Liu Zhulin , Luo Nuo , Zeng Yanwu , He Yong 
Published: November 2019

AbstractBackgroundImmune‐therapy with anti‐PD1 inhibitors, such as pembrolizumab, is revolutionizing the treatment of non‐small cell lung cancers (NSCLC). However, identifying patients for the potential therapeutic response and predicting therapy resistance and early relapse remains a challenge.MethodsBetween 2016 and 2018, 60 patients were treated with pembrolizumab, among who 12 NSCLC patients had both baseline (before treatment) and serial (on treatment) periodical circulating tumor DNA (ctDNA) samples. Those samples were sequenced on a 329 pan cancer‐related gene panel. Analyses of tumor burden, blood tumor mutational burden (bTMB), maximum somatic allele frequency (MSAF), and tumor clonal structure were performed in association with clinical response. Candidate resistance mutations involved in relapse and metastases were further investigated.ResultsctDNA was detected and mutational profiling was performed for each patient. Those with a high baseline bTMB level showed significantly improved progression‐free survival (PFS) after pembrolizumab treatment. Tumor burden and therapeutic response significantly correlated with the MSAF instead of the bTMB. Clone analysis detected tumor progression about 2‐4 months ahead of computed tomography (CT) scan. One mutation in gene PTCH1 (Protein patched homolog 1) and two acquired anti‐PD1 candidate resistance mutations of gene B2M (β2 microglobulin) were identified in association with distant metastasis. The evolutionary tree of a representative patient was also described.ConclusionThis pilot study showed that MSAF could be another good indicator of therapeutic response, and clonal analysis could be clinically useful in monitoring clonal dynamics and detecting remote metastasis and early relapse.
MYST1/KAT8 contributes to tumor progression by activating EGFR signaling in glioblastoma cells
Authors: Dong Zhen , Zou Jiahua , Li Jifu , Pang Yi , Liu Yudong , Deng Chaowei , Chen Fei , Cui Hongjuan 
Published: November 2019

AbstractWith short survival time, glioblastoma (GBM) is the most malignant tumor in the central nervous system. Recently, epigenetic enzymes play essential roles in the regulation of tumorigenesis and cancer development of GBM. However, little is known about MYST1/KAT8/MOF, a histone acetylation enzyme, in GBM. The present study shows that MYST1 promotes GBM progression through activating epidermal growth factor receptor (EGFR) signaling. MYST1 expression was increased in GBM and was negatively correlated with prognosis in patients with glioma and GBM. Knockdown of MYST1 reduced cell proliferation and BrdU incorporation in LN229, U87, and A172 GBM cells. Besides, MYST1 downregulation also induced cell cycle arrest at G2M phase, as well as the reduced expression of CDK1, Cyclin A, Cyclin B1, and increased expression of p21CIP1/Waf1. Meanwhile, Self‐renewal capability in vitro and tumorigenecity in vivo were also impaired after MYST1 knockdown. Importantly, MYST1 expression was lowly expressed in mesenchymal subtype of GBM and was positively correlated with EGFR expression in a cohort from The Cancer Genome Atlas. Western blot subsequently confirmed that phosphorylation and activation of p‐Try1068 of EGFR, p‐Ser473 of AKT and p‐Thr202/Tyr204 of Erk1/2 were also decreased by MYST1 knockdown. Consistent with the results above, overexpression of MYST1 promoted GBM growth and activated EGFR signaling in vitro and in vivo. In addition, erlotinib, a US Food and Drug Administration approved cancer drug which targets EGFR, was able to rescue MYST1‐promoted cell proliferation and EGFR signaling pathway. Furthermore, the transcription of EGF, an EFGR ligand, was shown to be positively regulated by MYST1 possibly via H4K16 acetylation. Our findings elucidate MYST1 as a tumor promoter in GBM and an EGFR activator, and may be a potential drug target for GBM treatment.
Advances in DNA Origami–Cell Interfaces
Authors: Mishra Shubham , Feng Yihong , Endo Masayuki , Sugiyama Hiroshi 
Published: November 2019

AbstractThe nascent field of DNA nanotechnology has undergone rapid growth since its inception. By using DNA as a biologically “safe” material, DNA nanotechnology shows great promise in applications such as drug‐delivery systems. Further progress, however, relies on understanding the different ways in which DNA nanostructures behave in and interact with cells, tissues and even whole organisms. Moreover, this knowledge must then be harnessed in innovative ways to improve existing DNA nanostructures and design new ones, so that they can perform more diverse functions more effectively. There have been many developments in this regard in the past few years, and herein some of these are highlighted, with respect to both works that improve our understanding of what happens to DNA nanostructures once they are at their target site, and those that utilise clever design to accomplish desired functions.
Validation of the Slow Off‐Kinetics of Sirtuin‐Rearranging Ligands (SirReals) by Means of Label‐Free Electrically Switchable Nanolever Technology
Authors: Schiedel Matthias , Daub Herwin , Itzen Aymelt , Jung Manfred 
Published: November 2019

