bluuebunny/crossref_metadata_2025_split huggingface dataset:
Osteocalcin triggers Fas/FasL-mediated necroptosis in adipocytes via activation of p300
Authors: Otani Takahito , Matsuda Miho , Mizokami Akiko , Kitagawa Norio , Takeuchi Hiroshi , Jimi Eijiro , Inai Tetsuichiro , Hirata Masato 
Published: December 2018

AbstractThe uncarboxylated form of osteocalcin (GluOC) regulates glucose and lipid metabolism in mice. We previously showed that low-dose (≤10 ng/ml) GluOC induces the expression of adiponectin and peroxisome proliferator-activated receptor γ (PPARγ) via a cAMP–PKA–ERK–CREB signaling pathway in 3T3-L1 adipocytes. We also noticed that high-dose (≥20 ng/ml) GluOC inhibits the expression of adiponectin and PPARγ in these cells. We have here explored the mechanism underlying these effects of high-dose GluOC. High-dose GluOC triggered morphological changes in 3T3-L1 adipocytes suggestive of the induction of cell death. It activated the putative GluOC receptor GPRC6A and thereby induced the production of cAMP and activation of protein kinase A (PKA), similar to signaling by low-dose GluOC with the exception that the catalytic subunit of PKA also entered the nucleus. Cytosolic PKA induced phosphorylation of cAMP response element-binding protein (CREB) at serine-133 via extracellular signal-regulated kinase (ERK). Nuclear PKA appeared to mediate the inhibitory phosphorylation of salt-inducible kinase 2 (SIK2) at serine-358 and thereby to alleviate the inhibitory phosphorylation of the CREB co-activator p300 at serine-89. The activation of CREB and p300 resulted in increased expression of the transcription factor FoxO1 and consequent upregulation of Fas ligand (FasL) at the plasma membrane. The interaction of FasL with Fas on neighboring adipocytes triggered the phosphorylation at threonine-357/serine-358 and homotrimerization of mixed-lineage kinase domain-like protein (MLKL), a key regulator of necroptosis, as well as Ca2+ influx via transient receptor potential melastatin 7 (TRPM7), the generation of reactive oxygen species and lipid peroxides, and dephosphorylation of dynamin-related protein 1 (DRP1) at serine-637, resulting in mitochondrial fragmentation. Together, our results indicate that high-dose GluOC triggers necroptosis through upregulation of FasL at the plasma membrane in a manner dependent of activation of CREB-p300, followed by the activation of Fas signaling in neighboring adipocytes.
SRPK1 maintains acute myeloid leukemia through effects on isoform usage of epigenetic regulators including BRD4
Authors: Tzelepis Konstantinos , De Braekeleer Etienne , Aspris Demetrios , Barbieri Isaia , Vijayabaskar M. S. , Liu Wen-Hsin , Gozdecka Malgorzata , Metzakopian Emmanouil , Toop Hamish D. , Dudek Monika , Robson Samuel C. , Hermida-Prado Francisco , Yang Yu Hsuen , Babaei-Jadidi Roya , Garyfallos Dimitrios A. , Ponstingl Hannes , Dias Joao M. L. , Gallipoli Paolo , Seiler Michael , Buonamici Silvia , Vick Binje , Bannister Andrew J. , Rad Roland , Prinjha Rab K. , Marioni John C. , Huntly Brian , Batson Jennifer , Morris Jonathan C. , Pina Cristina , Bradley Allan , Jeremias Irmela , Bates David O. , Yusa Kosuke , Kouzarides Tony , Vassiliou George S. 
Published: December 2018

