bluuebunny/crossref_metadata_2025 huggingface dataset:
Three-dimensional motion and deformation of a red blood cell in bifurcated microvessels
Authors: Ye Ting , Peng Lina , Li Yu
Published: February 2018

Microvessels are generally not simple straight tubes, but rather they continually bifurcate (namely, diverging bifurcation) and merge with other microvessels (namely, converging bifurcation). This paper presents a simulation study on the three-dimensional motion and deformation of a red blood cell (RBC) in a bifurcated microvessel with both diverging and converging bifurcations. The motion of the fluids inside and outside of the RBC is modeled by smooth dissipative particle dynamics. The RBC membrane is modeled as a triangular network, having the ability to not only resist the stretching and bending deformations, but also to conserve the RBC volume and surface area. The bifurcation configurations have been studied, including the bifurcated angle and the branch diameter, as well as the RBC properties, including the initial shape, shear modulus, and bending modulus. The simulation results show that the RBC deformation can be divided into five stages, when the RBC flows through a diverging-converging bifurcated microvessel. In these five stages, the RBCs have similar deformation trends but different deformation indices, subject to different bifurcation configurations or different RBC properties. If the shear modulus is large enough, the RBC membrane presents several folds; if the bending modulus is large enough, the RBC loses the symmetry completely with the long shape. These results are helpful in understanding the motion and deformation of healthy or unhealthy cells in blood microcirculation.
Near-field plasmonic beam engineering with complex amplitude modulation based on metasurface
Authors: Song Xu , Huang Lingling , Sun Lin , Zhang Xiaomeng , Zhao Ruizhe , Li Xiaowei , Wang Jia , Bai Benfeng , Wang Yongtian
Published: February 2018

Metasurfaces have recently intrigued extensive interest due to their ability to locally manipulate electromagnetic waves, which provide great feasibility for tailoring both propagation waves and surface plasmon polaritons (SPPs). Manipulation of SPPs with arbitrary complex fields is an important issue in integrated nanophotonics due to their capability of guiding waves with subwavelength footprints. Here, an approach with metasurfaces composed of nanoaperture arrays is proposed and experimentally demonstrated which can effectively manipulate the complex amplitude of SPPs in the near-field regime. Tailoring the azimuthal angles of individual nanoapertures and simultaneously tuning their geometric parameters, the phase and amplitude are controlled based on the Pancharatnam-Berry phases and their individual transmission coefficients. For the verification of the concept, Airy plasmons and axisymmetric Airy-SPPs are generated. The results of numerical simulations and near-field imaging are consistent with each other. Besides the rigorous simulations, we applied a 2D dipole analysis for additional analysis. This strategy of complex amplitude manipulation with metasurfaces can be used for potential applications in plasmonic beam shaping, integrated optoelectronic systems, and surface wave holography.
Microstructural and electrical characteristics of rare earth oxides doped ZnO varistor films
Authors: Jiao Lei , Mei Yunzhu , Xu Dong , Zhong Sujuan , Ma Jia , Zhang Lei , Bao Li
Published: February 2018

ZnO-Bi2O3 varistor films doped with two kinds of rare earth element oxides (Lu2O3 and Yb2O3) were prepared by the sol-gel method. The effects of Lu2O3/Yb2O3 doping on the microstructure and electrical characteristics of ZnO-Bi2O3 varistor films were investigated. All samples show a homogenized morphology and an improved nonlinear relationship between the electric field (E) and current density (I). Both Yb2O3 and Lu2O3 doping can decrease the grain size of ZnO-Bi2O3 varistor films and improve the electrical properties, which have a positive effect on the development of ZnO varistor ceramics. Yb2O3 doping significantly increases the dielectric constant at low frequency. 0.2 mol. % Yb2O3 doped ZnO-Bi2O3 varistor films exhibit the highest nonlinear coefficient (2.5) and the lowest leakage current (328 μA) among Lu2O3/Yb2O3 doped ZnO-Bi2O3 varistor films. Similarly, 0.1 mol. % Lu2O3 doping increases the nonlinear coefficient to 1.9 and decrease the leakage current to 462 μA.
Application of windowless energy dispersive spectroscopy to determine Li distribution in Li-Si alloys
Authors: Lin Huiwen , Noguchi Hidenori , Uosaki Kohei
Published: February 2018

The composition of Li-Si alloys in a lithiated single crystal Si(111) was studied using windowless energy dispersive spectroscopy (EDS), scanning electron microscopy (SEM), and soft X-ray emission spectroscopy (SXES). The intensities of Li Kα and Si L2,3 were obtained after deconvolution of the windowless EDS spectra. The Li Kα, Si L2,3, and Si Kα intensity changes along a line scan revealed a clear layered structure with varied Li concentrations. The Li distribution in Li-Si alloys was obtained by windowless EDS through the X-ray emission intensity change analysis. In addition, it was found the Li concentration decreases gradually within the 3rd alloy layer by combining the analysis of windowless EDS and SXES. The thickness of each Li-Si layer could be precisely determined, even for the 3rd layer which cannot be observed clearly by SEM.
Anion dependent ion pairing in concentrated ytterbium halide solutions
Authors: Klinkhammer Christina , Böhm Fabian , Sharma Vinay , Schwaab Gerhard , Seitz Michael , Havenith Martina
Published: February 2018

