bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sorbitol Is a Severity Biomarker for PMM2‐CDG with Therapeutic Implications
Authors: Ligezka Anna N. , Radenkovic Silvia , Saraswat Mayank , Garapati Kishore , Ranatunga Wasantha , Krzysciak Wirginia , Yanaihara Hitoshi , Preston Graeme , Brucker William , McGovern Renee M. , Reid Joel M. , Cassiman David , Muthusamy Karthik , Johnsen Christin , Mercimek‐Andrews Saadet , Larson Austin , Lam Christina , Edmondson Andrew C. , Ghesquière Bart , Witters Peter , Raymond Kimiyo , Oglesbee Devin , Pandey Akhilesh , Perlstein Ethan O. , Kozicz Tamas , Morava Eva 
Published: October 2021

ObjectiveEpalrestat, an aldose reductase inhibitor increases phosphomannomutase (PMM) enzyme activity in a PMM2‐congenital disorders of glycosylation (CDG) worm model. Epalrestat also decreases sorbitol level in diabetic neuropathy. We evaluated the genetic, biochemical, and clinical characteristics, including the Nijmegen Progression CDG Rating Scale (NPCRS), urine polyol levels and fibroblast glycoproteomics in patients with PMM2‐CDG.MethodsWe performed PMM enzyme measurements, multiplexed proteomics, and glycoproteomics in PMM2‐deficient fibroblasts before and after epalrestat treatment. Safety and efficacy of 0.8 mg/kg/day oral epalrestat were studied in a child with PMM2‐CDG for 12 months.ResultsPMM enzyme activity increased post‐epalrestat treatment. Compared with controls, 24% of glycopeptides had reduced abundance in PMM2‐deficient fibroblasts, 46% of which improved upon treatment. Total protein N‐glycosylation improved upon epalrestat treatment bringing overall glycosylation toward the control fibroblasts’ glycosylation profile. Sorbitol levels were increased in the urine of 74% of patients with PMM2‐CDG and correlated with the presence of peripheral neuropathy, and CDG severity rating scale. In the child with PMM2‐CDG on epalrestat treatment, ataxia scores improved together with significant growth improvement. Urinary sorbitol levels nearly normalized in 3 months and blood transferrin glycosylation normalized in 6 months.InterpretationEpalrestat improved PMM enzyme activity, N‐glycosylation, and glycosylation biomarkers in vitro. Leveraging cellular glycoproteome assessment, we provided a systems‐level view of treatment efficacy and discovered potential novel biosignatures of therapy response. Epalrestat was well‐tolerated and led to significant clinical improvements in the first pediatric patient with PMM2‐CDG treated with epalrestat. We also propose urinary sorbitol as a novel biomarker for disease severity and treatment response in future clinical trials in PMM2‐CDG. ANN NEUROL 20219999:n/a–n/a
Chemoselective and Diastereoselective Synthesis of C‐Aryl Nucleoside Analogues by Nickel‐Catalyzed Cross‐Coupling of Furanosyl Acetates with Aryl Iodides
Authors: Li Yuxi , Wang Zheng , Li Luyang , Tian Xiaoying , Shao Feng , Li Chao 
Published: October 2021

AbstractCanonical nucleosides are vulnerable to enzymatic and chemical degradation, yet their stable mimics—C‐aryl nucleosides—have demonstrated potential utility in medicinal chemistry, chemical biology, and synthetic biology, although current synthetic methods remain limited in terms of scope and selectivity. Herein, we report a cross‐electrophile coupling to prepare C‐aryl nucleoside analogues from readily available furanosyl acetates and aryl iodides. This nickel‐catalyzed modular approach is characterized by mild reaction conditions, broad substrate scope, excellent β‐selectivity, and high functional‐group compatibility. The exclusive chemoselectivity with respect to the aryl iodide enables efficient preparation of a variety of C‐aryl halide furanosides suitable for various downstream transformations. The practicality of this transformation is demonstrated through the synthesis of a potent analogue of a naturally occurring NF‐κB activator.
A Unified View on Varied Ultrafast Dynamics of the Primary Process in Microbial Rhodopsins
Authors: Chang Chun‐Fu , Kuramochi Hikaru , Singh Manish , Abe‐Yoshizumi Rei , Tsukuda Tatsuya , Kandori Hideki , Tahara Tahei 
Published: October 2021

