Hydroclimate variability during the last 2700 years based on stalagmite multi-proxy records in the central-western Mediterranean

This study presents the first high-resolution speleothem-based hydrological reconstruction for much of the last 2.7 kyr in the central-western Mediterranean. The paleohydrological information comes from a combination of five U-Th dated stalagmites from two Mallorca island caves. Interpretations are based on high-resolution records of d18O, d13C and trace element analyses combined with information from mineralogical X-ray diffraction, fabrics and morphological features, and cave monitoring data. None of the studied stalagmites cover the whole 2.7 kyr period but they provide sufficient overlap to replicate most of the discussed climatic intervals with the exception of the Medieval Climate Anomaly (MCA), which is represented by a hiatus. Taking into account the results of five years farmed calcite collected in glass plates and cave environmental parameters, we argue that main patterns in the stalagmite geochemical records are mostly controlled by changing rates of prior calcite precipitation (PCP) that respond to hydrological changes in the region. We apply a principal component analysis to the stalagmite geochemical data set and a composite d18O record to obtain a robust regional hydrological record. This record supports wet conditions for the early Roman Period (RP), the first half of the Early Middle Ages (EMA) and the Little Ice Age (LIA), and drier conditions for the late RP, the late EMA and the entire MCA. These results are discussed in the context of other climatic and oceanographic records from the region including paleo North Atlantic Oscillation (NAO) records. This ocean-atmosphere approach suggests complex non-stationary climate patterns for the last 2.7 kyr, including the occurrence of both wetwarm and wet-cold intervals and underlying the complex interaction of factors controlling climate evolution in the region. Overall, positive (negative) NAO phases appear coincident with drier (wetter) conditions for all the examined period at decadal time-scale

Crowdsourced assessment of common genetic contribution to predicting anti-TNF treatment response in rheumatoid arthritis

Correction: vol 7, 13205, 2016, doi:10.1038/ncomms13205Rheumatoid arthritis (RA) affects millions world-wide. While anti-TNF treatment is widely used to reduce disease progression, treatment fails in Bone-third of patients. No biomarker currently exists that identifies non-responders before treatment. A rigorous community-based assessment of the utility of SNP data for predicting anti-TNF treatment efficacy in RA patients was performed in the context of a DREAM Challenge (http://www.synapse.org/RA_Challenge). An open challenge framework enabled the comparative evaluation of predictions developed by 73 research groups using the most comprehensive available data and covering a wide range of state-of-the-art modelling methodologies. Despite a significant genetic heritability estimate of treatment non-response trait (h(2) = 0.18, P value = 0.02), no significant genetic contribution to prediction accuracy is observed. Results formally confirm the expectations of the rheumatology community that SNP information does not significantly improve predictive performance relative to standard clinical traits, thereby justifying a refocusing of future efforts on collection of other data.Peer reviewe

Viral replication modes in single-peak fitness landscapes: A dynamical systems analysis

Positive-sense, single-stranded RNA viruses are important pathogens infecting almost all types of organisms. Experimental evidence from distributions of mutations and from viral RNA amplification suggest that these pathogens may follow different RNA replication modes, ranging from the stamping machine replication (SMR) to the geometric replication (GR) mode. Although previous theoretical work has focused on the evolutionary dynamics of RNA viruses amplifying their genomes with different strategies, little is known in terms of the bifurcations and transitions involving the so-called error threshold (mutation-induced dominance of mutants) and lethal mutagenesis (extinction of all sequences due to mutation accumulation and demographic stochasticity). Here we analyze a dynamical system describing the intracellular amplification of viral RNA genomes evolving on a single-peak fitness landscape focusing on three cases considering neutral, deleterious, and lethal mutants. We analytically derive the critical mutation rates causing lethal mutagenesis and error threshold, governed by transcritical bifurcations that depend on parameters α (parameter introducing the mode of replication), replicative fitness of mutants (k1), and on the spontaneous degradation rates of the sequences (ϵ). Our results relate the error catastrophe with lethal mutagenesis in a model with continuous populations of viral genomes. The former case involves dominance of the mutant sequences, while the latter, a deterministic extinction of the viral RNAs during replication due to increased mutation. For the lethal case the critical mutation rate involving lethal mutagenesis is µc = 1−ε √α. Here, the SMR involves lower critical mutation rates, being the system more robust to lethal mutagenesis replicating closer to the GR mode. This result is also found for the neutral and deleterious cases, but for these later cases lethal mutagenesis can shift to the error threshold once the replication mode surpasses a threshold given by √α = €/k1.The research leading to these results has received funding from “la Caixa” Foundation and from a Ministerio de Economia y Competitividad grant awarded to the Barcelona Graduate School of Mathematics (BGSMath) under the “María de Maeztu” Program (grant MDM-2014-0445). JS has been also funded by a Ramón y Cajal Fellowship (RYC-2017-22243). JS and TA have been partially funded by the CERCA Programme of the Generalitat de Catalunya. JTL has been partially supported by the MINECO/FEDER grant MTM2015-65715-P, by the Catalan grant 2014SGR-504 and by the Russian Scientific Foundation grants 14-41-00044 and 14-12-00811. TA is also supported by the AGAUR (grant 2014SGR-1307) and the MINECO (grant MTM2015-71509-C2-1-R). SFE has been supported by MINECO-FEDER grant BFU2015-65037-P and by Generalitat Valenciana grant PROMETEOII/2014/021.Peer reviewe

Viral replication modes in single-peak fitness landscapes: A dynamical systems analysis

Positive-sense, single-stranded RNA viruses are important pathogens infecting almost all types of organ- isms. Experimental evidence from distributions of mutations and from viral RNA amplification suggest that these pathogens may follow different RNA replication modes, ranging from the stamping machine replication (SMR) to the geometric replication (GR) mode. Although previous theoretical work has focused on the evolutionary dynamics of RNA viruses amplifying their genomes with different strategies, little is known in terms of the bifurcations and transitions involving the so-called error threshold (mutation- induced dominance of mutants) and lethal mutagenesis (extinction of all sequences due to mutation ac- cumulation and demographic stochasticity). Here we analyze a dynamical system describing the intracel- lular amplification of viral RNA genomes evolving on a single-peak fitness landscape focusing on three cases considering neutral, deleterious, and lethal mutants. We analytically derive the critical mutation rates causing lethal mutagenesis and error threshold, governed by transcritical bifurcations that depend on parameters α(parameter introducing the mode of replication), replicative fitness of mutants ( k 1 ), and on the spontaneous degradation rates of the sequences ( ). Our results relate the error catastrophe with lethal mutagenesis in a model with continuous populations of viral genomes. The former case involves dominance of the mutant sequences, while the latter, a deterministic extinction of the viral RNAs during replication due to increased mutation. For the lethal case the critical mutation rate involving lethal mu- tagenesis is μc = 1 −ε/ √ α. Here, the SMR involves lower critical mutation rates, being the system more robust to lethal mutagenesis replicating closer to the GR mode. This result is also found for the neutral and deleterious cases, but for these later cases lethal mutagenesis can shift to the error threshold once the replication mode surpasses a threshold given by √ α= /k 1