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Structural Biology
Benchmark Relative Energies for Large Water Clusters with the Generalized Energy-Based Fragmentation Method
May 08, 2017   Journal Of Chemical Theory And Computation
Yuan D, Li Y, Ni Z, Pulay P, Li W, Li S
Benchmark Relative Energies for Large Water Clusters with the Generalized Energy-Based Fragmentation Method
May 08, 2017
Journal Of Chemical Theory And Computation
The generalized energy-based fragmentation (GEBF) method has been applied to investigate relative energies of large water clusters (H2O)n (n = 32, 64) with the coupled-cluster singles and doubles with noniterative triple excitations (CCSD(T)) and second-order Møller-Plesset perturbation theory (MP2) at the complete basis set (CBS) limit. Here large water clusters are chosen to be representative structures sampled from molecular dynamics (MD) simulations of liquid water. Our calculations show that the GEBF method is capable of providing highly accurate relative energies for these water clusters in a cost-effective way. We demonstrate that the relative energies from GEBF-MP2/CBS are in excellent agreement with those from GEBF-CCSD(T)/CBS for these water clusters. With the GEBF-CCSD(T)/CBS relative energies as the benchmark results, we have assessed the performance of several theoretical methods widely used for ab initio MD simulations of liquids and aqueous solutions. These methods include density functional theory (DFT) with a number of different functionals, MP2, and density functional tight-binding (the third generation, DFTB3 in short). We find that MP2/aug-cc-pVDZ and several DFT methods (such as LC-ωPBE-D3 and ωB97XD) with the aug-cc-pVTZ basis set can provide satisfactory descriptions for these water clusters. Some widely used functionals (such as B3LYP, PBE0) and DFTB3 are not accurate enough for describing the relative energies of large water clusters. Although the basis set dependence of DFT is less than that of ab initio electron correlation methods, we recommend the combination of a few best functionals and large basis sets (at least aug-cc-pVTZ) in theoretical studies on water clusters or aqueous solutions.
An Atomic Structure of the Human Spliceosome
May 15, 2017   Cell
Zhang X, Yan C, Hang J, Finci LI, Lei J, Shi Y
An Atomic Structure of the Human Spliceosome
May 15, 2017
Cell
Mechanistic understanding of pre-mRNA splicing requires detailed structural information on various states of the spliceosome. Here we report the cryo electron microscopy (cryo-EM) structure of the human spliceosome just before exon ligation (the C∗ complex) at an average resolution of 3.76 Å. The splicing factor Prp17 stabilizes the active site conformation. The step II factor Slu7 adopts an extended conformation, binds Prp8 and Cwc22, and is poised for selection of the 3'-splice site. Remarkably, the intron lariat traverses through a positively charged central channel of RBM22; this unusual organization suggests mechanisms of intron recruitment, confinement, and release. The protein PRKRIP1 forms a 100-Å α helix linking the distant U2 snRNP to the catalytic center. A 35-residue fragment of the ATPase/helicase Prp22 latches onto Prp8, and the quaternary exon junction complex (EJC) recognizes upstream 5'-exon sequences and associates with Cwc22 and the GTPase Snu114. These structural features reveal important mechanistic insights into exon ligation. Copyright © 2017 Elsevier Inc. All rights reserved.
Preparation and coherent manipulation of pure quantum states of a single molecular ion
May 11, 2017   Nature Add nature.com free-link Cancel
Chou CW, Kurz C, Hume DB, Plessow PN, Leibrandt DR, Leibfried D
Preparation and coherent manipulation of pure quantum states of a single molecular ion
May 11, 2017
Nature
Laser cooling and trapping of atoms and atomic ions has led to advances including the observation of exotic phases of matter, the development of precision sensors and state-of-the-art atomic clocks. The same level of control in molecules could also lead to important developments such as controlled chemical reactions and sensitive probes of fundamental theories, but the vibrational and rotational degrees of freedom in molecules pose a challenge for controlling their quantum mechanical states. Here we use quantum-logic spectroscopy, which maps quantum information between two ion species, to prepare and non-destructively detect quantum mechanical states in molecular ions. We develop a general technique for optical pumping and preparation of the molecule into a pure initial state. This enables us to observe high-resolution spectra in a single ion (CaH+) and coherent phenomena such as Rabi flopping and Ramsey fringes. The protocol requires a single, far-off-resonant laser that is not specific to the molecule, so many other molecular ions, including polyatomic species, could be treated using the same methods in the same apparatus by changing the molecular source. Combined with the long interrogation times afforded by ion traps, a broad range of molecular ions could be studied with unprecedented control and precision. Our technique thus represents a critical step towards applications such as precision molecular spectroscopy, stringent tests of fundamental physics, quantum computing and precision control of molecular dynamics.