We have studied ion pairing of ytterbium halide solutions. THz spectra (30-400 cm−1) of aqueous YbCl3 and YbBr3 solutions reveal fundamental differences in the hydration structures of YbCl3 and YbBr3 at high salt concentrations: While for YbBr3 no indications for a changing local hydration environment of the ions were experimentally observed within the measured concentration range, the spectra of YbCl3 pointed towards formation of weak contact ion pairs. The proposed anion specificity for ion pairing was confirmed by supplementary Raman measurements.
Measurement and characterization of slippage and slip-law using a rigorous analysis in dynamics of oscillating rheometer: Newtonian fluid
Authors: Azese Martin Ndi
Published: February 2018

This article presents a rigorous calculation involving velocity slip of Newtonian fluid where we analyze and solve the unsteady Navier-Stokes equation with emphasis on its rheological implication. The goal of which is to model a simple yet effective non-invasive way of quantifying and characterizing slippage. Indeed this contrasts with previous techniques that exhibit inherent limitations whereby injecting foreign objects usually alter the flow. This problem is built on the Couette rheological flow system such that μ-Newton force and μ-stress are captured and processed to obtain wall slip. Our model leads to a linear partial differential equation and upon enforcing linear-Navier slip boundary conditions (BC) yields inhomogeneous and unsteady “Robin-type” BC. A dimensional analysis reveals salient dimensionless parameters: Roshko, Strouhal, and Reynolds while highlighting slip-numbers from BC. We also solve the slip-free case to corroborate and validate our results. Several graphs are generated showing slip effects, particularly, studying how slip-numbers, a key input, differentiate themselves to the outputs. We also confirm this in a graphical fashion by presenting the flow profile across channel width, velocity, and stress at both walls. A perturbation scheme is introduced to calculate long-time behavior when the system seats for long. More importantly, in the end, we justify the existence of a reverse mechanism, where an inverse transformation like Fourier transform uses the output data to retrieve slip-numbers and slip law, thus quantifying and characterizing slip. Therefore, we not only substantiate our analysis, but we also justify our claim, measurement and characterization, and theorize realizability of our proposition.
MC-PDFT can calculate singlet–triplet splittings of organic diradicals
Authors: Stoneburner Samuel J. , Truhlar Donald G. , Gagliardi Laura
Published: February 2018

The singlet–triplet splittings of a set of diradical organic molecules are calculated using multiconfiguration pair-density functional theory (MC-PDFT), and the results are compared with those obtained by Kohn-Sham density functional theory (KS-DFT) and complete active space second-order perturbation theory (CASPT2) calculations. We found that MC-PDFT, even with small and systematically defined active spaces, is competitive in accuracy with CASPT2, and it yields results with greater accuracy and precision than Kohn-Sham DFT with the parent functional. MC-PDFT also avoids the challenges associated with spin contamination in KS-DFT. It is also shown that MC-PDFT is much less computationally expensive than CASPT2 when applied to larger active spaces, and this illustrates the promise of this method for larger diradical organic systems.
Coupled ion acoustic and drift solitons in a magnetized bi-ion plasma with pseudo-potential approach
Authors: Shan Shaukat Ali
Published: February 2018

An analytical approach is employed to investigate the coupled drift and ion acoustic solitary structures in a bi-ion ionospheric oxygen-hydrogen (O-H) plasma having density and temperature inhomogeneities, as well as Kappa distributed electrons. We derive the nonlinear partial differential equation, which is then turned into a pseudo-potential energy equation. With the help of necessary conditions for the formation of solitons, we get the profiles of pseudo-potential and solitary pulses by employing the Sagdeev truncated method. It is shown that both rarefactive (dip) and compressive (hump) solitary structures are possible in a plasma having both density and temperature gradients. The dip structures are supersonic in nature, and hump structures are subsonic as reported by Freja satellite mission earlier.
Temperature dependent electrical properties of pulse laser deposited Au/Ni/β-(AlGa)2O3 Schottky diode
Authors: Feng Qian , Feng Zhaoqing , Hu Zhuangzhuang , Xing Xiangyu , Yan Guangshuo , Zhang Jincheng , Xu Yongkuan , Lian Xiaozheng , Hao Yue
Published: February 2018

We have demonstrated the epitaxial growth of a β-(Al0.08Ga0.92)2O3 film on a β-Ga2O3 (010) substrate through pulsed laser deposition. The temperature-dependent electrical characteristics of Au/Ni/β-(Al0.08Ga0.92)2O3 Schottky diodes were investigated in the temperature range of 300–573 K, using thermionic emission theory to calculate the Schottky diode parameters. The barrier height ϕb was found to increase, while the ideality factor n and the series resistance Rs were found to decrease with increasing temperatures. The calculated values of ϕb and n varied from 0.81 eV and 2.29 at 300 K to 1.02 eV and 1.65 at 573 K. The temperature-dependent I-V characteristics of the Schottky diode have shown the Gaussian distribution, yielding a mean barrier height of 1.23 eV and a standard deviation of 0.147 V, respectively. A modified Richardson plot of ln(Is/T2)−(q2σs2/2k2T2) versus q/2kT gives ϕb0¯ and A* as 1.24 eV and 44.3 A cm−2 K−2, showing the promise of Ni/β-(AlGa)2O3 as a Schottky diode rectifier.
The role of the tunneling matrix element and nuclear reorganization in the design of quantum-dot cellular automata molecules
Authors: Henry Jackson , Blair Enrique P.
Published: February 2018