AbstractWe have discovered the sirtuin‐rearranging ligands (SirReals) to be highly potent and selective inhibitors of the NAD+‐dependent lysine deacetylase Sirt2. Using a biotinylated SirReal in combination with biolayer interferometry, we previously observed a slow dissociation rate of the inhibitor–enzyme complex; this had been postulated to be the key to the high affinity and selectivity of SirReals. However, to attach biotin to the SirReal core, we introduced a triazole as a linking moiety; this was shown by X‐ray co‐crystallography to interact with Arg97 of the cofactor binding loop. Herein, we aim to elucidate whether the observed long residence time of the SirReals is induced mainly by triazole incorporation or is an inherent characteristic of the SirReal inhibitor core. We used the novel label‐free switchSENSE® technology, which is based on electrically switchable DNA nanolevers, to prove that the long residence time of the SirReals is indeed caused by the core scaffold.
Severe acute pancreatitis with inflammation extending to the scrotum
Authors: Fukushi Koh , Tominaga Keiichi , Takenaka Kazuhiro , Takahashi Fumiaki , Tsuchida Kouhei , Murohisa Toshimitsu , Iijima Makoto , Irisawa Atsushi 
Published: November 2019

AbstractExtension of inflammation into the scrotum is rare in acute pancreatitis. If inflammation spreads in the scrotum, it may become severe. Clinicians should be aware of this condition as a possible complication. Proactive imaging testing is recommended when complaining of cyst swelling or testicular pain.
Low‐Temperature Pretreatment of Lignocellulosic Biomass for Enhanced Biogas Production
Authors: Casaretto René , Agdal Emil Brohus Lassen , Cayenne Aadila , Chaturvedi Tanmay , Holm-Nielsen Jens Bo 
Published: November 2019

AbstractReadily available lignocellulosic biomass as substrate for biogas plants is gaining popularity amongst biogas plant operators. Results of low‐temperature pretreatment (light cooking) of wheat straw to remove waxes and prepare the biomass for microbial action are described. Benefits of light cooking are low thermal energy demand and low investment cost compared to conventional techniques such as steam explosion. The novelty lies in utilizing the low temperature range 25–100 °C for pre‐soaking the biomass. Two different types of wheat straws were pretreated at varying temperatures and sizes. The results were compared with Buswell's equation for theoretical maximum biomethane yield. Compared to untreated straw, pre‐soaking leads to a significantly higher methane yield. Size reduction combined with light‐cooking does not affect the methane yield in the same manner as pre‐soaking of the biomass.
Hydrothermal Synthesis of Tunable Olive‐Like Ni0.8Co0.1Mn0.1CO3 and its Transformation to LiNi0.8Co0.1Mn0.1O2 Cathode Materials for Li‐Ion Batteries
Authors: Lu Yan , Gan Zhanggen , Xia Jin , Du Ke , Peng Zhongdong , Cao Yanbing , Hu Guorong , Xiao Jin 
Published: November 2019

AbstractUniform olive‐like Ni0.8Co0.1Mn0.1CO3 carbonate precursors were successfully synthesized under hydrothermal conditions. Powder X‐ray diffraction, field emission scanning electron microscopy, optical microscopy, and inductively coupled plasma optical emission spectroscopy revealed that crystal size and elemental contents of carbonate precursors could be slightly tuned by regulating the molar ratio of urea and transition metal ions, moreover, a synergetic crystal evolution mechanism involving Ostwald ripening and crystal etching for the formation of olive‐like carbonate precursors was put forward for the first time. The improvement in temperature facilitated the increment in size of primary particles of oxides transformed from carbonate precursors. Vermiform LiNi0.8Co0.1Mn0.1O2 cathode materials transformed from olive‐like carbonate precursors exhibited high discharge capacity of 193.4 mAh g−1 at 0.2 C, and capacity retention of 85.4 % at 1 C after 100 cycles. Charge transfer impedance (Rct) and diffusion coefficient of lithium ion (DLi+) revealed the electrochemical properties of cathode materials.
Modeling and implementation of tandem polymer solar cells using wide‐bandgap front cells
Authors: Ko Seo‐Jin , Choi Hyosung , Hoang Quoc Viet , Song Chang Eun , Morin Pierre‐Olivier , Heo Jungwoo , Leclerc Mario , Yoon Sung Cheol , Woo Han Young , Shin Won Suk , Walker Bright , Kim Jin Young 
Published: November 2019

