Analysis of factor V in zebrafish demonstrates minimal levels needed for early hemostasis

In humans, coagulation factor V (FV) deficiency is a rare, clinically heterogeneous bleeding disorder, suggesting that genetic modifiers may contribute to disease expressivity. Zebrafish possess many distinct advantages including high fecundity, optical clarity, external development, and homology with the mammalian hemostatic system, features that make it ideal for genetic studies. Our aim was to study the role of FV in zebrafish through targeted mutagenesis and apply the model to the study of human F5 variants. CRISPR-mediated genome editing of the zebrafish f5 locus was performed, generating mutants homozygous for a 49 base pair deletion in exon 4. Thrombus formation secondary to vascular endothelial injury was absent in f52/2 mutant embryos and larvae. Despite this severe hemostatic defect, homozygous mutants survived before succumbing to severe hemorrhage in adulthood. Human F5 variants of uncertain significance from patients with FV deficiency were evaluated, and the causative mutations identified and stratified by their ability to restore thrombus formation in larvae. Analysis of these novel mutations demonstrates variable residual FV function, with minimal activity being required to restore hemostasis in response to laser-induced endothelial injury. This in vivo evaluation may be beneficial for patients whose factor activity levels lack correlation with bleeding symptomatology, although limitations exist. Furthermore, homozygous mutant embryos tolerate what is a severe and lethal defect in mammals, suggesting the possibility of species-specific factors enabling survival, and allowing further study not possible in the mouse. Identification of these factors or other genetic modifiers could lead to novel therapeutic modalities

Plasma formation from ultracold Rydberg gases

Recent experiments have demonstrated the spontaneous evolution of a gas of ultracold Rydberg atoms into an expanding ultracold plasma, as well as the reverse process of plasma recombination into highly excited atomic states. Treating the evolution of the plasma on the basis of kinetic equations, while ionization/excitation and recombination are incorporated using rate equations, we have investigated theoretically the Rydberg-to-plasma transition. Including the influence of spatial correlations on the plasma dynamics in an approximate way we find that ionic correlations change the results only quantitatively but not qualitatively

Fine-scale structure of the mid-mantle characterised by global stacks of PP precursors

Subduction zones are likely a major source of compositional heterogeneities in the mantle, which may preserve a record of the subduction history and mantle convection processes. The fine-scale structure associated with mantle heterogeneities can be studied using the scattered seismic wavefield that arrives as coda to or as energy preceding many body wave arrivals. In this study we analyse precursors to PP by creating stacks recorded at globally distributed stations. We create stacks aligned on the PP arrival in 5° distance bins (with range 70-120°) from 600 earthquakes recorded at 193 stations stacking a total of 7320 seismic records. As the energy trailing the direct P arrival, the P coda, interferes with the PP precursors, we suppress the P coda by subtracting a best fitting exponential curve to this energy. The resultant stacks show that PP precursors related to scattering from heterogeneities in the mantle are present for all distances. Lateral variations are explored by producing two regional stacks across the Atlantic and Pacific hemispheres, but we find only negligible differences in the precursory signature between these two regions. The similarity of these two regions suggests that well mixed subducted material can survive at upper and mid-mantle depth. To describe the scattered wavefield in the mantle, we compare the global stacks to synthetic seismograms generated using a Monte Carlo phonon scattering technique. We propose a best-fitting layered heterogeneity model, BRT2017, characterised by a three layer mantle with a background heterogeneity strength (ϵ = 0.8%) and a depth-interval of increased heterogeneity strength (ϵ = 1%) between 1000 km and 1800 km. The scalelength of heterogeneity is found to be 8 km throughout the mantle. Since mantle heterogeneity of 8 km scale may be linked to subducted oceanic crust, the detection of increased heterogeneity at mid-mantle depths could be associated with stalled slabs due to increases in viscosity, supporting recent observations of mantle viscosity increases due to the iron spin transition at depths of ~1000 k

