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Background: Alternative splicing is a key mechanism in eukaryotic cells to increase the effective number of functionally distinct gene products. Using bulk RNA sequencing, splicing variation has been studied both across human tissues and in genetically diverse individuals. This has identified disease-relevant splicing events, as well as associations between splicing and genomic variations, including sequence composition and conservation. However, variability in splicing between single cells from the same tissue and its determinants remain poorly understood.
Results: We applied parallel DNA methylation and transcriptome sequencing to differentiating human induced pluripotent stem cells to characterize splicing variation (exon skipping) and its determinants. Our results shows that splicing rates in single cells can be accurately predicted based on sequence composition and other genomic features. We also identified a moderate but significant contribution from DNA methylation to splicing variation across cells. By combining sequence information and DNA methylation, we derived an accurate model (AUC=0.85) for predicting different splicing modes of individual cassette exons. These explain conventional inclusion and exclusion patterns, but also more subtle modes of cell-to-cell variation in splicing. Finally, we identified and characterized associations between DNA methylation and splicing changes during cell differentiation.
Conclusions: Our study yields new insights into alternative splicing at the single-cell level and reveals a previously underappreciated component of DNA methylation variation on splicing.
Background: Alternative splicing is a key regulatory mechanism in eukaryotic cells and increases the effective number of functionally distinct gene products. Using bulk RNA sequencing, splicing variation has been studied across human tissues and in genetically diverse populations. This has identified disease-relevant splicing events, as well as associations between splicing and genomic variations, including sequence composition and conservation. However, variability in splicing between single cells from the same tissue or cell type and its determinants remain poorly understood.
Results: We applied parallel DNA methylation and transcriptome sequencing to differentiating human induced pluripotent stem cells to characterize splicing variation (exon skipping) and its determinants. Our results shows that variation in single-cell splicing can be accurately predicted based on local sequence composition and genomic features. We observe moderate but consistent contributions from local DNA methylation profiles to splicing variation across cells. A combined model that is built based on sequence as well as DNA methylation information accurately predicts different splicing modes of individual cassette exons (AUC=0.85). These categories include the conventional inclusion and exclusion patterns, but also more subtle modes of cell-to-cell variation in splicing. Finally, we identified and characterized associations between DNA methylation and splicing changes during cell differentiation.
Conclusions: Our study yields new insights into alternative splicing at the single-cell level and reveals a previously underappreciated link between DNA methylation variation and splicing.
b̄b̄ud tetraquark resonances in the Born-Oppenheimer approximation using lattice QCD potentials
(2018)
We study tetraquark resonances using lattice QCD potentials for a pair of static antiquarks b¯b¯ in the presence of two light quarks ud. The system is treated in the Born-Oppenheimer approximation and we use the emergent wave method. We focus on the isospin I=0 channel, but consider different orbital angular momenta l of the heavy antiquarks b¯b¯. We extract the phase shifts and search for S and T matrix poles on the second Riemann sheet. For orbital angular momentum l=1 we find a tetraquark resonance with quantum numbers I(JP)=0(1−), resonance mass m=10576+4−4MeV and decay width Γ=112+90−103MeV, which can decay into two B mesons.