Mixed-valence molecules provide an implementation for a high-speed, energy-efficient paradigm for classical computing known as quantum-dot cellular automata (QCA). The primitive device in QCA is a cell, a structure with multiple quantum dots and a few mobile charges. A single mixed-valence molecule can function as a cell, with redox centers providing quantum dots. The charge configuration of a molecule encodes binary information, and device switching occurs via intramolecular electron transfer between dots. Arrays of molecular cells adsorbed onto a substrate form QCA logic. Individual cells in the array are coupled locally via the electrostatic electric field. This device networking enables general-purpose computing. Here, a quantum model of a two-dot molecule is built in which the two-state electronic system is coupled to the dominant nuclear vibrational mode via a reorganization energy. This model is used to explore the effects of the electronic inter-dot tunneling (coupling) matrix element and the reorganization energy on device switching. A semi-classical reduction of the model also is made to investigate the competition between field-driven device switching and the electron-vibrational self-trapping. A strong electron-vibrational coupling (high reorganization energy) gives rise to self-trapping, which inhibits the molecule's ability to switch. Nonetheless, there remains an expansive area in the tunneling-reorganization phase space where molecules can support adequate tunneling. Thus, the relationship between the tunneling matrix element and the reorganization energy affords significant leeway in the design of molecules viable for QCA applications.
Stability of stationary solutions for inflow problem on the planar magnetohydrodynamics
Authors: Yin Haiyan
Published: February 2018

In this paper, stability of stationary solutions for the inflow problem on the planar magnetohydrodynamics is being investigated. Motivated by the relationship between magnetohydrodynamics and Navier-Stokes, we can prove that the global solutions of the planar magnetohydrodynamics asymptotically converge to the corresponding stationary solutions of Navier-Stokes equations when time t → ∞ in both the subsonic and transonic cases. The proof is based on the basic energy method.
Carbon Dioxide Utilisation for the Synthesis of Unsymmetrical Dialkyl and Cyclic Carbonates Promoted by Basic Ionic Liquids
Authors: Goodrich Peter , Gunaratne H. Q. Nimal , Jin Lili , Lei Yuntao , Seddon Kenneth R.
Published: February 2018

An efficient and greener synthesis of unsymmetrical organic carbonates mediated by Hünig’s base-appended basic ionic liquids, via carbon dioxide conversion, is described here. These ionic liquids were found to be effective bases for the fixation of carbon dioxide by various alcohols and benzyl bromide, at room temperature. When the alcohol and the halide functionalities are present within the same substrate, the reaction cleanly produces a cyclic carbonate. These functionalised basic ionic liquids were fully recyclable with no loss product yields.
Execution of saccadic eye movements affects speed perception
Authors: Goettker Alexander , Braun Doris I. , Schütz Alexander C. , Gegenfurtner Karl R.
Published: February 2018

Due to the foveal organization of our visual system we have to constantly move our eyes to gain precise information about our environment. Doing so massively alters the retinal input. This is problematic for the perception of moving objects, because physical motion and retinal motion become decoupled and the brain has to discount the eye movements to recover the speed of moving objects. Two different types of eye movements, pursuit and saccades, are combined for tracking. We investigated how the way we track moving targets can affect the perceived target speed. We found that the execution of corrective saccades during pursuit initiation modifies how fast the target is perceived compared with pure pursuit. When participants executed a forward (catch-up) saccade they perceived the target to be moving faster. When they executed a backward saccade they perceived the target to be moving more slowly. Variations in pursuit velocity without corrective saccades did not affect perceptual judgments. We present a model for these effects, assuming that the eye velocity signal for small corrective saccades gets integrated with the retinal velocity signal during pursuit. In our model, the execution of corrective saccades modulates the integration of these two signals by giving less weight to the retinal information around the time of corrective saccades.
Generic assembly patterns in complex ecological communities
Authors: Barbier Matthieu , Arnoldi Jean-François , Bunin Guy , Loreau Michel
Published: February 2018

Significance

Biodiversity may lead to the emergence of simple and robust relationships between ecosystem properties. Here we show that a wide range of models of species dynamics, in the limit of high diversity, exhibit generic behavior predictable from a few emergent parameters, which control ecosystem functioning and stability. Our work points toward ways to tackle the staggering complexity of ecological systems without relying on empirically unavailable details of their structure.
General amino acid control in fission yeast is regulated by a nonconserved transcription factor, with functions analogous to Gcn4/Atf4
Authors: Duncan Caia D. S. , Rodríguez-López María , Ruis Phil , Bähler Jürg , Mata Juan
Published: February 2018

Eukaryotes respond to amino acid starvation by enhancing the translation of mRNAs encoding b-ZIP family transcription factors (
GCN4
in
Saccharomyces cerevisiae
and
ATF4
in mammals), which launch transcriptional programs to counter this stress. This pathway involves phosphorylation of the eIF2 translation factor by Gcn2-protein kinases and is regulated by upstream ORFs (uORFs) in the
GCN4
/
ATF4
5′ leaders. Here, we present evidence that the transcription factors that mediate this response are not evolutionarily conserved. Although cells of the fission yeast
Schizosaccharomyces pombe
respond transcriptionally to amino acid starvation, they lack clear Gcn4 and Atf4 orthologs. We used ribosome profiling to identify mediators of this response in
S. pombe
, looking for transcription factors that behave like
GCN4
. We discovered a transcription factor (Fil1) translationally induced by amino acid starvation in a 5′ leader and Gcn2-dependent manner. Like Gcn4, Fil1 is required for the transcriptional response to amino acid starvation, and Gcn4 and Fil1 regulate similar genes. Despite their similarities in regulation, function, and targets, Fil1 and Gcn4 belong to different transcription factor families (GATA and b-ZIP, respectively). Thus, the same functions are performed by nonorthologous proteins under similar regulation. These results highlight the plasticity of transcriptional networks, which maintain conserved principles with nonconserved regulators.
Structural insights into the mechanism of inhibition of AHAS by herbicides
Authors: Lonhienne Thierry , Garcia Mario D. , Pierens Gregory , Mobli Mehdi , Nouwens Amanda , Guddat Luke W.
Published: February 2018

