bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pan-viral protection against arboviruses by targeting inoculation site-based skin macrophages
Authors: Bryden Steven R , Pingen Marieke , Lefteri Daniella A , Major Jack , Delang Leen , Jacobs Sofie , Abdelnabi Rana , Neyts Johan , Miltenburg Janne , Khalid Henna , Tuplin Andrew , Merits Andres , Pondeville Emilie , Edgar Julia , Graham Gerard J , Shams Kave , McKimmie Clive S 
Published: March 2019

AbstractArthropod-borne viruses (arboviruses) are important human pathogens for which there are no specific antiviral medicines. The large number of genetically-distinct arbovirus species, coupled with the unpredictable nature of their outbreaks, has made developing virus-specific anti-viral medicines challenging. Instead, we have defined and targeted a key aspect of the host innate immune response to virus at the arthropod bite that is common to all arbovirus infections, potentially circumventing the need for virus-specific therapies at this site. Using mouse models and human skin explants, we identify innate immune responses by dermal macrophages in the skin as a key determinant of disease severity. Post-exposure treatment of the inoculation site by a topical innate immune agonist significantly suppressed both the local and subsequent systemic course of infection and improved clinical outcome in mice to infection with a variety of arboviruses from the Alphavirus, Flavivirus and Orthobunyavirus genuses. In the absence of treatment, anti-viral interferon expression to virus in the skin was restricted to dermal dendritic cells. In contrast, targeting the more populous skin-resident macrophages with an immune agonist elicited protective responses in key cellular targets of virus that otherwise replicated virus to high levels. By defining and targeting a key aspect of the innate immune response to virus at the mosquito bite site, we have shown that it is possible to improve outcome to infection by targeting pathways activated at the site of inoculation, and thereby identified a putative new strategy for limiting disease following infection with a variety of genetically-distinct arboviruses.One-sentence summaryWe demonstrate that activation of innate immune responses to arbovirus at the mosquito bite is a limiting factor for preventing efficient systemic dissemination of virus and that therapeutic targeting of skin-resident macrophages can have defining inhibitory effects on the later systemic course.
Subtle, Seasonal and Potentially Important: Are Phytotoxic Foliage Leachates Overlooked in Plant Invasion Studies?
Authors: Jones Gruffydd , Tomlinson Max , Owen Rhys , Scullion John , Winters Ana , Jenkins Tom , Ratcliffe John , Gwynn-Jones Dylan 
Published: March 2019

AbstractInvasive species pose a threat to global biodiversity. Recently there has been a growth in research into the chemical aspect of invasions, with some plants reported to introduce compounds to the soil which impair the growth of competing native plants. One such species is Rhododendron ponticum, which has become a damaging invasive shrub in Britain. Here we investigate whether water-soluble compounds introduced from R. ponticum leaves in Ceredigion, Wales, suppressed seed germination, and whether this varied temporally. Leachates from leaf material collected monthly (March to July) were analysed for their chemical composition by liquid chromatography-mass spectrometry and Lactuca sotiva bioassays. In total, 19 compounds were identified, displaying both qualitative and quantitative seasonal variation. Total concentrations peaked in June, however L sativa germination inhibition was only found in leachates from April and May (15% and 17% respectively). The study provides evidence that phytotoxic chemical introduction from R. ponticum leaves is seasonal and most bioactive at a time of year when the seeds of other species germinate. We propose this is one of several mechanisms including shading, lowering of soil pH and the deposition of thick litter, that this species exploits when in competition with other species. We argue that for studies on the phytotoxicity of invasive plants, there is a need to consider temporal variation in the rate and quality of bioactive chemicals produced and released, local precipitation rates, persistence of chemicals in the soil plus synergistic interactions between individual chemicals.
Somatostatin-Expressing Interneurons Co-Release GABA and Glutamate onto Different Postsynaptic Targets in the Striatum
Authors: Cattaneo Stefano , Ripamonti Mattia , Bedogni Francesco , Sessa Alessandro , Taverna Stefano 
Published: March 2019

