bluuebunny/crossref_metadata_2025_split huggingface dataset:
Glucose-regulated protein 75 determines ER–mitochondrial coupling and sensitivity to oxidative stress in neuronal cells
Authors: Honrath Birgit , Metz Isabell , Bendridi Nadia , Rieusset Jennifer , Culmsee Carsten , Dolga Amalia M 
Published: November 2017

AbstractThe crosstalk between different organelles allows for the exchange of proteins, lipids and ions. Endoplasmic reticulum (ER) and mitochondria are physically linked and signal through the mitochondria-associated membrane (MAM) to regulate the transfer of Ca2+from ER stores into the mitochondrial matrix, thereby affecting mitochondrial function and intracellular Ca2+homeostasis. The chaperone glucose-regulated protein 75 (GRP75) is a key protein expressed at the MAM interface which regulates ER–mitochondrial Ca2+transfer. Previous studies revealed that modulation of GRP75 expression largely affected mitochondrial integrity and vulnerability to cell death. In the present study, we show that genetic ablation of GRP75, by weakening ER–mitochondrial junctions, provided protection against mitochondrial dysfunction and cell death in a model of glutamate-induced oxidative stress. Interestingly, GRP75 silencing attenuated both cytosolic and mitochondrial Ca2+overload in conditions of oxidative stress, blocked the formation of reactive oxygen species and preserved mitochondrial respiration. These data revealed a major role for GRP75 in regulating mitochondrial function, Ca2+and redox homeostasis. In line, GRP75 overexpression enhanced oxidative cell death induced by glutamate. Overall, our findings suggest weakening ER–mitochondrial connectivity by GRP75 inhibition as a novel protective approach in paradigms of oxidative stress in neuronal cells.
Supramammillary glutamate neurons are a key node of the arousal system
Authors: Pedersen Nigel P. , Ferrari Loris , Venner Anne , Wang Joshua L. , Abbott Stephen B. G. , Vujovic Nina , Arrigoni Elda , Saper Clifford B. , Fuller Patrick M. 
Published: November 2017

AbstractBasic and clinical observations suggest that the caudal hypothalamus comprises a key node of the ascending arousal system, but the cell types underlying this are not fully understood. Here we report that glutamate-releasing neurons of the supramammillary region (SuMvglut2) produce sustained behavioral and EEG arousal when chemogenetically activated. This effect is nearly abolished following selective genetic disruption of glutamate release from SuMvglut2 neurons. Inhibition of SuMvglut2 neurons decreases and fragments wake, also suppressing theta and gamma frequency EEG activity. SuMvglut2 neurons include a subpopulation containing both glutamate and GABA (SuMvgat/vglut2) and another also expressing nitric oxide synthase (SuMNos1/Vglut2). Activation of SuMvgat/vglut2 neurons produces minimal wake and optogenetic stimulation of SuMvgat/vglut2 terminals elicits monosynaptic release of both glutamate and GABA onto dentate granule cells. Activation of SuMNos1/Vglut2 neurons potently drives wakefulness, whereas inhibition reduces REM sleep theta activity. These results identify SuMvglut2 neurons as a key node of the wake−sleep regulatory system.
The emergence of piRNAs against transposon invasion to preserve mammalian genome integrity
Authors: Ernst Christina , Odom Duncan T. , Kutter Claudia 
Published: November 2017

AbstractTransposable elements (TEs) contribute to the large amount of repetitive sequences in mammalian genomes and have been linked to species-specific genome innovations by rewiring regulatory circuitries. However, organisms need to restrict TE activity to ensure genome integrity, especially in germline cells to protect the transmission of genetic information to the next generation. This review features our current understandings of mammalian PIWI-interacting RNAs (piRNAs) and their role in TE regulation in spermatogenesis. Here we discuss functional implication and explore additional molecular mechanisms that inhibit transposon activity and altogether illustrate the paradoxical arms race between genome evolution and stability.
Probing dopant segregation in distinct cation sites at perovskite oxide polycrystal interfaces
Authors: Yoon Hye-In , Lee Dong-Kyu , Bae Hyung Bin , Jo Gi-Young , Chung Hee-Suk , Kim Jin-Gyu , Kang Suk-Joong L. , Chung Sung-Yoon 
Published: November 2017