Acetohydroxyacid synthase (AHAS), the first enzyme in the branched amino acid biosynthesis pathway, is present only in plants and microorganisms, and it is the target of >50 commercial herbicides. Penoxsulam (PS), which is a highly effective broad-spectrum AHAS-inhibiting herbicide, is used extensively to control weed growth in rice crops. However, the molecular basis for its inhibition of AHAS is poorly understood. This is despite the availability of structural data for all other classes of AHAS-inhibiting herbicides. Here, crystallographic data for
Saccharomyces cerevisiae
AHAS (2.3 Å) and
Arabidopsis thaliana
AHAS (2.5 Å) in complex with PS reveal the extraordinary molecular mechanisms that underpin its inhibitory activity. The structures show that inhibition of AHAS by PS triggers expulsion of two molecules of oxygen bound in the active site, releasing them as substrates for an oxygenase side reaction of the enzyme. The structures also show that PS either stabilizes the thiamin diphosphate (ThDP)-peracetate adduct, a product of this oxygenase reaction, or traps within the active site an intact molecule of peracetate in the presence of a degraded form of ThDP: thiamine aminoethenethiol diphosphate. Kinetic analysis shows that PS inhibits AHAS by a combination of events involving FAD oxidation and chemical alteration of ThDP. With the emergence of increasing levels of resistance toward front-line herbicides and the need to optimize the use of arable land, these data suggest strategies for next generation herbicide design.
Changing character of rainfall in eastern China, 1951–2007
Authors: Day Jesse A. , Fung Inez , Liu Weihan
Published: February 2018

The topography and continental configuration of East Asia favor the year-round existence of storm tracks that extend thousands of kilometers from China into the northwestern Pacific Ocean, producing zonally elongated patterns of rainfall that we call “frontal rain events.” In spring and early summer (known as “Meiyu Season”), frontal rainfall intensifies and shifts northward during a series of stages collectively known as the East Asian summer monsoon. Using a technique called the Frontal Rain Event Detection Algorithm, we create a daily catalog of all frontal rain events in east China during 1951–2007, quantify their attributes, and classify all rainfall on each day as either frontal, resulting from large-scale convergence, or nonfrontal, produced by local buoyancy, topography, or typhoons. Our climatology shows that the East Asian summer monsoon consists of a series of coupled changes in frontal rain event frequency, latitude, and daily accumulation. Furthermore, decadal changes in the amount and distribution of rainfall in east China are overwhelmingly due to changes in frontal rainfall. We attribute the “South Flood–North Drought” pattern observed beginning in the 1980s to changes in the frequency of frontal rain events, while the years 1994–2007 witnessed an uptick in event daily accumulation relative to the rest of the study years. This particular signature may reflect the relative impacts of global warming, aerosol loading, and natural variability on regional rainfall, potentially via shifting the East Asian jet stream.
Cryo-EM reconstruction of AlfA from
Bacillus subtilis
reveals the structure of a simplified actin-like filament at 3.4-Å resolution
Authors: Szewczak-Harris Andrzej , Löwe Jan
Published: February 2018

Significance

Protein filaments perform a vast array of functions inside almost all living cells. Actin-like proteins in archaea and bacteria have previously been found to form a surprising diversity of filament architectures, reflecting their divergent cellular roles. Actin-like AlfA is unique in that it is much smaller than all other filament forming actin-like proteins. With an atomic structure of the AlfA filament, obtained by high-resolution electron cryo-microscopy, we have revealed—at near-atomic level of detail—how AlfA filaments form dynamic filaments capable of transporting plasmid DNA in cells and how these filaments arrange into antiparallel bundles required for the segregation mechanism.
CRISPR/Cas9 cleavages in budding yeast reveal templated insertions and strand-specific insertion/deletion profiles
Authors: Lemos Brenda R. , Kaplan Adam C. , Bae Ji Eun , Ferrazzoli Alexander E. , Kuo James , Anand Ranjith P. , Waterman David P. , Haber James E.
Published: February 2018

Significance

Using budding yeast, we address how Cas9 protein and its guide RNA (gRNA) create double-strand chromosome breaks (DSBs), and explore whether binding of Cas9::gRNA influences subsequent DSB repair by nonhomologous end-joining. We created pairs of gRNAs that are complementary to opposite DNA strands but direct cleavage at the same chromosomal location. The resulting repair profiles (insertion/deletions) are different for the two ostensibly identical DSBs. Most notably, there are frequent +1 insertions that are templated after cleavage creates a 1-nt 5′ overhang that is filled in before ends are ligated. DNA polymerase 4 is required for most +1 insertions and for longer (+2 and +3) insertions. We found similar templating of +1 insertions in published studies of mammalian DSBs created by Cas9.
Structure of a zosuquidar and UIC2-bound human-mouse chimeric ABCB1
Authors: Alam Amer , Küng Raphael , Kowal Julia , McLeod Robert A. , Tremp Nina , Broude Eugenia V. , Roninson Igor B. , Stahlberg Henning , Locher Kaspar P.
Published: February 2018

