Slow Conduction in the Border Zones of Patchy Fibrosis Stabilizes the Drivers for Atrial Fibrillation: Insights from Multi-Scale Human Atrial Modeling

Introduction: The genesis of atrial fibrillation (AF) and success of AF ablation therapy have been strongly linked with atrial fibrosis. Increasing evidence suggests that patient-specific distributions of fibrosis may determine the locations of electrical drivers (rotors) sustaining AF, but the underlying mechanisms are incompletely understood. This study aims to elucidate a missing mechanistic link between patient-specific fibrosis distributions and AF drivers. Methods: 3D atrial models integrated human atrial geometry, rule-based fiber orientation, region-specific electrophysiology, and AF-induced ionic remodeling. A novel detailed model for an atrial fibroblast was developed, and effects of myocyte-fibroblast (M-F) coupling were explored at single-cell, 1D tissue and 3D atria levels. Left atrial LGE MRI datasets from 3 chronic AF patients were segmented to provide the patient-specific distributions of fibrosis. The data was non-linearly registered and mapped to the 3D atria model. Six distinctive fibrosis levels (0–healthy tissue, 5–dense fibrosis) were identified based on LGE MRI intensity and modeled as progressively increasing M-F coupling and decreasing atrial tissue coupling. Uniform 3D atrial model with diffuse (level 2) fibrosis was considered for comparison. Results: In single cells and tissue, the largest effect of atrial M-F coupling was on the myocyte resting membrane potential, leading to partial inactivation of sodium current and reduction of conduction velocity (CV). In the 3D atria, further to the M-F coupling, effects of fibrosis on tissue coupling greatly reduce atrial CV. AF was initiated by fast pacing in each 3D model with either uniform or patient-specific fibrosis. High variation in fibrosis distributions between the models resulted in varying complexity of AF, with several drivers emerging. In the diffuse fibrosis models, waves randomly meandered through the atria, whereas in each the patient-specific models, rotors stabilized in fibrotic regions. The rotors propagated slowly around the border zones of patchy fibrosis (levels 3–4), failing to spread into inner areas of dense fibrosis. Conclusion: Rotors stabilize in the border zones of patchy fibrosis in 3D atria, where slow conduction enable the development of circuits within relatively small regions. Our results can provide a mechanistic explanation for the clinical efficacy of ablation around fibrotic regions

Promotion of cooperation induced by nonlinear attractive effect in spatial Prisoner's Dilemma game

We introduce nonlinear attractive effects into a spatial Prisoner's Dilemma game where the players located on a square lattice can either cooperate with their nearest neighbors or defect. In every generation, each player updates its strategy by firstly choosing one of the neighbors with a probability proportional to $\mathcal{A}^\alpha$ denoting the attractiveness of the neighbor, where $\mathcal{A}$ is the payoff collected by it and $\alpha$ ($\geq$0) is a free parameter characterizing the extent of the nonlinear effect; and then adopting its strategy with a probability dependent on their payoff difference. Using Monte Carlo simulations, we investigate the density $\rho_C$ of cooperators in the stationary state for different values of $\alpha$. It is shown that the introduction of such attractive effect remarkably promotes the emergence and persistence of cooperation over a wide range of the temptation to defect. In particular, for large values of $\alpha$, i.e., strong nonlinear attractive effects, the system exhibits two absorbing states (all cooperators or all defectors) separated by an active state (coexistence of cooperators and defectors) when varying the temptation to defect. In the critical region where $\rho_C$ goes to zero, the extinction behavior is power law-like $\rho_C$ $\sim$ $(b_c-b)^{\beta}$, where the exponent $\beta$ accords approximatively with the critical exponent ($\beta\approx0.584$) of the two-dimensional directed percolation and depends weakly on the value of $\alpha$.Comment: 7 pages, 4 figure

Analysis of United Kingdom Off-Highway Construction Machinery Market and Its Consumers Using New-Sales Data

The off-highway construction machinery market and its consumers have attracted minimal previous research. This study addresses that void by analyzing annual United Kingdom (UK) (volume/portfolio) new-sales data for the 10 most popular products within that market, 1990–2010 inclusive. Graphical, descriptive statistical, Pearson-correlational, autocorrelational, and elementary modeling are employed to identify contrasts in sales regarding (1) high- and low-volume items; (2) growth trends and significant recessionary effects on volumes; (3) a demand change point circa 1997, since when annual product portfolio has changed little; and (4) product associations in consumer demand. Significant association is demonstrated between demand and construction output, especially with the value of new housing. Subsequently, consumption of wheeled loaders is modeled using construction volume, and demand for mini and crawler excavators is modeled using new-housing data. Time series trends for these machinery types are presented and forecast through 2015. The primary contribution of this study is a deeper understanding of the UK new-machinery market and the predilections of its consumers over the last two decades (to present)

Degradation of human kininogens with the release of kinin peptides by extracellular proteinases of Candida spp.

