bluuebunny/crossref_metadata_2025_split huggingface dataset:
The transcription factor STAT5 catalyzes Mannich ligation reactions yielding inhibitors of leukemic cell proliferation
Authors: Wong Ee Lin , Nawrotzky Eric , Arkona Christoph , Kim Boo Geun , Beligny Samuel , Wang Xinning , Wagner Stefan , Lisurek Michael , Carstanjen Dirk , Rademann Jörg 
Published: January 2019

AbstractProtein-templated fragment ligations have been established as a powerful method for the assembly and detection of optimized protein ligands. Initially developed for reversible ligations, the method has been expanded to irreversible reactions enabling the formation of super-additive fragment combinations. Here, protein-induced Mannich ligations are discovered as a biocatalytic reaction furnishing inhibitors of the transcription factor STAT5. STAT5 protein catalyzes multicomponent reactions of a phosphate mimetic, formaldehyde, and 1H-tetrazoles yielding protein ligands with greatly increased binding affinity and ligand efficiency. Reactions are induced under physiological conditions selectively by native STAT5 but not by other proteins. Formation of ligation products and (auto-)inhibition of the reaction are quantified and the mechanism is investigated. Inhibitors assembled by STAT5 block specifically the phosphorylation of this protein in a cellular model of acute myeloid leukemia (AML), DNA-binding of STAT5 dimers, expression of downstream targets of the transcription factor, and the proliferation of cancer cells in mice.
Selective on-surface covalent coupling based on metal-organic coordination template
Authors: Xing Shuaipeng , Zhang Zhe , Fei Xiyu , Zhao Wei , Zhang Ran , Lin Tao , Zhao Danli , Ju Huanxin , Xu Hu , Fan Jian , Zhu Junfa , Ma Yu-qiang , Shi Ziliang 
Published: January 2019

AbstractControl over on-surface reaction pathways is crucial but challenging for the precise construction of conjugated nanostructures at the atomic level. Herein we demonstrate a selective on-surface covalent coupling reaction that is templated by metal-organic coordinative bonding, and achieve a porous nitrogen-doped carbon nanoribbon structure. In contrast to the inhomogeneous polymorphic structures resulting from the debrominated aryl-aryl coupling reaction on Au(111), the incorporation of an Fe-terpyridine (tpy) coordination motif into the on-surface reaction controls the molecular conformation, guides the reaction pathway, and finally yields pure organic sexipyridine-p-phenylene nanoribbons. Emergent molecular conformers and reaction products in the reaction pathways are revealed by scanning tunneling microscopy, density functional theory calculations and X-ray photoelectron spectroscopy, demonstrating the template effect of Fe-tpy coordination on the on-surface covalent coupling. Our approach opens an avenue for the rational design and synthesis of functional conjugated nanomaterials with atomic precision.
Emergence of a floral colour polymorphism by pollinator-mediated overdominance
Authors: Kellenberger Roman T. , Byers Kelsey J. R. P. , De Brito Francisco Rita M. , Staedler Yannick M. , LaFountain Amy M. , Schönenberger Jürg , Schiestl Florian P. , Schlüter Philipp M. 
Published: January 2019

AbstractMaintenance of polymorphism by overdominance (heterozygote advantage) is a fundamental concept in evolutionary biology. In most examples known in nature, overdominance is a result of homozygotes suffering from deleterious effects. Here we show that overdominance maintains a non-deleterious polymorphism with black, red and white floral morphs in the Alpine orchid Gymnadenia rhellicani. Phenotypic, metabolomic and transcriptomic analyses reveal that the morphs differ solely in cyanidin pigments, which are linked to differential expression of an anthocyanidin synthase (ANS) gene. This expression difference is caused by a premature stop codon in an ANS-regulating R2R3-MYB transcription factor, which is heterozygous in the red colour morph. Furthermore, field observations show that bee and fly pollinators have opposite colour preferences; this results in higher fitness (seed set) of the heterozygous morph without deleterious effects in either homozygous morph. Together, these findings demonstrate that genuine overdominance exists in nature.
Room-temperature electrochemical water–gas shift reaction for high purity hydrogen production
Authors: Cui Xiaoju , Su Hai-Yan , Chen Ruixue , Yu Liang , Dong Jinchao , Ma Chao , Wang Suheng , Li Jianfeng , Yang Fan , Xiao Jianping , Zhang Mengtao , Ma Ding , Deng Dehui , Zhang Dong H. , Tian Zhongqun , Bao Xinhe 
Published: January 2019