The multidrug transporter ABCB1 (P-glycoprotein) is an ATP-binding cassette transporter that has a key role in protecting tissues from toxic insult and contributes to multidrug extrusion from cancer cells. Here, we report the near-atomic resolution cryo-EM structure of nucleotide-free ABCB1 trapped by an engineered disulfide cross-link between the nucleotide-binding domains (NBDs) and bound to the antigen-binding fragment of the human-specific inhibitory antibody UIC2 and to the third-generation ABCB1 inhibitor zosuquidar. Our structure reveals the transporter in an occluded conformation with a central, enclosed, inhibitor-binding pocket lined by residues from all transmembrane (TM) helices of ABCB1. The pocket spans almost the entire width of the lipid membrane and is occupied exclusively by two closely interacting zosuquidar molecules. The external, conformational epitope facilitating UIC2 binding is also visualized, providing a basis for its inhibition of substrate efflux. Additional cryo-EM structures suggest concerted movement of TM helices from both halves of the transporters associated with closing the NBD gap, as well as zosuquidar binding. Our results define distinct recognition interfaces of ABCB1 inhibitory agents, which may be exploited for therapeutic purposes.
Detection of aneuploidy in patients with cancer through amplification of long interspersed nucleotide elements (LINEs)
Authors: Douville Christopher , Springer Simeon , Kinde Isaac , Cohen Joshua D. , Hruban Ralph H. , Lennon Anne Marie , Papadopoulos Nickolas , Kinzler Kenneth W. , Vogelstein Bert , Karchin Rachel
Published: February 2018

Aneuploidy is a feature of most cancer cells, and a myriad of approaches have been developed to detect it in clinical samples. We previously described primers that could be used to amplify ∼38,000 unique long interspersed nucleotide elements (LINEs) from throughout the genome. Here we have developed an approach to evaluate the sequencing data obtained from these amplicons. This approach, called Within-Sample AneupLoidy DetectiOn (WALDO), employs supervised machine learning to detect the small changes in multiple chromosome arms that are often present in cancers. We used WALDO to search for chromosome arm gains and losses in 1,677 tumors and in 1,522 liquid biopsies of blood from cancer patients or normal individuals. Aneuploidy was detected in 95% of cancer biopsies and in 22% of liquid biopsies. Using single-nucleotide polymorphisms within the amplified LINEs, WALDO concomitantly assesses allelic imbalances, microsatellite instability, and sample identification. WALDO can be used on samples containing only a few nanograms of DNA and as little as 1% neoplastic content and has a variety of applications in cancer diagnostics and forensic science.
Piezo2 channel regulates RhoA and actin cytoskeleton to promote cell mechanobiological responses
Authors: Pardo-Pastor Carlos , Rubio-Moscardo Fanny , Vogel-González Marina , Serra Selma A. , Afthinos Alexandros , Mrkonjic Sanela , Destaing Olivier , Abenza Juan F. , Fernández-Fernández José M. , Trepat Xavier , Albiges-Rizo Corinne , Konstantopoulos Konstantinos , Valverde Miguel A.
Published: February 2018

Significance

The actin cytoskeleton is central to many cellular processes involving changes in cell shape, migration, and adhesiveness. Therefore, there is a great interest in the identification of the signaling pathways leading to the regulation of actin polymerization and assembly into stress fibers (SFs). However, to date it is not well understood how the mechanical interactions between cells and their environment activate the assembly of SFs. Here, we demonstrate that the mechanosensitive Piezo2 channel is required to sense physical cues from the environment to generate a calcium signal that maintains RhoA active and the formation and orientation of SFs and focal adhesions. Besides, this Piezo2-initiated signaling pathway has implications for different hallmarks of cancer invasion and metastasis.
NAD
+
supplementation normalizes key Alzheimer’s features and DNA damage responses in a new AD mouse model with introduced DNA repair deficiency
Authors: Hou Yujun , Lautrup Sofie , Cordonnier Stephanie , Wang Yue , Croteau Deborah L. , Zavala Eduardo , Zhang Yongqing , Moritoh Kanako , O’Connell Jennifer F. , Baptiste Beverly A. , Stevnsner Tinna V. , Mattson Mark P. , Bohr Vilhelm A.
Published: February 2018

Emerging findings suggest that compromised cellular bioenergetics and DNA repair contribute to the pathogenesis of Alzheimer’s disease (AD), but their role in disease-defining pathology is unclear. We developed a DNA repair-deficient 3xTgAD/Polβ
+/−
mouse that exacerbates major features of human AD including phosphorylated Tau (pTau) pathologies, synaptic dysfunction, neuronal death, and cognitive impairment. Here we report that 3xTgAD/Polβ
+/−
mice have a reduced cerebral NAD
+
/NADH ratio indicating impaired cerebral energy metabolism, which is normalized by nicotinamide riboside (NR) treatment. NR lessened pTau pathology in both 3xTgAD and 3xTgAD/Polβ
+/−
mice but had no impact on amyloid β peptide (Aβ) accumulation. NR-treated 3xTgAD/Polβ
+/−
mice exhibited reduced DNA damage, neuroinflammation, and apoptosis of hippocampal neurons and increased activity of SIRT3 in the brain. NR improved cognitive function in multiple behavioral tests and restored hippocampal synaptic plasticity in 3xTgAD mice and 3xTgAD/Polβ
+/−
mice. In general, the deficits between genotypes and the benefits of NR were greater in 3xTgAD/Polβ
+/−
mice than in 3xTgAD mice. Our findings suggest a pivotal role for cellular NAD
+
depletion upstream of neuroinflammation, pTau, DNA damage, synaptic dysfunction, and neuronal degeneration in AD. Interventions that bolster neuronal NAD
+
levels therefore have therapeutic potential for AD.
Synergistic and additive effect of retinoic acid in circumventing resistance to p53 restoration
Authors: Larsson Connie A. , Moyer Sydney M. , Liu Bin , Michel Keith A. , Pant Vinod , Yang Peirong , Wong Justin , El-Naggar Adel K. , Krahe Ralf , Lozano Guillermina
Published: February 2018

