The importance of being divisible by three in alternative splicing

Alternative splicing events that are conserved in orthologous genes in different species are commonly viewed as reliable evidence of authentic, functionally significant alternative splicing events. Several recent bioinformatic analyses have shown that conserved alternative exons possess several features that distinguish them from alternative exons that are species-specific. One of the most striking differences between conserved and species-specific alternative exons is the high percentage of exons that preserve the reading frame (exons whose length is an exact multiple of 3, termed symmetrical exons) among the conserved alternative exons. Here, we examined conserved alternative exons and found several features that differentiate between symmetrical and non-symmetrical alternative exons. We show that symmetrical alternative exons have a strong tendency not to disrupt protein domain structures, whereas the tendency of non-symmetrical alternative exons to overlap with different fractions of protein domains is similar to that of constitutive exons. Additionally, skipping isoforms of non-symmetrical alternative exons are strongly underrepresented, compared with their including isoforms, suggesting that skipping of a large fraction of non-symmetrical alternative exons produces transcripts that are degraded by the nonsense-mediated mRNA decay mechanism. Non-symmetrical alternative exons also show a tendency to reside in the 5′ half of the CDS. These findings suggest that alternative splicing of symmetrical and non-symmetrical exons is governed by different selective pressures and serves different purposes

Efficient Triangle Counting in Large Graphs via Degree-based Vertex Partitioning

The number of triangles is a computationally expensive graph statistic which is frequently used in complex network analysis (e.g., transitivity ratio), in various random graph models (e.g., exponential random graph model) and in important real world applications such as spam detection, uncovering of the hidden thematic structure of the Web and link recommendation. Counting triangles in graphs with millions and billions of edges requires algorithms which run fast, use small amount of space, provide accurate estimates of the number of triangles and preferably are parallelizable. In this paper we present an efficient triangle counting algorithm which can be adapted to the semistreaming model. The key idea of our algorithm is to combine the sampling algorithm of Tsourakakis et al. and the partitioning of the set of vertices into a high degree and a low degree subset respectively as in the Alon, Yuster and Zwick work treating each set appropriately. We obtain a running time $O \left(m + \frac{m^{3/2} \Delta \log{n}}{t \epsilon^2} \right)$ and an $\epsilon$ approximation (multiplicative error), where $n$ is the number of vertices, $m$ the number of edges and $\Delta$ the maximum number of triangles an edge is contained. Furthermore, we show how this algorithm can be adapted to the semistreaming model with space usage $O\left(m^{1/2}\log{n} + \frac{m^{3/2} \Delta \log{n}}{t \epsilon^2} \right)$ and a constant number of passes (three) over the graph stream. We apply our methods in various networks with several millions of edges and we obtain excellent results. Finally, we propose a random projection based method for triangle counting and provide a sufficient condition to obtain an estimate with low variance.Comment: 1) 12 pages 2) To appear in the 7th Workshop on Algorithms and Models for the Web Graph (WAW 2010

Fault Rerupture during the July 2019 Ridgecrest Earthquake Pair from Joint Slip Inversion of InSAR, Optical Imagery, and GPS

International audienceThe Ridgecrest earthquake pair ruptured a previously unknown orthogonal fault system in the eastern California shear zone. The stronger of the two, an Mw 7.1 earthquake that occurred on 6 July 2019, was preceded by an Mw 6.4 foreshock that occurred 34 hr earlier. In this study, distinct final slip distributions for the two earthquakes are obtained via joint inversion of Interferometric Synthetic Aperture Radar (InSAR), optical imagery, and Global Positioning System (GPS) measurements. Special attention is paid to the merging of dense (e.g., InSAR and optical imagery) and sparse geodetic (e.g., GPS) datasets. In addition, a new approach is introduced for data and model discretization through intermittent model‐ and data‐space reconditioning that stabilizes the inversion, thus ensuring that small changes in the data space do not cause disproportionate large changes to the model space. Although the coseismic slip of the Mw 6.4 earthquake was complex, involving three distinct asperities distributed among an intersecting orthogonal set of faults, the coseismic slip of the Mw 7.1 earthquake was limited to the main northwest‐striking fault. In addition to the Mw 7.1 earthquake, that northwest‐striking fault plane also hosted one of the Mw 6.4 asperities. Slip on this coplanar foreshock asperity increased the shear stress at the future site of the Mw 7.1 hypocenter, and triggered a vigorous aftershock activity on the main northwest fault that culminated in its rupture. This, in turn, reactivated the coplanar foreshock asperity. In addition to failing twice within 34 hr, we find that the reruptured asperity slipped about six times more durin