AbstractAll‐trans to 13‐cis photoisomerization of the protonated retinal Schiff base (PRSB) chromophore is the primary step that triggers various biological functions of microbial rhodopsins. While this ultrafast primary process has been extensively studied, it has been recognized that the relevant excited‐state relaxation dynamics differ significantly from one rhodopsin to another. To elucidate the origin of the complicated ultrafast dynamics of the primary process in microbial rhodopsins, we studied the excited‐state dynamics of proteorhodopsin, its D97N mutant, and bacteriorhodopsin by femtosecond time‐resolved absorption (TA) spectroscopy in a wide pH range. The TA data showed that their excited‐state relaxation dynamics drastically change when pH approaches the pKa of the counterion residue of the PRSB chromophore in the ground state. This result reveals that the varied excited‐state relaxation dynamics in different rhodopsins mainly originate from the difference of the ground‐state heterogeneity (i.e., protonation/deprotonation of the PRSB counterion).
Binäre 3D‐Mesokristalle aus anisotropen Nanopartikeln
Authors: Jenewein Christian , Avaro Jonathan , Appel Christian , Liebi Marianne , Cölfen Helmut 
Published: October 2021

AbstractBinäre Mesokristalle ermöglichen die Kombination von Nanokristalleigenschaften in einer geordneten Überstruktur. Hier zeigen wir die simultane Selbstanordnung von Platin‐ und Eisenoxid‐Nanowürfeln zu μ‐großen 3D‐Mesokristallen mittels Gasphasendiffusion. Durch Zugabe geringer Mengen eines sekundären Partikeltyps, der auf nahezu identische Größe, Form und Oberflächenchemie zugeschnitten ist, erfolgte ein zufälliger Einbau von Fremdpartikeln in ein selbstorganisierendes Wirtgitter. Die zufällige Verteilung der binären Partikeltypen auf der Oberfläche und in ihrem Innern wurde mit Transmissions‐ und Rasterelektronenmikroskopie sichtbar gemacht. Die 20–40 μm großen binären Mesokristalle wurden mittels Weit‐ und Kleinwinkelstreuungstechniken genau charakterisiert, um eine Fernordnung auf atomarer Ebene im gesamten Kristall aufzuzeigen und Beweise dafür zu liefern, dass das Material aus einzelnen Bausteinen besteht. Durch Anpassung der Kristallisationsparameter ließ sich somit eine umgekehrte Überstruktur erzielen, bei der die inkorporierten Partikel und das Wirtgitter ihre Rollen tauschen.
Synergetic Cobalt‐Copper‐Based Bimetal–Organic Framework Nanoboxes toward Efficient Electrochemical Oxygen Evolution
Authors: Cheng Weiren , Wu Zhi‐Peng , Luan Deyan , Zang Shuang‐Quan , Lou Xiong Wen (David) 
Published: October 2021

AbstractThe development of efficient oxygen electrocatalysts and understanding their underlying catalytic mechanism are of significant importance for the high‐performance energy conversion and storage technologies. Herein, we report novel CoCu‐based bimetallic metal–organic framework nanoboxes (CoCu‐MOF NBs) as promising catalysts toward efficient electrochemical oxygen evolution reaction (OER), fabricated via a successive cation and ligand exchange strategy. With the highly exposed bimetal centers and the well‐designed architecture, the CoCu‐MOF NBs show excellent OER activity and stability, with a small overpotential of 271 mV at 10 mA cm−2 and a high turnover frequency value of 0.326 s−1 at an overpotential of 300 mV. In combination of quasi in situ X‐ray absorption fine structure spectroscopy and density‐functional theory calculations, the post‐formed CoCu‐based oxyhydroxide analogue during OER is believed to account for the high OER activity of CoCu‐MOF NBs, where the electronic synergy between Co and neighbouring Cu atoms promotes the O−O bond coupling toward fast OER kinetics.
Genetically Programmable Fusion Cellular Vesicles for Cancer Immunotherapy
Authors: Meng Qian‐Fang , Zhao Yuyue , Dong Chunbo , Liu Lujie , Pan Yuanwei , Lai Jialin , Liu Zhida , Yu Guang‐Tao , Chen Xiaoyuan , Rao Lang 
Published: October 2021