AbstractWe recently identified the splicing kinase gene SRPK1 as a genetic vulnerability of acute myeloid leukemia (AML). Here, we show that genetic or pharmacological inhibition of SRPK1 leads to cell cycle arrest, leukemic cell differentiation and prolonged survival of mice transplanted with MLL-rearranged AML. RNA-seq analysis demonstrates that SRPK1 inhibition leads to altered isoform levels of many genes including several with established roles in leukemogenesis such as MYB, BRD4 and MED24. We focus on BRD4 as its main isoforms have distinct molecular properties and find that SRPK1 inhibition produces a significant switch from the short to the long isoform at the mRNA and protein levels. This was associated with BRD4 eviction from genomic loci involved in leukemogenesis including BCL2 and MYC. We go on to show that this switch mediates at least part of the anti-leukemic effects of SRPK1 inhibition. Our findings reveal that SRPK1 represents a plausible new therapeutic target against AML.
Broad CD8+ T cell cross-recognition of distinct influenza A strains in humans
Authors: Grant Emma J. , Josephs Tracy M. , Loh Liyen , Clemens E. Bridie , Sant Sneha , Bharadwaj Mandvi , Chen Weisan , Rossjohn Jamie , Gras Stephanie , Kedzierska Katherine 
Published: December 2018

AbstractNewly-emerged and vaccine-mismatched influenza A viruses (IAVs) result in a rapid global spread of the virus due to minimal antibody-mediated immunity. In that case, established CD8+T-cells can reduce disease severity. However, as mutations occur sporadically within immunogenic IAV-derived T-cell peptides, understanding of T-cell receptor (TCRαβ) cross-reactivity towards IAV variants is needed for a vaccine design. Here, we investigate TCRαβ cross-strain recognition across IAV variants within two immunodominant human IAV-specific CD8+T-cell epitopes, HLA-B*37:01-restricted NP338-346(B37-NP338) and HLA-A*01:01-restricted NP44-52(A1-NP44). We find high abundance of cross-reactive TCRαβ clonotypes recognizing distinct IAV variants. Structures of the wild-type and variant peptides revealed preserved conformation of the bound peptides. Structures of a cross-reactive TCR-HLA-B37-NP338complex suggest that the conserved conformation of the variants underpins TCR cross-reactivity. Overall, cross-reactive CD8+T-cell responses, underpinned by conserved epitope structure, facilitates recognition of distinct IAV variants, thus CD8+T-cell-targeted vaccines could provide protection across different IAV strains.
Identification of ADAR1 adenosine deaminase dependency in a subset of cancer cells
Authors: Gannon Hugh S. , Zou Tao , Kiessling Michael K. , Gao Galen F. , Cai Diana , Choi Peter S. , Ivan Alexandru P. , Buchumenski Ilana , Berger Ashton C. , Goldstein Jonathan T. , Cherniack Andrew D. , Vazquez Francisca , Tsherniak Aviad , Levanon Erez Y. , Hahn William C. , Meyerson Matthew 
Published: December 2018

AbstractSystematic exploration of cancer cell vulnerabilities can inform the development of novel cancer therapeutics. Here, through analysis of genome-scale loss-of-function datasets, we identify adenosine deaminase acting on RNA (ADAR or ADAR1) as an essential gene for the survival of a subset of cancer cell lines. ADAR1-dependent cell lines display increased expression of interferon-stimulated genes. Activation of type I interferon signaling in the context of ADAR1 deficiency can induce cell lethality in non-ADAR1-dependent cell lines. ADAR deletion causes activation of the double-stranded RNA sensor, protein kinase R (PKR). Disruption of PKR signaling, through inactivation of PKR or overexpression of either a wildtype or catalytically inactive mutant version of the p150 isoform of ADAR1, partially rescues cell lethality after ADAR1 loss, suggesting that both catalytic and non-enzymatic functions of ADAR1 may contribute to preventing PKR-mediated cell lethality. Together, these data nominate ADAR1 as a potential therapeutic target in a subset of cancers.
CRISPR/Cas9-mediated glycolate oxidase disruption is an efficacious and safe treatment for primary hyperoxaluria type I
Authors: Zabaleta Nerea , Barberia Miren , Martin-Higueras Cristina , Zapata-Linares Natalia , Betancor Isabel , Rodriguez Saray , Martinez-Turrillas Rebeca , Torella Laura , Vales Africa , Olagüe Cristina , Vilas-Zornoza Amaia , Castro-Labrador Laura , Lara-Astiaso David , Prosper Felipe , Salido Eduardo , Gonzalez-Aseguinolaza Gloria , Rodriguez-Madoz Juan R. 
Published: December 2018

