bluuebunny/crossref_metadata_2025_split huggingface dataset:
Structure function and engineering of multifunctional non-heme iron dependent oxygenases in fungal meroterpenoid biosynthesis
Authors: Nakashima Yu , Mori Takahiro , Nakamura Hitomi , Awakawa Takayoshi , Hoshino Shotaro , Senda Miki , Senda Toshiya , Abe Ikuro 
Published: January 2018

AbstractNon-heme iron and α-ketoglutarate (αKG) oxygenases catalyze remarkably diverse reactions using a single ferrous ion cofactor. A major challenge in studying this versatile family of enzymes is to understand their structure–function relationship. AusE from Aspergillus nidulans and PrhA from Penicillium brasilianum are two highly homologous Fe(II)/αKG oxygenases in fungal meroterpenoid biosynthetic pathways that use preaustinoid A1 as a common substrate to catalyze divergent rearrangement reactions to form the spiro-lactone in austinol and cycloheptadiene moiety in paraherquonin, respectively. Herein, we report the comparative structural study of AusE and PrhA, which led to the identification of three key active site residues that control their reactivity. Structure-guided mutagenesis of these residues results in successful interconversion of AusE and PrhA functions as well as generation of the PrhA double and triple mutants with expanded catalytic repertoire. Manipulation of the multifunctional Fe(II)/αKG oxygenases thus provides an excellent platform for the future development of biocatalysts.
Punctuated evolution of canonical genomic aberrations in uveal melanoma
Authors: Field Matthew G. , Durante Michael A. , Anbunathan Hima , Cai Louis Z. , Decatur Christina L. , Bowcock Anne M. , Kurtenbach Stefan , Harbour J. William 
Published: January 2018

AbstractCancer is thought to arise through the accumulation of genomic aberrations evolving under Darwinian selection. However, it remains unclear when the aberrations associated with metastasis emerge during tumor evolution. Uveal melanoma (UM) is the most common primary eye cancer and frequently leads to metastatic death, which is strongly linked to BAP1 mutations. Accordingly, UM is ideally suited for studying the clonal evolution of metastatic competence. Here we analyze sequencing data from 151 primary UM samples using a customized bioinformatic pipeline, to improve detection of BAP1 mutations and infer the clonal relationships among genomic aberrations. Strikingly, we find BAP1 mutations and other canonical genomic aberrations usually arise in an early punctuated burst, followed by neutral evolution extending to the time of clinical detection. This implies that the metastatic proclivity of UM is “set in stone” early in tumor evolution and may explain why advances in primary treatment have not improved survival.
Integrated omics dissection of proteome dynamics during cardiac remodeling
Authors: Lau Edward , Cao Quan , Lam Maggie P. Y. , Wang Jie , Ng Dominic C. M. , Bleakley Brian J. , Lee Jessica M. , Liem David A. , Wang Ding , Hermjakob Henning , Ping Peipei 
Published: January 2018

AbstractTranscript abundance and protein abundance show modest correlation in many biological models, but how this impacts disease signature discovery in omics experiments is rarely explored. Here we report an integrated omics approach, incorporating measurements of transcript abundance, protein abundance, and protein turnover to map the landscape of proteome remodeling in a mouse model of pathological cardiac hypertrophy. Analyzing the hypertrophy signatures that are reproducibly discovered from each omics data type across six genetic strains of mice, we find that the integration of transcript abundance, protein abundance, and protein turnover data leads to 75% gain in discovered disease gene candidates. Moreover, the inclusion of protein turnover measurements allows discovery of post-transcriptional regulations across diverse pathways, and implicates distinct disease proteins not found in steady-state transcript and protein abundance data. Our results suggest that multi-omics investigations of proteome dynamics provide important insights into disease pathogenesis in vivo.
The peroxisomal AAA-ATPase Pex1/Pex6 unfolds substrates by processive threading
Authors: Gardner Brooke M. , Castanzo Dominic T. , Chowdhury Saikat , Stjepanovic Goran , Stefely Matthew S. , Hurley James H. , Lander Gabriel C. , Martin Andreas 
Published: January 2018