Microstructures, mechanical behavior and strengthening mechanism of TiSiCN nanocomposite films
May 19, 2017   Scientific Reports
Li W, Liu P, Xue Z, Ma F, Zhang K, Chen X, Feng R, Liaw PK
Microstructures, mechanical behavior and strengthening mechanism of TiSiCN nanocomposite films
May 19, 2017
Scientific Reports
Currently, the arguments have existed in the strengthening mechanism and microstructural model of the nanocomposite film due to lack of the convincible experimental evidences. In this investigation, the quarternary TiSiCN nanocomposite films with the different C and Si contents are synthesized by the reactive-magnetron-sputtering technique. The TiSiCN film is characterized as the nanocomposite structure with the TiN nanocrystallites surrounded by the (Si3N4 + C + CNx) interface phase. When the C/Si content ratio is 2:2, the TiSiCN nanocomposite film is remarkably strengthened with the maximal hardness and elastic modulus of 46.1 GPa and 425 GPa, respectively. Meanwhile, the (Si3N4 + C + CNx) interfaces exhibit as a crystallized form, which can coordinate the growth misorientations and maintain the coherently epitaxial growth between the TiN nanocrystallites and interfaces. Through the high-resolution transmission electron microscopy (HRTEM) observations, this investigation firstly provides the direct experimental evidence for the crystallized feature of the interfaces when the TiSiCN nanocomposite film is strengthened, suggesting that the strengthening effect of the TiSiCN nanocomposite film can be attributed to the coherent-interface strengthening mechanism, which is expressed as the "nc-TiN/c-Si3N4/c-C/c-CNx" model.
Structure of the full-length glucagon class B G-protein-coupled receptor
May 17, 2017   Nature Add nature.com free-link Cancel
Zhang H, Qiao A, Yang D, Yang L, Dai A,   . . . . . .   , Stevens RC, Zhao Q, Jiang H, Wang MW, Wu B
Structure of the full-length glucagon class B G-protein-coupled receptor
May 17, 2017
Nature
The human glucagon receptor, GCGR, belongs to the class B G-protein-coupled receptor family and plays a key role in glucose homeostasis and the pathophysiology of type 2 diabetes. Here we report the 3.0 Å crystal structure of full-length GCGR containing both the extracellular domain and transmembrane domain in an inactive conformation. The two domains are connected by a 12-residue segment termed the stalk, which adopts a β-strand conformation, instead of forming an α-helix as observed in the previously solved structure of the GCGR transmembrane domain. The first extracellular loop exhibits a β-hairpin conformation and interacts with the stalk to form a compact β-sheet structure. Hydrogen-deuterium exchange, disulfide crosslinking and molecular dynamics studies suggest that the stalk and the first extracellular loop have critical roles in modulating peptide ligand binding and receptor activation. These insights into the full-length GCGR structure deepen our understanding of the signalling mechanisms of class B G-protein-coupled receptors.
Whole-brain serial-section electron microscopy in larval zebrafish
May 10, 2017   Nature Add nature.com free-link Cancel
Hildebrand DGC, Cicconet M, Torres RM, Choi W, Quan TM,   . . . . . .   , Schier AF, Lee WA, Jeong WK, Lichtman JW, Engert F
Whole-brain serial-section electron microscopy in larval zebrafish
May 10, 2017
Nature
High-resolution serial-section electron microscopy (ssEM) makes it possible to investigate the dense meshwork of axons, dendrites, and synapses that form neuronal circuits. However, the imaging scale required to comprehensively reconstruct these structures is more than ten orders of magnitude smaller than the spatial extents occupied by networks of interconnected neurons, some of which span nearly the entire brain. Difficulties in generating and handling data for large volumes at nanoscale resolution have thus restricted vertebrate studies to fragments of circuits. These efforts were recently transformed by advances in computing, sample handling, and imaging techniques, but high-resolution examination of entire brains remains a challenge. Here, we present ssEM data for the complete brain of a larval zebrafish (Danio rerio) at 5.5 days post-fertilization. Our approach utilizes multiple rounds of targeted imaging at different scales to reduce acquisition time and data management requirements. The resulting dataset can be analysed to reconstruct neuronal processes, permitting us to survey all myelinated axons (the projectome). These reconstructions enable precise investigations of neuronal morphology, which reveal remarkable bilateral symmetry in myelinated reticulospinal and lateral line afferent axons. We further set the stage for whole-brain structure-function comparisons by co-registering functional reference atlases and in vivo two-photon fluorescence microscopy data from the same specimen. All obtained images and reconstructions are provided as an open-access resource.