Pseudomonas aeruginosa is a human pathogen that causes health-care associated blood stream infections (BSI). Although P. aeruginosa BSI are associated with high mortality rates, the clinical relevance of pathogen-derived prognostic biomarker to identify patients at risk for unfavorable outcome remains largely unexplored. We found novel pathogen-derived prognostic biomarker candidates by applying a multi-omics approach on a multicenter sepsis patient cohort. Multi-level Cox regression was used to investigate the relation between patient characteristics and pathogen features (2298 accessory genes, 1078 core protein levels, 107 parsimony-informative variations in reported virulence factors) with 30-day mortality. Our analysis revealed that presence of the helP gene encoding a putative DEAD-box helicase was independently associated with a fatal outcome (hazard ratio 2.01, p = 0.05). helP is located within a region related to the pathogenicity island PAPI-1 in close proximity to a pil gene cluster, which has been associated with horizontal gene transfer. Besides helP, elevated protein levels of the bacterial flagellum protein FliL (hazard ratio 3.44, p < 0.001) and of a bacterioferritin-like protein (hazard ratio 1.74, p = 0.003) increased the risk of death, while high protein levels of a putative aminotransferase were associated with an improved outcome (hazard ratio 0.12, p < 0.001). The prognostic potential of biomarker candidates and clinical factors was confirmed with different machine learning approaches using training and hold-out datasets. The helP genotype appeared the most attractive biomarker for clinical risk stratification due to its relevant predictive power and ease of detection.
Rhythmic neural spiking and attentional sampling arising from cortical receptive field interactions
(2018)
Summary: Growing evidence suggests that distributed spatial attention may invoke theta (3-9 Hz) rhythmic sampling processes. The neuronal basis of such attentional sampling is however not fully understood. Here we show using array recordings in visual cortical area V4 of two awake macaques that presenting separate visual stimuli to the excitatory center and suppressive surround of neuronal receptive fields elicits rhythmic multi-unit activity (MUA) at 3-6 Hz. This neuronal rhythm did not depend on small fixational eye movements. In the context of a distributed spatial attention task, during which the monkeys detected a spatially and temporally uncertain target, reaction times (RT) exhibited similar rhythmic fluctuations. RTs were fast or slow depending on the target occurrence during high or low MUA, resulting in rhythmic MUA-RT cross-correlations at at theta frequencies. These findings suggest that theta-rhythmic neuronal activity arises from competitive receptive field interactions and that this rhythm may subserve attentional sampling.
Highlights:
* Center-surround interactions induce theta-rhythmic MUA of visual cortex neurons
* The MUA rhythm does not depend on small fixational eye movements
* Reaction time fluctuations lock to the neuronal rhythm under distributed attention
Measurement of the inclusive J/ψ polarization at forward rapidity in pp collisions at √s = 8 TeV
(2018)
We report on the measurement of the inclusive J/ψ polarization parameters in pp collisions at a center of mass energy s√=8 TeV with the ALICE detector at the LHC. The analysis is based on a data sample corresponding to an integrated luminosity of 1.23 pb−1. J/ψ resonances are reconstructed in their di-muon decay channel in the rapidity interval 2.5<y<4.0 and over the transverse-momentum interval 2<pT<15 GeV/c. The three polarization parameters (λθ, λφ, λθφ) are measured as a function of pT both in the helicity and Collins-Soper reference frames. The measured J/ψ polarization parameters are found to be compatible with zero within uncertainties, contrary to expectations from all available predictions. The results are compared with the measurement in pp collisions at s√=7 TeV.
ϕ meson measurements provide insight into strangeness production, which is one of the key observables for the hot medium formed in high-energy heavy-ion collisions. ALICE measured ϕ production through its decay in muon pairs in Pb-Pb collisions at sNN−−−√ = 2.76 TeV in the intermediate transverse momentum range 2<pT<5 GeV/c and in the rapidity interval 2.5<y<4. The ϕ yield was measured as a function of the transverse momentum and collision centrality. The nuclear modification factor was obtained as a function of the average number of participating nucleons. Results were compared with the ones obtained via the kaon decay channel in the same pT range at midrapidity. The values of the nuclear modification factor in the two rapidity regions are in agreement within uncertainties.