TP53
mutations occur in ∼50% of all human tumors, with increased frequency in aggressive cancers that are notoriously difficult to treat. Additionally, p53 missense mutations are remarkably predictive of refractoriness to chemo/radiotherapy in various malignancies. These observations have led to the development of mutant p53-targeting agents that restore p53 function. An important unknown is which p53-mutant tumors will respond to p53 reactivation-based therapies. Here, we found a heterogeneous impact on therapeutic response to p53 restoration, suggesting that it will unlikely be effective as a monotherapy. Through gene expression profiling of
p53

R172H

-mutant lymphomas, we identified retinoic acid receptor gamma (RARγ) as an actionable target and demonstrated that pharmacological activation of RARγ with a synthetic retinoid sensitizes resistant p53-mutant lymphomas to p53 restoration, while additively improving outcome and survival in inherently sensitive tumors.
Liprin-α3 controls vesicle docking and exocytosis at the active zone of hippocampal synapses
Authors: Wong Man Yan , Liu Changliang , Wang Shan Shan H. , Roquas Aram C. F. , Fowler Stephen C. , Kaeser Pascal S.
Published: February 2018

Significance

The presynaptic active zone is important for precise and fast information transfer at central nervous synapses. Invertebrate studies have indicated that Liprin-α proteins are important for active zone assembly and function, but localization and function of vertebrate Liprin-α proteins have remained enigmatic, and pre- or postsynaptic localization and roles have been proposed. Here we used stimulated emission depletion microscopy to directly show that Liprin-α3, but not Liprin-α2, prominently localizes to the active zone. We then generated Liprin-α3–KO mice and found that active zone structure and synaptic vesicle docking and exocytosis are impaired at their synapses. These data establish important functions of Liprin-α3 at the active zone of vertebrate synapses.
High-order above-threshold dissociation of molecules
Authors: Lu Peifen , Wang Junping , Li Hui , Lin Kang , Gong Xiaochun , Song Qiying , Ji Qinying , Zhang Wenbin , Ma Junyang , Li Hanxiao , Zeng Heping , He Feng , Wu Jian
Published: February 2018

Significance

Above-threshold ionization of atoms in strong laser fields is extensively studied for its overwhelming importance and universality. However, its counterpart, above-threshold dissociation of molecules in strong laser fields, is hard to be observed, although it has been predicted for decades. In this paper, by measuring the momenta of photoelectron and dissociative fragments coincidently, we successfully obtained distinct nuclear energy peaks of the high-order above-threshold dissociation, which must appear simultaneously with the above-threshold ionization. The coexistence of high-order above-threshold dissociation and high-order above-threshold ionization in molecular dissociative ionization offers a perspective to disentangle the complex electron–nuclear correlation in molecules and to image the molecular orbitals, and so on.
Targeting the cMET pathway augments radiation response without adverse effect on hearing in NF2 schwannoma models
Authors: Zhao Yingchao , Liu Pinan , Zhang Na , Chen Jie , Landegger Lukas D. , Wu Limeng , Zhao Fu , Zhao Yanxia , Zhang Yanling , Zhang Jing , Fujita Takeshi , Stemmer-Rachamimov Anat , Ferraro Gino B. , Liu Hao , Muzikansky Alona , Plotkin Scott R. , Stankovic Konstantina M. , Jain Rakesh K. , Xu Lei
Published: February 2018

Significance

In patients with progressive vestibular schwannoma (VS), radiotherapy is associated with the risk of debilitating hearing loss. There is an urgent need to identify an adjunct therapy that, by enhancing the efficacy of radiation, can help lower the radiation dose and preserve hearing. In our newly developed cerebellopontine angle model of schwannomas that faithfully recapitulates the tumor-induced hearing loss, we demonstrate that cMET blockade sensitizes schwannomas to radiation therapy (RT) in neurofibromatosis type II schwannoma animal models without any adverse effects on hearing. Using an organoid brain slice culture model, cMET blockade inhibited the growth of patient-derived schwannomas. Our study provides the rationale and critical data for the clinical translation of combined cMET blockade with RT in patients with VSs.
Role of ubiquitylation of components of mitotic checkpoint complex in their dissociation from anaphase-promoting complex/cyclosome
Authors: Sitry-Shevah Danielle , Kaisari Sharon , Teichner Adar , Miniowitz-Shemtov Shirly , Hershko Avram
Published: February 2018

Significance

The mitotic checkpoint system is important for ensuring the correct segregation of chromosomes in mitosis. When chromosomes are not attached correctly to the mitotic spindle, a mitotic checkpoint complex (MCC) is formed that prevents chromosome separation by inhibiting the action of the anaphase-promoting complex/cyclosome (APC/C) ubiquitin ligase. MCC is disassembled when the checkpoint is turned off. The disassembly of APC/C-bound MCC was known to require ubiquitylation, but the mechanisms of this process remained unknown. Here we show that two different components of MCC may be ubiquitylated and suggest that these ubiquitylation events lead to their dissociation from each other and from APC/C. Thus, this investigation provides insight into the molecular events responsible for the inactivation of the mitotic checkpoint.
Ridding fMRI data of motion-related influences: Removal of signals with distinct spatial and physical bases in multiecho data
Authors: Power Jonathan D. , Plitt Mark , Gotts Stephen J. , Kundu Prantik , Voon Valerie , Bandettini Peter A. , Martin Alex
Published: February 2018