AbstractAlthough theoretical studies and experimental investigations have demonstrated the presence of space-charge-induced dopant segregation, most work has been confined largely to the crystal-free surface and some special grain boundaries, and to the best of our knowledge there has been no systematic comparison to understand how the segregation varies at different types of interfaces in polycrystals. Here, through atomic-column resolved scanning transmission electron microscopy in real polycrystalline samples, we directly elucidate the space-charge segregation features at five distinct types of interfaces in an ABO3 perovskite oxide doped with A- and B-site donors. A series of observations reveals that both the interfacial atomic structure and the subsequent segregation behaviour are invariant regardless of the interface type. The findings in this study thus suggest that the electrostatic potential variation by the interface excess charge and compensating space charge provides a crucial contribution to determining not only the distribution of dopants but also the interfacial structure in oxides.
Structural basis of arrestin-3 activation and signaling
Authors: Chen Qiuyan , Perry Nicole A. , Vishnivetskiy Sergey A. , Berndt Sandra , Gilbert Nathaniel C. , Zhuo Ya , Singh Prashant K. , Tholen Jonas , Ohi Melanie D. , Gurevich Eugenia V. , Brautigam Chad A. , Klug Candice S. , Gurevich Vsevolod V. , Iverson T. M. 
Published: November 2017

AbstractA unique aspect of arrestin-3 is its ability to support both receptor-dependent and receptor-independent signaling. Here, we show that inositol hexakisphosphate (IP6) is a non-receptor activator of arrestin-3 and report the structure of IP6-activated arrestin-3 at 2.4-Å resolution. IP6-activated arrestin-3 exhibits an inter-domain twist and a displaced C-tail, hallmarks of active arrestin. IP6 binds to the arrestin phosphate sensor, and is stabilized by trimerization. Analysis of the trimerization surface, which is also the receptor-binding surface, suggests a feature called the finger loop as a key region of the activation sensor. We show that finger loop helicity and flexibility may underlie coupling to hundreds of diverse receptors and also promote arrestin-3 activation by IP6. Importantly, we show that effector-binding sites on arrestins have distinct conformations in the basal and activated states, acting as switch regions. These switch regions may work with the inter-domain twist to initiate and direct arrestin-mediated signaling.
Global patterns of nitrate storage in the vadose zone
Authors: Ascott M. J. , Gooddy D. C. , Wang L. , Stuart M. E. , Lewis M. A. , Ward R. S. , Binley A. M. 
Published: November 2017

AbstractGlobal-scale nitrogen budgets developed to quantify anthropogenic impacts on the nitrogen cycle do not explicitly consider nitrate stored in the vadose zone. Here we show that the vadose zone is an important store of nitrate that should be considered in future budgets for effective policymaking. Using estimates of groundwater depth and nitrate leaching for 1900–2000, we quantify the peak global storage of nitrate in the vadose zone as 605–1814 Teragrams (Tg). Estimates of nitrate storage are validated using basin-scale and national-scale estimates and observed groundwater nitrate data. Nitrate storage per unit area is greatest in North America, China and Europe where there are thick vadose zones and extensive historical agriculture. In these areas, long travel times in the vadose zone may delay the impact of changes in agricultural practices on groundwater quality. We argue that in these areas use of conventional nitrogen budget approaches is inappropriate.
Live imaging molecular changes in junctional tension upon VE-cadherin in zebrafish
Authors: Lagendijk Anne Karine , Gomez Guillermo A. , Baek Sungmin , Hesselson Daniel , Hughes William E. , Paterson Scott , Conway Daniel E. , Belting Heinz-Georg , Affolter Markus , Smith Kelly A. , Schwartz Martin A. , Yap Alpha S. , Hogan Benjamin M. 
Published: November 2017

AbstractForces play diverse roles in vascular development, homeostasis and disease. VE-cadherin at endothelial cell-cell junctions links the contractile acto-myosin cytoskeletons of adjacent cells, serving as a tension-transducer. To explore tensile changes across VE-cadherin in live zebrafish, we tailored an optical biosensor approach, originally established in vitro. We validate localization and function of a VE-cadherin tension sensor (TS) in vivo. Changes in tension across VE-cadherin observed using ratio-metric or lifetime FRET measurements reflect acto-myosin contractility within endothelial cells. Furthermore, we apply the TS to reveal biologically relevant changes in VE-cadherin tension that occur as the dorsal aorta matures and upon genetic and chemical perturbations during embryonic development.
Real-space and real-time dynamics of CRISPR-Cas9 visualized by high-speed atomic force microscopy
Authors: Shibata Mikihiro , Nishimasu Hiroshi , Kodera Noriyuki , Hirano Seiichi , Ando Toshio , Uchihashi Takayuki , Nureki Osamu 
Published: November 2017