AbstractCRISPR/Cas9 technology offers novel approaches for the development of new therapies for many unmet clinical needs, including a significant number of inherited monogenic diseases. However, in vivo correction of disease-causing genes is still inefficient, especially for those diseases without selective advantage for corrected cells. We reasoned that substrate reduction therapies (SRT) targeting non-essential enzymes could provide an attractive alternative. Here we evaluate the therapeutic efficacy of an in vivo CRISPR/Cas9-mediated SRT to treat primary hyperoxaluria type I (PH1), a rare inborn dysfunction in glyoxylate metabolism that results in excessive hepatic oxalate production causing end-stage renal disease. A single systemic administration of an AAV8-CRISPR/Cas9 vector targeting glycolate oxidase, prevents oxalate overproduction and kidney damage, with no signs of toxicity in Agxt1−/− mice. Our results reveal that CRISPR/Cas9-mediated SRT represents a promising therapeutic option for PH1 that can be potentially applied to other metabolic diseases caused by the accumulation of toxic metabolites.
Pressure-driven phase transitions and reduction of dimensionality in 2D silicon nanosheets
Authors: Hwang Gil Chan , Blom Douglas A. , Vogt Thomas , Lee Jaejun , Choi Heon-Jin , Shao Sen , Ma Yanming , Lee Yongjae 
Published: December 2018

AbstractIn-situ high-pressure synchrotron X-ray powder diffraction studies up to 21 GPa of CVD-grown silicon 2D-nanosheets establish that the structural phase transitions depend on size and shape. For sizes between 9.3(7) nm and 15.2(8) nm we observe an irreversible phase transition sequence from I (cubic) → II (tetragonal) → V (hexagonal) during pressure increase and during decompression below 8 GPa the emergence of an X-ray amorphous phase. High-angle annular dark field scanning transmission electron microscopy (HAADF-STEM) and atomic force microscopy (AFM) images of this X-ray amorphous phase reveal the formation of significant numbers of 1D nanowires with aspect ratios > 10, which are twinned and grow along the <111> direction. We discovered a reduction of dimensionality under pressure from a 2D morphology to a 1D wire in a material with a diamond structure. MD simulations indicate the reduction of thermal conductivity in such nanowires.
Nucleotide-dependent DNA gripping and an end-clamp mechanism regulate the bacteriophage T4 viral packaging motor
Authors: Ordyan Mariam , Alam Istiaq , Mahalingam Marthandan , Rao Venigalla B. , Smith Douglas E. 
Published: December 2018

AbstractATP-powered viral packaging motors are among the most powerful biomotors known. Motor subunits arranged in a ring repeatedly grip and translocate the DNA to package viral genomes into capsids. Here, we use single DNA manipulation and rapid solution exchange to quantify how nucleotide binding regulates interactions between the bacteriophage T4 motor and DNA substrate. With no nucleotides, there is virtually no gripping and rapid slipping occurs with only minimal friction resisting. In contrast, binding of an ATP analog engages nearly continuous gripping. Occasional slips occur due to dissociation of the analog from a gripping motor subunit, or force-induced rupture of grip, but multiple other analog-bound subunits exert high friction that limits slipping. ADP induces comparably infrequent gripping and variable friction. Independent of nucleotides, slipping arrests when the end of the DNA is about to exit the capsid. This end-clamp mechanism increases the efficiency of packaging by making it essentially irreversible.
Probing multi-spinon excitations outside of the two-spinon continuum in the antiferromagnetic spin chain cuprate Sr2CuO3
Authors: Schlappa J. , Kumar U. , Zhou K. J. , Singh S. , Mourigal M. , Strocov V. N. , Revcolevschi A. , Patthey L. , Rønnow H. M. , Johnston S. , Schmitt T. 
Published: December 2018

