Introduction: The social life of time

This is the final version. Available on open access from SAGE Publications via the DOI in this recordWellcome Trus

Angst Springs Eternal:Dangerous Times and the Dangers of Timing the “Arab Spring”

Various reflections on the ‘Arab Spring’ evince a common view of the relationship between change and time that imbues events with a sense of intrinsic peril. Based on a framework developed from Norbert Elias’s concept of timing, this article elaborates the relationship between time and the ‘Arab Spring’ by unpacking and explaining three rhetorical tropes prevalent in academic responses to the revolts. The first two construct a problem to which the third proffers a solution. First, analysts treat time itself as a problematic force confounding stability and progress. Second, they deploy fluvial metaphors to present dynamic events as inherently insecure. Third, they use temporal Othering to retrofit the ‘Arab Spring’ to the familiar arc of liberal democracy, which renders the revolts intelligible and amenable to external intervention. These moves prioritize certainty and order over other considerations and constrain open-ended transformations within a familiar rubric of political progress. They also constitute an active timing effort based on a conservative standard, with important implications for our understanding of security and for scholarly reflexivity. The article concludes with three temporal alternatives for engaging novel changes like the ‘Arab Spring’

Ciprofloxacin, diclofenac, ibuprofen and 17α-ethinylestradiol differentially affect the activity of acetogens and methanogens in anaerobic communities

Pharmaceutical compounds end up in wastewater treatment plants but little is known on their effect towards the different microbial groups in anaerobic communities. In this work, the effect of the antibiotic Ciprooxacin (CIP), the non-steroidal anti-inammatory drugs Diclofenac (DCF) and Ibuprofen (IBP), and the hormone 17-ethinylestradiol (EE2), on the activity of acetogens and methanogens in anaerobic communities, was investigated. Microbial communities were more affected by CIP, followed by EE2, DCF and IBP, but the response of the different microbial groups was dissimilar. For concentrations of 0.01 to 0.1 mg/L, the specic methanogenic activity was not affected. Acetogenic bacteria were sensitive to CIP concentrations above 1 mg/L, while DCF and EE2 toxicity was only detected for concentrations higher than 10 mg/L, and IBP had no effect in all concentrations tested. Acetoclastic methanogens showed higher sensitivity to the presence of these micropollutants, being affect by all the tested pharmaceutical compounds although at different degrees. Hydrogenotrophic methanogens were not affected by any concentration, indicating their lower sensitivity to these compounds when compared to acetoclasts and acetogens.e Portuguese Foundation for Science and Technology (FCT) under the scope of the strategic funding of UID/BIO/04469/2019 unit and BioTecNorte operation (NORTE-01-0145-FEDER-000004) funded by the European Regional Development Fund under the scope of Norte2020 - Programa Operacional Regional do Norte. Ana Rita Silva holds a Grant from FCT, reference SFRH/BD/131905/2017info:eu-repo/semantics/publishedVersio

Computational Design of a PDZ Domain Peptide Inhibitor that Rescues CFTR Activity

The cystic fibrosis transmembrane conductance regulator (CFTR) is an epithelial chloride channel mutated in patients with cystic fibrosis (CF). The most prevalent CFTR mutation, ΔF508, blocks folding in the endoplasmic reticulum. Recent work has shown that some ΔF508-CFTR channel activity can be recovered by pharmaceutical modulators (“potentiators” and “correctors”), but ΔF508-CFTR can still be rapidly degraded via a lysosomal pathway involving the CFTR-associated ligand (CAL), which binds CFTR via a PDZ interaction domain. We present a study that goes from theory, to new structure-based computational design algorithms, to computational predictions, to biochemical testing and ultimately to epithelial-cell validation of novel, effective CAL PDZ inhibitors (called “stabilizers”) that rescue ΔF508-CFTR activity. To design the “stabilizers”, we extended our structural ensemble-based computational protein redesign algorithm to encompass protein-protein and protein-peptide interactions. The computational predictions achieved high accuracy: all of the top-predicted peptide inhibitors bound well to CAL. Furthermore, when compared to state-of-the-art CAL inhibitors, our design methodology achieved higher affinity and increased binding efficiency. The designed inhibitor with the highest affinity for CAL (kCAL01) binds six-fold more tightly than the previous best hexamer (iCAL35), and 170-fold more tightly than the CFTR C-terminus. We show that kCAL01 has physiological activity and can rescue chloride efflux in CF patient-derived airway epithelial cells. Since stabilizers address a different cellular CF defect from potentiators and correctors, our inhibitors provide an additional therapeutic pathway that can be used in conjunction with current methods