“Functional connectivity” techniques are commonplace tools for studying brain organization. A critical element of these analyses is to distinguish variance due to neurobiological signals from variance due to nonneurobiological signals. Multiecho fMRI techniques are a promising means for making such distinctions based on signal decay properties. Here, we report that multiecho fMRI techniques enable excellent removal of certain kinds of artifactual variance, namely, spatially focal artifacts due to motion. By removing these artifacts, multiecho techniques reveal frequent, large-amplitude blood oxygen level-dependent (BOLD) signal changes present across all gray matter that are also linked to motion. These whole-brain BOLD signals could reflect widespread neural processes or other processes, such as alterations in blood partial pressure of carbon dioxide (pCO
2
) due to ventilation changes. By acquiring multiecho data while monitoring breathing, we demonstrate that whole-brain BOLD signals in the resting state are often caused by changes in breathing that co-occur with head motion. These widespread respiratory fMRI signals cannot be isolated from neurobiological signals by multiecho techniques because they occur via the same BOLD mechanism. Respiratory signals must therefore be removed by some other technique to isolate neurobiological covariance in fMRI time series. Several methods for removing global artifacts are demonstrated and compared, and were found to yield fMRI time series essentially free of motion-related influences. These results identify two kinds of motion-associated fMRI variance, with different physical mechanisms and spatial profiles, each of which strongly and differentially influences functional connectivity patterns. Distance-dependent patterns in covariance are nearly entirely attributable to non-BOLD artifacts.
Rewiring
Yarrowia lipolytica
toward triacetic acid lactone for materials generation
Authors: Markham Kelly A. , Palmer Claire M. , Chwatko Malgorzata , Wagner James M. , Murray Clare , Vazquez Sofia , Swaminathan Arvind , Chakravarty Ishani , Lynd Nathaniel A. , Alper Hal S.
Published: February 2018

Significance

Polyketides are important molecules for both their bioactive traits and their potential as chemical building blocks. However, production of these molecules through chemistry and biocatalysts is restricted in yield and titer. Here, we demonstrate that the nonconventional yeast
Yarrowia lipolytica
can serve as a potent host for such production. This work provides a comprehensive evaluation of three separate pathways toward acetyl–CoA and malonyl–CoA in this host, enabling high-titer production of triacetic acid lactone. Beyond achieving unprecedented titers and appreciable yields, this production capacity allows for both purification from fermentation broth and conversion into a material using simple reaction conditions.
Pivotal roles of PCNA loading and unloading in heterochromatin function
Authors: Janke Ryan , King Grant A. , Kupiec Martin , Rine Jasper
Published: February 2018

Significance

DNA replication poses a unique logistical challenge for cells in that structural features of chromatin and their regulatory functions must be carefully coordinated with the passage of replication machinery so faithful duplication of both the genome and its chromatin structures may be achieved. Nucleosome assembly is fundamental to reestablishment of chromatin in the wake of DNA replication. Here, a mechanism for coordinating nucleosome assembly with DNA replication to maintain silenced chromatin is described.
Cu
+
-specific CopB transporter: Revising P
1B
-type ATPase classification
Authors: Purohit Rahul , Ross Matthew O. , Batelu Sharon , Kusowski April , Stemmler Timothy L. , Hoffman Brian M. , Rosenzweig Amy C.
Published: February 2018

Significance

Copper is an important biological cofactor, but can also be toxic in excess. Members of the P
1B
-ATPase family of membrane transporters couple the energy of ATP hydrolysis to translocation of metal ions across membranes. P
1B
-ATPases have been classified into groups on the basis of sequence and metal ion specificity. Two subfamilies, the P
1B-1
-ATPases, which are linked to human diseases of copper metabolism, and the P
1B-3
-ATPases, found only in bacteria, have been assigned as Cu
+
and Cu
2+
transporters, respectively. Here we show that the P
1B-3
-ATPases are actually Cu
+
transporters, necessitating revision of the classification scheme. These findings are consistent with the presence of only Cu
+
in the cytoplasm, which eliminates the need for a Cu
2+
efflux pump.
Assembly of the membrane domain of ATP synthase in human mitochondria
Authors: He Jiuya , Ford Holly C. , Carroll Joe , Douglas Corsten , Gonzales Evvia , Ding Shujing , Fearnley Ian M. , Walker John E.
Published: February 2018

Significance

Mitochondria generate the cellular fuel ATP to sustain complex life. Production of ATP depends on the oxidation of energy-rich compounds to produce the proton motive force (pmf), a chemical potential difference for protons, across the inner membrane. The pmf drives the ATP synthase, a molecular machine with a rotary action, to synthesize ATP. We have shown that the assembly of human ATP synthase in the inner organellar membrane involves the formation of a monomeric intermediate made from 25 nuclear-encoded proteins into which the two mitochondrially encoded subunits are inserted and then sealed by association of another nuclear-encoded protein, thereby dimerizing the complex. Association of a final nuclear protein oligomerizes the dimers back-to-face along the cristae edges.
Reporter–nanobody fusions (RANbodies) as versatile, small, sensitive immunohistochemical reagents
Authors: Yamagata Masahito , Sanes Joshua R.
Published: February 2018