AbstractTraditional water–gas shift reaction provides one primary route for industrial production of clean-energy hydrogen. However, this process operates at high temperatures and pressures, and requires additional separation of H2from products containing CO2, CH4and residual CO. Herein, we report a room-temperature electrochemical water–gas shift process for direct production of high purity hydrogen (over 99.99%) with a faradaic efficiency of approximately 100%. Through rational design of anode structure to facilitate CO diffusion and PtCu catalyst to optimize CO adsorption, the anodic onset potential is lowered to almost 0 volts versus the reversible hydrogen electrode at room temperature and atmospheric pressure. The optimized PtCu catalyst achieves a current density of 70.0 mA cm−2at 0.6 volts which is over 12 times that of commercial Pt/C (40 wt.%) catalyst, and remains stable for even more than 475 h. This study opens a new and promising route of producing high purity hydrogen.
Highly modified and immunoactive N-glycans of the canine heartworm
Authors: Martini Francesca , Eckmair Barbara , Štefanić Saša , Jin Chunsheng , Garg Monika , Yan Shi , Jiménez-Castells Carmen , Hykollari Alba , Neupert Christine , Venco Luigi , Varón Silva Daniel , Wilson Iain B. H. , Paschinger Katharina 
Published: January 2019

AbstractThe canine heartworm (Dirofilaria immitis) is a mosquito-borne parasitic nematode whose range is extending due to climate change. In a four-dimensional analysis involving HPLC, MALDI-TOF–MS and MS/MS in combination with chemical and enzymatic digestions, we here reveal an N-glycome of unprecedented complexity. We detect N-glycans of up to 7000 Da, which contain long fucosylated HexNAc-based repeats, as well as glucuronylated structures. While some modifications including LacdiNAc, chitobiose, α1,3-fucose and phosphorylcholine are familiar, anionic N-glycans have previously not been reported in nematodes. Glycan array data show that the neutral glycans are preferentially recognised by IgM in dog sera or by mannose binding lectin when antennal fucose and phosphorylcholine residues are removed; this pattern of reactivity is reversed for mammalian C-reactive protein, which can in turn be bound by the complement component C1q. Thereby, the N-glycans of D. immitis contain features which may either mediate immunomodulation of the host or confer the ability to avoid immune surveillance.
Online photochemical derivatization enables comprehensive mass spectrometric analysis of unsaturated phospholipid isomers
Authors: Zhang Wenpeng , Zhang Donghui , Chen Qinhua , Wu Junhan , Ouyang Zheng , Xia Yu 
Published: January 2019

AbstractMass spectrometry-based lipidomics is the primary tool for the structural analysis of lipids but the effective localization of carbon–carbon double bonds (C=C) in unsaturated lipids to distinguish C=C location isomers remains challenging. Here, we develop a large-scale lipid analysis platform by coupling online C=C derivatization through the Paternò-Büchi reaction with liquid chromatography-tandem mass spectrometry. This provides rich information on lipid C=C location isomers, revealing C=C locations for more than 200 unsaturated glycerophospholipids in bovine liver among which we identify 55 groups of C=C location isomers. By analyzing tissue samples of patients with breast cancer and type 2 diabetes plasma samples, we find that the ratios of C=C isomers are much less affected by interpersonal variations than their individual abundances, suggesting that isomer ratios may be used for the discovery of lipid biomarkers.
Fibril formation and therapeutic targeting of amyloid-like structures in a yeast model of adenine accumulation
Authors: Laor Dana , Sade Dorin , Shaham-Niv Shira , Zaguri Dor , Gartner Myra , Basavalingappa Vasantha , Raveh Avi , Pichinuk Edward , Engel Hamutal , Iwasaki Keita , Yamamoto Tatsuyuki , Noothalapati Hemanth , Gazit Ehud 
Published: January 2019

AbstractThe extension of the amyloid hypothesis to include non-protein metabolite assemblies invokes a paradigm for the pathology of inborn error of metabolism disorders. However, a direct demonstration of the assembly of metabolite amyloid-like structures has so far been provided only in vitro. Here, we established an in vivo model of adenine self-assembly in yeast, in which toxicity is associated with intracellular accumulation of the metabolite. Using a strain blocked in the enzymatic pathway downstream to adenine, we observed a non-linear dose-dependent growth inhibition. Both the staining with an indicative amyloid dye and anti-adenine assemblies antibodies demonstrated the accumulation of adenine amyloid-like structures, which were eliminated by lowering the supplied adenine levels. Treatment with a polyphenol inhibitor reduced the occurrence of amyloid-like structures while not affecting the dramatic increase in intracellular adenine concentration, resulting in inhibition of cytotoxicity, further supporting the notion that toxicity is triggered by adenine assemblies.
Identity crisis in alchemical space drives the entropic colloidal glass transition
Authors: Teich Erin G. , van Anders Greg , Glotzer Sharon C. 
Published: January 2019