SummaryThe functional contribution of somatostatin-expressing interneurons (SST-INs) to the synaptic organization of the striatum is poorly understood. Using electrophysiological recordings, optogenetic stimulation, and single-cell PCR analysis, we investigated functional patterns of synaptic connectivity in striatal SST-INs expressing channelrhodopsin-2. Photostimulation of these cells induced both glutamatergic excitatory postsynaptic currents (EPSCs) and GABAergic inhibitory postsynaptic currents (IPSCs) in striatal spiny projection neurons (SPNs) and fast-spiking interneurons (FSIs). The two synaptic components showed equally fast onset latencies, suggesting a mechanism of co-transmission. Accordingly, single-cell PCR analysis revealed that individual striatal SST-INs expressed mRNAs for both glutamate and GABA vesicular transporters (VGLUT1 and VGAT, respectively). During relatively prolonged optical stimuli (0.5-1s), IPSC arrays consistently outlasted EPSCs. As a result, photostimulation of SST-INs caused a transient burst of action potentials followed by a prolonged inhibition in postsynaptic cells.These data suggest that striatal SST-INs are specialized to locally project synapses exerting a composite excitatory and inhibitory effect through GABA/glutamate co-transmission onto different postsynaptic targets.
Molecular characterization of CHAD domains as inorganic polyphosphate binding modules
Authors: Lorenzo-Orts Laura , Hohmann Ulrich , Zhu Jinsheng , Hothorn Michael 
Published: March 2019

AbstractInorganic polyphosphates (polyPs) are long polymers of orthophosphate units (Pi), linked by energy-rich phosphoanhydride bonds. Conserved histidine α-helical (CHAD) domains of unknown biochemical function are often located at the C-terminus of polyP-metabolizing triphosphate tunnel metalloenzymes (TTMs), or can be found as stand-alone proteins in bacterial operons harboring polyP kinases or phosphatases. Here we report that bacterial, archaeal and eukaryotic CHAD domains are specific polyP binding modules. Crystal structures reveal that CHAD domains are formed by two four-helix bundles, giving rise to a central cavity surrounded by two conserved basic surface patches. Different CHAD domains bind polyPs with dissociation constants ranging from the nano-to mid-micromolar range, but not DNA or other Pi-containing ligands. A 2.1 Å CHAD - polyP complex structure reveals the phosphate polymer binding across a central pore and along the two basic patches. Mutational analysis of CHAD – polyP interface residues validates the complex structure and reveals that CHAD domains evolved to bind long-chain polyPs. The presence of a CHAD domain in the polyPase ygiF enhances its enzymatic activity. In plants, CHAD domains bind polyPin vivoand localize to the nucleus and nucleolus, suggesting that plants harbor polyP stores in these compartments. We propose that CHAD domains may be used to engineer the properties of polyP-metabolizing enzymes and to specifically localize polyP stores in eukaryotic cells and tissues.SignificanceA domain of unknown function termed CHAD, present in all kingdoms of life, is characterized as a specific inorganic polyphosphate binding domain. The small size of the domain and its high specificity for inorganic polyphosphates suggest that it could be used as a tool to locate inorganic polyphosphate stores in pro- and eukaryotic cells and tissues.
RedundantSCARECROWgenes pattern distinct cell layers in roots and leaves of maize
Authors: Hughes Thomas E. , Sedelnikova Olga V. , Wu Hao , Becraft Philip W. , Langdale Jane A. 
Published: March 2019

ABSTRACTThe highly efficient C4 photosynthetic pathway is facilitated by ‘Kranz’ leaf anatomy. In Kranz leaves, closely spaced veins are encircled by concentric layers of photosynthetic bundle sheath (inner) and mesophyll (outer) cells. Here we demonstrate that in the C4 monocot maize, Kranz patterning is regulated by redundant function of SCARECROW 1 (ZmSCR1) and a previously uncharacterized homeolog ZmSCR1h.ZmSCR1andZmSCR1htranscripts accumulate in ground meristem cells of developing leaf primordia and inZmscr1;Zmscr1hmutant leaves, most veins are separated by one rather than two mesophyll cells; many veins have sclerenchyma above and/or below instead of mesophyll cells; and supernumerary bundle sheath cells develop. The mutant defects are unified by compromised mesophyll cell development. In addition to Kranz defects,Zmscr1;Zmscr1hmutants fail to form an organized endodermal layer in the root. Collectively, these data indicate that ZmSCR1 and ZmSCR1h redundantly regulate cell-type patterning in both leaves and roots of maize. Leaf and root pathways are distinguished, however, by the cell layer in which they operate – mesophyll at a two-cell distance from leaf veins versus endodermis immediately adjacent to root vasculature.Summary statementTwo duplicated maizeSCARECROWgenes control the development of the endodermis in roots and the mesophyll in leaves
Increasing the value of raw bulk milk quality based on mammary glands as production units vs. the udder in dairy cows with mastitis
Authors: Leitner Gabriel , Lavon Yaniv , Merin Uzi , Jacoby Shamay , Blum Shlomo E. , Krifucks Oleg , Silanikove Nissim 
Published: March 2019