High Differentiation among Eight Villages in a Secluded Area of Sardinia Revealed by Genome-Wide High Density SNPs Analysis

To better design association studies for complex traits in isolated populations it's important to understand how history and isolation moulded the genetic features of different communities. Population isolates should not “a priori” be considered homogeneous, even if the communities are not distant and part of a small region. We studied a particular area of Sardinia called Ogliastra, characterized by the presence of several distinct villages that display different history, immigration events and population size. Cultural and geographic isolation characterized the history of these communities. We determined LD parameters in 8 villages and defined population structure through high density SNPs (about 360 K) on 360 unrelated people (45 selected samples from each village). These isolates showed differences in LD values and LD map length. Five of these villages show high LD values probably due to their reduced population size and extreme isolation. High genetic differentiation among villages was detected. Moreover population structure analysis revealed a high correlation between genetic and geographic distances. Our study indicates that history, geography and biodemography have influenced the genetic features of Ogliastra communities producing differences in LD and population structure. All these data demonstrate that we can consider each village an isolate with specific characteristics. We suggest that, in order to optimize the study design of complex traits, a thorough characterization of genetic features is useful to identify the presence of sub-populations and stratification within genetic isolates

A922 Sequential measurement of 1 hour creatinine clearance (1-CRCL) in critically ill patients at risk of acute kidney injury (AKI)

Meeting abstrac

Changes in the composition of the RNA virome mark evolutionary transitions in green plants