In-situ STEM imaging of growth and phase change of individual CuAlX precipitates in Al alloy
May 20, 2017   Scientific Reports
Liu C, Malladi SK, Xu Q, Chen J, Tichelaar FD, Zhuge X, Zandbergen HW
In-situ STEM imaging of growth and phase change of individual CuAlX precipitates in Al alloy
May 20, 2017
Scientific Reports
Age-hardening in Al alloys has been used for over a century to improve its mechanical properties. However, the lack of direct observation limits our understanding of the dynamic nature of the evolution of nanoprecipitates during age-hardening. Using in-situ (scanning) transmission electron microscopy (S/TEM) while heating an Al-Cu alloy, we were able to follow the growth of individual nanoprecipitates at atomic scale. The heat treatments carried out at 140, 160, 180 and 200 °C reveal a temperature dependence on the kinetics of precipitation and three kinds of interactions of nano-precipitates. These are precipitate-matrix, precipitate-dislocation, and precipitate-precipitate interactions. The diffusion of Cu and Al during these interactions, results in diffusion-controlled individual precipitate growth, an accelerated growth when interactions with dislocations occur and a size dependent precipitate-precipitate interaction: growth and shrinkage. Precipitates can grow and shrink at opposite ends at the same time resulting in an effective displacement. Furthermore, the evolution of the crystal structure within an individual nanoprecipiate, specifically the mechanism of formation of the strengthening phase, θ', during heat-treatment is elucidated by following the same precipitate through its intermediate stages for the first time using in-situ S/TEM studies.
Fluorescence correlation spectroscopy reveals a cooperative unfolding of monomeric amyloid-β 42 with a low Gibbs free energy
May 20, 2017   Scientific Reports
Schneider M, Walta S, Cadek C, Richtering W, Willbold D
Fluorescence correlation spectroscopy reveals a cooperative unfolding of monomeric amyloid-β 42 with a low Gibbs free energy
May 20, 2017
Scientific Reports
The amyloid-beta peptide (Aβ) plays a major role in the progression of Alzheimer's disease. Due to its high toxicity, the 42 amino acid long isoform Aβ42 has become of considerable interest. The Aβ42 monomer is prone to aggregation down to the nanomolar range which makes conventional structural methods such as NMR or X-ray crystallography infeasible. Conformational information, however, will be helpful to understand the different aggregation pathways reported in the literature and will allow to identify potential conditions that favour aggregation-incompetent conformations. In this study, we applied fluorescence correlation spectroscopy (FCS) to investigate the unfolding of Alexa Fluor 488 labelled monomeric Aβ42 using guanidine hydrochloride as a denaturant. We show that our Aβ42 pre-treatment and the low-nanomolar concentrations, typically used for FCS measurements, strongly favour the presence of monomers. Our results reveal that there is an unfolding/folding behaviour of monomeric Aβ42. The existence of a cooperative unfolding curve suggests the presence of structural elements with a Gibbs free energy of unfolding of about 2.8 kcal/mol.
Computationally-driven engineering of sublattice ordering in a hexagonal AlHfScTiZr high entropy alloy
May 20, 2017   Scientific Reports
Rogal L, Bobrowski P, Körmann F, Divinski S, Stein F, Grabowski B
Computationally-driven engineering of sublattice ordering in a hexagonal AlHfScTiZr high entropy alloy
May 20, 2017
Scientific Reports
Multi-principle element alloys have enormous potential, but their exploration suffers from the tremendously large range of configurations. In the last decade such alloys have been designed with a focus on random solid solutions. Here we apply an experimentally verified, combined thermodynamic and first-principles design strategy to reverse the traditional approach and to generate a new type of hcp Al-Hf-Sc-Ti-Zr high entropy alloy with a hitherto unique structure. A phase diagram analysis narrows down the large compositional space to a well-defined set of candidates. First-principles calculations demonstrate the energetic preference of an ordered superstructure over the competing disordered solid solutions. The chief ingredient is the Al concentration, which can be tuned to achieve a D019 ordering on the hexagonal lattice. The computationally designed D019 superstructure is experimentally confirmed by transmission electron microscopy and X-ray studies. Our scheme enables the exploration of a new class of high entropy alloys.