AbstractThe current study measured the influence of milk of subclinically infected glands by different bacteria species on the cow’s milk and suggests different parameters for milk payment. The effects of bacterial infection or inflammation on gland milk yield were related to the bacteria species that caused the infection. The volume of milk of the inflamed gland from the cow’s milk yield was significantly lower (P<0.001) for the glands previously infected byEscherichia coli(PIEc) and those infected withStreptococcus dysgalactiae.Coagulation properties, rennet clotting time (RCT) and curd firmness (CF) also depended on the bacteria causing the infection. RCT values of all the inflamed glands were significantly longer (P<0.001) and CF values were significantly lower than that of the healthy ones. Moreover, in the whole milk, CF was also significantly lower and not proportional to the volume of the milk from the inflamed gland of the cow’s milk. Calculating the predicted 40% dry matter curd weight (PCW) on the cow level, including the healthy and inflamed glands or the healthy glands alone, found that for 9 of 13 PIEc cows, the presence of the affected gland’s milk in the whole cow milk resulted in a negative PCW value. Likewise, 5 of 20 cows infected byS. dysgalactiaehad negative delta values. Unlike the latter bacteria, PCW from milk of glands infected with CNS increased, although in a lower magnitude than in the healthy glands. No correlation was found between logSCC in the whole cow milk (healthy and inflamed glands) and PCW.
EML4-ALK V3 drives cell migration through NEK9 and NEK7 kinases in non-small-cell lung cancer
Authors: O’Regan Laura , Barone Giancarlo , Adib Rozita , Woo Chang Gok , Jeong Hui Jeong , Richardson Emily L. , Richards Mark W. , Muller Patricia A.J. , Collis Spencer J. , Fennell Dean A. , Choi Jene , Bayliss Richard , Fry Andrew M. 
Published: March 2019

ABSTRACTEML4-ALK is an oncogenic fusion present in ∼5% lung adenocarcinomas. However, distinct EML4-ALK variants differ in the length of the EML4 microtubule-associated protein encoded within the fusion and are associated with a poorly understood variability in disease progression and therapeutic response. Here, we show that EML4-ALK variant 3, which is linked to accelerated metastatic spread and worse patient outcome, causes microtubule stabilization, formation of extended cytoplasmic protrusions, loss of cell polarity and increased cell migration. Strikingly, this is dependent upon the NEK9 kinase that interacts with the N-terminal region of EML4. Overexpression of wild-type EML4, as well as constitutive activation of NEK9, also perturbs cell morphology and accelerates cell migration in a manner that requires the downstream kinase NEK7 but not ALK activity. Moreover, elevated NEK9 is associated in patients with EML4-ALK V3 expression, as well as reduced progression-free and overall survival. Hence, we propose that EML4-ALK V3 promotes microtubule stabilization through recruitment of NEK9 and NEK7 to increase cell migration and that this represents a novel actionable pathway that drives disease progression in lung cancer.
Fragment-based screening identifies molecules targeting the substrate-binding ankyrin repeat domains of tankyrase
Authors: Pollock Katie , Liu Manjuan , Zaleska Mariola , Pfuhl Mark , Collins Ian , Guettler Sebastian 
Published: March 2019