AbstractHerein, we report that genetically programmable fusion cellular vesicles (Fus‐CVs) displaying high‐affinity SIRPα variants and PD‐1 can activate potent antitumor immunity through both innate and adaptive immune effectors. Dual‐blockade of CD47 and PD‐L1 with Fus‐CVs significantly increases the phagocytosis of cancer cells by macrophages, promotes antigen presentation, and activates antitumor T‐cell immunity. Moreover, the bispecific targeting design of Fus‐CVs ensures better targeting on tumor cells, but less on other cells, which reduces systemic side effects and enhances therapeutic efficacies. In malignant melanoma and mammary carcinoma models, we demonstrate that Fus‐CVs significantly improve overall survival of model animals by inhibiting post‐surgery tumor recurrence and metastasis. The Fus‐CVs are suitable for protein display by genetic engineering. These advantages, integrated with other unique properties inherited from source cells, make Fus‐CVs an attractive platform for multi‐targeting immune checkpoint blockade therapy.
Unlocking the Stereoselectivity and Substrate Acceptance of Enzymes: Proline‐Induced Loop Engineering Test
Authors: Qu Ge , Bi Yuexin , Liu Beibei , Li Junkuan , Han Xu , Liu Weidong , Jiang Yingying , Qin Zongmin , Sun Zhoutong 
Published: October 2021

AbstractProtein stability and evolvability influence each other. Although protein dynamics play essential roles in various catalytically important properties, their high flexibility and diversity makes it difficult to incorporate such properties into rational engineering. Therefore, how to unlock the potential evolvability in a user‐friendly rational design process remains a challenge. In this endeavor, we describe a method for engineering an enantioselective alcohol dehydrogenase. It enables synthetically important substrate acceptance for 4‐chlorophenyl pyridine‐2‐yl ketone, and perfect stereocontrol of both (S)‐ and (R)‐configured products. Thermodynamic analysis unveiled the subtle interaction between enzyme stability and evolvability, while computational studies provided insights into the origin of selectivity and substrate recognition. Preparative‐scale synthesis of the (S)‐product (73 % yield; >99 % ee) was performed on a gram‐scale. This proof‐of‐principle study demonstrates that interfaced proline residues can be rationally engineered to unlock evolvability and thus provide access to new biocatalysts with highly improved catalytic performance.
Transition‐Metal‐Catalyzed Monofluoroalkylation: Strategies for the Synthesis of Alkyl Fluorides by C−C Bond Formation
Authors: Butcher Trevor W. , Amberg Willi M. , Hartwig John F. 
Published: October 2021

AbstractAlkyl fluorides modulate the conformation, lipophilicity, metabolic stability, and pKa of compounds containing aliphatic motifs and, therefore, have been valuable for medicinal chemistry. Despite significant research in organofluorine chemistry, the synthesis of alkyl fluorides, especially chiral alkyl fluorides, remains a challenge. Most commonly, alkyl fluorides are prepared by the formation of C−F bonds (fluorination), and numerous strategies for nucleophilic, electrophilic, and radical fluorination have been reported in recent years. Although strategies to access alkyl fluorides by C−C bond formation (monofluoroalkylation) are inherently convergent and complexity‐generating, they have been studied less than methods based on fluorination. This Review provides an overview of recent developments in the synthesis of chiral (enantioenriched or racemic) secondary and tertiary alkyl fluorides by monofluoroalkylation catalyzed by transition‐metal complexes. We expect this contribution will illuminate the potential of monofluoroalkylations to simplify the synthesis of complex alkyl fluorides and suggest further research directions in this growing field.
Single‐Cell Metabolomics by Mass Spectrometry: Opportunities and Challenges
Authors: Dolatmoradi Marjan , Samarah Laith Z. , Vertes Akos 
Published: October 2021

