bluuebunny/crossref_metadata_2025_split huggingface dataset:
Bioinspired one-pot furan-thiol-amine multicomponent reaction for making heterocycles and its applications
Authors: Wang Yuwen , Czabala Patrick , Raj Monika 
Published: July 2023

AbstractOne-pot multicomponent coupling of different units in a chemoselective manner and their late-stage diversification has wide applicability in varying chemistry fields. Here, we report a simple multicomponent reaction inspired by enzymes that combines thiol and amine nucleophiles in one pot via a furan-based electrophile to generate stable pyrrole heterocycles independent of the diverse functionalities on furans, thiols and amines under physiological conditions. The resulting pyrrole provides a reactive handle to introduce diverse payloads. We demonstrate the application of Furan-Thiol-Amine (FuTine) reaction for the selective and irreversible labeling of peptides, synthesis of macrocyclic and stapled peptides, selective modification of twelve different proteins with varying payloads, homogeneous engineering of proteins, homogeneous stapling of proteins, dual modification of proteins with different fluorophores using the same chemistry and labeling of lysine and cysteine in a complex human proteome.
Establishing mammalian GLUT kinetics and lipid composition influences in a reconstituted-liposome system
Authors: Suades Albert , Qureshi Aziz , McComas Sarah E. , Coinçon Mathieu , Rudling Axel , Chatzikyriakidou Yurie , Landreh Michael , Carlsson Jens , Drew David 
Published: July 2023

AbstractGlucose transporters (GLUTs) are essential for organism-wide glucose homeostasis in mammals, and their dysfunction is associated with numerous diseases, such as diabetes and cancer. Despite structural advances, transport assays using purified GLUTs have proven to be difficult to implement, hampering deeper mechanistic insights. Here, we have optimized a transport assay in liposomes for the fructose-specific isoform GLUT5. By combining lipidomic analysis with native MS and thermal-shift assays, we replicate the GLUT5 transport activities seen in crude lipids using a small number of synthetic lipids. We conclude that GLUT5 is only active under a specific range of membrane fluidity, and that human GLUT1-4 prefers a similar lipid composition to GLUT5. Although GLUT3 is designated as the high-affinity glucose transporter, in vitro D-glucose kinetics demonstrates that GLUT1 and GLUT3 actually have a similar KM, but GLUT3 has a higher turnover. Interestingly, GLUT4 has a high KM for D-glucose and yet a very slow turnover, which may have evolved to ensure uptake regulation by insulin-dependent trafficking. Overall, we outline a much-needed transport assay for measuring GLUT kinetics and our analysis implies that high-levels of free fatty acid in membranes, as found in those suffering from metabolic disorders, could directly impair glucose uptake.
Mechanism of ATP hydrolysis dependent rotation of bacterial ATP synthase
Authors: Nakano Atsuki , Kishikawa Jun-ichi , Mitsuoka Kaoru , Yokoyama Ken 
Published: July 2023

AbstractF1 domain of ATP synthase is a rotary ATPase complex in which rotation of central γ-subunit proceeds in 120° steps against a surrounding α3β3 fueled by ATP hydrolysis. How the ATP hydrolysis reactions occurring in three catalytic αβ dimers are coupled to mechanical rotation is a key outstanding question. Here we describe catalytic intermediates of the F1 domain in FoF1 synthase from Bacillus PS3 sp. during ATP mediated rotation captured using cryo-EM. The structures reveal that three catalytic events and the first 80° rotation occur simultaneously in F1 domain when nucleotides are bound at all the three catalytic αβ dimers. The remaining 40° rotation of the complete 120° step is driven by completion of ATP hydrolysis at αDβD, and proceeds through three sub-steps (83°, 91°, 101°, and 120°) with three associated conformational intermediates. All sub-steps except for one between 91° and 101° associated with phosphate release, occur independently of the chemical cycle, suggesting that the 40° rotation is largely driven by release of intramolecular strain accumulated by the 80° rotation. Together with our previous results, these findings provide the molecular basis of ATP driven rotation of ATP synthases.
In situ activation of flexible magnetoelectric membrane enhances bone defect repair
Authors: Liu Wenwen , Zhao Han , Zhang Chenguang , Xu Shiqi , Zhang Fengyi , Wei Ling , Zhu Fangyu , Chen Ying , Chen Yumin , Huang Ying , Xu Mingming , He Ying , Heng Boon Chin , Zhang Jinxing , Shen Yang , Zhang Xuehui , Huang Houbing , Chen Lili , Deng Xuliang 
Published: July 2023