AbstractThe PARP enzyme and scaffolding protein tankyrase (TNKS, TNKS2) uses its ankyrin repeat clusters (ARCs) to bind a wide range of proteins and thereby controls diverse cellular functions. A number of these are implicated in cancer-relevant processes, including Wnt/β-catenin signaling and telomere maintenance. The ARCs recognise a conserved tankyrase-binding peptide motif (TBM). All currently available tankyrase inhibitors target the catalytic domain and inhibit tankyrase’s poly(ADP-ribosyl)ation function. However, there is emerging evidence that catalysis-independent “scaffolding” mechanisms contribute to tankyrase function. Here we report a fragment-based screening program against tankyrase ARC domains, using a combination of biophysical assays, including differential scanning fluorimetry (DSF) and nuclear magnetic resonance (NMR). We identify fragment molecules that will serve as starting points for the development of tankyrase substrate binding antagonists. Such compounds will enable probing the scaffolding functions of tankyrase, and may, in the future, provide potential alternative therapeutic approaches to inhibiting tankyrase activity in cancer and other conditions.
Decoding mouse behavior to explain single-trial decisions and their relationship with neural activity
Authors: Weissenberger Yves , King Andrew J. , Dahmen Johannes C. 
Published: March 2019

AbstractModels of behavior typically focus on sparse measurements of motor output over long timescales, limiting their ability to explain momentary decisions or neural activity. We developed data-driven models relating experimental variables to videos of behavior. Applied to mouse operant behavior, they revealed behavioral encoding of cognitive variables. Model-based decoding of videos yielded an accurate account of single-trial behavior in terms of the relationship between cognition, motor output and cortical activity.
Ant collective behavior is heritable and shaped by selection
Authors: Walsh Justin T. , Garnier Simon , Linksvayer Timothy A. 
Published: March 2019

AbstractCollective behaviors are widespread in nature and usually assumed to be strongly shaped by natural selection. However, the degree to which variation in collective behavior is heritable and has fitness consequences -- the two prerequisites for evolution by natural selection -- is largely unknown. We used a new pharaoh ant (Monomorium pharaonis) mapping population to estimate the heritability, genetic correlations, and fitness consequences of three collective behaviors (foraging, aggression, and exploration) as well as body size, sex ratio, and caste ratio. Heritability estimates for the collective behaviors were moderate, ranging from 0.17 to 0.32, but lower than our estimates for the heritability of caste ratio, sex ratio, and the body size of new workers, queens, and males. Moreover, variation among colonies in collective behaviors was phenotypically correlated, suggesting that selection may shape multiple colony collective behaviors simultaneously. Finally, we found evidence for directional selection that was similar in strength to estimates of selection in natural populations. Altogether, our study begins to elucidate the genetic architecture of collective behavior and is one of the first studies to demonstrate that it is shaped by selection.
Dispersal dynamics and local filtering vary with climate across a grassland landscape
Authors: Guittar John , Goldberg Deborah , Klanderud Kari , Berge Astrid , Boixaderas Marta Ramírez , Meineri Eric , Töpper Joachim , Vandvik Vigdis 
Published: March 2019

ABSTRACTDispersal dynamics and local filtering interactively generate regional vegetation patterns, but empirical evidence of their combined influence in nature is scarce, representing a missing link between our theoretical understanding of community assembly and real-world observation. Here, we compare seed and adult plant communities at twelve grassland sites with different climates in southern Norway to explore the degree to which community membership is shaped by dispersal limitation and local niche-based filtering, and how this varies with climate. To do this, we first divide species at each site into two groups: “locally-transient” species, which occur as seeds but are rare or absent as adults (i.e., they arrive but are filtered out), or “locally-persistent” species, which occur consistently as adults in annual vegetation surveys. We then ask questions to reveal where, when, why, and how locally-transient species are systematically disfavored during community assembly. Our results led to four main conclusions: (1) the strength of local filtering on community membership increased with temperature, (2) surprisingly, local filtering was stronger during seedling emergence than during seedling establishment, (3) climate-based niche differences drove differential performance among species, especially for seeds dispersing outside of their realized climate niches into more stressful (colder and drier) climates, and (4) locally-transient species had traits that may made them better dispersers (smaller seeds) but poorer competitors for light (shorter statures, less persistent clonal connections) than locally-persistent species, providing a potential explanation for why they arrived to new sites but failed to establish persistent adult populations. Our study is one of the first to combine seed, seedling, and adult survey data across multiple sites with different climates to provide a rigorous empirical evaluation of the combined influence of dispersal limitation and local filtering on the generation and maintenance of climate-associated vegetation patterns.
Machine-learning a virus assembly fitness landscape
Authors: Dechant Pierre-Philippe , He Yang-Hui 
Published: March 2019