Significance

Conventional antibodies are often poorly defined, limited in amount, and difficult to store permanently. Nanobodies, recombinant antigen-binding proteins derived from single-chain camelid antibodies, circumvent many of these limitations. To maximize the potential of nanobodies, we fused them to highly sensitive reporters and appended sequences to enable ready production and purification. These RANbodies (reporter and nanobody fusions) can be readily produced in cultured cells, purified in a single step, used to label cells or tissue, and stored indefinitely in the form of DNA or DNA sequences. Given the rapidly increasing rate of nanobody generation, the RANbody platform provides a versatile and scalable platform for immunohistochemical and biochemical analyses.
Analysis of politeness strategies in Japanese and Korean conversations between males
Authors: Lee Eun Mi
Published: February 2018

This study analyzed the uses and functions of speech levels and speech level shifts in natural conversations between two unacquainted males. Similarities and differences between Japanese and Korean languages have been investigated. For the Japanese language, speech levels do not clearly reflect the hierarchical relationships based on the interlocutors’ age by utilizing “non-marked utterance (NM)” This finding implies that modern Japanese people tend to avoid the use of honorifics which clearly indicates the hierarchical relationships between speakers at the sentence level. On the other hand, speech level shifts reflect hierarchical relationships between speakers, which means that Japanese seem to conform to normative language use at the discourse level. For the Korean language, both speech levels and speech level shifts clearly reflect the hierarchical relationships based on the interlocutors’ age. This result suggests that Korean have a strong tendency to preserve the normative honorific usage of polite forms according to age difference both at the sentence level and at the discourse level. These results suggest that speech levels, considered to be socio-pragmatically obligatory, have a strategic-use aspect for both languages, including the use of “non-marked utterances” and that of downshifts. It was also discovered that Japanese tend to use speech levels more strategically than Korean. Consequently, Japanese uses honorifics strategically in order to evade hierarchical relationships based on age, whereas Koreans tend to conform to social norms that derive from tenets of Confucianism, a philosophy emphasizing politeness toward older people; such practice encourages younger people to use polite forms to their elders.
An overview of the Japanese quotative itta and itte ita
Authors: Nishi Hironori
Published: February 2018

The present study provides an overview of the quotative utterances made with itta (past form of iu ‘to say’) and itte ita (the combination of iu and the past form of the -te iru construction) in naturally occurring conversations in Japanese. The examination of approximately 13 hours of conversations shows that itta is used in 91.1% of first-person quotations (‘I said that…’). In second-person (‘you said that…’) and third-person (‘he/she said that…’) quotations, itte ita is used in 90.0%, and 77.3% of the cases, respectively. The present study argues that the high percentage of itte ita for second- and third-person quotative utterances is due to the fact that the -te iru construction, which is included in itte ita, is used as an evidential marker. The present study also analyzes the deviant cases from the dominant pattern (i.e. using itta for third-person utterances), and demonstrates how -te iru’s evidential function is utilized manipulatively in conversation.
Centrobin controls primary ciliogenesis in vertebrates
Authors: Ogungbenro Yetunde Adesanya , Tena Teresa Casar , Gaboriau David , Lalor Pierce , Dockery Peter , Philipp Melanie , Morrison Ciaran G.
Published: February 2018

The BRCA2 interactor, centrobin, is a centrosomal protein that has been implicated in centriole duplication and microtubule stability. We used genome editing to ablate CNTROB in hTERT-RPE1 cells and observed an increased frequency of monocentriolar and acentriolar cells. Using a novel monoclonal antibody, we found that centrobin primarily localizes to daughter centrioles but also associates with mother centrioles upon serum starvation. Strikingly, centrobin loss abrogated primary ciliation upon serum starvation. Ultrastructural analysis of centrobin nulls revealed defective axonemal extension after mother centriole docking. Ciliogenesis required a C-terminal portion of centrobin that interacts with CP110 and tubulin. We also depleted centrobin in zebrafish embryos to explore its roles in an entire organism. Centrobin-depleted embryos showed microcephaly, with curved and shorter bodies, along with marked defects in laterality control, morphological features that indicate ciliary dysfunction. Our data identify new roles for centrobin as a positive regulator of vertebrate ciliogenesis.
SLAMF1 is required for TLR4-mediated TRAM-TRIF–dependent signaling in human macrophages
Authors: Yurchenko Maria , Skjesol Astrid , Ryan Liv , Richard Gabriel Mary , Kandasamy Richard Kumaran , Wang Ninghai , Terhorst Cox , Husebye Harald , Espevik Terje
Published: February 2018

Signaling lymphocytic activation molecule family 1 (SLAMF1) is an Ig-like receptor and a costimulatory molecule that initiates signal transduction networks in a variety of immune cells. In this study, we report that SLAMF1 is required for Toll-like receptor 4 (TLR4)-mediated induction of interferon β (IFNβ) and for killing of Gram-negative bacteria by human macrophages. We found that SLAMF1 controls trafficking of the Toll receptor–associated molecule (TRAM) from the endocytic recycling compartment (ERC) to Escherichia coli phagosomes. In resting macrophages, SLAMF1 is localized to ERC, but upon addition of E. coli, it is trafficked together with TRAM from ERC to E. coli phagosomes in a Rab11-dependent manner. We found that endogenous SLAMF1 protein interacted with TRAM and defined key interaction domains as amino acids 68 to 95 of TRAM as well as 15 C-terminal amino acids of SLAMF1. Interestingly, the SLAMF1–TRAM interaction was observed for human but not mouse proteins. Overall, our observations suggest that SLAMF1 is a new target for modulation of TLR4–TRAM–TRIF inflammatory signaling in human cells.