AbstractFor bone defect repair under co-morbidity conditions, the use of biomaterials that can be non-invasively regulated is highly desirable to avoid further complications and to promote osteogenesis. However, it remains a formidable challenge in clinical applications to achieve efficient osteogenesis with stimuli-responsive materials. Here, we develop polarized CoFe2O4@BaTiO3/poly(vinylidene fluoridetrifluoroethylene) [P(VDF-TrFE)] core-shell particle-incorporated composite membranes with high magnetoelectric conversion efficiency for activating bone regeneration. An external magnetic field force conduct on the CoFe2O4 core can increase charge density on the BaTiO3 shell and strengthens the β-phase transition in the P(VDF-TrFE) matrix. This energy conversion increases the membrane surface potential, which hence activates osteogenesis. Skull defect experiments on male rats showed that repeated magnetic field applications on the membranes enhanced bone defect repair, even when osteogenesis repression is elicited by dexamethasone or lipopolysaccharide-induced inflammation. This study provides a strategy of utilizing stimuli-responsive magnetoelectric membranes to efficiently activate osteogenesis in situ.
Structures of a FtsZ single protofilament and a double-helical tube in complex with a monobody
Authors: Fujita Junso , Amesaka Hiroshi , Yoshizawa Takuya , Hibino Kota , Kamimura Natsuki , Kuroda Natsuko , Konishi Takamoto , Kato Yuki , Hara Mizuho , Inoue Tsuyoshi , Namba Keiichi , Tanaka Shun-ichi , Matsumura Hiroyoshi 
Published: July 2023

AbstractFtsZ polymerizes into protofilaments to form the Z-ring that acts as a scaffold for accessory proteins during cell division. Structures of FtsZ have been previously solved, but detailed mechanistic insights are lacking. Here, we determine the cryoEM structure of a single protofilament of FtsZ from Klebsiella pneumoniae (KpFtsZ) in a polymerization-preferred conformation. We also develop a monobody (Mb) that binds to KpFtsZ and FtsZ from Escherichia coli without affecting their GTPase activity. Crystal structures of the FtsZ–Mb complexes reveal the Mb binding mode, while addition of Mb in vivo inhibits cell division. A cryoEM structure of a double-helical tube of KpFtsZ–Mb at 2.7 Å resolution shows two parallel protofilaments. Our present study highlights the physiological roles of the conformational changes of FtsZ in treadmilling that regulate cell division.
IL-9 aggravates SARS-CoV-2 infection and exacerbates associated airway inflammation
Authors: Sadhu Srikanth , Dalal Rajdeep , Dandotiya Jyotsna , Binayke Akshay , Singh Virendra , Tripathy Manas Ranjan , Das Vinayaka , Goswami Sandeep , Kumar Shakti , Rizvi Zaigham Abbas , Awasthi Amit 
Published: July 2023

AbstractSARS-CoV-2 infection is known for causing broncho-alveolar inflammation. Interleukin 9 (IL-9) induces airway inflammation and bronchial hyper responsiveness in respiratory viral illnesses and allergic inflammation, however, IL-9 has not been assigned a pathologic role in COVID-19. Here we show, in a K18-hACE2 transgenic (ACE2.Tg) mouse model, that IL-9 contributes to and exacerbates viral spread and airway inflammation caused by SARS-CoV-2 infection. ACE2.Tg mice with CD4+ T cell-specific deficiency of the transcription factor Forkhead Box Protein O1 (Foxo1) produce significantly less IL-9 upon SARS-CoV-2 infection than the wild type controls and they are resistant to the severe inflammatory disease that characterises the control mice. Exogenous IL-9 increases airway inflammation in Foxo1-deficient mice, while IL-9 blockade reduces and suppresses airway inflammation in SARS-CoV-2 infection, providing further evidence for a Foxo1-Il-9 mediated Th cell-specific pathway playing a role in COVID-19. Collectively, our study provides mechanistic insight into an important inflammatory pathway in SARS-CoV-2 infection, and thus represents proof of principle for the development of host-directed therapeutics to mitigate disease severity.
Lysine methylation promotes NFAT5 activation and determines temozolomide efficacy in glioblastoma
Authors: Li Yatian , Gao Zhenyue , Wang Yuhong , Pang Bo , Zhang Binbin , Hu Ruxin , Wang Yuqing , Liu Chao , Zhang Xuebin , Yang Jingxuan , Mei Mei , Wang Yongzhi , Zhou Xuan , Li Min , Ren Yu 
Published: July 2023