BNT162b2 Vaccine Effectiveness against Omicron in Children 5 to 11 Years of Age

BackgroundLimited evidence is available on the real-world effectiveness of the BNT162b2 vaccine against coronavirus disease 2019 (Covid-19) and specifically against infection with the omicron variant among children 5 to 11 years of age. MethodsUsing data from the largest health care organization in Israel, we identified a cohort of children 5 to 11 years of age who were vaccinated on or after November 23, 2021, and matched them with unvaccinated controls to estimate the vaccine effectiveness of BNT162b2 among newly vaccinated children during the omicron wave. Vaccine effectiveness against documented severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and symptomatic Covid-19 was estimated after the first and second vaccine doses. The cumulative incidence of each outcome in the two study groups through January 7, 2022, was estimated with the use of the Kaplan-Meier estimator, and vaccine effectiveness was calculated as 1 minus the risk ratio. Vaccine effectiveness was also estimated in age subgroups. ResultsAmong 136,127 eligible children who had been vaccinated during the study period, 94,728 were matched with unvaccinated controls. The estimated vaccine effectiveness against documented infection was 17% (95% confidence interval [CI], 7 to 25) at 14 to 27 days after the first dose and 51% (95% CI, 39 to 61) at 7 to 21 days after the second dose. The absolute risk difference between the study groups at days 7 to 21 after the second dose was 1905 events per 100,000 persons (95% CI, 1294 to 2440) for documented infection and 599 events per 100,000 persons (95% CI, 296 to 897) for symptomatic Covid-19. The estimated vaccine effectiveness against symptomatic Covid-19 was 18% (95% CI, -2 to 34) at 14 to 27 days after the first dose and 48% (95% CI, 29 to 63) at 7 to 21 days after the second dose. We observed a trend toward higher vaccine effectiveness in the youngest age group (5 or 6 years of age) than in the oldest age group (10 or 11 years of age). ConclusionsOur findings suggest that as omicron was becoming the dominant variant, two doses of the BNT162b2 messenger RNA vaccine provided moderate protection against documented SARS-CoV-2 infection and symptomatic Covid-19 in children 5 to 11 years of age. (Funded by the European Union through the VERDI project and others.)Covid-19 Vaccination in Children 5 to 11 Years of AgeTwo doses of the BNT162b2 vaccine were associated mainly with low-grade local adverse effects that lasted 2 days or less and afforded nearly 50% protection against omicron infection and symptomatic illness, which was lower than that seen against delta. Greater protection in the youngest group was noted

Dysregulated miRNA biogenesis downstream of cellular stress and ALS-causing mutations: a new mechanism for ALS

Interest in RNA dysfunction in amyotrophic lateral sclerosis (ALS) recently aroused upon discovering causative mutations in RNA-binding protein genes. Here, we show that extensive down-regulation of miRNA levels is a common molecular denominator for multiple forms of human ALS. We further demonstrate that pathogenic ALS-causing mutations are sufficient to inhibit miRNA biogenesis at the Dicing step. Abnormalities of the stress response are involved in the pathogenesis of neurodegeneration, including ALS. Accordingly, we describe a novel mechanism for modulating microRNA biogenesis under stress, involving stress granule formation and re-organization of DICER and AGO2 protein interactions with their partners. In line with this observation, enhancing DICER activity by a small molecule, enoxacin, is beneficial for neuromuscular function in two independent ALS mouse models. Characterizing miRNA biogenesis downstream of the stress response ties seemingly disparate pathways in neurodegeneration and further suggests that DICER and miRNAs affect neuronal integrity and are possible therapeutic targets