The acceleration of superrotation in simulated hot Jupiter atmospheres

This is the author accepted manuscript. The final version is available from the publisher via the DOI in this recordContext. Atmospheric superrotating flows at the equator are a nearly ubiquitous result when conducting simulations of hot Jupiters. One theory explaining how this zonally-coherent flow reaches equilibrium has already been developed in the literature. This understanding, however, relies on the existence of either an initial superrotating flow or a sheared flow, coupled with a slow evolution that permits a linear steady state to be reached. Aims. A consistent physical understanding of superrotation is needed for arbitrary drag and radiative timescales, along with the relevance of taking linear steady states into account, needs to be assessed. Methods. We obtained an analytical expression for the structure, frequency, and decay rate of propagating waves in hot Jupiter atmospheres around a state at rest in the 2D shallow-water β–plane limit. We solved this expression numerically and confirmed the robustness of our results with a 3D linear wave algorithm. We then compared it with 3D simulations of hot Jupiter atmospheres and studied the nonlinear momentum fluxes. Results. We show that under strong day-night heating, the dynamics do not transit through a linear steady state when starting from an initial atmosphere in solid body rotation. We further demonstrate that non–linear effects favor the initial spin-up of superrotation and that acceleration due to the vertical component of the eddy–momentum flux is critical to the initial development of superrotation . Conclusions. We describe the initial phases of the acceleration of superrotation, including the consideration of differing radiative and drag timescales, and we conclude that eddy-momentum-driven superrotating equatorial jets are robust, physical phenomena in simulations of hot Jupiter atmospheres.Leverhulme TrustScience and Technology Facilities Counci

Engineering of Three-Finger Fold Toxins Creates Ligands with Original Pharmacological Profiles for Muscarinic and Adrenergic Receptors

Protein engineering approaches are often a combination of rational design and directed evolution using display technologies. Here, we test “loop grafting,” a rational design method, on three-finger fold proteins. These small reticulated proteins have exceptional affinity and specificity for their diverse molecular targets, display protease-resistance, and are highly stable and poorly immunogenic. The wealth of structural knowledge makes them good candidates for protein engineering of new functionality. Our goal is to enhance the efficacy of these mini-proteins by modifying their pharmacological properties in order to extend their use in imaging, diagnostics and therapeutic applications. Using the interaction of three-finger fold toxins with muscarinic and adrenergic receptors as a model, chimeric toxins have been engineered by substituting loops on toxin MT7 by those from toxin MT1. The pharmacological impact of these grafts was examined using binding experiments on muscarinic receptors M1 and M4 and on the α1A-adrenoceptor. Some of the designed chimeric proteins have impressive gain of function on certain receptor subtypes achieving an original selectivity profile with high affinity for muscarinic receptor M1 and α1A-adrenoceptor. Structure-function analysis supported by crystallographic data for MT1 and two chimeras permits a molecular based interpretation of these gains and details the merits of this protein engineering technique. The results obtained shed light on how loop permutation can be used to design new three-finger proteins with original pharmacological profiles

Comprehensive evaluation of Toxoplasma gondii VEG and Neospora caninum LIV genomes with tachyzoite stage transcriptome and proteome defines novel transcript features.

Toxoplasma gondii is an important protozoan parasite that infects all warm-blooded animals and causes opportunistic infections in immuno-compromised humans. Its closest relative, Neospora caninum, is an important veterinary pathogen that causes spontaneous abortion in livestock. Comparative genomics of these two closely related coccidians has been of particular interest to identify genes that contribute to varied host cell specificity and disease. Here, we describe a manual evaluation of these genomes based on strand-specific RNA sequencing and shotgun proteomics from the invasive tachyzoite stages of these two parasites. We have corrected predicted structures of over one third of the previously annotated gene models and have annotated untranslated regions (UTRs) in over half of the predicted protein-coding genes. We observe distinctly long UTRs in both the organisms, almost four times longer than other model eukaryotes. We have also identified a putative set of cis-natural antisense transcripts (cis-NATs) and long intergenic non-coding RNAs (lincRNAs). We have significantly improved the annotation quality in these genomes that would serve as a manually curated dataset for Toxoplasma and Neospora research communities

A randomised phase II multicentre trial of irinotecan (CPT-11) using four different schedules in patients with metastatic colorectal cancer