AbstractTandem device architectures offer a route to greatly increase the maximum possible power conversion efficiencies (PCEs) of polymer solar cells, however, the complexity of tandem cell device fabrication (such as selecting bandgaps of the front and back cells, current matching, thickness, and recombination layer optimization) often result in lower PCEs than are observed in single‐junction devices. In this study, we analyze the influence of front cell and back cell bandgaps and use transfer matrix modeling to rationally design and optimize effective tandem solar cell structures before actual device fabrication. Our approach allows us to estimate tandem device parameters based on known absorption coefficients and open‐circuit voltages of different active layer materials and design devices without wasting valuable time and materials. Using this approach, we have investigated a series of wide bandgap, high voltage photovoltaic polymers as front cells in tandem devices with PTB7‐Th as a back cell. In this way, we have been able to demonstrate tandem devices with PCE of up to 12.8% with minimal consumption of valuable photoactive materials in tandem device optimization. This value represents one of the highest PCE values to date for fullerene‐based tandem solar cells.
Modulating the Charge‐Transfer Step of a p–n Heterojunction with Nitrogen‐Doped Carbon: A Promising Strategy To Improve Photocatalytic Performance
Authors: Yuan Yusheng , Sun Liming , Zeng Suyuan , Zhan Wenwen , Wang Xiaojun , Han Xiguang 
Published: November 2019

AbstractEngineering p–n heterojunctions among metal oxide semiconductors to provide a built‐in electric field is an efficient strategy to facilitate the separation of photogenerated electrons and holes and improve their photocatalytic activities. However, the inherent poor conductivity of p–n heterojunctions still limits the charge‐transfer step and thus hampers their practical application in photocatalysis. In this work, a nitrogen‐doped carbon‐coated NiO/TiO2 p–n (NCNT) heterojunction with hierarchical mesoporous sphere morphology was synthesized by in situ pyrolytic decomposition of nickel–titanium complexes. The NiO/TiO2 p–n heterojunction in NCNT was fully characterized by several techniques, supported by theoretical calculations and Mott–Schottky plots. On coating with a thin nitrogen‐doped carbon layer, the electron transfer of the obtained p–n heterojunction could be significantly enhanced. On account of the favorable structural features of the p–n heterojunction with nitrogen‐doped carbon coating and hierarchical mesoporous structure, NCNT exhibited excellent photocatalytic activity toward various reaction systems, including the hydrogen evolution reaction and the visible‐light‐induced hydroxylation of phenylboronic acids.
Vocal divergence is concordant with genomic evidence for strong reproductive isolation in grasshopper mice (Onychomys)
Authors: Campbell Polly , Arévalo Lena , Martin Heather , Chen Charles , Sun Shuzhen , Rowe Ashlee H. , Webster Michael S. , Searle Jeremy B. , Pasch Bret 
Published: November 2019

AbstractBehavioral barriers to gene flow often evolve faster than intrinsic incompatibilities and can eliminate the opportunity for hybridization between interfertile species. While acoustic signal divergence is a common driver of premating isolation in birds and insects, its contribution to speciation in mammals is less studied. Here we characterize the incidence of, and potential barriers to, hybridization among three closely related species of grasshopper mice (genus Onychomys). All three species use long‐distance acoustic signals to attract and localize mates; Onychomys arenicola and Onychomys torridus are acoustically similar and morphologically cryptic whereas Onychomys leucogaster is larger and acoustically distinct. We used genotyping‐by‐sequencing (GBS) to test for evidence of introgression in 227 mice from allopatric and sympatric localities in the western United States and northern Mexico. We conducted laboratory mating trials for all species pairs to assess reproductive compatibility, and recorded vocalizations from O. arenicola and O. torridus in sympatry and allopatry to test for evidence of acoustic character displacement. Hybridization was rare in nature and, contrary to prior evidence for O. torridus/O. arenicola hybrids, only involved O. leucogaster and O. arenicola. In contrast, laboratory crosses between O. torridus and O. arenicola produced litters whereas O. leucogaster and O. arenicola crosses did not. Call fundamental frequency in O. torridus and O. arenicola was indistinguishable in allopatry but significantly differentiated in sympatry, a pattern consistent with reproductive character displacement. These results suggest that assortative mating based on a long‐distance signal is an important isolating mechanism between O. torridus and O. arenicola and highlight the importance of behavioral barriers in determining the permeability of species boundaries.