Formation of singularities for equivariant 2+1 dimensional wave maps into the two-sphere

In this paper we report on numerical studies of the Cauchy problem for equivariant wave maps from 2+1 dimensional Minkowski spacetime into the two-sphere. Our results provide strong evidence for the conjecture that large energy initial data develop singularities in finite time and that singularity formation has the universal form of adiabatic shrinking of the degree-one harmonic map from $\mathbb{R}^2$ into $S^2$.Comment: 14 pages, 5 figures, final version to be published in Nonlinearit

Disturbance and Predictability of Flowering Patterns in Bird-Pollinated Cloud Forest Plants

The distribution and flowering patterns of hummingbird—pollinated plants were compared from July 1981 to June 1983 in three patch types in cloud forest at Monteverde, Costa Rica. Study plots were: (1) four recent, large (1100—2500 m2) disturbances ("cutovers") produced by cutting vegetation, (2) six recent, smaller (200—600 m2) disturbances caused by treefalls, and (3) four plots (1600—1800 m2) of canopied forest. Based on published literature dealing with communities that characterize different regimes of disturbance, we tested one assumption and two hypotheses. Assumption: Plant species composition differs among the three patch types. Hypothesis 1: Phenotypic specialization by plants for co—evolved interactions with hummingbirds will be lowest in large gaps, highest in forest, and intermediate in treefalls. Hypothesis 2: Predictability of flowering phenologies and nectar production will be lowest in large gaps, highest in forest, intermediate in treefalls. Neither the assumption nor the hypotheses were supported by the results. The patch mosaic in this cloud forest was not associated with major differences in species composition of bird—pollinated plants. Most species studied were self—compatible. Most abundant in cutovers were species with long corollas, relatively specialized for attracting long—billed hummingbirds. Species with short corollas, which can be visited by many hummingbird species and some insects, were most abundant in treefalls and forest. Variation in phenological patterns showed no consistent trends among patch types. Predictability of flower and nectar production tended to be greatest in treefalls, which are foci of concentrated flowering activity by all species. Discrepancies between our results and previous studies can be ascribed to two facts. (1) Much of the literature dealing with ecological consequences of disturbance has dealt with large—scale anthropogenic disturbances such as old fields of the eastern USA, whereas we studied small, natural, or quasi—natural disturbances. (2) Studies of forest disturbance have focused on the tree layer, whereas we studied the understory herbs, shrubs, and epiphytes. Natural disturbance usually involves death and replacement of one or more trees, whereas individuals of other life forms may persist through the disturbance

Safety and efficacy of pegunigalsidase alfa in patients with Fabry disease who were previously treated with agalsidase alfa: results from BRIDGE, a phase 3 open-label study

BACKGROUND: Pegunigalsidase alfa is a novel, PEGylated α-galactosidase-A enzyme-replacement therapy approved in the EU and US to treat patients with Fabry disease (FD). OBJECTIVE/METHODS: BRIDGE is a phase 3 open-label, switch-over study designed to assess safety and efficacy of 12 months of pegunigalsidase alfa (1 mg/kg every 2 weeks) treatment in adults with FD who had been previously treated with agalsidase alfa (0.2 mg/kg every 2 weeks) for ≥ 2 years. RESULTS: Twenty-seven patients were screened; 22 met eligibility criteria; and 20 (13 men, 7 women) completed the study. Pegunigalsidase alfa was well-tolerated, with 97% of treatment-emergent adverse events (TEAEs) being of mild or moderate severity. The incidence of treatment-related TEAEs was low, with 2 (9%) discontinuations due to TEAEs. Five patients (23%) reported infusion-related reactions. Overall mean (SD; n = 22) baseline estimated glomerular filtration rate (eGFR) was 82.5 (23.4) mL/min/1.73 m2 and plasma lyso-Gb3 level was 38.3 (41.2) nmol/L (men: 49.7 [45.8] nmol/L; women: 13.8 [6.1] nmol/L). Before switching to pegunigalsidase alfa, mean (standard error [SE]) annualized eGFR slope was − 5.90 (1.34) mL/min/1.73 m2/year; 12 months post-switch, the mean eGFR slope was − 1.19 (1.77) mL/min/1.73 m2/year; and mean plasma lyso-Gb3 reduced by 31%. Seven (35%) out of 20 patients were positive for pegunigalsidase alfa antidrug antibodies (ADAs) at ≥ 1 study timepoint, two of whom had pre-existing ADAs at baseline. Mean (SE) changes in eGFR slope for ADA-positive and ADA-negative patients were + 5.47 (3.03) and + 4.29 (3.15) mL/min/1.73 m2/year, respectively, suggesting no negative impact of anti-pegunigalsidase alfa ADAs on eGFR slope. CONCLUSION: Pegunigalsidase alfa may offer a safe and effective treatment option for patients with FD, including those previously treated with agalsidase alfa. TRN: NCT03018730. Date of registration: January 2017