The purpose of this phase II trial was to compare the efficacy, safety and pharmacokinetics of four irinotecan schedules for the treatment of metastatic colorectal cancer. In total, 174 5-fluorouracil pretreated patients were randomised to: arm A (n=41), 350 mg m(-2) irinotecan as a 90-min i.v. infusion q3 weeks; arm B (n=38), 125 mg m(-2) irinotecan as a 90-min i.v. infusion weekly x 4 weeks q6 weeks; arm C (n=46), 250 mg m(-2) irinotecan as a 90-min i.v. infusion q2 weeks; or arm D (n=49), 10 mg m(-2) day(-1) irinotecan as a 14-day continuous infusion q3 weeks. No significant differences in efficacy across the four arms were observed, although a shorter time to treatment failure was noted for arm D (1.7 months; P=0.02). Overall response rates were in the range 5-11%. Secondary end points included median survival (6.4-9.4 months), and time to progression (2.7-3.8 months) and treatment failure (1.7-3.2 months). Similarly, there were no significant differences in the incidence of grade 3-4 toxicities, although the toxicity profile between arms A, B, and C and D did differ. Generally, significantly less haematologic toxicity, alopecia and cholinergic syndrome were observed in arm D; however, there was a trend for increased gastrointestinal toxicity. Irinotecan is an effective and safe second-line treatment for colorectal cancer. The schedules examined yielded equivalent results, indicating that there is no advantage of the prolonged vs short infusion schedule

The reference human nuclear mitochondrial sequences compilation validated and implemented on the UCSC genome browser

<p>Abstract</p> <p>Background</p> <p>Eukaryotic nuclear genomes contain fragments of mitochondrial DNA called NumtS (Nuclear mitochondrial Sequences), whose mode and time of insertion, as well as their functional/structural role within the genome are debated issues. Insertion sites match with chromosomal breaks, revealing that micro-deletions usually occurring at non-homologous end joining <it>loci </it>become reduced in presence of NumtS. Some NumtS are involved in recombination events leading to fragment duplication. Moreover, NumtS are polymorphic, a feature that renders them candidates as population markers. Finally, they are a cause of contamination during human mtDNA sequencing, leading to the generation of false heteroplasmies.</p> <p>Results</p> <p>Here we present RHNumtS.2, the most exhaustive human NumtSome catalogue annotating 585 NumtS, 97% of which were here validated in a European individual and in HapMap samples. The NumtS complete dataset and related features have been made available at the UCSC Genome Browser. The produced sequences have been submitted to INSDC databases. The implementation of the RHNumtS.2 tracks within the UCSC Genome Browser has been carried out with the aim to facilitate browsing of the NumtS tracks to be exploited in a wide range of research applications.</p> <p>Conclusions</p> <p>We aimed at providing the scientific community with the most exhaustive overview on the human NumtSome, a resource whose aim is to support several research applications, such as studies concerning human structural variation, diversity, and disease, as well as the detection of false heteroplasmic mtDNA variants. Upon implementation of the NumtS tracks, the application of the BLAT program on the UCSC Genome Browser has now become an additional tool to check for heteroplasmic artefacts, supported by data available through the NumtS tracks.</p

Complementarity and Discriminatory Power of Genotype and Otolith Shape in Describing the Fine-Scale Population Structure of an Exploited Fish, the Common Sole of the Eastern English Channel

Marine organisms show population structure at a relatively fine spatial scale, even in open habitats. The tools commonly used to assess subtle patterns of connectivity have diverse levels of resolution and can complement each other to inform on population structure. We assessed and compared the discriminatory power of genetic markers and otolith shape to reveal the population structure on evolutionary and ecological time scales of the common sole (Solea solea), living in the Eastern English Channel (EEC) stock off France and the UK. First, we genotyped fish with Single Nucleotide Polymorphisms to assess population structure at an evolutionary scale. Then, we tested for spatial segregation of the subunits using otolith shape as an integrative tracer of life history. Finally, a supervised machine learning framework was applied to genotypes and otolith phenotypes to probabilistically assign adults to subunits and assess the discriminatory power of each approach. Low but significant genetic differentiation was found among subunits. Moreover, otolith shape appeared to vary spatially, suggesting spatial population structure at fine spatial scale. However, results of the supervised discriminant analyses failed to discriminate among subunits, especially for otolith shape. We suggest that the degree of population segregation may not be strong enough to allow for robust fish assignments. Finally, this study revealed a weak yet existing metapopulation structure of common sole at the fine spatial scale of the EEC based on genotypes and otolith shape, with one subunit being more isolated. Our study argues for the use of complementary tracers to investigate marine population structure