A Molecular Basis for Selective Antagonist Destabilization of Dopamine D3 Receptor Quaternary Organization
May 19, 2017   Scientific Reports
Marsango S, Caltabiano G, Jiménez-Rosés M, Millan MJ, Pediani JD, Ward RJ, Milligan G
A Molecular Basis for Selective Antagonist Destabilization of Dopamine D3 Receptor Quaternary Organization
May 19, 2017
Scientific Reports
The dopamine D3 receptor (D3R) is a molecular target for both first-generation and several recently-developed antipsychotic agents. Following stable expression of this mEGFP-tagged receptor, Spatial Intensity Distribution Analysis indicated that a substantial proportion of the receptor was present within dimeric/oligomeric complexes and that increased expression levels of the receptor favored a greater dimer to monomer ratio. Addition of the antipsychotics, spiperone or haloperidol, resulted in re-organization of D3R quaternary structure to promote monomerization. This action was dependent on ligand concentration and reversed upon drug washout. By contrast, a number of other antagonists with high affinity at the D3R, did not alter the dimer/monomer ratio. Molecular dynamics simulations following docking of each of the ligands into a model of the D3R derived from the available atomic level structure, and comparisons to the receptor in the absence of ligand, were undertaken. They showed that, in contrast to the other antagonists, spiperone and haloperidol respectively increased the atomic distance between reference α carbon atoms of transmembrane domains IV and V and I and II, both of which provide key interfaces for D3R dimerization. These results offer a molecular explanation for the distinctive ability of spiperone and haloperidol to disrupt D3R dimerization.
Cryo-Electron Microscopy Structure of the Macrobrachium rosenbergii Nodavirus Capsid at 7 Angstroms Resolution
May 19, 2017   Scientific Reports
Ho KL, Kueh CL, Beh PL, Tan WS, Bhella D
Cryo-Electron Microscopy Structure of the Macrobrachium rosenbergii Nodavirus Capsid at 7 Angstroms Resolution
May 19, 2017
Scientific Reports
White tail disease in the giant freshwater prawn Macrobrachium rosenbergii causes significant economic losses in shrimp farms and hatcheries and poses a threat to food-security in many developing countries. Outbreaks of Macrobrachium rosenbergii nodavirus (MrNV), the causative agent of white tail disease (WTD) are associated with up to 100% mortality rates. There are no interventions available to treat or prevent MrNV disease however. Here we show the structure of MrNV virus-like particles (VLPs) produced by recombinant expression of the capsid protein, using cryogenic electron microscopy. Our data show that MrNV VLPs package nucleic acids in a manner reminiscent of other known nodavirus structures. The structure of the capsid however shows striking differences from insect and fish infecting nodaviruses, which have been shown to assemble trimer-clustered T = 3 icosahedral virus particles. MrNV particles have pronounced dimeric blade-shaped spikes extending up to 6 nm from the outer surface of the capsid shell. Our structural analysis supports the assertion that MrNV may belong to a new genus of the Nodaviridae. Moreover, our study provides the first structural view of an important pathogen affecting aquaculture industries across the world.
Ligand chain length drives activation of lipid G protein-coupled receptors
May 18, 2017   Scientific Reports
Troupiotis-Tsaïlaki A, Zachmann J, González-Gil I, Gonzalez A, Ortega-Gutiérrez S, López-Rodríguez ML, Pardo L, Govaerts C
Ligand chain length drives activation of lipid G protein-coupled receptors
May 18, 2017
Scientific Reports
Sphingosine-1-phosphate (S1P) is a lipid mediator that can activate five cell membrane G protein-coupled receptors (GPCRs) which carry a variety of essential functions and are promising drug targets. S1P is composed of a polar zwitterionic head-group and a hydrophobic alkyl chain. This implies an activation mechanism of its cognate receptor that must be significantly different from what is known for prototypical GPCRs (ie receptor to small hydrophilic ligands). Here we aim to identify the structural features responsible for S1P agonism by combining molecular dynamics simulations and functional assays using S1P analogs of different alkyl chain lengths. We propose that high affinity binding involves polar interactions between the lipid head-group and receptor side chains while activation is due to hydrophobic interactions between the lipid tail and residues in a distinct binding site. We observe that ligand efficacy is directly related to alkyl chain length but also varies with receptor subtypes in correlation with the size of this binding pocket. Integrating experimental and computational data, we propose an activation mechanism for the S1P receptors involving agonist-induced conformational events that are conserved throughout class A GPCRs.
Variation of Nanostructures, Molecular Interactions, and Anisotropic Elastic Moduli of Lignocellulosic Cell Walls with Moisture
May 18, 2017   Scientific Reports
Youssefian S, Jakes JE, Rahbar N
Variation of Nanostructures, Molecular Interactions, and Anisotropic Elastic Moduli of Lignocellulosic Cell Walls with Moisture
May 18, 2017
Scientific Reports
A combination of experimental, theoretical and numerical studies is used to investigate the variation of elastic moduli of lignocellulosic (bamboo) fiber cell walls with moisture content (MC). Our Nanoindentation results show that the longitudinal elastic modulus initially increased to a maximum value at about 3% MC and then decreased linearly with increasing MC. In contrast, the transverse moduli decrease linearly with MC. We showed that amorphous materials in cell walls have key roles in the variation of elastic modulus with increasing MC. Elastic modulus of lignin, calculated by molecular dynamics simulations, increases initially with increasing MC, and then decreases. In contrast, elastic modulus of hemicellulose decreases constantly with MC. Below 10% MC, water molecules tend to break hydrogen bonds between polymer chains and form new hydrogen bond bridges between the polymer chains, while above 10% MC, water molecules aggregate together and create nano-droplets inside the materials. During the process of bridging, the fractional free volume of lignin decreases. The free volume reduction along with formation of hydrogen bond bridges causes a growth in elastic modulus of lignin at low MC. The constant increase of hemicellulose free volume, however, causes the aggregation of voids in the system and diminution of elastic properties.