AbstractThe CRISPR-associated endonuclease Cas9 binds to a guide RNA and cleaves double-stranded DNA with a sequence complementary to the RNA guide. The Cas9–RNA system has been harnessed for numerous applications, such as genome editing. Here we use high-speed atomic force microscopy (HS-AFM) to visualize the real-space and real-time dynamics of CRISPR-Cas9 in action. HS-AFM movies indicate that, whereas apo-Cas9 adopts unexpected flexible conformations, Cas9–RNA forms a stable bilobed structure and interrogates target sites on the DNA by three-dimensional diffusion. These movies also provide real-time visualization of the Cas9-mediated DNA cleavage process. Notably, the Cas9 HNH nuclease domain fluctuates upon DNA binding, and subsequently adopts an active conformation, where the HNH active site is docked at the cleavage site in the target DNA. Collectively, our HS-AFM data extend our understanding of the action mechanism of CRISPR-Cas9.
Outflow of cerebrospinal fluid is predominantly through lymphatic vessels and is reduced in aged mice
Authors: Ma Qiaoli , Ineichen Benjamin V. , Detmar Michael , Proulx Steven T. 
Published: November 2017

AbstractCerebrospinal fluid (CSF) has been commonly accepted to drain through arachnoid projections from the subarachnoid space to the dural venous sinuses. However, a lymphatic component to CSF outflow has long been known. Here, we utilize lymphatic-reporter mice and high-resolution stereomicroscopy to characterize the anatomical routes and dynamics of outflow of CSF. After infusion into a lateral ventricle, tracers spread into the paravascular spaces of the pia mater and cortex of the brain. Tracers also rapidly reach lymph nodes using perineural routes through foramina in the skull. Using noninvasive imaging techniques that can quantify the transport of tracers to the blood and lymph nodes, we find that lymphatic vessels are the major outflow pathway for both large and small molecular tracers in mice. A significant decline in CSF lymphatic outflow is found in aged compared to young mice, suggesting that the lymphatic system may represent a target for age-associated neurological conditions.
Electrostrictive microelectromechanical fibres and textiles
Authors: Khudiyev Tural , Clayton Jefferson , Levy Etgar , Chocat Noémie , Gumennik Alexander , Stolyarov Alexander M. , Joannopoulos John , Fink Yoel 
Published: November 2017

AbstractMicroelectromechanical systems (MEMS) enable many modern-day technologies, including actuators, motion sensors, drug delivery systems, projection displays, etc. Currently, MEMS fabrication techniques are primarily based on silicon micromachining processes, resulting in rigid and low aspect ratio structures. In this study, we report on the discovery of MEMS functionality in fibres, thereby opening a path towards flexible, high-aspect ratio, and textile MEMS. The method used for generating these MEMS fibres leverages a preform-to-fibre thermal drawing process, in which the MEMS architecture and materials are embedded into a preform and drawn into kilometers of microstructured multimaterial fibre devices. The fibre MEMS functionality is enabled by an electrostrictive P(VDF-TrFE-CFE) ferrorelaxor terpolymer layer running the entire length of the fibre. Several modes of operation are investigated, including thickness-mode actuation with over 8% strain at 25 MV m−1, bending-mode actuation due to asymmetric positioning of the electrostrictive layer, and resonant fibre vibration modes tunable under AC-driving conditions.
Natural variation of YELLOW SEEDLING1 affects photosynthetic acclimation of Arabidopsis thaliana
Authors: van Rooijen Roxanne , Kruijer Willem , Boesten René , van Eeuwijk Fred A. , Harbinson Jeremy , Aarts Mark G. M. 
Published: November 2017

AbstractExploiting genetic variation for more efficient photosynthesis is an underexplored route towards new crop varieties. This study demonstrates the genetic dissection of higher plant photosynthesis efficiency down to the genomic DNA level, by confirming that allelic sequence variation at the Arabidopsis thaliana YELLOW SEEDLING1 (YS1) gene explains natural diversity in photosynthesis acclimation to high irradiance. We use a genome-wide association study to identify quantitative trait loci (QTLs) involved in the Arabidopsis photosynthetic acclimation response. Candidate genes underlying the QTLs are prioritized according to functional clues regarding gene ontology, expression and function. Reverse genetics and quantitative complementation confirm the candidacy of YS1, which encodes a pentatrico-peptide-repeat (PPR) protein involved in RNA editing of plastid-encoded genes (anterograde signalling). Gene expression analysis and allele sequence comparisons reveal polymorphisms in a light-responsive element in the YS1 promoter that affect its expression, and that of its downstream targets, resulting in the variation in photosynthetic acclimation.
Nanoscale design of polarization in ultrathin ferroelectric heterostructures
Authors: De Luca Gabriele , Strkalj Nives , Manz Sebastian , Bouillet Corinne , Fiebig Manfred , Trassin Morgan 
Published: November 2017