AbstractCellular heterogeneity is an inherent property of cell populations with a wide spectrum of biological manifestations, ranging from barely observable variations that enhance organismal adaptation, to life‐threatening differences. Single‐cell metabolomics can reveal molecular information and variations in metabolite concentrations between cells that are masked in cell‐population studies. These differences are quantitatively captured by the abundance distributions for the population and their statistical analysis can reveal the presence of latent subpopulations. In recent years, mass spectrometry (MS), combined with novel sampling and ionization techniques, has become an important tool for single‐cell metabolomics. These new techniques must contend with significant challenges in the form of small cell sizes and volumes, ultratrace metabolite amounts per cell, and potentially interfering high turnover rates and rapid diffusion. Owing to the ultrasmall sample volume, low abundance of some metabolites, and poor ionization efficiencies, metabolite detection, identification, and accurate quantitation remain a major challenge. The ability of some techniques to analyze tissue‐embedded cells opens the door for spatial metabolomics, potentially revealing cellular synergism in organ level metabolism. In this Concept article, we present a bird's eye view of these major themes in single cell metabolomics and some of the relevant MS‐based methods.
Identification of Novel Risk Loci for Behçet's Disease–Related Uveitis in a Chinese Population in a Genome‐Wide Association Study
Authors: Su Guannan , Zhong Zhenyu , Zhou Qingyun , Du Liping , Ye Zi , Li Fuzhen , Zhuang Wenjuan , Wang Chaokui , Liang Liang , Ji Yan , Cao Qingfeng , Wang Qingfeng , Chang Rui , Tan Handan , Yi Shenglan , Li Yujing , Feng Xiaojie , Liao Weiting , Zhang Wanyun , Shu Jia , Tan Shiyao , Xu Jing , Pan Su , Li Hongxi , Shi Jing , Chen Zhijun , Zhu Ying , Ye Xingsheng , Tan Xiao , Zhang Jun , Liu Zhangluxi , Huang Fanfan , Yuan Gangxiang , Pang Tingting , Liu Yizong , Ding Jiadong , Gao Yingnan , Zhang Meifen , Chi Wei , Liu Xiaoli , Wang Yuqin , Chen Ling , Meguro Akira , Takeuchi Masaki , Mizuki Nobuhisa , Ohno Shigeaki , Zuo Xianbo , Kijlstra Aize , Yang Peizeng 
Published: October 2021

ObjectiveTo explore susceptibility loci associated with uveitis in Behçet's disease (BD).MethodsWe conducted a 2‐stage study, consisting of a genome‐wide association study (GWAS) stage and a replication stage, in a Chinese population. The GWAS stage included 978 cases with BD‐related uveitis and 4,388 controls, and the replication stage included 953 cases with BD‐related uveitis and 2,129 controls. Luciferase reporter analysis and chromatin immunoprecipitation assay were performed to explore the functional role of susceptibility genetic variants near ZMIZ1.ResultsThree independent HLA alleles (HLA–B51 [3.75 × 10−190], HLA–A26 [1.50 × 10−18], and HLA–C0704 [3.44 × 10−16]) were identified as having a genome‐wide association with BD‐related uveitis. In the non‐HLA region, in addition to confirming 7 previously reported loci, we identified 22 novel susceptibility variants located in 16 loci. Meta‐analysis of the Chinese cohort consisting of 1,931 cases and 6,517 controls and a published Japanese cohort of 611 cases and 737 controls showed genome‐wide significant associations with ZMIZ1, RPS6KA4, IL10RA, SIPA1‐FIBP‐FOSL1, and VAMP1. Functional experiments demonstrated that genetic variants of ZMIZ1 were associated with enhanced transcription activity and increased expression of ZMIZ1.ConclusionThis GWAS study identified a novel set of genetic variants that are associated with susceptibility to uveitis in BD. These findings enrich our understanding of the contribution of genetic factors to the disease.
Ammonia induces autophagy via circ‐IFNLR1/miR‐2188‐5p/RNF182 axis in tracheas of chickens
Authors: Zhang Tian‐yi , Chen Ting , Hu Wan‐ying , Li Ji‐chang , Guo Meng‐yao 
Published: October 2021