AbstractTemozolomide (TMZ) therapy offers minimal clinical benefits in patients with glioblastoma multiforme (GBM) with high EGFR activity, underscoring the need for effective combination therapy. Here, we show that tonicity-responsive enhancer binding protein (NFAT5) lysine methylation, is a determinant of TMZ response. Mechanistically, EGFR activation induces phosphorylated EZH2 (Ser21) binding and triggers NFAT5 methylation at K668. Methylation prevents NFAT5 cytoplasm interaction with E3 ligase TRAF6, thus blocks NFAT5 lysosomal degradation and cytosol localization restriction, which was mediated by TRAF6 induced K63-linked ubiquitination, resulting in NFAT5 protein stabilization, nuclear accumulation and activation. Methylated NFAT5 leads to the upregulation of MGMT, a transcriptional target of NFAT5, which is responsible for unfavorable TMZ response. Inhibition of NFAT5 K668 methylation improved TMZ efficacy in orthotopic xenografts and patient-derived xenografts (PDX) models. Notably, NFAT5 K668 methylation levels are elevated in TMZ-refractory specimens and confer poor prognosis. Our findings suggest targeting NFAT5 methylation is a promising therapeutic strategy to improve TMZ response in tumors with EGFR activation.
Histone H1 facilitates restoration of H3K27me3 during DNA replication by chromatin compaction
Authors: Liu Cuifang , Yu Juan , Song Aoqun , Wang Min , Hu Jiansen , Chen Ping , Zhao Jicheng , Li Guohong 
Published: July 2023

AbstractDuring cell renewal, epigenetic information needs to be precisely restored to maintain cell identity and genome integrity following DNA replication. The histone mark H3K27me3 is essential for the formation of facultative heterochromatin and the repression of developmental genes in embryonic stem cells. However, how the restoration of H3K27me3 is precisely achieved following DNA replication is still poorly understood. Here we employ ChOR-seq (Chromatin Occupancy after Replication) to monitor the dynamic re-establishment of H3K27me3 on nascent DNA during DNA replication. We find that the restoration rate of H3K27me3 is highly correlated with dense chromatin states. In addition, we reveal that the linker histone H1 facilitates the rapid post-replication restoration of H3K27me3 on repressed genes and the restoration rate of H3K27me3 on nascent DNA is greatly compromised after partial depletion of H1. Finally, our in vitro biochemical experiments demonstrate that H1 facilitates the propagation of H3K27me3 by PRC2 through compacting chromatin. Collectively, our results indicate that H1-mediated chromatin compaction facilitates the propagation and restoration of H3K27me3 after DNA replication.
Roving methyltransferases generate a mosaic epigenetic landscape and influence evolution in Bacteroides fragilis group
Authors: Tisza Michael J. , Smith Derek D. N. , Clark Andrew E. , Youn Jung-Ho ,   NISC Comparative Sequencing Program, Barnabas Beatrice B. , Black Sean , Bouffard Gerard G. , Brooks Shelise Y. , Crawford Juyun , Marfani Holly , Dekhtyar Lyudmila , Han Joel , Ho Shi-Ling , Legaspi Richelle , Maduro Quino L. , Masiello Catherine A. , McDowell Jennifer C. , Montemayor Casandra , Mullikin James C. , Park Morgan , Schandler Karen , Schmidt Brian , Sison Christina , Stantripop Sirintorn , Thomas James W. , Thomas Pamela J. , Vemulapalli Meghana , Young Alice C. , Khil Pavel P. , Dekker John P. 
Published: July 2023

AbstractThree types of DNA methyl modifications have been detected in bacterial genomes, and mechanistic studies have demonstrated roles for DNA methylation in physiological functions ranging from phage defense to transcriptional control of virulence and host-pathogen interactions. Despite the ubiquity of methyltransferases and the immense variety of possible methylation patterns, epigenomic diversity remains unexplored for most bacterial species. Members of theBacteroides fragilisgroup (BFG) reside in the human gastrointestinal tract as key players in symbiotic communities but also can establish anaerobic infections that are increasingly multi-drug resistant. In this work, we utilize long-read sequencing technologies to perform pangenomic (n = 383) and panepigenomic (n = 268) analysis of clinical BFG isolates cultured from infections seen at the NIH Clinical Center over four decades. Our analysis reveals that single BFG species harbor hundreds of DNA methylation motifs, with most individual motif combinations occurring uniquely in single isolates, implying immense unsampled methylation diversity within BFG epigenomes. Mining of BFG genomes identified more than 6000 methyltransferase genes, approximately 1000 of which were associated with intact prophages. Network analysis revealed substantial gene flow among disparate phage genomes, implying a role for genetic exchange between BFG phages as one of the ultimate sources driving BFG epigenome diversity.
Real-time multiaxial strain mapping using computer vision integrated optical sensors
Authors: Hong Sunguk , Rachim Vega Pradana , Baek Jin-Hyeok , Park Sung-Min 
Published: July 2023