FREE ORAL COMMUNICATIONS 2: ALCOHOL AND LIVER—CLINICAL RESEARCHO2.1RAPID DECLINE OF LIVER STIFFNESS WITH ALCOHOL WITHDRAWAL IN HEAVY DRINKERS

Background and aims. Measurement of liver stiffness using real-time elastography appears as a promising tool to evaluate the severity of chronic liver diseases. Previous studies in patients with alcoholic liver disease have suggested that fibrosis was the only histological parameter to influence liver stiffness. To challenge this hypothesis, we have prospectively tested the short-term impact of alcohol withdrawal on liver stiffness value. Methods. All patients hospitalized for alcohol withdrawal in our Liver Unit between September 2008 and December 2010 had a liver stiffness determination (using a FibroScan® device) at entry (D0) and 7 days after alcohol withdrawal (D7). Stiffness values were compared using non-parametric test for paired-values. We compared (i) the 10 measures performed at D0 and at D7 for each patient; (ii) the variation of the median result of all patients (using Wilcoxon test in both cases). Results. A total of 138 patients were included in the study [median alcohol consumption: 150g/day (range: 40-400); hepatitis C: n=22 (15.9%); cirrhosis: n=29 (21.0%)]. From D0 to D7, the liver stiffness decreased significantly in 61 patients (44.2%) and increased significantly in 18 (13.0%). Considering all patients, median liver stiffness value decreased from 7.25 to kPa (P<0.001). The stage of fibrosis indicated by liver stiffness changed in 47 patients between D0 and D7 (decrease in 33 and increase in 14). Conclusion. Liver stiffness decreases significantly in nearly half of alcoholic patients after only 7 days of abstinence. This result strongly suggests that non-fibrotic lesions (such as inflammatory ones) may influence liver stiffness. From a practical point of view, it also shows that variation in alcohol consumption must be taken into account for the interpretation of liver stiffness valu

Expected Performance of the ATLAS Experiment - Detector, Trigger and Physics

A detailed study is presented of the expected performance of the ATLAS detector. The reconstruction of tracks, leptons, photons, missing energy and jets is investigated, together with the performance of b-tagging and the trigger. The physics potential for a variety of interesting physics processes, within the Standard Model and beyond, is examined. The study comprises a series of notes based on simulations of the detector and physics processes, with particular emphasis given to the data expected from the first years of operation of the LHC at CERN

The current role of next-generation DNA sequencing in routine care of patients with hereditary cardiovascular conditions: a viewpoint paper of the European Society of Cardiology working group on myocardial and pericardial diseases and members of the European Society of Human Genetics