Novel Fabrication and Enhanced Photocatalytic MB Degradation of Hierarchical Porous Monoliths of MoO3 Nanoplates
May 13, 2017   Scientific Reports
Liu Y, Feng P, Wang Z, Jiao X, Akhtar F
Novel Fabrication and Enhanced Photocatalytic MB Degradation of Hierarchical Porous Monoliths of MoO3 Nanoplates
May 13, 2017
Scientific Reports
Porous monoliths of MoO3 nanoplates were synthesized from ammonium molybdate (AHM) by freeze-casting and subsequent thermal treatment from 300 to 600 °C. Pure orthorhombic MoO3 phase was obtained at thermal treatment temperature of 400 °C and above. MoO3 monoliths thermally treated at 400 °C displayed bimodal pore structure, including large pore channels replicating the ice crystals and small pores from MoO3 sheets stacking. Transmission electron microscopy (TEM) images revealed that the average thicknesses of MoO3 sheet were 50 and 300 nm in porous monoliths thermally treated at 400 °C. The photocatalytic performance of MoO3 was evaluated through degradation of methylene blue (MB) under visible light radiation and MoO3 synthesized at 400 °C exhibited strong adsorption performance and best photocatalytic activity for photodegradation of MB of 99.7% under visible illumination for 60 min. MoO3 photocatalyst displayed promising cyclic performance, and the decolorization efficiency of MB solution was 98.1% after four cycles.
Mesporous 3C-SiC Hollow Fibers
May 16, 2017   Scientific Reports
Liu Y, Hou H, He X, Yang W
Mesporous 3C-SiC Hollow Fibers
May 16, 2017
Scientific Reports
In the present work, for the first time, we reported the exploration of mesoporous 3C-SiC hollow fibers via single-spinneret electrospinning of polyureasilazane (PSN) and polyvinylpyrrolidone (PVP) solution followed by high-temperature pyrolysis treatment. The resultant products were characterized by X-ray diffraction (XRD), field emission scanning electron microscopy (FESEM), high-resolution transmission electron microscopy (HRTEM) and N2 adsorption. The as-prepared hollow fibers with totally mesoporous walls were uniformly sized in diameter and high purity in morphology. They were composed of single-crystalline 3C-SiC nanoparticles with a surface area of 21.75 m2/g and average pore diameter of ~34 nm. The PSN concentration played a determined role on the formation of hollow fibers rather than the conventional solid counterparts, enabling their growth in a tunable manner. A possible mechanism was proposed for the formation of mesoporous SiC hollow fiber.
Different Polyubiquitinated Bodies in Human Dendritic Cells: IL-4 Causes PaCS During Differentiation while LPS or IFNα Induces DALIS During Maturation
May 13, 2017   Scientific Reports
Montagna D, Sommi P, Necchi V, Vitali A, Montini E, Turin I, Ferraro D, Ricci V, Solcia E
Different Polyubiquitinated Bodies in Human Dendritic Cells: IL-4 Causes PaCS During Differentiation while LPS or IFNα Induces DALIS During Maturation
May 13, 2017
Scientific Reports
Two types of polyubiquitin-reactive cytoplasmic bodies, particulate cytoplasmic structures (PaCS) and dendritic cell (DC) aggresome-like induced structures (DALIS), were analyzed by electron microscopy, immunocytochemistry, immunoblotting, and flow cytometry in DC obtained from human blood monocytes incubated with GM-CSF plus IL-4 (IL4-DC), GM-CSF plus IFNα (IFN-DC), or GM-CSF alone (GM-DC), with or without LPS maturation. PaCS developed as monomorphic aggregates of proteasome-reactive barrel-like particles only in ribosomes-rich cytoplasmic areas of differentiating IL4-DC. In contrast, DALIS formed as vesicular bodies storing K63-linked ubiquitinated proteins by coalescence of increased endosomal structures, in IFN-DC or after LPS maturation of GM-DC. DALIS-forming cells showed incomplete morphological and functional DC-type differentiation when compared to PaCS-forming IL4-DC. PaCS and DALIS may have different function as well as different origin and cytochemistry. DALIS may be a transient accumulation site of potentially antigenic polyubiquitinated proteins during their processing and presentation. PaCS are found under physiologic or pathologic conditions associated with increased/deranged protein synthesis and increased ubiquitin-proteasome activity. Given its high heat-shock protein content PaCS may work as a quality control structure for newly synthesized, cytosolic proteins. This comparative analysis suggests that PaCS and DALIS have distinctive roles in DC.
