Developmental Restriction of Retrotransposition Activated in Arabidopsis by Environmental Stress

Retrotransposons (RTs) may rapidly increase in copy number due to periodic bursts of transposition. Such bursts are mutagenic and thus potentially deleterious. However, certain transposition-induced gain-of-function or regulatory mutations may be of selective advantage. How an optimal balance between these opposing effects arises is not well characterized. Here, we studied transposition bursts of a heat-activated retrotransposon family in Arabidopsis. We recorded a high inter- and intra-plant variation in the number and chromosomal position of new insertions, which usually did not affect plant fertility and were equally well transmitted through male and female gametes, even though 90% of them were within active genes. We found that a highly heterogeneous distribution of these new retroelement copies result from a combination of two mechanisms, of which the first prevents multiple transposition bursts in a given somatic cell lineage that later contributes to differentiation of gametes, and the second restricts the regulatory influence of new insertions towards neighbouring chromosomal DNA. As a whole, such regulatory characteristics of this family of RTs ensure its rapid but stepwise accumulation in plant populations experiencing transposition bursts accompanied by high diversity of chromosomal sites harbouring new RT insertions.This work was supported by European Research Council (EVOBREED) [322621] and Gatsby Fellowship [AT3273/GLE]

Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease

Background: Experimental and clinical data suggest that reducing inflammation without affecting lipid levels may reduce the risk of cardiovascular disease. Yet, the inflammatory hypothesis of atherothrombosis has remained unproved. Methods: We conducted a randomized, double-blind trial of canakinumab, a therapeutic monoclonal antibody targeting interleukin-1β, involving 10,061 patients with previous myocardial infarction and a high-sensitivity C-reactive protein level of 2 mg or more per liter. The trial compared three doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneously every 3 months) with placebo. The primary efficacy end point was nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. RESULTS: At 48 months, the median reduction from baseline in the high-sensitivity C-reactive protein level was 26 percentage points greater in the group that received the 50-mg dose of canakinumab, 37 percentage points greater in the 150-mg group, and 41 percentage points greater in the 300-mg group than in the placebo group. Canakinumab did not reduce lipid levels from baseline. At a median follow-up of 3.7 years, the incidence rate for the primary end point was 4.50 events per 100 person-years in the placebo group, 4.11 events per 100 person-years in the 50-mg group, 3.86 events per 100 person-years in the 150-mg group, and 3.90 events per 100 person-years in the 300-mg group. The hazard ratios as compared with placebo were as follows: in the 50-mg group, 0.93 (95% confidence interval [CI], 0.80 to 1.07; P = 0.30); in the 150-mg group, 0.85 (95% CI, 0.74 to 0.98; P = 0.021); and in the 300-mg group, 0.86 (95% CI, 0.75 to 0.99; P = 0.031). The 150-mg dose, but not the other doses, met the prespecified multiplicity-adjusted threshold for statistical significance for the primary end point and the secondary end point that additionally included hospitalization for unstable angina that led to urgent revascularization (hazard ratio vs. placebo, 0.83; 95% CI, 0.73 to 0.95; P = 0.005). Canakinumab was associated with a higher incidence of fatal infection than was placebo. There was no significant difference in all-cause mortality (hazard ratio for all canakinumab doses vs. placebo, 0.94; 95% CI, 0.83 to 1.06; P = 0.31). Conclusions: Antiinflammatory therapy targeting the interleukin-1β innate immunity pathway with canakinumab at a dose of 150 mg every 3 months led to a significantly lower rate of recurrent cardiovascular events than placebo, independent of lipid-level lowering. (Funded by Novartis; CANTOS ClinicalTrials.gov number, NCT01327846.