AbstractThe success of oxide electronics depends on the ability to design functional properties such as ferroelectricity with atomic accuracy. However, despite tremendous advances in ferroelectric heterostructures, the development towards multilevel architectures with precise layer-by-layer command over the polarization is impeded by the lack of continuous control over the balance of electrostatics, strain, chemistry and film thickness during growth. Moreover, the polarization in the deeper layers becomes inaccessible when these are buried by the ongoing deposition. Taking ferroelectric BaTiO3 and multiferroic BiFeO3 as model systems, we observe and engineer the emergence, orientation and interaction of ferroelectric polarization in ultrathin heterostructures with monolayer accuracy. We achieve this by optical second harmonic generation which tracks the evolution of spontaneous polarization in real time throughout the deposition process. Such direct and in situ access to the polarization during growth leads us to heterostructures with user-defined polarization sequences—towards a new class of functional ferroic materials.
Allogeneic stem cell transplantation in fully MHC-matched Mauritian cynomolgus macaques recapitulates diverse human clinical outcomes
Authors: Burwitz Benjamin J. , Wu Helen L. , Abdulhaqq Shaheed , Shriver-Munsch Christine , Swanson Tonya , Legasse Alfred W. , Hammond Katherine B. , Junell Stephanie L. , Reed Jason S. , Bimber Benjamin N. , Greene Justin M. , Webb Gabriela M. , Northrup Mina , Laub Wolfram , Kievit Paul , MacAllister Rhonda , Axthelm Michael K. , Ducore Rebecca , Lewis Anne , Colgin Lois M. A. , Hobbs Theodore , Martin Lauren D. , Ferguson Betsy , Thomas Charles R. , Panoskaltsis-Mortari Angela , Meyers Gabrielle , Stanton Jeffrey J. , Maziarz Richard T. , Sacha Jonah B. 
Published: November 2017

AbstractAllogeneic hematopoietic stem cell transplantation (HSCT) is a critically important therapy for hematological malignancies, inborn errors of metabolism, and immunodeficiency disorders, yet complications such as graft-vs.-host disease (GvHD) limit survival. Development of anti-GvHD therapies that do not adversely affect susceptibility to infection or graft-vs.-tumor immunity are hampered by the lack of a physiologically relevant, preclinical model of allogeneic HSCT. Here we show a spectrum of diverse clinical HSCT outcomes including primary and secondary graft failure, lethal GvHD, and stable, disease-free full donor engraftment using reduced intensity conditioning and mobilized peripheral blood HSCT in unrelated, fully MHC-matched Mauritian-origin cynomolgus macaques. Anti-GvHD prophylaxis of tacrolimus, post-transplant cyclophosphamide, and CD28 blockade induces multi-lineage, full donor chimerism and recipient-specific tolerance while maintaining pathogen-specific immunity. These results establish a new preclinical allogeneic HSCT model for evaluation of GvHD prophylaxis and next-generation HSCT-mediated therapies for solid organ tolerance, cure of non-malignant hematological disease, and HIV reservoir clearance.
Unique architecture of thermophilic archaeal virus APBV1 and its genome packaging
Authors: Ptchelkine Denis , Gillum Ashley , Mochizuki Tomohiro , Lucas-Staat Soizick , Liu Ying , Krupovic Mart , Phillips Simon E. V. , Prangishvili David , Huiskonen Juha T. 
Published: November 2017

AbstractArchaeal viruses have evolved to infect hosts often thriving in extreme conditions such as high temperatures. However, there is a paucity of information on archaeal virion structures, genome packaging, and determinants of temperature resistance. The rod-shaped virus APBV1 (Aeropyrum pernix bacilliform virus 1) is among the most thermostable viruses known; it infects a hyperthermophile Aeropyrum pernix, which grows optimally at 90 °C. Here we report the structure of APBV1, determined by cryo-electron microscopy at near-atomic resolution. Tight packing of the major virion glycoprotein (VP1) is ensured by extended hydrophobic interfaces, and likely contributes to the extreme thermostability of the helical capsid. The double-stranded DNA is tightly packed in the capsid as a left-handed superhelix and held in place by the interactions with positively charged residues of VP1. The assembly is closed by specific capping structures at either end, which we propose to play a role in DNA packing and delivery.
Origin of the omnipotence of eukaryotic release factor 1
Authors: Lind Christoffer , Oliveira Ana , Åqvist Johan 
Published: November 2017