The elliptic (v2), triangular (v3), and quadrangular (v4) flow coefficients of π±, K±, p+p¯¯¯, Λ+Λ¯¯¯¯, K0S, and the ϕ-meson are measured in Pb-Pb collisions at sNN−−−√=5.02 TeV. Results obtained with the scalar product method are reported for the rapidity range |y|< 0.5 as a function of transverse momentum, pT, at different collision centrality intervals between 0-70%, including ultra-central (0-1%) collisions for π±, K±, and p+p¯¯¯. For pT<3 GeV/c, the flow coefficients exhibit a particle mass dependence. At intermediate transverse momenta (3<pT<~8-10 GeV/c), particles show an approximate grouping according to their type (i.e., mesons and baryons). The ϕ-meson v2, which tests both particle mass dependence and type scaling, follows p+p¯¯¯ v2 at low pT and π± v2 at intermediate pT. The evolution of the shape of vn(pT) as a function of centrality and harmonic number n is studied for the various particle species. Flow coefficients of π±, K±, and p+p¯¯¯ for pT<3 GeV/c are compared to iEBE-VISHNU and MUSIC hydrodynamical calculations coupled to a hadronic cascade model (UrQMD). The iEBE-VISHNU calculations describe the results fairly well for pT<2.5 GeV/c, while MUSIC calculations reproduce the measurements for pT<1 GeV/c. A comparison to vn coefficients measured in Pb-Pb collisions at sNN−−−√ = 2.76 TeV is also provided.
Measurements of anisotropic flow coefficients with two- and multi-particle cumulants for inclusive charged particles in Pb-Pb collisions at sNN−−−√=5.02 and 2.76 TeV are reported in the pseudorapidity range |η|<0.8 and transverse momentum 0.2<pT<50 GeV/c. The full data sample collected by the ALICE detector in 2015 (2010), corresponding to an integrated luminosity of 12.7 (2.0) μb−1 in the centrality range 0-80%, is analysed. Flow coefficients up to the sixth flow harmonic (v6) are reported and a detailed comparison among results at the two energies is carried out. The pT dependence of anisotropic flow coefficients and its evolution with respect to centrality and harmonic number n are investigated. An approximate power-law scaling of the form vn(pT)∼pn/3T is observed for all flow harmonics at low pT (0.2<pT<3 GeV/c). At the same time, the ratios vn/vn/mm are observed to be essentially independent of pT for most centralities up to about pT=10 GeV/c. Analysing the differences among higher-order cumulants of elliptic flow (v2), which have different sensitivities to flow fluctuations, a measurement of the standardised skewness of the event-by-event v2 distribution P(v2) is reported and constraints on its higher moments are provided. The Elliptic Power distribution is used to parametrise P(v2), extracting its parameters from fits to cumulants. The measurements are compared to different model predictions in order to discriminate among initial-state models and to constrain the temperature dependence of the shear viscosity to entropy-density ratio.
A measurement of the production of prompt Λ+c baryons in Pb-Pb collisions at sNN−−−√=5.02 TeV with the ALICE detector at the LHC is reported. The Λ+c and Λ¯¯¯¯−c were reconstructed at midrapidity (|y|<0.5) via the hadronic decay channel Λ+c→pK0S (and charge conjugate) in the transverse momentum and centrality intervals 6<pT<12 GeV/c and 0-80%. The Λ+c/D0 ratio, which is sensitive to the charm quark hadronisation mechanisms in the medium, is measured and found to be larger than the ratio measured in minimum-bias pp collisions at s√=7 TeV and in p-Pb collisions at sNN−−−√=5.02 TeV. In particular, the values in p-Pb and Pb-Pb collisions differ by about two standard deviations of the combined statistical and systematic uncertainties. The Λ+c/D0 ratio is also compared with model calculations including different implementations of charm quark hadronisation. The measured ratio is reproduced by models implementing a pure coalescence scenario, while adding a fragmentation contribution leads to an underestimation. The Λ+c nuclear modification factor, RAA, is also presented. The measured values of the RAA of Λ+c, Ds and non-strange D mesons are compatible within the combined statistical and systematic uncertainties. They show, however, a hint of a hierarchy (RD0AA<RDsAA<RΛ+cAA), conceivable with a contribution of recombination mechanisms to charm hadron formation in the medium.