AbstractRealistic evolutionary fitness landscapes are notoriously difficult to construct. A recent cutting-edge model of virus assembly consists of a dodecahedral capsid with 12 corresponding packaging signals in three affinity bands. This whole genome/phenotype space consisting of 312genomes has been explored via computationally expensive stochastic assembly models, giving a fitness landscape in terms of the assembly efficiency. Using latest machine-learning techniques by establishing a neural network, we show that the intensive computation can be short-circuited in a matter of minutes to astounding accuracy.
FUSALS-causative mutations impactFUSautoregulation and the processing of RNA-binding proteins through intron retention
Authors: Humphrey Jack , Birsa Nicol , Milioto Carmelo , Robaldo David , Eberle Andrea B , Kräuchi Rahel , Bentham Matthew , Ule Agnieszka M. , Jarvis Seth , Bodo Cristian , Garone Maria Giovanna , Devoy Anny , Rosa Alessandro , Bozzoni Irene , Fisher Elizabeth MC , Ruepp Marc-David , Mühlemann Oliver , Schiavo Giampietro , Isaacs Adrian M , Plagnol Vincent , Fratta Pietro 
Published: March 2019

AbstractMutations in the RNA-binding protein FUS cause amyotrophic lateral sclerosis (ALS), a devastating neurodegenerative disease in which the loss of motor neurons induces progressive weakness and death from respiratory failure, typically only 3-5 years after onset. FUS plays a role in numerous aspects of RNA metabolism, including mRNA splicing. However, the impact of ALS-causative mutations on splicing has not been fully characterised, as most disease models have been based on FUS overexpression, which in itself alters its RNA processing functions. To overcome this, we and others have recently created knock-in models, and have generated high depth RNA-sequencing data on FUS mutants in parallel to FUS knockout. We combined three independent datasets with a joint modelling approach, allowing us to compare the mutation-induced changes to genuine loss of function. We find that FUS ALS-mutations induce a widespread loss of function on expression and splicing, with a preferential effect on RNA binding proteins. Mutant FUS induces intron retention changes through RNA binding, and we identify an intron retention event in FUS itself that is associated with its autoregulation. Altered FUS regulation has been linked to disease, and intriguingly, we find FUS autoregulation to be altered not only by FUS mutations, but also in other genetic forms of ALS, including those caused by TDP-43, VCP and SOD1 mutations, supporting the concept that multiple ALS genes interact in a regulatory network.
Role of α-Catenin and its mechanosensing properties in the regulation of Hippo/YAP-dependent tissue growth
Authors: Sarpal Ritu , Yan Victoria , Kazakova Lidia , Sheppard Luka , Tepass Ulrich 
Published: March 2019

Abstractα-catenin is a key protein of adherens junctions (AJs) with mechanosensory properties. It also acts as a tumor suppressor that limits tissue growth. Here we analyzed the function of Drosophila α-Catenin (α-Cat) in growth regulation of the wing epithelium. We found that different α-Cat levels led to a differential activation of Hippo/Yorkie or JNK signaling causing tissue overgrowth or degeneration, respectively. α-Cat can modulate Yorkie-dependent tissue growth through recruitment of Ajuba, a negative regulator of Hippo signaling, to AJs but also through a mechanism that does not involve junctional recruitment of Ajuba. Further, both mechanosensory regions of α-Cat, the M region and the actin-binding domain (ABD), contribute to growth regulation. Whereas M is dispensable for α-Cat function in the wing, individual M domains (M1, M2, M3) have opposing effects on growth regulation. In particular, M1 limits Ajuba recruitment. Loss of M1 cause Ajuba hyper-recruitment to AJs promoting tissue-tension independent overgrowth. Although M1 binds Vinculin, Vinculin it is not responsible for this effect. Moreover, disruption of mechanosensing of the α-Cat actin-binding domain affects tissue growth, with enhanced actin interactions stabilizing junctions and leading to tissue overgrowth. Together, our findings indicate that α-Cat acts through multiple mechanisms to control tissue growth, including regulation of AJ stability, mechanosensitive Ajuba recruitment, and dynamic direct F-actin interactions.