AbstractTermination of protein synthesis on the ribosome requires that mRNA stop codons are recognized with high fidelity. This is achieved by specific release factor proteins that are very different in bacteria and eukaryotes. Hence, while there are two release factors with overlapping specificity in bacteria, the single omnipotent eRF1 release factor in eukaryotes is able to read all three stop codons. This is particularly remarkable as it is able to select three out of four combinations of purine bases in the last two codon positions. With recently determined 3D structures of eukaryotic termination complexes, it has become possible to explore the origin of eRF1 specificity by computer simulations. Here, we report molecular dynamics free energy calculations on these termination complexes, where relative eRF1 binding free energies to different cognate and near-cognate codons are evaluated. The simulations show a high and uniform discrimination against the near-cognate codons, that differ from the cognate ones by a single nucleotide, and reveal the structural mechanisms behind the precise decoding by eRF1.
Thermostability improvement of a Talaromyces leycettanus xylanase by rational protein engineering
Authors: Wang Xiaoyu , Ma Rui , Xie Xiangming , Liu Weina , Tu Tao , Zheng Fei , You Shuai , Ge Jianzhong , Xie Huifang , Yao Bin , Luo Huiying 
Published: November 2017

AbstractThermophilic xylanases with high catalytic efficiency are of great interest in the biofuel, food and feed industries. This study identified a GH11 xylanase gene, Tlxyn11B, in Talaromyces leycettanus JCM12802. Recombinant TlXyn11B produced in Pichia pastoris is distinguished by high specific activity (8259 ± 32 U/mg with beechwood xylan as substrate) and excellent pH stability (from 1.0 to 10.5). The beechwood xylan hydrolysates consisted mainly of xylobiose, xylotriose and xylotetraose, thus TlXyn11B could be used for the production of prebiotic xylooligosaccharide. By using the structure-based rational approach, the N-terminal sequence of TlXyn11B was modified for thermostability improvement. Mutants S3F and S3F/D35V/I/Q/M had elevated Tm values of 60.01 to 67.84 °C, with S3F/D35I the greatest. Homology modeling and molecular dynamics (MD) simulation analysis revealed that the substituted F3 and I35 formed a sandwich structure with S45 and T47, which may enhance the overall structure rigidity with lowered RMSD values. This study verifies the efficiency of rational approach in thermostability improvement and provides a xylanase candidate of GH11 with great commercialization potential.
Structural and Functional Insight of Sphingosine 1-Phosphate-Mediated Pathogenic Metabolic Reprogramming in Sickle Cell Disease
Authors: Sun Kaiqi , D’Alessandro Angelo , Ahmed Mostafa H. , Zhang Yujin , Song Anren , Ko Tzu-Ping , Nemkov Travis , Reisz Julie A. , Wu Hongyu , Adebiyi Morayo , Peng Zhangzhe , Gong Jing , Liu Hong , Huang Aji , Wen Yuan Edward , Wen Alexander Q. , Berka Vladimir , Bogdanov Mikhail V. , Abdulmalik Osheiza , Han Leng , Tsai Ah-lim , Idowu Modupe , Juneja Harinder S. , Kellems Rodney E. , Dowhan William , Hansen Kirk C. , Safo Martin K. , Xia Yang 
Published: November 2017

AbstractElevated sphingosine 1-phosphate (S1P) is detrimental in Sickle Cell Disease (SCD), but the mechanistic basis remains obscure. Here, we report that increased erythrocyte S1P binds to deoxygenated sickle Hb (deoxyHbS), facilitates deoxyHbS anchoring to the membrane, induces release of membrane-bound glycolytic enzymes and in turn switches glucose flux towards glycolysis relative to the pentose phosphate pathway (PPP). Suppressed PPP causes compromised glutathione homeostasis and increased oxidative stress, while enhanced glycolysis induces production of 2,3-bisphosphoglycerate (2,3-BPG) and thus increases deoxyHbS polymerization, sickling, hemolysis and disease progression. Functional studies revealed that S1P and 2,3-BPG work synergistically to decrease both HbA and HbS oxygen binding affinity. The crystal structure at 1.9 Å resolution deciphered that S1P binds to the surface of 2,3-BPG-deoxyHbA and causes additional conformation changes to the T-state Hb. Phosphate moiety of the surface bound S1P engages in a highly positive region close to α1-heme while its aliphatic chain snakes along a shallow cavity making hydrophobic interactions in the “switch region”, as well as with α2-heme like a molecular “sticky tape” with the last 3–4 carbon atoms sticking out into bulk solvent. Altogether, our findings provide functional and structural bases underlying S1P-mediated pathogenic metabolic reprogramming in SCD and novel therapeutic avenues.