AbstractOne-dimensional (1D) magnetic insulators have attracted significant interest as a platform for studying quasiparticle fractionalization, quantum criticality, and emergent phenomena. The spin-1/2 Heisenberg chain with antiferromagnetic nearest neighbour interactions is an important reference system; its elementary magnetic excitations are spin-1/2 quasiparticles called spinons that are created in even numbers. However, while the excitation continuum associated with two-spinon states is routinely observed, the study of four-spinon and higher multi-spinon states is an open area of research. Here we show that four-spinon excitations can be accessed directly in Sr2CuO3 using resonant inelastic x-ray scattering (RIXS) in a region of phase space clearly separated from the two-spinon continuum. Our finding is made possible by the fundamental differences in the correlation function probed by RIXS in comparison to other probes. This advance holds promise as a tool in the search for novel quantum states and quantum spin liquids.
Contemporaneous radiations of fungi and plants linked to symbiosis
Authors: Lutzoni François , Nowak Michael D. , Alfaro Michael E. , Reeb Valérie , Miadlikowska Jolanta , Krug Michael , Arnold A. Elizabeth , Lewis Louise A. , Swofford David L. , Hibbett David , Hilu Khidir , James Timothy Y. , Quandt Dietmar , Magallón Susana 
Published: December 2018

AbstractInteractions between fungi and plants, including parasitism, mutualism, and saprotrophy, have been invoked as key to their respective macroevolutionary success. Here we evaluate the origins of plant-fungal symbioses and saprotrophy using a time-calibrated phylogenetic framework that reveals linked and drastic shifts in diversification rates of each kingdom. Fungal colonization of land was associated with at least two origins of terrestrial green algae and preceded embryophytes (as evidenced by losses of fungal flagellum, ca. 720 Ma), likely facilitating terrestriality through endomycorrhizal and possibly endophytic symbioses. The largest radiation of fungi (Leotiomyceta), the origin of arbuscular mycorrhizae, and the diversification of extant embryophytes occurred ca. 480 Ma. This was followed by the origin of extant lichens. Saprotrophic mushrooms diversified in the Late Paleozoic as forests of seed plants started to dominate the landscape. The subsequent diversification and explosive radiation of Agaricomycetes, and eventually of ectomycorrhizal mushrooms, were associated with the evolution of Pinaceae in the Mesozoic, and establishment of angiosperm-dominated biomes in the Cretaceous.
The utility of serology for elimination surveillance of trachoma
Authors: Pinsent Amy , Solomon Anthony W. , Bailey Robin L. , Bid Rhiannon , Cama Anaseini , Dean Deborah , Goodhew Brook , Gwyn Sarah E. , Jack Kelvin R. , Kandel Ram Prasad , Kama Mike , Massae Patrick , Macleod Colin , Mabey David C. W. , Migchelsen Stephanie , Müller Andreas , Sandi Frank , Sokana Oliver , Taoaba Raebwebwe , Tekeraoi Rabebe , Martin Diana L. , White Michael. T. 
Published: December 2018