Angiotensin II type 1/adenosine A 2A receptor oligomers: a novel target for tardive dyskinesia
May 13, 2017   Scientific Reports
Oliveira PA, Dalton JAR, López-Cano M, Ricarte A, Morató X, Matheus FC, Cunha AS, Müller CE, Takahashi RN, Fernández-Dueñas V, Giraldo J, Prediger RD, Ciruela F
Angiotensin II type 1/adenosine A 2A receptor oligomers: a novel target for tardive dyskinesia
May 13, 2017
Scientific Reports
Tardive dyskinesia (TD) is a serious motor side effect that may appear after long-term treatment with neuroleptics and mostly mediated by dopamine D2 receptors (D2Rs). Striatal D2R functioning may be finely regulated by either adenosine A2A receptor (A2AR) or angiotensin receptor type 1 (AT1R) through putative receptor heteromers. Here, we examined whether A2AR and AT1R may oligomerize in the striatum to synergistically modulate dopaminergic transmission. First, by using bioluminescence resonance energy transfer, we demonstrated a physical AT1R-A2AR interaction in cultured cells. Interestingly, by protein-protein docking and molecular dynamics simulations, we described that a stable heterotetrameric interaction may exist between AT1R and A2AR bound to antagonists (i.e. losartan and istradefylline, respectively). Accordingly, we subsequently ascertained the existence of AT1R/A2AR heteromers in the striatum by proximity ligation in situ assay. Finally, we took advantage of a TD animal model, namely the reserpine-induced vacuous chewing movement (VCM), to evaluate a novel multimodal pharmacological TD treatment approach based on targeting the AT1R/A2AR complex. Thus, reserpinized mice were co-treated with sub-effective losartan and istradefylline doses, which prompted a synergistic reduction in VCM. Overall, our results demonstrated the existence of striatal AT1R/A2AR oligomers with potential usefulness for the therapeutic management of TD.
Symmetry breaking during homodimeric assembly activates an E3 ubiquitin ligase
May 12, 2017   Scientific Reports
Ye Z, Needham PG, Estabrooks SK, Whitaker SK, Garcia BL, Misra S, Brodsky JL, Camacho CJ
Symmetry breaking during homodimeric assembly activates an E3 ubiquitin ligase
May 12, 2017
Scientific Reports
C-terminus of Hsc/p70-Interacting Protein (CHIP) is a homodimeric E3 ubiquitin ligase. Each CHIP monomer consists of a tetratricopeptide-repeat (TPR), helix-turn-helix (HH), and U-box domain. In contrast to nearly all homodimeric proteins, CHIP is asymmetric. To uncover the origins of asymmetry, we performed molecular dynamics simulations of dimer assembly. We determined that a CHIP monomer is most stable when the HH domain has an extended helix that supports intra-monomer TPR-U-box interaction, blocking the E2-binding surface of the U-box. We also discovered that monomers first dimerize symmetrically through their HH domains, which then triggers U-box dimerization. This brings the extended helices into close proximity, including a repulsive stretch of positively charged residues. Unable to smoothly unwind, this conflict bends the helices until the helix of one protomer breaks to relieve the repulsion. The abrupt snapping of the helix forces the C-terminal residues of the other protomer to disrupt that protomer's TPR-U-box tight binding interface, swiftly exposing and activating one of the E2 binding sites. Mutagenesis and biochemical experiments confirm that C-terminal residues are necessary both to maintain CHIP stability and function. This novel mechanism indicates how a ubiquitin ligase maintains an inactive monomeric form that rapidly activates only after asymmetric assembly.
An Aqueous-Based Approach for Fabrication of PVDF/MWCNT Porous Composites
May 12, 2017   Scientific Reports
Rezvantalab H, Ghazi N, Ambrusch MJ, Infante J, Shojaei-Zadeh S
An Aqueous-Based Approach for Fabrication of PVDF/MWCNT Porous Composites
May 12, 2017
Scientific Reports
In this paper, we demonstrate the fabrication of conductive porous polymers based on foaming of an aqueous dispersion of polymeric particles and multi-walled carbon nanotubes (CNT). By tuning the surface energy of the constituents, we direct their preferential adsorption at the air-liquid (bubble) interface or within the liquid film between the bubbles. Sintering this bi-constituent foam yields solid closed-cell porous structure which can be electrically conductive if CNT are able to form a conductive path. We measure transport (electrical and thermal), mechanical, and morphological properties of such porous structures as a function of CNT loading and the method used for their surface functionalization. For a fixed polymer volume fraction, we demonstrate the limit in which increasing CNT results in decreasing the mechanical strength of the sample due to lack of adequate polymer-CNT bond. Such lightweight conductive porous composites are considered in applications including EMI shielding, electrostatic discharge protection, and electrets.