Molecular signatures of the rediae, cercariae and adult stages in the complex life cycles of parasitic flatworms (Digenea: Psilostomatidae)

BACKGROUND: Parasitic flatworms (Trematoda: Digenea) represent one of the most remarkable examples of drastic morphological diversity among the stages within a life cycle. Which genes are responsible for extreme differences in anatomy, physiology, behavior, and ecology among the stages? Here we report a comparative transcriptomic analysis of parthenogenetic and amphimictic generations in two evolutionary informative species of Digenea belonging to the family Psilostomatidae. METHODS: In this study the transcriptomes of rediae, cercariae and adult worm stages of Psilotrema simillimum and Sphaeridiotrema pseudoglobulus, were sequenced and analyzed. High-quality transcriptomes were generated, and the reference sets of protein-coding genes were used for differential expression analysis in order to identify stage-specific genes. Comparative analysis of gene sets, their expression dynamics and Gene Ontology enrichment analysis were performed for three life stages within each species and between the two species.RESULTS: Reference transcriptomes for P. simillimum and S. pseudoglobulus include 21,433 and 46,424 sequences, respectively. Among 14,051 orthologous groups (OGs), 1354 are common and specific for two analyzed psilostomatid species, whereas 13 and 43 OGs were unique for P. simillimum and S. pseudoglobulus, respectively. In contrast to P. simillimum, where more than 60% of analyzed genes were active in the redia, cercaria and adult worm stages, in S. pseudoglobulus less than 40% of genes had such a ubiquitous expression pattern. In general, 7805 (36.41%) and 30,622 (65.96%) of genes were preferentially expressed in one of the analyzed stages of P. simillimum and S. pseudoglobulus, respectively. In both species 12 clusters of co-expressed genes were identified, and more than a half of the genes belonging to the reference sets were included into these clusters. Functional specialization of the life cycle stages was clearly supported by Gene Ontology enrichment analysis.CONCLUSIONS: During the life cycles of the two species studied, most of the genes change their expression levels considerably, consequently the molecular signature of a stage is not only a unique set of expressed genes, but also the specific levels of their expression. Our results indicate unexpectedly high level of plasticity in gene regulation between closely related species. Transcriptomes of P. simillimum and S. pseudoglobulus provide high quality reference resource for future evolutionary studies and comparative analyses

noisyR: Enhancing biological signal in sequencing datasets by characterising random technical noise

High-throughput sequencing enables an unprecedented resolution in transcript quantification, at the cost of magnifying the impact of technical noise. The consistent reduction of random background noise to capture functionally meaningful biological signals is still challenging. Intrinsic sequencing variability introducing low-level expression variations can obscure patterns in downstream analyses. We introduce noisyR, a comprehensive noise filter to assess the variation in signal distribution and achieve an optimal information-consistency across replicates and samples; this selection also facilitates meaningful pattern recognition outside the background-noise range. noisyR is applicable to count matrices and sequencing data; it outputs samplespecific signal/noise thresholds and filtered expression matrices. We exemplify the effects of minimising technical noise on several datasets, across various sequencing assays: coding, non-coding RNAs and interactions, at bulk and single-cell level. An immediate consequence of filtering out noise is the convergence of predictions (differential-expression calls, enrichment analyses and inference of gene regulatory networks) across different approaches

Push and park: uma opção técnica no tratamento do ateroembolismo agudo dos membros inferiores Push and park: a technical option for the management of acute lower limb atheroembolism