AbstractRobust surveillance methods are needed for trachoma control and recrudescence monitoring, but existing methods have limitations. Here, we analyse data from nine trachoma-endemic populations and provide operational thresholds for interpretation of serological data in low-transmission and post-elimination settings. Analyses with sero-catalytic and antibody acquisition models provide insights into transmission history within each population. To accurately estimate sero-conversion rates (SCR) for trachoma in populations with high-seroprevalence in adults, the model accounts for secondary exposure to Chlamydia trachomatis due to urogenital infection. We estimate the population half-life of sero-reversion for anti-Pgp3 antibodies to be 26 (95% credible interval (CrI): 21–34) years. We show SCRs below 0.015 (95% confidence interval (CI): 0.0–0.049) per year correspond to a prevalence of trachomatous inflammation—follicular below 5%, the current threshold for elimination of active trachoma as a public health problem. As global trachoma prevalence declines, we may need cross-sectional serological survey data to inform programmatic decisions.
Structure of a human intramembrane ceramidase explains enzymatic dysfunction found in leukodystrophy
Authors: Vasiliauskaité-Brooks Ieva , Healey Robert D. , Rochaix Pascal , Saint-Paul Julie , Sounier Rémy , Grison Claire , Waltrich-Augusto Thierry , Fortier Mathieu , Hoh François , Saied Essa M. , Arenz Christoph , Basu Shibom , Leyrat Cédric , Granier Sébastien 
Published: December 2018

AbstractAlkaline ceramidases (ACERs) are a class of poorly understood transmembrane enzymes controlling the homeostasis of ceramides. They are implicated in human pathophysiology, including progressive leukodystrophy, colon cancer as well as acute myeloid leukemia. We report here the crystal structure of the human ACER type 3 (ACER3). Together with computational studies, the structure reveals that ACER3 is an intramembrane enzyme with a seven transmembrane domain architecture and a catalytic Zn2+ binding site in its core, similar to adiponectin receptors. Interestingly, we uncover a Ca2+ binding site physically and functionally connected to the Zn2+ providing a structural explanation for the known regulatory role of Ca2+ on ACER3 enzymatic activity and for the loss of function in E33G-ACER3 mutant found in leukodystrophic patients.
Oxygen-dependent proteolysis regulates the stability of angiosperm polycomb repressive complex 2 subunit VERNALIZATION 2
Authors: Gibbs Daniel J. , Tedds Hannah M. , Labandera Anne-Marie , Bailey Mark , White Mark D. , Hartman Sjon , Sprigg Colleen , Mogg Sophie L. , Osborne Rory , Dambire Charlene , Boeckx Tinne , Paling Zachary , Voesenek Laurentius A. C. J. , Flashman Emily , Holdsworth Michael J. 
Published: December 2018

AbstractThe polycomb repressive complex 2 (PRC2) regulates epigenetic gene repression in eukaryotes. Mechanisms controlling its developmental specificity and signal-responsiveness are poorly understood. Here, we identify an oxygen-sensitive N-terminal (N-) degron in the plant PRC2 subunit VERNALIZATION(VRN) 2, a homolog of animal Su(z)12, that promotes its degradation via the N-end rule pathway. We provide evidence that this N-degron arose early during angiosperm evolution via gene duplication and N-terminal truncation, facilitating expansion of PRC2 function in flowering plants. We show that proteolysis via the N-end rule pathway prevents ectopic VRN2 accumulation, and that hypoxia and long-term cold exposure lead to increased VRN2 abundance, which we propose may be due to inhibition of VRN2 turnover via its N-degron. Furthermore, we identify an overlap in the transcriptional responses to hypoxia and prolonged cold, and show that VRN2 promotes tolerance to hypoxia. Our work reveals a mechanism for post-translational regulation of VRN2 stability that could potentially link environmental inputs to the epigenetic control of plant development.
Impacts of climate on the biodiversity-productivity relationship in natural forests
Authors: Fei Songlin , Jo Insu , Guo Qinfeng , Wardle David A. , Fang Jingyun , Chen Anping , Oswalt Christopher M. , Brockerhoff Eckehard G. 
Published: December 2018