AbstractAmmonia (NH3), an air pollutant in the living environment, has many toxic effects on various tissues and organs. However, the underlying mechanisms of NH3‐induced tracheal cell autophagy remains poorly understood. In present study, chickens and LMH cells were used as NH3 exposure models to investigate toxic effects. The change of tracheal tissues ultrastructure showed that NH3 exposure induced autolysosomes. The differential expression of 12 circularRNAs (circRNAs) was induced by NH3 exposure using circRNAs transcriptome analysis in broiler tracheas. We further found that circ‐IFNLR1 was down‐regulated, and miR‐2188‐5p was up‐regulated in tracheal tissues under NH3 exposure. Bioinformatics analysis and dual luciferase reporter system showed that circ‐IFNLR1 bound directly to miR‐2188‐5p and regulated each other, and miR‐2188‐5p regulated RNF182. Overexpression of miR‐2188‐5p caused autophagy and its inhibition partially reversed autophagy in LMH cells which were caused by ammonia stimulation or knockdown of circ‐IFNLR1. The expressions of three autophagy‐related genes (LC3, Beclin 1, and BNIP3) were observably up‐regulated. Our results indicated that NH3 exposure caused autophagy through circ‐IFNLR1/miR‐2188‐5p/RNF182. These results provided new insights for the study of ammonia on environmental toxicology on ceRNA and circRNAs in vivo and vitro.
Compliance with mass marketing solicitation: The role of verbatim and gist processing
Authors: Nolte Julia , Hanoch Yaniv , Wood Stacey A. , Reyna Valerie F. 
Published: October 2021

AbstractIntroductionMass marketing scams threaten financial and personal well‐being. Grounded in fuzzy‐trace theory, we examined whether verbatim and gist‐based risk processing predicts susceptibility to scams and whether such processing can be altered.MethodsSeven hundred and one participants read a solicitation letter online and indicated willingness to call an “activation number” to claim an alleged $500,000 sweepstakes prize. Participants focused on the solicitation's verbatim details (hypothesized to increase risk‐taking) or its broad gist (hypothesized to decrease risk‐taking).ResultsAs expected, measures of verbatim‐based processing positively predicted contact intentions, whereas measures of gist‐based processing negatively predicted contact intentions. Contrary to hypotheses, experimental conditions did not influence intentions (43% across conditions). Contact intentions were associated with perceptions of low risk, high benefit, and the offer's apparent genuineness, as well as self‐reported decision regret, subjective vulnerability to scams, and prior experience falling for scams.ConclusionsOverall, message perceptions and prior susceptibility, rather than experimental manipulations, mattered in predicting scam susceptibility.
The transcription factor interferon regulatory factor‐1 is an endogenous mediator of myocardial ischemia reperfusion injury
Authors: Jiang Wenlong , Chen Guoxiong , Pu Jun 
Published: October 2021