AbstractSoft strain sensors pose great potential for emerging human–machine interfaces. However, their real-world applications have been limited due to challenges such as low reproducibility, susceptibility to environmental noise, and short lifetimes, which are attributed to nanotechnologies, including microfabrication techniques. In this study, we present a computer vision-based optical strain (CVOS) sensor system that integrates computer vision with streamlined microfabrication techniques to overcome these challenges and facilitate real-time multiaxial strain mapping. The proposed CVOS sensor consists of an easily fabricated soft silicone substrate with micro-markers and a tiny camera for highly sensitive marker detection. Real-time multiaxial strain mapping allows for measuring and distinguishing complex multi-directional strain patterns, providing the proposed CVOS sensor with higher scalability. Our results indicate that the proposed CVOS sensor is a promising approach for the development of highly sensitive and versatile human–machine interfaces that can operate long-term under real-world conditions.
A lipidated TLR7/8 adjuvant enhances the efficacy of a vaccine against fentanyl in mice
Authors: Miller Shannon M. , Crouse Bethany , Hicks Linda , Amin Hardik , Cole Shelby , Bazin Helene G. , Burkhart David J. , Pravetoni Marco , Evans Jay T. 
Published: July 2023

AbstractOpioid use disorders (OUD) and opioid-related fatal overdoses are a public health concern in the United States. Approximately 100,000 fatal opioid-related overdoses occurred annually from mid-2020 to the present, the majority of which involved fentanyl or fentanyl analogs. Vaccines have been proposed as a therapeutic and prophylactic strategy to offer selective and long-lasting protection against accidental or deliberate exposure to fentanyl and closely related analogs. To support the development of a clinically viable anti-opioid vaccine suitable for human use, the incorporation of adjuvants will be required to elicit high titers of high-affinity circulating antibodies specific to the target opioid. Here we demonstrate that the addition of a synthetic TLR7/8 agonist, INI-4001, but not a synthetic TLR4 agonist, INI-2002, to a candidate conjugate vaccine consisting of a fentanyl-based hapten, F1, conjugated to the diphtheria cross-reactive material (CRM), significantly increased generation of high-affinity F1-specific antibody concentrations, and reduced drug distribution to the brain after fentanyl administration in mice.
Integrated internal ion-gated organic electrochemical transistors for stand-alone conformable bioelectronics
Authors: Cea Claudia , Zhao Zifang , Wisniewski Duncan J. , Spyropoulos George D. , Polyravas Anastasios , Gelinas Jennifer N. , Khodagholy Dion 
Published: July 2023

AbstractOrganic electronics can be biocompatible and conformable, enhancing the ability to interface with tissue. However, the limitations of speed and integration have, thus far, necessitated reliance on silicon-based technologies for advanced processing, data transmission and device powering. Here we create a stand-alone, conformable, fully organic bioelectronic device capable of realizing these functions. This device, vertical internal ion-gated organic electrochemical transistor (vIGT), is based on a transistor architecture that incorporates a vertical channel and a miniaturized hydration access conduit to enable megahertz-signal-range operation within densely packed integrated arrays in the absence of crosstalk. These transistors demonstrated long-term stability in physiologic media, and were used to generate high-performance integrated circuits. We leveraged the high-speed and low-voltage operation of vertical internal ion-gated organic electrochemical transistors to develop alternating-current-powered conformable circuitry to acquire and wirelessly communicate signals. The resultant stand-alone device was implanted in freely moving rodents to acquire, process and transmit neurophysiologic brain signals. Such fully organic devices have the potential to expand the utility and accessibility of bioelectronics to a wide range of clinical and societal applications.
Adeno-associated viral vectors for functional intravenous gene transfer throughout the non-human primate brain
Authors: Chuapoco Miguel R. , Flytzanis Nicholas C. , Goeden Nick , Christopher Octeau J. , Roxas Kristina M. , Chan Ken Y. , Scherrer Jon , Winchester Janet , Blackburn Roy J. , Campos Lillian J. , Man Kwun Nok Mimi , Sun Junqing , Chen Xinhong , Lefevre Arthur , Singh Vikram Pal , Arokiaraj Cynthia M. , Shay Timothy F. , Vendemiatti Julia , Jang Min J. , Mich John K. , Bishaw Yemeserach , Gore Bryan B. , Omstead Victoria , Taskin Naz , Weed Natalie , Levi Boaz P. , Ting Jonathan T. , Miller Cory T. , Deverman Benjamin E. , Pickel James , Tian Lin , Fox Andrew S. , Gradinaru Viviana 
Published: July 2023