AbstractA universally accepted explanation for why liquids sometimes vitrify rather than crystallize remains hotly pursued, despite the ubiquity of glass in our everyday lives, the utilization of the glass transition in innumerable modern technologies, and nearly a century of theoretical and experimental investigation. Among the most compelling hypothesized mechanisms underlying glass formation is the development in the fluid phase of local structures that somehow prevent crystallization. Here, we explore that mechanism in the case of hard particle glasses by examining the glass transition in an extended alchemical (here, shape) space; that is, a space where particle shape is treated as a thermodynamic variable. We investigate simple systems of hard polyhedra, with no interactions aside from volume exclusion, and show via Monte Carlo simulation that glass formation in these systems arises from a multiplicity of competing local motifs, each of which is prevalent in—and predictable from—nearby ordered structures in alchemical space.
Surface diffusion-limited lifetime of silver and copper nanofilaments in resistive switching devices
Authors: Wang Wei , Wang Ming , Ambrosi Elia , Bricalli Alessandro , Laudato Mario , Sun Zhong , Chen Xiaodong , Ielmini Daniele 
Published: January 2019

AbstractSilver/copper-filament-based resistive switching memory relies on the formation and disruption of a metallic conductive filament (CF) with relatively large surface-to-volume ratio. The nanoscale CF can spontaneously break after formation, with a lifetime ranging from few microseconds to several months, or even years. Controlling and predicting the CF lifetime enables device engineering for a wide range of applications, such as non-volatile memory for data storage, tunable short/long term memory for synaptic neuromorphic computing, and fast selection devices for crosspoint arrays. However, conflictive explanations for the CF retention process are being proposed. Here we show that the CF lifetime can be described by a universal surface-limited self-diffusion mechanism of disruption of the metallic CF. The surface diffusion process provides a new perspective of ion transport mechanism at the nanoscale, explaining the broad range of reported lifetimes, and paving the way for material engineering of resistive switching device for memory and computing applications.
Genome-wide profiling of adenine base editor specificity by EndoV-seq
Authors: Liang Puping , Xie Xiaowei , Zhi Shengyao , Sun Hongwei , Zhang Xiya , Chen Yu , Chen Yuxi , Xiong Yuanyan , Ma Wenbin , Liu Dan , Huang Junjiu , Songyang Zhou 
Published: January 2019

AbstractThe adenine base editor (ABE), capable of catalyzing A•T to G•C conversions, is an important gene editing toolbox. Here, we systematically evaluate genome-wide off-target deamination by ABEs using the EndoV-seq platform we developed. EndoV-seq utilizes Endonuclease V to nick the inosine-containing DNA strand of genomic DNA deaminated by ABE in vitro. The treated DNA is then whole-genome sequenced to identify off-target sites. Of the eight gRNAs we tested with ABE, 2–19 (with an average of 8.0) off-target sites are found, significantly fewer than those found for canonical Cas9 nuclease (7–320, 160.7 on average). In vivo off-target deamination is further validated through target site deep sequencing. Moreover, we demonstrated that six different ABE-gRNA complexes could be examined in a single EndoV-seq assay. Our study presents the first detection method to evaluate genome-wide off-target effects of ABE, and reveals possible similarities and differences between ABE and canonical Cas9 nuclease.
Inward- and outward-facing X-ray crystal structures of homodimeric P-glycoprotein CmABCB1
Authors: Kodan Atsushi , Yamaguchi Tomohiro , Nakatsu Toru , Matsuoka Keita , Kimura Yasuhisa , Ueda Kazumitsu , Kato Hiroaki 
Published: January 2019

AbstractP-glycoprotein extrudes a large variety of xenobiotics from the cell, thereby protecting tissues from their toxic effects. The machinery underlying unidirectional multidrug pumping remains unknown, largely due to the lack of high-resolution structural information regarding the alternate conformational states of the molecule. Here we report a pair of structures of homodimeric P-glycoprotein: an outward-facing conformational state with bound nucleotide and an inward-facing apo state, at resolutions of 1.9 Å and 3.0 Å, respectively. Features that can be clearly visualized at this high resolution include ATP binding with octahedral coordination of Mg2+; an inner chamber that significantly changes in volume with the aid of tight connections among transmembrane helices (TM) 1, 3, and 6; a glutamate−arginine interaction that stabilizes the outward-facing conformation; and extensive interactions between TM1 and TM3, a property that distinguishes multidrug transporters from floppases. These structural elements are proposed to participate in the mechanism of the transporter.
Promotion of homology-directed DNA repair by polyamines
Authors: Lee Chih-Ying , Su Guan-Chin , Huang Wen-Yen , Ko Min-Yu , Yeh Hsin-Yi , Chang Geen-Dong , Lin Sung-Jan , Chi Peter 
Published: January 2019