AbstractMyocardial ischemia reperfusion (MIR) injury negatively affects the prognosis of acute myocardial infarction (AMI), while effective suppression of MIR injury remains a largely unmet clinical need. Interferon regulatory factors (IRF) are key players in chronic cardiac disorders such as cardiac remodeling. However, their roles in acute MIR injury remain largely unknown. In the current study, microarray data indicated that IRF1 expression was consistently changed in the human ischemic heart and ischemic reperfused mouse heart. Western blot analysis confirmed the expression alterations of IRF1 in ischemic reperfused mouse heart. Cardiac‐specific IRF1 knockdown significantly decreased infarct size, improved cardiac function, and suppressed myocardial apoptosis after MIR injury. Conversely, cardiac‐specific IRF1 overexpression significantly promoted MIR injury. Further investigation revealed that IRF1 transcriptionally regulated the expression of inducible nitric oxide synthase (iNOS), and augmented oxidative stress. Taken together, we presented the first direct evidence that IRF1 served as a mediator of MIR injury, and IRF1 may represent a potential therapeutic target for alleviating MIR injury.
Long noncoding RNA HAGLR sponges miR‐338‐3p to promote 5‐Fu resistance in gastric cancer through targeting the LDHA‐glycolysis pathway
Authors: Hu Jing , Huang Lujie , Ding Qi , Lv Jiaming , Chen Zhe 
Published: October 2021

AbstractGastric cancer (GC) is one of the most common human malignancies due to its invasiveness and metastasis. 5‐Fu is a widely applied chemotherapeutic agent against GC. Although 5‐Fu therapy has achieved improvements in GC treatment, a large fraction of patients developed drug resistance which significantly limited its clinical applications. Recent studies revealed the pivotal roles of long noncoding RNAs (lncRNAs) in tumorigenesis and progressions of various tumors, including GC. However, the biological roles and molecular mechanisms of lncRNA HAGLR in GC remain unclear. Here, we report HAGLR was upregulated in both GC tissues and cell lines. In addition, HAGLR was associated with a poorly survival rate of GC patients. Blocking HAGLR inhibited GC cells proliferation and sensitized GC cells to 5‐Fu. Bioinformatical analysis and luciferase assay demonstrated that HAGLR sponged microRNA (miR)‐338‐3p, which functions as a tumor suppressor in GC to downregulate its expressions. Moreover, from the established 5‐Fu resistant GC cell line (HGC27 5‐Fu R), we detected significantly elevated HAGLR, downregulated miR‐338‐3p, and glucose metabolism compared with parental HGC27 cells. We identified lactate dehydrogenase‐A (LDHA), a glucose metabolism key enzyme, was the direct target of miR‐338‐3p in GC cells. Rescue experiments demonstrated that restoration of miR‐338‐3p in HAGLR‐overexpressing HGC27 5‐Fu R cells successfully overrode the HAGLR‐promoted 5‐Fu resistance through targeting LDHA. Taken together, this study revealed essential roles and molecular mechanisms for the HAGLR‐mediated 5‐Fu resistance in GC, contributing to the development of new noncoding RNA‐based therapeutic strategies against chemoresistant GC.
Activation of Molecular O2 on CoFe2O4 (001) Surfaces: An Embedded Cluster Study
Authors: Rushiti Arjeta , Hättig Christof 
Published: October 2021

AbstractDioxygen activation pathways on the (001) surfaces of cobalt ferrite, CoFe2O4, were investigated computationally using density functional theory and the hybrid Perdew‐Burke‐Ernzerhof exchange‐correlation functional (PBE0) within the periodic electrostatic embedded cluster model. We considered two terminations: the A‐layer exposing Fe2+ and Co2+ metal sites in tetrahedral and octahedral positions, respectively, and the B‐layer exposing octahedrally coordinated Co3+. On the A‐layer, molecular oxygen is chemisorbed as a superoxide on the Fe monocenter or bridging a Fe−Co cation pair, whereas on the B‐layer it is adsorbed at the most stable anionic vacancy. Activation is promoted by transfer of electrons provided by the d metal centers onto the adsorbed oxygen. The subsequent dissociation of dioxygen into monoatomic species and surface reoxidation have been identified as the most critical steps that may limit the rate of the oxidation processes. Of the reactive metal‐O species, [FeIII−O]2+ is thermodynamically most stable, while the oxygen of the Co−O species may easily migrate across the A‐layer with barriers smaller than the associative desorption.