AbstractUnderstanding biodiversity-productivity relationships (BPRs) is of theoretical importance, and has important management implications. Most work on BPRs has focused on simple and/or experimentally assembled communities, and it is unclear how these observed BPRs can be extended to complex natural forest ecosystems. Using data from over 115,000 forest plots across the contiguous United States, we show that the bivariate BPRs are positive in dry climates and hump-shaped in mesic climates. When considering other site characteristics, BPRs change to neutral in dry climates and remain hump-shaped in humid sites. Our results indicate that climatic variation is an underlying determinant of contrasting BPRs observed across a large spatial extent, while both biotic factors (e.g., stand age and density) and abiotic factors (e.g., soil properties) can impact BPRs within a given climate unit. These findings suggest that tradeoffs need be made when considering whether to maximize productivity vs. conserve biodiversity, especially in mesic climates.
A quasi-integral controller for adaptation of genetic modules to variable ribosome demand
Authors: Huang Hsin-Ho , Qian Yili , Del Vecchio Domitilla 
Published: December 2018

AbstractThe behavior of genetic circuits is often poorly predictable. A gene’s expression level is not only determined by the intended regulators, but also affected by changes in ribosome availability imparted by expression of other genes. Here we design a quasi-integral biomolecular feedback controller that enables the expression level of any gene of interest (GOI) to adapt to changes in available ribosomes. The feedback is implemented through a synthetic small RNA (sRNA) that silences the GOI’s mRNA, and uses orthogonal extracytoplasmic function (ECF) sigma factor to sense the GOI’s translation and to actuate sRNA transcription. Without the controller, the expression level of the GOI is reduced by 50% when a resource competitor is activated. With the controller, by contrast, gene expression level is practically unaffected by the competitor. This feedback controller allows adaptation of genetic modules to variable ribosome demand and thus aids modular construction of complicated circuits.
Hybrid Surface Plasmon Polariton Wave Generation and Modulation by Chiral-Graphene-Metal (CGM) Structure
Authors: Yaqoob M. Z. , Ghaffar A. , Alkanhal Majeed , Rehman Sajjad ur , Razzaz Faroq 
Published: December 2018

AbstractTheoretical investigations are carried out to study hybrid SPP wave propagation along the Chiral-Graphene-Metal (CGM) interface. The Kubo formulism is used for the physical modeling of single-layer graphene and the impedance boundary conditions approach is applied at the CGM interface to compute the dispersion relationship for hybrid SPP waves. It is demonstrated that the chirality (ξ) and chemical potential (μc) parameters can be used to modulate the resonance surface plasmon frequencies of the upper and lower propagating modes. Furthermore, the propagation bandgap between the upper and the lower modes can be tuned by changing the chirality parameter. The effect of the chemical potential (μc)and the relaxation time (τ) on the normalized propagation constant, propagation length, and the effective refractive index is studied. The present work may have potential applications in optical and chiral sensing in the terahertz frequency range.
On the contribution of internal variability and external forcing factors to the Cooling trend over the Humid Subtropical Indo-Gangetic Plain in India
Authors: Nath Reshmita , Luo Yong , Chen Wen , Cui Xuefeng 
Published: December 2018

AbstractThe summer surface air temperature (SAT) in the Humid Subtropical Climate Zone in India, exhibits a significant cooling trend (~−3 °C/40 yrs.) in CRU observational data during 1961–2000. Here we investigate the contribution of internal and external factors, which are driving this cooling trend. Using the Community Earth System Model-Large Ensemble (CESM-LE), we analyze the historical climate change in presence of internal climate variability. Most of the model ensemble members could reproduce this amplified cooling (<−3 °C) as shown from CRU data. Further analyses reveals that external forcing displays a strong cooling effect over this region, while internal variability displays mixed cooling (in most cases) and warming signals. The signal to noise ratio i.e. the ratio of external forcings and internal climatic variability is less than 1, which indicates that internal climatic variability dominates over the forced response. Furthermore, to quantify the role of different external forcing factors we used the CCSM4 single forcing simulations. The simulation results from CESM-LE and CCSM4 suggest that the cooling trend over the region is primarily due to the combined influence of internal variability (~73%) and partly due to aerosol (~10%) and ozone only forcing, which strongly mask the warming effect of GHG and solar forcing.