AbstractPolyamines, often elevated in cancer cells, have been shown to promote cell growth and proliferation. Whether polyamines regulate other cell functions remains unclear. Here, we explore whether and how polyamines affect genome integrity. When DNA double-strand break (DSB) is induced in hair follicles by ionizing radiation, reduction of cellular polyamines augments dystrophic changes with delayed regeneration. Mechanistically, polyamines facilitate homologous recombination-mediated DSB repair without affecting repair via non-homologous DNA end-joining and single-strand DNA annealing. Biochemical reconstitution and functional analyses demonstrate that polyamines enhance the DNA strand exchange activity of RAD51 recombinase. The effect of polyamines on RAD51 stems from their ability to enhance the capture of homologous duplex DNA and synaptic complex formation by the RAD51-ssDNA nucleoprotein filament. Our work demonstrates a novel function of polyamines in the maintenance of genome integrity via homology-directed DNA repair.
Munc18 and Munc13 serve as a functional template to orchestrate neuronal SNARE complex assembly
Authors: Wang Shen , Li Yun , Gong Jihong , Ye Sheng , Yang Xiaofei , Zhang Rongguang , Ma Cong 
Published: January 2019

AbstractThe transition of the Munc18-1/syntaxin-1 complex to the SNARE complex, a key step involved in exocytosis, is regulated by Munc13-1, SNAP-25 and synaptobrevin-2, but the underlying mechanism remains elusive. Here, we identify an interaction between Munc13-1 and the membrane-proximal linker region of synaptobrevin-2, and reveal its essential role in transition and exocytosis. Upon this interaction, Munc13-1 not only recruits synaptobrevin-2-embedded vesicles to the target membrane but also renders the synaptobrevin-2 SNARE motif more accessible to the Munc18-1/syntaxin-1 complex. Afterward, the entry of SNAP-25 leads to a half-zippered SNARE assembly, which eventually dissociates the Munc18-1/syntaxin-1 complex to complete SNARE complex formation. Our data suggest that Munc18-1 and Munc13-1 together serve as a functional template to orchestrate SNARE complex assembly.
RNA-binding protein ZFP36L1 regulates osteoarthritis by modulating members of the heat shock protein 70 family
Authors: Son Young-Ok , Kim Hyo-Eun , Choi Wan-Su , Chun Churl-Hong , Chun Jang-Soo 
Published: January 2019

AbstractOsteoarthritis (OA) is a whole-joint disease characterized by cartilage destruction and other whole-joint pathological changes. There is currently no effective disease-modifying therapy. Here we investigate the post-transcriptional mRNA regulation of OA-modulating proteins in chondrocytes and show that the ZFP36 family member, ZFP36L1, is specifically upregulated in OA chondrocytes and OA cartilage of humans and mice. Adenovirus-mediated overexpression of ZFP36L1 alone in mouse knee-joint tissue does not modulate OA pathogenesis. However, genetic ablation or silencing of Zfp36l1 significantly abrogates experimental OA in mice. Knockdown of Zfp36l1 increases the mRNA expression of two heat shock protein 70 (HSP70) family members, which act as its direct targets. Furthermore, overexpression of HSPA1A in joint tissues protects mice against experimental OA by inhibiting chondrocyte apoptosis. Our results indicate that the RNA-binding protein, ZFP36L1, regulates HSP70 family members that appear to protect against OA pathogenesis by inhibiting chondrocyte apoptosis.
Repurposing of idebenone as a potential anti-cancer agent
Authors: Damiani Elisabetta , Yuecel Raif , Wallace Heather M. 
Published: January 2019