A aterotrombose é uma doença multissistêmica associada a elevada morbidade e mortalidade. A manipulação das artérias com fios-guia ou cateteres pode gerar trauma mecânico, com conseqüente deslocamento de material ateromatoso da parede vascular. Um paciente de 82 anos, no qual uma ponte fêmoro-poplítea distal com veia safena in situ havia sido realizada por nós há 10 anos, apresentou dor, palidez, hipotermia, diminuição da sensibilidade e força do pé direito 6 horas após coronariografia com acesso pela artéria femoral direita (classe 2b de Rutherford). Arteriografia diagnóstica evidenciou perviedade do enxerto, com múltiplas irregularidades em seu terço distal, compatíveis com material ateroembólico, além de pobreza extrema de circulação distal. Optamos pela revascularização do membro inferior direito em caráter de urgência, associando técnicas convencionais a métodos endovasculares. Empregando a técnica de push and park, cruzamos a lesão ateroembólica com fio-guia e tratamos todo o eixo arterial acometido com manobras de angioplastia. O paciente apresentou boa evolução, boa perfusão distal, adequado enchimento capilar, eliminação da dor e melhora acentuada imediata do déficit motor e sensitivo.<br>Atherothrombosis is a multisystemic disease associated with high morbidity and mortality rates. Management of arteries with guide-wires or catheters may cause mechanical trauma, with consequent detachment of atheromatous material from the vascular wall. An 82-year-old patient, in whom a distal femoropopliteal in situ saphenous vein graft bypass had been performed 10 years before, presented with pain, pallor, hypothermia, loss of sensibility and motor activity on the right lower limb 6 hours after coronary angiography from the femoral artery (Rutherford class 2b). Arteriography demonstrated bypass patency, with multiple irregularities in its distal third, compatible with atheroembolic material, and very poor distal circulation. We indicated lower limb revascularization on an emergency basis, by both conventional and endovascular techniques. Using the "push and park" technique, the atheroembolic obstruction was crossed by guide-wire and the whole affected arterial axis was treated by angioplasty. The patient progressed well, with good distal perfusion, adequate capillary refill, relief of pain and immediate recovery of sensory and motor function

Improved atmospheric circulation over Europe by the new generation of CMIP6 earth system models

ABSTRACT: Global Climate Models (GCMs) generally exhibit significant biases in the representation of large-scale atmospheric circulation. Even after a sensible bias adjustment these errors remain and are inherited to some extent by the derived downscaling products, impairing the credibility of future regional projections. In this study we perform a process-based evaluation of state-of-the-art GCMs from CMIP5 and CMIP6, with a focus on the simulation of the synoptic climatological patterns having a most prominent effect on the European climate. To this aim, we use the Lamb Weather Type Classification (LWT, Lamb British isles weather types and a register of the daily sequence 736 of circulation patterns 1861-1971. METEOROL OFF, GEOPHYS MEM; 737 GB; DA 1972; NO 116; PP 1-85; BIBL 2P1/2, 1972), a subjective classification of circulation weather types constructed upon historical simulations of daily mean sea level pressure. Observational uncertainty has been taken into account by considering four different reanalysis products of varying characteristics. Our evaluation unveils an overall improvement of salient atmospheric circulation features consistent across observational references, although this is uneven across models and large frequency biases still remain for the main LWTs. Some CMIP6 models attain similar or even worse results than their CMIP5 counterparts, although in most cases consistent improvements have been found, demonstrating the ability of the new models to better capture key synoptic conditions. In light of the large differences found across models, we advocate for a careful selection of driving GCMs in downscaling experiments with a special focus on large-scale atmospheric circulation aspects.We acknowledge the World Climate Research Pro-gram’s Working Group on Coupled Modelling, which is responsible for CMIP, and we thank the climate modeling groups (listed in Table 1) 3538 J. A. Fernandez-Granja et al.1 3for producing and making available their model output. J.A.F., A.C and J.B. acknowledge funding from the Project INDECIS, part of Euro-pean Research Area for Climate Services Consortium (ERA4CS) with co-funding by the European Union Grant 690462. J.F. acknowledges support from the Spanish R&D Program through project INSIGNIA (CGL2016-79210-R), co-funded by the European Regional Develop-ment Fund (ERDF/ FEDER). We also thank the Santander Climate Data Service (http://scds.es) and our colleagues Antonio Cofiño and Ezequiel Cimadevilla for their support. Sixto Herrera and José M. Gutiérrez provided useful comments on earlier stages of this study. Finally, we thank two anonymous referees for their insightful comments that helped to improve the original manuscrip