AbstractCrossing the blood–brain barrier in primates is a major obstacle for gene delivery to the brain. Adeno-associated viruses (AAVs) promise robust, non-invasive gene delivery from the bloodstream to the brain. However, unlike in rodents, few neurotropic AAVs efficiently cross the blood–brain barrier in non-human primates. Here we report on AAV.CAP-Mac, an engineered variant identified by screening in adult marmosets and newborn macaques, which has improved delivery efficiency in the brains of multiple non-human primate species: marmoset, rhesus macaque and green monkey. CAP-Mac is neuron biased in infant Old World primates, exhibits broad tropism in adult rhesus macaques and is vasculature biased in adult marmosets. We demonstrate applications of a single, intravenous dose of CAP-Mac to deliver functional GCaMP for ex vivo calcium imaging across multiple brain areas, or a cocktail of fluorescent reporters for Brainbow-like labelling throughout the macaque brain, circumventing the need for germline manipulations in Old World primates. As such, CAP-Mac is shown to have potential for non-invasive systemic gene transfer in the brains of non-human primates.
Spatial differences and influence mechanisms of construction land development intensity in China, 2002–2020
Authors: Gu Guanhai , Wu Bin , Chen Qichen , Zhang Wenzhu , Lu Rucheng , Lu Shengquan , Feng Xiaoling , Liao Wenhui 
Published: July 2023

AbstractConstruction land development intensity is a spatial mapping of modern urbanization level, which integrally reflects urban development strategy, land use efficiency, and population carrying intensity. This article analyzed the spatial and temporal evolution of construction land development intensity using panel data of 31 provincial administrative divisions in China from 2002 to 2020, with the application of the Theil index and spatial autocorrelation. To further investigate the relationship between human activities and land development, the article used geographic detectors to analyze the influencing mechanisms. The results showed that: (1) The average intensity of construction land development of Chinese provinces from 2002 to 2020 showed a trend of "steady increase, a short decline, and then a steady increase," and there were significant differences in the characteristics of construction land development intensity changes in different regions. (2) The regional differences in construction land development intensity between provinces showed a decreasing trend. There were uneven differences among regions, with more minor regional differences in Central, South, and North China but more significant differences in Northwest, East, Southwest, and Northeast China. (3) The spatial agglomeration of construction land development intensity in the region increased initially and then decreased during the study period. The overall pattern was "small agglomeration and large dispersion." (4) Economic development factors such as GDP per land, industrial structure, and fixed asset investment completion significantly affect land development intensity. The interaction between the factors was apparent, and the effect of “1 + 1 > 2” was produced. Based on the study's results, it is suggested that scientific regional development planning, guiding inter-provincial factor flow, and rational control of land development efforts are the key to promoting sustainable regional development.
Single event response of ferroelectric spacer engineered SOI FinFET at 14 nm technology node
Authors: Liu Baojun , Zhu Jing 
Published: July 2023

AbstractThe impact of spacer on the single event response of SOI FinFET at 14 nm technology node is investigated. Based on the device TCAD model, well-calibrated by the experimental data, it is found that the spacer presents the enhancement on single event transient (SET) compared with no spacer configuration. For single spacer configuration, due to enhanced gate control capability and fringing field, the increments in SET current peak and collected charge for HfO2 are the least with 2.21%, 0.97%, respectively. Four possible dual ferroelectric spacer configurations are proposed. The placement of ferroelectric spacer at S side and HfO2 spacer at D side brings to weaken SET with the variation in current peak and collected charge by 6.93%, 1.86%, respectively. The reason may be its enhanced gate controllability over the S/D extension region, which improves the driven current. With linear energy transfer increasing, SET current peak and collected charge present the trend of increase while the bipolar amplification coefficient reduces.