Abstract
Glioblastoma (GB) represents the most common and aggressive form of malignant primary brain tumour associated with high rates of morbidity and mortality. In the present study, we considered the potential use of idebenone (IDE), a Coenzyme Q10 analogue, as a novel chemotherapeutic agent for GB. On two GB cell lines, U373MG and U87MG, IDE decreased the viable cell number and enhanced the cytotoxic effects of two known anti-proliferative agents: temozolomide and oxaliplatin. IDE also affected the clonogenic and migratory capacity of both GB cell lines, at 25 and 50 µM, a concentration equivalent to that transiently reached in plasma after oral intake that is deemed safe for humans. p21 protein expression was decreased in both cell lines, indicating that IDE likely exerts its effects through cell cycle dysregulation, and this was confirmed in U373MG cells only by flow cytometric cell cycle analysis which showed S-phase arrest. Caspase-3 protein expression was also significantly decreased in U373MG cells indicating IDE-induced apoptosis that was confirmed by flow cytometric Annexin V/propidium iodide staining. No major decrease in caspase-3 expression was observed in U87MG cells nor apoptosis as observed by flow cytometry analysis. Overall, the present study demonstrates that IDE has potential as an anti-proliferative agent for GB by interfering with several features of glioma pathogenesis such as proliferation and migration, and hence might be a drug that could be repurposed for aiding cancer treatments. Furthermore, the synergistic combinations of IDE with other agents aimed at different pathways involved in this type of cancer are promising.
LncRNA POU3F3 promotes cancer cell migration and invasion in nasopharyngeal carcinoma by up-regulating TGF-β1
Authors: Li Wei , Wu Xingyu , She Wensheng 
Published: January 2019

Abstract
Up-regulation of lncRNA POU3F3 has been observed in esophageal squamous cell carcinomas, while its expression pattern and functionality in other human disease is unknown. Our study showed that plasma levels of lncRNA POU3F3 and TGF-β1 (transforming growth factor-β) were both increased in nasopharyngeal carcinoma patients than in healthy controls. Plasma levels of lncRNA POU3F3 were not affected by the diameter of primary tumors but increased in patients with tumor metastasis. Plasma levels of lncRNA POU3F3 and TGF-β1 were positively correlated only in nasopharyngeal carcinoma patients but not in healthy controls. Follow-up study showed that high plasma levels of lncRNA POU3F3 were significantly correlated with poor overall survival. LncRNA POU3F3 overexpression and exogenous TGF-β1 treatment led to promoted, while TGF-β1 inhibitor led to inhibited migration and invasion of nasopharyngeal carcinoma cells. TGF-β1 inhibitor partially rescued the inhibited cancer cell migration and invasion caused by lncRNA POU3F3 overexpression. LncRNA POU3F3 overexpression led to down-regulated TGF-β1 expression, while exogenous TGF-β1 and TGF-β1 inhibitor treatment did not significantly change the expression level of lncRNA POU3F3. Therefore, lncRNA POU3F3 may promote cancer cell migration and invasion in nasopharyngeal carcinoma by up-regulating TGF-β1.
Minerval (2-hydroxyoleic acid) causes cancer cell selective toxicity by uncoupling oxidative phosphorylation and compromising bioenergetic compensation capacity
Authors: Massalha Wessal , Markovits Mark , Pichinuk Edward , Feinstein-Rotkopf Yael , Tarshish Mark , Mishra Kumudesh , Llado Victoria , Weil Miguel , Escriba Pablo V. , Kakhlon Or 
Published: January 2019

AbstractThis work tests bioenergetic and cell-biological implications of the synthetic fatty acid Minerval (2-hydroxyoleic acid), previously demonstrated to act by activation of sphingomyelin synthase in the plasma membrane (PM) and lowering of phosphatidylethanolamine (PE) and phosphatidylcholine (PC) and their carcinogenic signaling. We show here that Minerval also acts, selectively in cancer cell lines, as an ATP depleting uncoupler of mitochondrial oxidative phosphorylation (OxPhos). As a function of its exposure time, Minerval compromised the capacity of glioblastoma U87-MG cells to compensate for aberrant respiration by up-modulation of glycolysis. This effect was not exposure time-dependent in the lung carcinoma A549 cell line, which was more sensitive to Minerval. Compared with OxPhos inhibitors FCCP (uncoupler), rotenone (electron transfer inhibitor), and oligomycin (F1F0-ATPase inhibitor), Minerval action was similar only to that of FCCP. This similarity was manifested by mitochondrial membrane potential (MMP) depolarization, facilitation of oxygen consumption rate (OCR), restriction of mitochondrial and cellular reactive oxygen species (ROS) generation and mitochondrial fragmentation. Additionally, compared with other OxPhos inhibitors, Minerval uniquely induced ER stress in cancer cell lines. These new modes of action for Minerval, capitalizing on the high fatty acid requirements of cancer cells, can potentially enhance its cancer-selective toxicity and improve its therapeutic capacity.