Synergistic assembly of human pre-spliceosomes across introns and exons

Most human genes contain multiple introns, necessitating mechanisms to effectively define exons and ensure their proper connection by spliceosomes. Human spliceosome assembly involves both cross-intron and cross-exon interactions, but how these work together is unclear. We examined in human nuclear extracts dynamic interactions of single pre-mRNA molecules with individual fluorescently tagged spliceosomal subcomplexes to investigate how cross-intron and cross-exon processes jointly promote pre-spliceosome assembly. U1 subcomplex bound to the 5\u27 splice site of an intron acts jointly with U1 bound to the 5\u27 splice site of the next intron to dramatically increase the rate and efficiency by which U2 subcomplex is recruited to the branch site/3\u27 splice site of the upstream intron. The flanking 5\u27 splice sites have greater than additive effects implying distinct mechanisms facilitating U2 recruitment. This synergy of 5\u27 splice sites across introns and exons is likely important in promoting correct and efficient splicing of multi-intron pre-mRNAs

Two PABPC1-binding sites in GW182 proteins promote miRNA-mediated gene silencing

Previous studies have suggested that the mechanism of miRNA-mediated silencing may differ between human and Drosophila cells. Here, a direct comparison demonstrates that the mechanism is conserved and the GW182–PABP interaction is required for silencing in vivo

The C-terminal α–α superhelix of Pat is required for mRNA decapping in metazoa

Pat proteins regulate the transition of mRNAs from a state that is translationally active to one that is repressed, committing targeted mRNAs to degradation. Pat proteins contain a conserved N-terminal sequence, a proline-rich region, a Mid domain and a C-terminal domain (Pat-C). We show that Pat-C is essential for the interaction with mRNA decapping factors (i.e. DCP2, EDC4 and LSm1–7), whereas the P-rich region and Mid domain have distinct functions in modulating these interactions. DCP2 and EDC4 binding is enhanced by the P-rich region and does not require LSm1–7. LSm1–7 binding is assisted by the Mid domain and is reduced by the P-rich region. Structural analysis revealed that Pat-C folds into an α–α superhelix, exposing conserved and basic residues on one side of the domain. This conserved and basic surface is required for RNA, DCP2, EDC4 and LSm1–7 binding. The multiplicity of interactions mediated by Pat-C suggests that certain of these interactions are mutually exclusive and, therefore, that Pat proteins switch decapping partners allowing transitions between sequential steps in the mRNA decapping pathway

HPat provides a link between deadenylation and decapping in metazoa

A proline-rich region in the Drosophila Pat1 homologue works with the protein's C-terminal domain to recruit decapping and deadenylase complexes to target mRNAs

The Spin Structure Function g1pg_1^{\rm p} of the Proton and a Test of the Bjorken Sum Rule

New results for the double spin asymmetry $A_1^{\rm p}$ and the proton longitudinal spin structure function $g_1^{\rm p}$ are presented. They were obtained by the COMPASS collaboration using polarised 200 GeV muons scattered off a longitudinally polarised NH$_3$ target. The data were collected in 2011 and complement those recorded in 2007 at 160\,GeV, in particular at lower values of $x$. They improve the statistical precision of $g_1^{\rm p}(x)$ by about a factor of two in the region $x\lesssim 0.02$. A next-to-leading order QCD fit to the $g_1$ world data is performed. It leads to a new determination of the quark spin contribution to the nucleon spin, $\Delta \Sigma$ ranging from 0.26 to 0.36, and to a re-evaluation of the first moment of $g_1^{\rm p}$. The uncertainty of $\Delta \Sigma$ is mostly due to the large uncertainty in the present determinations of the gluon helicity distribution. A new evaluation of the Bjorken sum rule based on the COMPASS results for the non-singlet structure function $g_1^{\rm NS}(x,Q^2)$ yields as ratio of the axial and vector coupling constants $|g_{\rm A}/g_{\rm V}| = 1.22 \pm 0.05~({\rm stat.}) \pm 0.10~({\rm syst.})$, which validates the sum rule to an accuracy of about 9\%.Comment: 19 pages, 8 figures and table

Collins and Sivers asymmetries in muonproduction of pions and kaons off transversely polarised proton

Measurements of the Collins and Sivers asymmetries for charged pions and charged and neutral kaons produced in semi-inclusive deep-inelastic scattering of high energy muons off transversely polarised protons are presented. The results were obtained using all the available COMPASS proton data, which were taken in the years 2007 and 2010. The Collins asymmetries exhibit in the valence region a non-zero signal for pions and there are hints of non-zero signal also for kaons. The Sivers asymmetries are found to be positive for positive pions and kaons and compatible with zero otherwise.Comment: 15 pages, 13 figures and 1 tabl

Search for exclusive photoproduction of Zc±_c^{\pm}(3900) at COMPASS

A search for the exclusive production of the $Z_c^{\pm}(3900)$ hadron by virtual photons has been performed in the channel $Z_c^{\pm}(3900)\rightarrow J/\psi \pi^{\pm}$. The data cover the range from 7 GeV to 19 GeV in the centre-of-mass energy of the photon-nucleon system. The full set of the COMPASS data set collected with a muon beam between 2002 and 2011 has been used. An upper limit for the ratio $BR(Z_c^{\pm}(3900)\rightarrow J/\psi \pi^{\pm} )\times \sigma_{ \gamma~N \rightarrow Z_c^{\pm}(3900)~ N} /\sigma_{\gamma~N \rightarrow J/\psi~ N}$ of $3.7\times10^{-3}$ has been established at the confidence level of 90%.Comment: 8 pages, 3 figures, 1 tabl