AbstractPex1 and Pex6 form a heterohexameric motor essential for peroxisome biogenesis and function, and mutations in these AAA-ATPases cause most peroxisome-biogenesis disorders in humans. The tail-anchored protein Pex15 recruits Pex1/Pex6 to the peroxisomal membrane, where it performs an unknown function required for matrix-protein import. Here we determine that Pex1/Pex6 from S. cerevisiae is a protein translocase that unfolds Pex15 in a pore-loop-dependent and ATP-hydrolysis-dependent manner. Our structural studies of Pex15 in isolation and in complex with Pex1/Pex6 illustrate that Pex15 binds the N-terminal domains of Pex6, before its C-terminal disordered region engages with the pore loops of the motor, which then processively threads Pex15 through the central pore. Furthermore, Pex15 directly binds the cargo receptor Pex5, linking Pex1/Pex6 to other components of the peroxisomal import machinery. Our results thus support a role of Pex1/Pex6 in mechanical unfolding of peroxins or their extraction from the peroxisomal membrane during matrix-protein import.
Unidirectional spin-Hall and Rashba−Edelstein magnetoresistance in topological insulator-ferromagnet layer heterostructures
Authors: Lv Yang , Kally James , Zhang Delin , Lee Joon Sue , Jamali Mahdi , Samarth Nitin , Wang Jian-Ping 
Published: January 2018

AbstractThe large spin−orbit coupling in topological insulators results in helical spin-textured Dirac surface states that are attractive for topological spintronics. These states generate an efficient spin−orbit torque on proximal magnetic moments. However, memory or logic spin devices based upon such switching require a non-optimal three-terminal geometry, with two terminals for the writing current and one for reading the state of the device. An alternative two-terminal device geometry is now possible by exploiting the recent discovery of the unidirectional spin Hall magnetoresistance in heavy metal/ferromagnet bilayers and unidirectional magnetoresistance in magnetic topological insulators. Here, we report the observation of such unidirectional magnetoresistance in a technologically relevant device geometry that combines a topological insulator with a conventional ferromagnetic metal. Our devices show a figure of merit (magnetoresistance per current density per total resistance) that is more than twice as large as the highest reported values in all-metal Ta/Co bilayers.
Differential Pd-nanocrystal facets demonstrate distinct antibacterial activity against Gram-positive and Gram-negative bacteria
Authors: Fang Ge , Li Weifeng , Shen Xiaomei , Perez-Aguilar Jose Manuel , Chong Yu , Gao Xingfa , Chai Zhifang , Chen Chunying , Ge Cuicui , Zhou Ruhong 
Published: January 2018

AbstractNoble metal-based nanomaterials have shown promise as potential enzyme mimetics, but the facet effect and underlying molecular mechanisms are largely unknown. Herein, with a combined experimental and theoretical approach, we unveil that palladium (Pd) nanocrystals exhibit facet-dependent oxidase and peroxidase-like activities that endow them with excellent antibacterial properties via generation of reactive oxygen species. The antibacterial efficiency of Pd nanocrystals against Gram-positive bacteria is consistent with the extent of their enzyme-like activity, that is {100}-faceted Pd cubes with higher activities kill bacteria more effectively than {111}-faceted Pd octahedrons. Surprisingly, a reverse trend of antibacterial activity is observed against Gram-negative bacteria, with Pd octahedrons displaying stronger penetration into bacterial membranes than Pd nanocubes, thereby exerting higher antibacterial activity than the latter. Our findings provide a deeper understanding of facet-dependent enzyme-like activities and might advance the development of noble metal-based nanomaterials with both enhanced and targeted antibacterial activities.
Tectonically-triggered sediment and carbon export to the Hadal zone
Authors: Bao Rui , Strasser Michael , McNichol Ann P. , Haghipour Negar , McIntyre Cameron , Wefer Gerold , Eglinton Timothy I. 
Published: January 2018