Background: The known plant viruses mostly infect angiosperm hosts and have RNA or small DNA genomes. The only other lineage of green plants with a relatively well-studied virome, unicellular chlorophyte algae, is mostly infected by viruses with large DNA genomes. Thus RNA viruses and small DNA viruses seem to completely displace large DNA virus genomes in late branching angiosperms. To understand better the expansion of RNA viruses in the taxonomic span between algae and angiosperms, we analyzed the transcriptomes of 66 non-angiosperm plants characterized by the 1000 Plants Genomes Project. Results: We found homologs of virus RNA-dependent RNA polymerases in 28 non-angiosperm plant species, including algae, mosses, liverworts (Marchantiophyta), hornworts (Anthocerotophyta), lycophytes, a horsetail Equisetum, and gymnosperms. Polymerase genes in algae were most closely related to homologs from double-stranded RNA viruses leading latent or persistent lifestyles. Land plants, in addition, contained polymerases close to the homologs from single-stranded RNA viruses of angiosperms, capable of productive infection and systemic spread. For several polymerases, a cognate capsid protein was found in the same library. Another virus hallmark gene family, encoding the 30 K movement proteins, was found in lycophytes and monilophytes but not in mosses or algae. Conclusions: The broadened repertoire of RNA viruses suggests that colonization of land and growth in anatomical complexity in land plants coincided with the acquisition of novel sets of viruses with different strategies of infection and reproduction.We thank the colleagues at the 1000 Plant Genomes Project for helping us to access the transcriptomes used in this study via the iPlant Collaborative. We are grateful to Javier Forment (IBMCP-CSIC), Vincent Lefort (PhyML), and the E-Biothon team (E-Biothon platform is supported by CNRS, IBM, INRIA, l'Institut Francais de Bioinformatique and SysFera) for expert help with high-performance computing; to Yuri Wolf, Jan Kreuze, Eddie Holmes, and Mang Shi for sharing sequence data and alignments; to Sejo Sabanadzovic, Jan Kreuze, and the anonymous reviewers for helpful virtual discussions and critical remarks; and to Natalia Mushegian for technical assistance. SFF was supported by grants BFU2015-65037P from Spain Ministry of Economy and Competitiveness and PROMETEOII/2014/021 from Generalitat Valenciana. ARM is a Program Director at the US National Science Foundation (NSF); his work on this project was supported by the NSF Independent Research and Development Program, but the statements and opinions expressed herein are made in the personal capacity and do not constitute the endorsement by NSF or the government of the United States.Mushegian, A.; Shipunov, A.; Elena Fito, SF. (2016). Changes in the composition of the RNA virome mark evolutionary transitions in green plants. BMC Biology. 14(68):1-14. https://doi.org/10.1186/s12915-016-0288-8S1141468Roossinck MJ. Plant virus metagenomics: biodiversity and ecology. Annu Rev Genet. 2012;46:357–67.Koonin EV, Dolja VV, Krupovic M. Origins and evolution of viruses of eukaryotes: The ultimate modularity. Virology. 2015;479-480:2–25.Yamada T, Onimatsu H, Van Etten JL. Chlorella viruses. Adv Virus Res. 2006;66:293–336.Van Etten JL, Dunigan DD. Chloroviruses: not your everyday plant virus. Trends Plant Sci. 2012;17:1–8.Zhang T, Jiang Y, Dong W. A novel monopartite dsRNA virus isolated from the phytopathogenic fungus Ustilaginoidea virens and ancestrally related to a mitochondria-associated dsRNA in the green alga Bryopsis. Virology. 2014;462:227–35.Wilson WH, Van Etten JL, Allen MJ. The Phycodnaviridae: the story of how tiny giants rule the world. Curr Top Microbiol Immunol. 2009;328:1–42.Iyer LM, Balaji S, Koonin EV, Aravind L. Evolutionary genomics of nucleo-cytoplasmic large DNA viruses. Virus Res. 2006;117:156–84.Colson P, De Lamballerie X, Yutin N, Asgari S, Bigot Y, Bideshi DK, et al. “Megavirales”, a proposed new order for eukaryotic nucleocytoplasmic large DNA viruses. Arch Virol. 2013;158:2517–21.Gibbs AJ, Torronen M, Mackenzie AM, Wood 2nd JT, Amstrong JS, Kondo H, et al. The enigmatic genome of Chara australis virus. J Gen Virol. 2011;92:2679–90.Valverde RA, Sabanadzovic S. A novel plant virus with unique properties infecting Japanese holly fern. J Gen Virol. 2009;90:42–9.Han SS, Karasev AV, Ieki H, Iwanami T. Nucleotide sequence and taxonomy of Cycas necrotic stunt virus. Brief report. Arch Virol. 2002;147:2207–14.Lockhart B, Fetzer JL, Olszewski NE. Preliminary characterization of Cycad leaf necrosis virus, the first badnavirus identified in cycads. Phytopathology. 2006;96:S70.Mushegian AR, Elena SF. Evolution of plant virus movement proteins from the 30 K superfamily and of their homologs integrated in plant genomes. Virology. 2015;476:304–15.Maumus F, Epert A, Nogué F, Blanc G. Plant genomes enclose footprints of past infections by giant virus relatives. Nat Commun. 2014;5:4268.Wickett NJ, Mirarab S, Nguyen N, Warnow T, Carpenter E, Matasci N, et al. Phylotranscriptomic analysis of the origin and early diversification of land plants. Proc Natl Acad Sci USA. 2014;111:E4859–68.Merchant N, Lyons E, Goff S, Vaughn M, Ware D, Micklos D, et al. The iPlant collaborative: cyberinfrastructure for enabling data to discovery for the life sciences. PLoS Biol. 2016;14:e1002342.Becker B, Marin B. Streptophyte algae and the origin of embryophytes. Ann Bot. 2009;103:999–1004.Koonin EV, Dolja VV. A virocentric perspective on the evolution of life. Curr Op Virol. 2013;3:546–57.Matasci N, Huang LH, Yan Z, Carpenter EJ, Wickett NJ, Mirarab S, et al. Data access for the 1000 plants (1KP) project. Gigascience. 