Structural insights into a 20.8-kDa tegumental-allergen-like (TAL) protein from Clonorchis sinensis
May 12, 2017   Scientific Reports
Jo CH, Son J, Kim S, Oda T, Kim J, Lee MR, Sato M, Kim HT, Unzai S, Park SY, Hwang KY
Structural insights into a 20.8-kDa tegumental-allergen-like (TAL) protein from Clonorchis sinensis
May 12, 2017
Scientific Reports
Survival of Clonorchis sinensis, a cause of human clonorchiasis, requires tegument proteins, which are localized to the tegumental outer surface membrane. These proteins play an important role in a host response and parasite survival. Thus, these proteins are interesting molecular targets for vaccine and drug development. Here, we have determined two crystal structures of the calmodulin like domain (amino acid [aa] positions 1-81) and dynein light chain (DLC)-like domain (aa 83-177) of a 20.8-kDa tegumental-allergen-like protein from Clonorchis sinensis (CsTAL3). The calmodulin like domain has two Ca2+-binding sites (named CB1 and CB2), but Ca2+ binds to only one site, CB1. The DLC-like domain has a dimeric conformation; the interface is formed mainly by hydrogen bonds between the main chain atoms. In addition, we have determined full-length structure of CsTAL3 in solution and showed the conformational change of CsTAL3 induced by Ca2+ ion binding using small-angle X-ray scattering analysis and molecular dynamics simulations. The Ca2+-bound form has a more extended conformation than the Ca2+-free from does. These structural and biochemical analyses will advance the understanding of the biology of this liver fluke and may contribute to our understanding of the molecular mechanism of calcium-responsive and tegumental-allergen-like proteins.
Direct atomic scale determination of magnetic ion partition in a room temperature multiferroic material
May 12, 2017   Scientific Reports
Keeney L, Downing C, Schmidt M, Pemble ME, Nicolosi V, Whatmore RW
Direct atomic scale determination of magnetic ion partition in a room temperature multiferroic material
May 12, 2017
Scientific Reports
The five-layer Aurivillius phase Bi6TixFeyMnzO18 system is a rare example of a single-phase room temperature multiferroic material. To optimise its properties and exploit it for future memory storage applications, it is necessary to understand the origin of the room temperature magnetisation. In this work we use high resolution scanning transmission electron microscopy, EDX and EELS to discover how closely-packed Ti/Mn/Fe cations of similar atomic number are arranged, both within the perfect structure and within defect regions. Direct evidence for partitioning of the magnetic cations (Mn and Fe) to the central three of the five perovskite (PK) layers is presented, which reveals a marked preference for Mn to partition to the central layer. We infer this is most probably due to elastic strain energy considerations. The observed increase (>8%) in magnetic cation content at the central PK layers engenders up to a 90% increase in potential ferromagnetic spin alignments in the central layer and this could be significant in terms of creating pathways to the long-range room temperature magnetic order observed in this distinct and intriguing material system.
Epitaxial growth of Cu(001) thin films onto Si(001) using a single-step HiPIMS process
May 11, 2017   Scientific Reports
Cemin F, Lundin D, Furgeaud C, Michel A, Amiard G, Minea T, Abadias G
Epitaxial growth of Cu(001) thin films onto Si(001) using a single-step HiPIMS process
May 11, 2017
Scientific Reports
We report on a new route to grow epitaxial copper (Cu) ultra-thin films (up to 150 nm thick) at ambient temperature on Si(001) wafers covered with native oxide without any prior chemical etching or plasma cleaning of the substrate. It consists of a single-step deposition process using high power impulse magnetron sputtering (HiPIMS) and substrate biasing. For a direct current (DC) substrate bias voltage of -130 V, Cu/Si heteroepitaxial growth is achieved by HiPIMS following the Cu(001) [100]//Si(001) [110] orientation, while under the same average deposition conditions, but using conventional DC magnetron sputtering, polycrystalline Cu films with [111] preferred orientation are deposited. In addition, the intrinsic stress has been measured in situ during growth by real-time monitoring of the wafer curvature. For this particular HiPIMS case, the stress is slightly compressive (-0.1 GPa), but almost fully relaxes after growth is terminated. As a result of epitaxy, the Cu surface morphology exhibits a regular pattern consisting of square-shaped mounds with a lateral size of typically 150 nm. For all samples, X-ray diffraction pole figures and scanning/transmission electron microscopy reveal the formation of extensive twinning of the Cu {111} planes.