AbstractSediments in deep ocean trenches may contain crucial information on past earthquake history and constitute important sites of carbon burial. Here we present 14C data on bulk organic carbon (OC) and its thermal decomposition fractions produced by ramped pyrolysis/oxidation for a core retrieved from the >7.5 km-deep Japan Trench. High-resolution 14C measurements, coupled with distinctive thermogram characteristics of OC, reveal hemipelagic sedimentation interrupted by episodic deposition of pre-aged OC in the trench. Low δ13C values and diverse 14C ages of thermal fractions imply that the latter material originates from the adjacent margin, and the co-occurrence of pre-aged OC with intervals corresponding to known earthquake events implies tectonically triggered, gravity-flow-driven supply. We show that 14C ages of thermal fractions can yield valuable chronological constraints on sedimentary sequences. Our findings shed new light on links between tectonically driven sedimentological processes and marine carbon cycling, with implications for carbon dynamics in hadal environments.
Phf8 histone demethylase deficiency causes cognitive impairments through the mTOR pathway
Authors: Chen Xuemei , Wang Shuai , Zhou Ying , Han Yanfei , Li Shengtian , Xu Qing , Xu Longyong , Zhu Ziqi , Deng Youming , Yu Lu , Song Lulu , Chen Adele Pin , Song Juan , Takahashi Eiki , He Guang , He Lin , Li Weidong , Chen Charlie Degui 
Published: January 2018

AbstractEpigenomic abnormalities caused by genetic mutation in epigenetic regulators can result in neurodevelopmental disorders, deficiency in neural plasticity and mental retardation. As a histone demethylase, plant homeodomain finger protein 8 (Phf8) is a candidate gene for syndromal and non-specific forms of X-chromosome-linked intellectual disability (XLID). Here we report that Phf8 knockout mice displayed impaired learning and memory, and impaired hippocampal long-term potentiation (LTP) without gross morphological defects. We also show that mTOR signaling pathway is hyperactive in hippocampus in Phf8 knockout mouse. Mechanistically, we show that demethylation of H4K20me1 by Phf8 results in transcriptional suppression of RSK1 and homeostasis of mTOR signaling. Pharmacological suppression of mTOR signaling with rapamycin in Phf8 knockout mice recovers the weakened LTP and cognitive deficits. Together, our results indicate that loss of Phf8 in animals causes deficient learning and memory by epigenetic disruption of mTOR signaling, and provides a potential therapeutic drug target to treat XLID.
Click beetle luciferase mutant and near infrared naphthyl-luciferins for improved bioluminescence imaging
Authors: Hall Mary P. , Woodroofe Carolyn C. , Wood Monika G. , Que Ivo , van’t Root Moniek , Ridwan Yanto , Shi Ce , Kirkland Thomas A. , Encell Lance P. , Wood Keith V. , Löwik Clemens , Mezzanotte Laura 
Published: January 2018

AbstractThe sensitivity of bioluminescence imaging in animals is primarily dependent on the amount of photons emitted by the luciferase enzyme at wavelengths greater than 620 nm where tissue penetration is high. This area of work has been dominated by firefly luciferase and its substrate, D-luciferin, due to the system’s peak emission (~ 600 nm), high signal to noise ratio, and generally favorable biodistribution of D-luciferin in mice. Here we report on the development of a codon optimized mutant of click beetle red luciferase that produces substantially more light output than firefly luciferase when the two enzymes are compared in transplanted cells within the skin of black fur mice or in deep brain. The mutant enzyme utilizes two new naphthyl-luciferin substrates to produce near infrared emission (730 nm and 743 nm). The stable luminescence signal and near infrared emission enable unprecedented sensitivity and accuracy for performing deep tissue multispectral tomography in mice.
Picosecond pulse shaping of single photons using quantum dots
Authors: Pursley B. C. , Carter S. G. , Yakes M. K. , Bracker A. S. , Gammon D. 
Published: January 2018