2014;3:17.Makarova KS, Aravind L, Grishin NV, Rogozin IB, Koonin EV. A DNA repair system specific for thermophilic Archaea and bacteria predicted by genomic context analysis. Nucleic Acids Res. 2002;30:482–96.Majumdar I, Kinch LN, Grishin NV. A database of domain definitions for proteins with complex interdomain geometry. PLoS ONE. 2009;4:e5084.Černý J, Černá Bolfíková B, Zanotto PMA, Grubhoffer L, Růžek D. A deep phylogeny of viral and cellular right-hand polymerases. Infec Genet Evol. 2015;36:275–86.Iyer LM, Koonin EV, Aravind L. Evolutionary connection between the catalytic subunits of DNA-dependent RNA polymerases and eukaryotic RNA-dependent RNA polymerases and the origin of RNA polymerases. BMC Struct Biol. 2003;3:1.Altschul SF, Madden TL, Schäffer AA, Zhang J, Zhang Z, Miller W, et al. Gapped BLAST and PSI-BLAST: a new generation of protein database search programs. Nucleic Acids Res. 1997;25:3389–402.Koga R, Horiuchi H, Fukuhara T. Double-stranded RNA replicons associated with chloroplasts of a green alga, Bryopsis cinicola. Plant Mol Biol. 2003;51:991–9.Jablonski SA, Morrow CD. Mutation of the aspartic acid residues of the GDD sequence motif of poliovirus RNA-dependent RNA polymerase results in enzymes with altered metal ion requirements for activity. J Virol. 1995;69:1532–9.Morin B, Whelan SPJ. La protéine L des Mononegavirales. Virologie. 2012;16:258–68.Liang B, Li Z, Jenni S, Rahmeh AA, Morin BM, Grant T, et al. Structure of the L protein of Vesicular stomatitis virus from electron cryomicroscopy. Cell. 2015;162:314–27.Chabannes M, Iskra-Caruana ML. Endogenous pararetroviruses – a reservoir of virus infection in plants. Curr Opin Virol. 2013;3:615–20.Bousios A, Darzentas N. Sirevirus LTR retrotransposons: phylogenetic misconceptions in the plant world. Mob DNA. 2013;4:9.Bertsch C, Beuve M, Dolja VV, Wirth M, Pelsy F, Herrbach E, et al. Retention of the virus-derived sequences in the nuclear genome of grapevine as a potential pathway to virus resistance. Biol Direct. 2009;4:21.Roossinck MJ. Lifestyle of plant viruses. Philos Trans R Soc B. 2010;365:1899–905.Nibert ML, Ghabrial SA, Maiss E, Lesker T, Vainio EJ, Jiang D, et al. Taxonomic reorganization of family Partitiviridae and other recent progress in partitivirus research. Virus Res. 2014;188:128–41.Koonin EV, Wolf YI, Nagasaki K, Dolja VV. The Big Bang of picorna-like virus evolution antedates the radiation of eukaryotic supergroups. Nat Rev Microbiol. 2008;6:925–39.Poch O, Sauvaget I, Delarue M, Tordo N. Identification of four conserved motifs among the RNA-dependent polymerase encoding elements. EMBO J. 1989;8:3867–74.Guindon S, Dufayard JF, Lefort V, Anisimova M, Hordijk W, Gascuel O. New algorithms and methods to estimate maximum-likelihood phylogenies: assessing the performance of PhyML 3.0. Syst Biol. 2010;59:307–21.Letunic I, Bork P. Interactive tree of life (iTOL) v3: an online tool for the display and annotation of phylogenetic and other trees. Nucleic Acids Res. 2016;44(W1):W242.Li CX, Shi M, Tian JH, Lin XD, Kang YJ, Chen LJ, et al. Unprecedented genomic diversity of RNA viruses in arthropods reveals the ancestry of negative-sense RNA viruses. eLife. 2015;29:4.Yutin N, Wolf YI, Raoult D, Koonin EV. Eukaryotic large nucleo-cytoplasmic DNA viruses: clusters of orthologous genes and reconstruction of viral genome evolution. Virol J. 2009;6:223.Liu H, Fu Y, Xie J, Cheng J, Ghabrial SA, Li G, et al. Evolutionary genomics of mycovirus-related dsRNA viruses reveals cross-family horizontal gene transfer and evolution of diverse viral lineages. BMC Evol Biol. 2012;12:91.Atsatt PR, Whiteside MD. Novel symbiotic protoplasts formed by endophytic fungi explain their hidden existence, lifestyle switching, and diversity within the plant kingdom. PLoS ONE. 2014;9:e95266.Hom EF, Murray AW. Plant-fungal ecology. Niche engineering demonstrates a latent capacity for fungal-algal mutualism. Science. 2014;345:94–8.Magallón S, Hilu KW, Quandt D. Land plant evolutionary timeline: gene effects are secondary to fossil constraints in relaxed clock estimation of age and substitution rates. Am J Bot. 2013;100:556–73.Johnson MT, Carpenter EJ, Tian Z, Bruskiewich R, Burris JN, Carrigan CT, et al. Evaluating methods for isolating total RNA and predicting the success of sequencing phylogenetically diverse plant transcriptomes. PLoS One. 2012;7:e50226.Kreuze J. siRNA deep sequencing and assembly: piecing together viral infections. In: Gullino ML, Bonants PJM, editors. Detection and diagnostics of plant pathogens. Dordrecht: Springer; 2014. p. 21–38.Chávez Montes RA, de Fátima R-CF, De Paoli E, Accerbi M, Rymarquis LA, Mahalingam G, et al. Sample sequencing of vascular plants demonstrates widespread conservation and divergence of microRNAs. Nat Commun. 2014;5:3722.Marchler-Bauer A, Derbyshire MK, Gonzales NR, Lu S, Chitsaz F, Geer LY, et al. CDD: NCBI’s conserved domain database. Nucl Acids Res. 2015;43:D222–6.Edgar RC. MUSCLE: a multiple sequence alignment method with reduced time and space complexity. BMC Bioinformatics. 2004;5:113.Söding J, Biegert A, Lupas AN. The HHpred interactive server for protein homology detection and structure prediction. Nucleic Acids Res. 2015;33:W244–8.Le SQ, Gascuel O. An improved general amino acid replacement matrix. Mol Biol Evol. 2008;25(7):1307–20.Daydé M, Depardon B, Franc A, Gibrat JF, Guillier R, Karami Y, Sutter F, Taddese B, Chabbert M, Thérond S. E-Biothon: an experimental platform for bioinformatics. 2015 Computer Science and Information Technologies (CSIT) 2015;1-4.Okuno K, Hama T, Takeshita M, Furuya N, Takanami Y. New potyvirus isolated from Cryptotaenia japonica. J Gen Plant Pathol. 2003;69:138–42