Enhancing the Oxidation of Toluene with External Electric Fields: a Reactive Molecular Dynamics Study
May 11, 2017   Scientific Reports
Tan S, Xia T, Shi Y, Pfaendtner J, Zhao S, He Y
Enhancing the Oxidation of Toluene with External Electric Fields: a Reactive Molecular Dynamics Study
May 11, 2017
Scientific Reports
The effects of external electric field (Efield) on chemical reactions were studied with the reactive molecular dynamics (ReaxFF MD) simulations by using the oxidation of toluene as a model system. We observed that Efields may greatly enhance the oxidation rate of toluene. The initial reaction time of toluene is also reduced remarkably in Efields. A stronger Efield leads to a faster oxidation rate of toluene. Further studies reveal that the applying of a Efield may result in the oxidation of toluene at 2100 K which is otherwise not able to happen when the Efield is not present. The oxidation rate of toluene at 2100 K in a Efield is comparable with the oxidation rate of toluene at 2900 K when the Efield is not applied. In addition, Efields were observed to significantly enhance the occurrence of the initial radical generation for different pathways of toluene oxidation but they do not seem to favor any of the pathways. Finally, Efields do not seem to enhance the polarization of toluene during its transition state, which suggests that a polarizable charge equilibration method (PQEq) method might be needed to take the effects of Efields into consideration.
Structural Basis for Importin-α Binding of the Human Immunodeficiency Virus Tat
May 11, 2017   Scientific Reports
Smith KM, Himiari Z, Tsimbalyuk S, Forwood JK
Structural Basis for Importin-α Binding of the Human Immunodeficiency Virus Tat
May 11, 2017
Scientific Reports
HIV-1 has caused 35 million deaths globally, and approximately the same number is currently living with HIV-1. The trans-activator of transcription (Tat) protein of HIV-1 plays an important regulatory function in the virus life cycle, responsible for regulating the reverse transcription of the viral genome RNA. Tat is found in the nucleus of infected cells, but can also invade uninfected neighbouring cells. Regions within Tat responsible for these cellular localisations are overlapping and include a nuclear localisation signal (NLS) spanning 48GRKKRR, and a cell penetrating peptide (CPP) signal spanning 48GRKKRRQRRRAPQN. However, the mechanism by which this NLS/CPP region mediates interaction with the nuclear import receptors remains to be resolved structurally. Here, we establish that the HIV-1 Tat:NLS/CPP is able to form a stable and direct interaction with the classical nuclear import receptor importin-α and using x-ray crystallography, we have determined the molecular interface and binding determinants to a resolution of 2.0 Å. We show for the first time that the interface is the same as host factors such as Ku70 and Ku80, rather than other virus proteins such as Ebola VP24 that bind on the outer surface of importin-α.
Radiopaque Resorbable Inferior Vena Cava Filter Infused with Gold Nanoparticles
May 20, 2017   Scientific Reports
Tian L, Lee P, Singhana B, Chen A, Qiao Y, Lu L, Martinez JO, Tasciotti E, Melancon A, Huang S, Eggers M, Melancon MP
Radiopaque Resorbable Inferior Vena Cava Filter Infused with Gold Nanoparticles
May 20, 2017
Scientific Reports
Failure to remove a retrievable inferior vena cava (IVC) filter can cause severe complications with high treatment costs. Polydioxanone (PPDO) has been shown to be a good candidate material for resorbable IVC filters. However, PPDO is radioluscent under conventional imaging modalities. Thus, the positioning and integrity of these PPDO filters cannot be monitored by computed tomography (CT) or x-ray. Here we report the development of radiopaque PPDO IVC filters based on gold nanoparticles (AuNPs). Commercially available PPDO sutures were infused with AuNPs. Scanning electron microscopy analysis confirmed the presence of AuNP on the surface of PPDO. Micro-CT and x-ray images of the AuNP-infused PPDO sutures showed significant signal enhancement compared to untreated PPDO sutures. Elemental analysis showed that gold loading exceeded 2000 ppm. Tensile strength and in vitro cytotoxicity showed no significant difference between AuNP-infused and untreated PPDO. In a 10-week stability study, neither the gold content nor the radiopacity of the infused PPDO sutures significantly changed in the first 6 weeks. The increased attenuation of AuNP-infused PPDO sutures indicates their major advantage as a radiopaque resorbable filter material, as the radiopacity allows monitoring of the position and integrity of the filter, thereby increasing its safety and efficacy.

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