AbstractQuantum dots (QDs) are an excellent single-photon source that can be combined with a spin quantum memory. Many quantum technologies require increased control over the characteristics of emitted photons. A powerful approach is to trigger coherent Raman photons from QDs with a Λ energy-level system, such as the spin singlet–triplet system in two coupled QDs. The temporal and spectral behavior of single Raman photons can be varied simply by modifying the excitation source. Here, we demonstrate control of the single-photon pulse shape in a solid-state system on a timescale much shorter than the radiative lifetime, in addition to control of the frequency and bandwidth. We achieve a photon pulse width of 80 ps—an order of magnitude shorter than the exciton lifetime. Possible applications include time-bin encoding of quantum information, matching photons from different sources, and efficient single-photon transfer in a quantum network.
3D single-molecule super-resolution microscopy with a tilted light sheet
Authors: Gustavsson Anna-Karin , Petrov Petar N. , Lee Maurice Y. , Shechtman Yoav , Moerner W. E. 
Published: January 2018

AbstractTilted light sheet microscopy with 3D point spread functions (TILT3D) combines a novel, tilted light sheet illumination strategy with long axial range point spread functions (PSFs) for low-background, 3D super-localization of single molecules as well as 3D super-resolution imaging in thick cells. Because the axial positions of the single emitters are encoded in the shape of each single-molecule image rather than in the position or thickness of the light sheet, the light sheet need not be extremely thin. TILT3D is built upon a standard inverted microscope and has minimal custom parts. The result is simple and flexible 3D super-resolution imaging with tens of nm localization precision throughout thick mammalian cells. We validate TILT3D for 3D super-resolution imaging in mammalian cells by imaging mitochondria and the full nuclear lamina using the double-helix PSF for single-molecule detection and the recently developed tetrapod PSFs for fiducial bead tracking and live axial drift correction.
Nanoparticle elasticity directs tumor uptake
Authors: Guo Peng , Liu Daxing , Subramanyam Kriti , Wang Biran , Yang Jiang , Huang Jing , Auguste Debra T. , Moses Marsha A. 
Published: January 2018

AbstractTo date, the role of elasticity in drug delivery remains elusive due to the inability to measure microscale mechanics and alter rheology without affecting chemistry. Herein, we describe the in vitro cellular uptake and in vivo tumor uptake of nanolipogels (NLGs). NLGs are composed of identical lipid bilayers encapsulating an alginate core, with tunable elasticity. The elasticity of NLGs was evaluated by atomic force microscopy, which demonstrated that they exhibit Young’s moduli ranging from 45 ± 9 to 19,000 ± 5 kPa. Neoplastic and non-neoplastic cells exhibited significantly greater uptake of soft NLGs (Young’s modulus <1.6 MPa) relative to their elastic counterparts (Young’s modulus >13.8 MPa). In an orthotopic breast tumor model, soft NLGs accumulated significantly more in tumors, whereas elastic NLGs preferentially accumulated in the liver. Our findings demonstrate that particle elasticity directs tumor accumulation, suggesting that it may be a design parameter to enhance tumor delivery efficiency.
Mechanism and structural diversity of exoribonuclease-resistant RNA structures in flaviviral RNAs
Authors: MacFadden Andrea , O’Donoghue Zoe , Silva Patricia A. G. C. , Chapman Erich G. , Olsthoorn René C. , Sterken Mark G. , Pijlman Gorben P. , Bredenbeek Peter J. , Kieft Jeffrey S. 
Published: January 2018

