Efficient adaptivity for simulating cardiac electrophysiology with spectral deferred correction methods

The locality of solution features in cardiac electrophysiology simulations calls for adaptive methods. Due to the overhead incurred by established mesh refinement and coarsening, however, such approaches failed in accelerating the computations. Here we investigate a different route to spatial adaptivity that is based on nested subset selection for algebraic degrees of freedom in spectral deferred correction methods. This combination of algebraic adaptivity and iterative solvers for higher order collocation time stepping realizes a multirate integration with minimal overhead. This leads to moderate but significant speedups in both monodomain and cell-by-cell models of cardiac excitation, as demonstrated at four numerical examples.Comment: 12 pages, 12 figure

Nod1 signaling overcomes resistance of S. pneumoniae to opsonophagocytic killing

Airway infection by the Gram-positive pathogen Streptococcus pneumoniae (Sp) leads to recruitment of neutrophils but limited bacterial killing by these cells. Co-colonization by Sp and a Gram-negative species, Haemophilus influenzae (Hi), provides sufficient stimulus to induce neutrophil and complement-mediated clearance of Sp from the mucosal surface in a murine model. Products from Hi, but not Sp, also promote killing of Sp by ex vivo neutrophil-enriched peritoneal exudate cells. Here we identify the stimulus from Hi as its peptidoglycan. Enhancement of opsonophagocytic killing was facilitated by signaling through nucleotide-binding oligomerization domain-1 (Nod1), which is involved in recognition of γ-D-glutamyl-meso-diaminopimelic acid (meso-DAP) contained in cell walls of Hi but not Sp. Neutrophils from mice treated with Hi or compounds containing meso-DAP, including synthetic peptidoglycan fragments, showed increased Sp killing in a Nod1-dependent manner. Moreover, Nod1-/- mice showed reduced Hi-induced clearance of Sp during co-colonization. These observations offer insight into mechanisms of microbial competition and demonstrate the importance of Nod1 in neutrophil-mediated clearance of bacteria in vivo

Simple renormalizable flavor symmetry for neutrino oscillations

pre-printThe recent measurement of a nonzero neutrino mixing angle θ13 requires a modification of the tri-bimaximal mixing pattern that predicts a zero value for it. We propose a new neutrino mixing pattern based on a spontaneously broken A4 flavor symmetry and a type-I seesaw mechanism. Our model allows for approximate tri-bimaximal mixing and nonzero θ13, and contains a natural way to implement low- and high-energy CP violations in neutrino oscillations, and leptogenesis with a renormalizable Lagrangian. Both normal and inverted mass hierarchies are permitted within 3σ experimental bounds, with the prediction of small (large) deviations from maximality in the atmospheric mixing angle for the normal (inverted) case. Interestingly, we show that the inverted case is excluded by the global analysis in 1σ experimental bounds, while the most recent MINOS data seem to favor the inverted case. Our model make predictions for the Dirac CP phase in the normal and inverted hierarchies, which can be tested in near-future neutrino oscillation experiments. Our model also predicts the effective mass |mee| measurable in neutrinoless double beta decay to be in the range 0:04 ≤ |mee| ≤ 0:15 eV for the normal hierarchy and 0:06 ≤ |mee| ≤ 0:11 eV for the inverted hierarchy, both of which are within the sensitivity of the next generation experiments

A Real-time Impedance-Based Screening Assay for Drug-Induced Vascular Leakage

Vascular leakage is a serious side effect of therapies based on monoclonal antibodies or cytokines which may lead to life-threatening situations. With the steady increase of new drug development programs for large molecules, there is an urgent need for reliable tools to assess this potential liability of new medicines in a rapid and cost-effective manner. Using human umbilical vein endothelial cells (HUVECs) as a model for endothelium, we established an impedance-based assay measuring the integrity of the endothelial cell monolayer in real time. We could demonstrate that the HUVEC monolayer in our system was a relevant model as cells expressed major junctional proteins known to be responsible for maintaining tightness as well as receptors targeted by molecules known to induce vascular leakage in vivo. We assessed the time-dependent loss of barrier function using impedance and confirmed that signals obtained corresponded well to those from standard transwell assays. We assayed a series of reference molecules which led to the expected change of barrier integrity. A nonspecific cytotoxic effect could be excluded by using human fibroblasts as a nonresponder cell line. Finally, we could show reversibility of vascular permeability induced by histamine, IL-1β, or TNF-α by coincubation with established antagonists, further demonstrating relevance of this new model. Taken together, our results suggest that impedance in combination with HUVECs as a specific model can be applied to assess clinically relevant vascular leakage on an in vitro leve