Spin alignment and violation of the OZI rule in exclusive ω\omega and ϕ\phi production in pp collisions

Exclusive production of the isoscalar vector mesons $\omega$ and $\phi$ is measured with a 190 GeV$/c$ proton beam impinging on a liquid hydrogen target. Cross section ratios are determined in three intervals of the Feynman variable $x_{F}$ of the fast proton. A significant violation of the OZI rule is found, confirming earlier findings. Its kinematic dependence on $x_{F}$ and on the invariant mass $M_{p\mathrm{V}}$ of the system formed by fast proton $p_\mathrm{fast}$ and vector meson $V$ is discussed in terms of diffractive production of $p_\mathrm{fast}V$ resonances in competition with central production. The measurement of the spin density matrix element $\rho_{00}$ of the vector mesons in different selected reference frames provides another handle to distinguish the contributions of these two major reaction types. Again, dependences of the alignment on $x_{F}$ and on $M_{p\mathrm{V}}$ are found. Most of the observations can be traced back to the existence of several excited baryon states contributing to $\omega$ production which are absent in the case of the $\phi$ meson. Removing the low-mass $M_{p\mathrm{V}}$ resonant region, the OZI rule is found to be violated by a factor of eight, independently of $x_\mathrm{F}$.Comment: 23 pages, 13 figures and 5 table

Complex Evolutionary History of the Aeromonas veronii Group Revealed by Host Interaction and DNA Sequence Data

Aeromonas veronii biovar sobria, Aeromonas veronii biovar veronii, and Aeromonas allosaccharophila are a closely related group of organisms, the Aeromonas veronii Group, that inhabit a wide range of host animals as a symbiont or pathogen. In this study, the ability of various strains to colonize the medicinal leech as a model for beneficial symbiosis and to kill wax worm larvae as a model for virulence was determined. Isolates cultured from the leech out-competed other strains in the leech model, while most strains were virulent in the wax worms. Three housekeeping genes, recA, dnaJ and gyrB, the gene encoding chitinase, chiA, and four loci associated with the type three secretion system, ascV, ascFG, aexT, and aexU were sequenced. The phylogenetic reconstruction failed to produce one consensus tree that was compatible with most of the individual genes. The Approximately Unbiased test and the Genetic Algorithm for Recombination Detection both provided further support for differing evolutionary histories among this group of genes. Two contrasting tests detected recombination within aexU, ascFG, ascV, dnaJ, and gyrB but not in aexT or chiA. Quartet decomposition analysis indicated a complex recent evolutionary history for these strains with a high frequency of horizontal gene transfer between several but not among all strains. In this study we demonstrate that at least for some strains, horizontal gene transfer occurs at a sufficient frequency to blur the signal from vertically inherited genes, despite strains being adapted to distinct niches. Simply increasing the number of genes included in the analysis is unlikely to overcome this challenge in organisms that occupy multiple niches and can exchange DNA between strains specialized to different niches. Instead, the detection of genes critical in the adaptation to specific niches may help to reveal the physiological specialization of these strains

Progressive skin fibrosis is associated with a decline in lung function and worse survival in patients with diffuse cutaneous systemic sclerosis in the European Scleroderma Trials and Research (EUSTAR) cohort.

Objectives To determine whether progressive skin fibrosis is associated with visceral organ progression and mortality during follow-up in patients with diffuse cutaneous systemic sclerosis (dcSSc). Methods We evaluated patients from the European Scleroderma Trials and Research database with dcSSc, baseline modified Rodnan skin score (mRSS) ≥7, valid mRSS at 12±3 months after baseline and ≥1 annual follow-up visit. Progressive skin fibrosis was defined as an increase in mRSS >5 and ≥25% from baseline to 12±3 months. Outcomes were pulmonary, cardiovascular and renal progression, and all-cause death. Associations between skin progression and outcomes were evaluated by Kaplan-Meier survival analysis and multivariable Cox regression. Results Of 1021 included patients, 78 (7.6%) had progressive skin fibrosis (skin progressors). Median follow-up was 3.4 years. Survival analyses indicated that skin progressors had a significantly higher probability of FVC decline ≥10% (53.6% vs 34.4%; p<0.001) and all-cause death (15.4% vs 7.3%; p=0.003) than non-progressors. These significant associations were also found in subgroup analyses of patients with either low baseline mRSS (≤22/51) or short disease duration (≤15 months). In multivariable analyses, skin progression within 1 year was independently associated with FVC decline ≥10% (HR 1.79, 95% CI 1.20 to 2.65) and all-cause death (HR 2.58, 95% CI 1.31 to 5.09). Conclusions Progressive skin fibrosis within 1 year is associated with decline in lung function and worse survival in dcSSc during follow-up. These results confirm mRSS as a surrogate marker in dcSSc, which will be helpful for cohort enrichment in future trials and risk stratification in clinical practice