AbstractFlaviviruses such as Yellow fever, Dengue, West Nile, and Zika generate disease-linked viral noncoding RNAs called subgenomic flavivirus RNAs. Subgenomic flavivirus RNAs result when the 5′–3′ progression of cellular exoribonuclease Xrn1 is blocked by RNA elements called Xrn1-resistant RNAs located within the viral genome’s 3′-untranslated region that operate without protein co-factors. Here, we show that Xrn1-resistant RNAs can halt diverse exoribonucleases, revealing a mechanism in which they act as general mechanical blocks that ‘brace’ against an enzyme’s surface, presenting an unfolding problem that confounds further enzyme progression. Further, we directly demonstrate that Xrn1-resistant RNAs exist in a diverse set of flaviviruses, including some specific to insects or with no known arthropod vector. These Xrn1-resistant RNAs comprise two secondary structural classes that mirror previously reported phylogenic analysis. Our discoveries have implications for the evolution of exoribonuclease resistance, the use of Xrn1-resistant RNAs in synthetic biology, and the development of new therapies.
Peptidomimetic blockade of MYB in acute myeloid leukemia
Authors: Ramaswamy Kavitha , Forbes Lauren , Minuesa Gerard , Gindin Tatyana , Brown Fiona , Kharas Michael G. , Krivtsov Andrei V. , Armstrong Scott A. , Still Eric , de Stanchina Elisa , Knoechel Birgit , Koche Richard , Kentsis Alex 
Published: January 2018

AbstractAberrant gene expression is a hallmark of acute leukemias. MYB-driven transcriptional coactivation with CREB-binding protein (CBP)/P300 is required for acute lymphoblastic and myeloid leukemias, including refractory MLL-rearranged leukemias. Using structure-guided molecular design, we developed a peptidomimetic inhibitor MYBMIM that interferes with the assembly of the molecular MYB:CBP/P300 complex and rapidly accumulates in the nuclei of AML cells. Treatment of AML cells with MYBMIM led to the dissociation of the MYB:CBP/P300 complex in cells, its displacement from oncogenic enhancers enriched for MYB binding sites, and downregulation of MYB-dependent gene expression, including of MYC and BCL2 oncogenes. AML cells underwent mitochondrial apoptosis in response to MYBMIM, which was partially rescued by ectopic expression of BCL2. MYBMIM impeded leukemia growth and extended survival of immunodeficient mice engrafted with primary patient-derived MLL-rearranged leukemia cells. These findings elucidate the dependence of human AML on aberrant transcriptional coactivation, and establish a pharmacologic approach for its therapeutic blockade.
TDRD5 binds piRNA precursors and selectively enhances pachytene piRNA processing in mice
Authors: Ding Deqiang , Liu Jiali , Midic Uros , Wu Yingjie , Dong Kunzhe , Melnick Ashley , Latham Keith E. , Chen Chen 
Published: January 2018

AbstractPachytene piRNAs are the most abundant piRNAs in mammalian adult testes. They are generated from long precursor transcripts by the primary piRNA biogenesis pathway but the factors involved in pachytene piRNA precursors processing are poorly understood. Here we show that the Tudor domain-containing 5 (TDRD5) protein is essential for pachytene piRNA biogenesis in mice. Conditional inactivation of TDRD5 in mouse postnatal germ cells reveals that TDRD5 selectively regulates the production of pachytene piRNAs from abundant piRNA-producing precursors, with little effect on low-abundant piRNAs. Unexpectedly, TDRD5 is not required for the 5′ end processing of the precursors, but is crucial for promoting production of piRNAs from the other regions of the transcript. Furthermore, we show that TDRD5 is an RNA-binding protein directly associating with piRNA precursors. These observations establish TDRD5 as a piRNA biogenesis factor and reveal two genetically separable steps at the start of pachytene piRNA processing.
Weakly perturbative imaging of interfacial water with submolecular resolution by atomic force microscopy
Authors: Peng Jinbo , Guo Jing , Hapala Prokop , Cao Duanyun , Ma Runze , Cheng Bowei , Xu Limei , Ondráček Martin , Jelínek Pavel , Wang Enge , Jiang Ying 
Published: January 2018