Measurement of the Bottom-Strange Meson Mixing Phase in the Full CDF Data Set

We report a measurement of the bottom-strange meson mixing phase \beta_s using the time evolution of B0_s -> J/\psi (->\mu+\mu-) \phi (-> K+ K-) decays in which the quark-flavor content of the bottom-strange meson is identified at production. This measurement uses the full data set of proton-antiproton collisions at sqrt(s)= 1.96 TeV collected by the Collider Detector experiment at the Fermilab Tevatron, corresponding to 9.6 fb-1 of integrated luminosity. We report confidence regions in the two-dimensional space of \beta_s and the B0_s decay-width difference \Delta\Gamma_s, and measure \beta_s in [-\pi/2, -1.51] U [-0.06, 0.30] U [1.26, \pi/2] at the 68% confidence level, in agreement with the standard model expectation. Assuming the standard model value of \beta_s, we also determine \Delta\Gamma_s = 0.068 +- 0.026 (stat) +- 0.009 (syst) ps-1 and the mean B0_s lifetime, \tau_s = 1.528 +- 0.019 (stat) +- 0.009 (syst) ps, which are consistent and competitive with determinations by other experiments.Comment: 8 pages, 2 figures, Phys. Rev. Lett 109, 171802 (2012

Discovery of widespread transcription initiation at microsatellites predictable by sequence-based deep neural network

Using the Cap Analysis of Gene Expression (CAGE) technology, the FANTOM5 consortium provided one of the most comprehensive maps of transcription start sites (TSSs) in several species. Strikingly, ~72% of them could not be assigned to a specific gene and initiate at unconventional regions, outside promoters or enhancers. Here, we probe these unassigned TSSs and show that, in all species studied, a significant fraction of CAGE peaks initiate at microsatellites, also called short tandem repeats (STRs). To confirm this transcription, we develop Cap Trap RNA-seq, a technology which combines cap trapping and long read MinION sequencing. We train sequence-based deep learning models able to predict CAGE signal at STRs with high accuracy. These models unveil the importance of STR surrounding sequences not only to distinguish STR classes, but also to predict the level of transcription initiation. Importantly, genetic variants linked to human diseases are preferentially found at STRs with high transcription initiation level, supporting the biological and clinical relevance of transcription initiation at STRs. Together, our results extend the repertoire of non-coding transcription associated with DNA tandem repeats and complexify STR polymorphism

PCLake+ : A process-based ecological model to assess the trophic state of stratified and non-stratified freshwater lakes worldwide

The lake ecosystem model PCLake is a process-based model that was developed to simulate water quality based on ecological interactions in shallow, non-stratifying lakes in the temperate climate zone. Here we present PCLake+, which extends the PCLake model to cover a wide range of freshwater lakes that differ in stratification regime and climate-related processes. To this end, the model was extended with a hypolimnion layer that can be invoked and configured by forcing functions or by simple built-in empirical relationships that impose stratification. Further adjustments to the original PCLake model have been made with respect to the calculation of 1) light irradiation in the water column, 2) evaporation processes and 3) phenology of macrophytes. The simulation output of PCLake+ for different types of lakes complies well with generally accepted limnological knowledge, thus holding promise for future contributions to ecological theory and application to lakes around the globe.</p

PCLake+ : A process-based ecological model to assess the trophic state of stratified and non-stratified freshwater lakes worldwide

The lake ecosystem model PCLake is a process-based model that was developed to simulate water quality based on ecological interactions in shallow, non-stratifying lakes in the temperate climate zone. Here we present PCLake+, which extends the PCLake model to cover a wide range of freshwater lakes that differ in stratification regime and climate-related processes. To this end, the model was extended with a hypolimnion layer that can be invoked and configured by forcing functions or by simple built-in empirical relationships that impose stratification. Further adjustments to the original PCLake model have been made with respect to the calculation of 1) light irradiation in the water column, 2) evaporation processes and 3) phenology of macrophytes. The simulation output of PCLake+ for different types of lakes complies well with generally accepted limnological knowledge, thus holding promise for future contributions to ecological theory and application to lakes around the globe