The ERK and JNK pathways in the regulation of metabolic reprogramming.

Most tumor cells reprogram their glucose metabolism as a result of mutations in oncogenes and tumor suppressors, leading to the constitutive activation of signaling pathways involved in cell growth. This metabolic reprogramming, known as aerobic glycolysis or the Warburg effect, allows tumor cells to sustain their fast proliferation and evade apoptosis. Interfering with oncogenic signaling pathways that regulate the Warburg effect in cancer cells has therefore become an attractive anticancer strategy. However, evidence for the occurrence of the Warburg effect in physiological processes has also been documented. As such, close consideration of which signaling pathways are beneficial targets and the effect of their inhibition on physiological processes are essential. The MAPK/ERK and MAPK/JNK pathways, crucial for normal cellular responses to extracellular stimuli, have recently emerged as key regulators of the Warburg effect during tumorigenesis and normal cellular functions. In this review, we summarize our current understanding of the roles of the ERK and JNK pathways in controlling the Warburg effect in cancer and discuss their implication in controlling this metabolic reprogramming in physiological processes and opportunities for targeting their downstream effectors for therapeutic purposes.Brunel Research Initiative & Enterprise Fund, Brunel University of London (to CB), Kay Kendall Leukemia Fund (KKL443) (to CB), 250 Great Minds Fellowship, University of Leeds (to SP), AMMF Cholangiocarcinoma Charity (to SP and PMC), and Bloodwise (17014) (to SP and CB)