AbstractScanning probe microscopy has been extensively applied to probe interfacial water in many interdisciplinary fields but the disturbance of the probes on the hydrogen-bonding structure of water has remained an intractable problem. Here, we report submolecular-resolution imaging of the water clusters on a NaCl(001) surface within the nearly noninvasive region by a qPlus-based noncontact atomic force microscopy. Comparison with theoretical simulations reveals that the key lies in probing the weak high-order electrostatic force between the quadrupole-like CO-terminated tip and the polar water molecules at large tip–water distances. This interaction allows the imaging and structural determination of the weakly bonded water clusters and even of their metastable states with negligible disturbance. This work may open an avenue for studying the intrinsic structure and dynamics of ice or water on surfaces, ion hydration, and biological water with atomic precision.
Guiding of relativistic electron beams in dense matter by laser-driven magnetostatic fields
Authors: Bailly-Grandvaux M. , Santos J. J. , Bellei C. , Forestier-Colleoni P. , Fujioka S. , Giuffrida L. , Honrubia J. J. , Batani D. , Bouillaud R. , Chevrot M. , Cross J. E. , Crowston R. , Dorard S. , Dubois J.-L. , Ehret M. , Gregori G. , Hulin S. , Kojima S. , Loyez E. , Marquès J.-R. , Morace A. , Nicolaï Ph. , Roth M. , Sakata S. , Schaumann G. , Serres F. , Servel J. , Tikhonchuk V. T. , Woolsey N. , Zhang Z. 
Published: January 2018

AbstractIntense lasers interacting with dense targets accelerate relativistic electron beams, which transport part of the laser energy into the target depth. However, the overall laser-to-target energy coupling efficiency is impaired by the large divergence of the electron beam, intrinsic to the laser–plasma interaction. Here we demonstrate that an efficient guiding of MeV electrons with about 30 MA current in solid matter is obtained by imposing a laser-driven longitudinal magnetostatic field of 600 T. In the magnetized conditions the transported energy density and the peak background electron temperature at the 60-μm-thick target's rear surface rise by about a factor of five, as unfolded from benchmarked simulations. Such an improvement of energy-density flux through dense matter paves the ground for advances in laser-driven intense sources of energetic particles and radiation, driving matter to extreme temperatures, reaching states relevant for planetary or stellar science as yet inaccessible at the laboratory scale and achieving high-gain laser-driven thermonuclear fusion.
Zika virus infection induces host inflammatory responses by facilitating NLRP3 inflammasome assembly and interleukin-1β secretion
Authors: Wang Wenbiao , Li Geng , De Wu  , Luo Zhen , Pan Pan , Tian Mingfu , Wang Yingchong , Xiao Feng , Li Aixin , Wu Kailang , Liu Xiaohong , Rao Lang , Liu Fang , Liu Yingle , Wu Jianguo 
Published: January 2018

AbstractZika virus (ZIKV) infection is a public health emergency and host innate immunity is essential for the control of virus infection. The NLRP3 inflammasome plays a key role in host innate immune responses by activating caspase-1 to facilitate interleukin-1β (IL-1β) secretion. Here we report that ZIKV stimulates IL-1β secretion in infected patients, human PBMCs and macrophages, mice, and mice BMDCs. The knockdown of NLRP3 in cells and knockout of NLRP3 in mice inhibit ZIKV-mediated IL-1β secretion, indicating an essential role for NLRP3 in ZIKV-induced IL-1β activation. Moreover, ZIKV NS5 protein is required for NLRP3 activation and IL-1β secretion by binding with NLRP3 to facilitate the inflammasome complex assembly. Finally, ZIKV infection in mice activates IL-1β secretion, leading to inflammatory responses in the mice brain, spleen, liver, and kidney. Thus we reveal a mechanism by which ZIKV induces inflammatory responses by facilitating NLRP3 inflammasome complex assembly and IL-1β activation.