Cardiomyopathies, arrhythmic syndromes, aortopathies, and other cardiovascular diseases with Mendelian inheritance are relatively frequent conditions for which genetic testing is recommended in various guidelines.1,2 The most widely recognized indication for genetic testing in patients with these conditions is to identify a causative mutation and subsequently provide pre-symptomatic or predictive testing of relatives who are at risk of developing the same disease at a later stage. This process of cascade screening of family members ensures adequate clinical surveillance of mutation carriers and allows non-carriers to be discharged from clinical follow-up. A number of studies have reported a greater cost-effectiveness combining molecular screening with clinical screening compared with isolated clinical investigations.3 Previously, genetic testing was based on conventional techniques like Sanger sequencing analysing genes one by one, but recent advances in DNA sequencing technologies have made it possible to investigate large numbers of disease genes simultaneously, making mutation analysis much faster and cheaper. These new methods are known as next-generation sequencing (NGS) and represent a major advance in the ability to identify causative mutations in families affected by genetic diseases (see Supplementary material online, Figure S1).4,5 However, analysis of large numbers of genes may identify a number of sequence variants of uncertain clinical significance (VUS). As a result, cardiologists and clinical geneticists who counsel and manage families with inherited cardiovascular disorders are facing a major challenge in determining the clinical relevance of NGS results.6,7 This paper gives a brief overview of the principles of NGS, discusses the general strategies for the interpretation of sequencing results, and reviews the implications of NGS for cardio-genetic services. In addition, issues related to genetic counselling and ethical considerations are discussed. A summary of viewpoints is given in Table 1

Local Absence of Secondary Structure Permits Translation of mRNAs that Lack Ribosome-Binding Sites

The initiation of translation is a fundamental and highly regulated process in gene expression. Translation initiation in prokaryotic systems usually requires interaction between the ribosome and an mRNA sequence upstream of the initiation codon, the so-called ribosome-binding site (Shine-Dalgarno sequence). However, a large number of genes do not possess Shine-Dalgarno sequences, and it is unknown how start codon recognition occurs in these mRNAs. We have performed genome-wide searches in various groups of prokaryotes in order to identify sequence elements and/or RNA secondary structural motifs that could mediate translation initiation in mRNAs lacking Shine-Dalgarno sequences. We find that mRNAs without a Shine-Dalgarno sequence are generally less structured in their translation initiation region and show a minimum of mRNA folding at the start codon. Using reporter gene constructs in bacteria, we also provide experimental support for local RNA unfoldedness determining start codon recognition in Shine-Dalgarno–independent translation. Consistent with this, we show that AUG start codons reside in single-stranded regions, whereas internal AUG codons are usually in structured regions of the mRNA. Taken together, our bioinformatics analyses and experimental data suggest that local absence of RNA secondary structure is necessary and sufficient to initiate Shine-Dalgarno–independent translation. Thus, our results provide a plausible mechanism for how the correct translation initiation site is recognized in the absence of a ribosome-binding site

Variable Levels Of Drift In Tunicate Cardiopharyngeal Gene Regulatory Elements

Background: Mutations in gene regulatory networks often lead to genetic divergence without impacting gene expression or developmental patterning. The rules governing this process of developmental systems drift, including the variable impact of selective constraints on different nodes in a gene regulatory network, remain poorly delineated. Results: Here we examine developmental systems drift within the cardiopharyngeal gene regulatory networks of two tunicate species, Corella inflata and Ciona robusta. Cross-species analysis of regulatory elements suggests that trans-regulatory architecture is largely conserved between these highly divergent species. In contrast, cis-regulatory elements within this network exhibit distinct levels of conservation. In particular, while most of the regulatory elements we analyzed showed extensive rearrangements of functional binding sites, the enhancer for the cardiopharyngeal transcription factor FoxF is remarkably well-conserved. Even minor alterations in spacing between binding sites lead to loss of FoxF enhancer function, suggesting that bound trans-factors form position-dependent complexes. Conclusions: Our findings reveal heterogeneous levels of divergence across cardiopharyngeal cis-regulatory elements. These distinct levels of divergence presumably reflect constraints that are not clearly associated with gene function or position within the regulatory network. Thus, levels of cis-regulatory divergence or drift appear to be governed by distinct structural constraints that will be difficult to predict based on network architecture