The secretion of proteolytic enzymes by pathogenic microorganisms is one of the most successful strategies used by pathogens to colonize and infect the host organism. The extracellular microbial proteinases can seriously deregulate the homeostatic proteolytic cascades of the host, including the kinin-forming system, repeatedly reported to he activated during bacterial infection. The current study assigns a kinin-releasing activity to secreted proteinases of Candida spp. yeasts, the major fungal pathogens of humans. Of several Candida species studied, C. parapsilosis and C. albicans in their invasive filamentous forms are shown to produce proteinases which most effectively degrade proteinaceous kinin precursors, the kininogens. These enzymes, classified as aspartyl proteinases, have the highest kininogen-degrading activity at low pH (approx. 3.5), but the associated production of bradykinin-related peptides from a small fraction of kininogen molecules is optimal at neutral pH (6.5). The peptides effectively interact with cellular B2-type kinin receptors. Moreover, kinin-related peptides capable of interacting with inflammation-induced B1-type receptors are also formed, but with a reversed pH dependence. The presented variability of the potential extracellular kinin production by secreted aspartyl proteinases of Candida spp. is consistent with the known adaptability of these opportunistic pathogens to different niches in the host organism

Phase transitions and volunteering in spatial public goods games

Cooperative behavior among unrelated individuals in human and animal societies represents a most intriguing puzzle to scientists in various disciplines. Here we present a simple yet effective mechanism promoting cooperation under full anonymity by allowing for voluntary participation in public goods games. This natural extension leads to rock--scissors--paper type cyclic dominance of the three strategies cooperate, defect and loner i.e. those unwilling to participate in the public enterprise. In spatial settings with players arranged on a regular lattice this results in interesting dynamical properties and intriguing spatio-temporal patterns. In particular, variations of the value of the public good leads to transitions between one-, two- and three-strategy states which are either in the class of directed percolation or show interesting analogies to Ising-type models. Although volunteering is incapable of stabilizing cooperation, it efficiently prevents successful spreading of selfish behavior and enables cooperators to persist at substantial levels.Comment: 4 pages, 5 figure

Sirtuin1 Over-Expression Does Not Impact Retinal Vascular and Neuronal Degeneration in a Mouse Model of Oxygen-Induced Retinopathy

Proliferative retinopathy is a leading cause of blindness, including retinopathy of prematurity (ROP) in children and diabetic retinopathy in adults. Retinopathy is characterized by an initial phase of vessel loss, leading to tissue ischemia and hypoxia, followed by sight threatening pathologic neovascularization in the second phase. Previously we found that Sirtuin1 (Sirt1), a metabolically dependent protein deacetylase, regulates vascular regeneration in a mouse model of oxygen-induced proliferative retinopathy (OIR), as neuronal depletion of Sirt1 in retina worsens retinopathy. In this study we assessed whether over-expression of Sirtuin1 in retinal neurons and vessels achieved by crossing Sirt1 over-expressing flox mice with Nestin-Cre mice or Tie2-Cre mice, respectively, may protect against retinopathy. We found that over-expression of Sirt1 in Nestin expressing retinal neurons does not impact vaso-obliteration or pathologic neovascularization in OIR, nor does it influence neuronal degeneration in OIR. Similarly, increased expression of Sirt1 in Tie2 expressing vascular endothelial cells and monocytes/macrophages does not protect retinal vessels in OIR. In addition to the genetic approaches, dietary supplement with Sirt1 activators, resveratrol or SRT1720, were fed to wild type mice with OIR. Neither treatment showed significant vaso-protective effects in retinopathy. Together these results indicate that although endogenous Sirt1 is important as a stress-induced protector in retinopathy, over-expression of Sirt1 or treatment with small molecule activators at the examined doses do not provide additional protection against retinopathy in mice. Further studies are needed to examine in depth whether increasing levels of Sirt1 may serve as a potential therapeutic approach to treat or prevent retinopathy

Secondary LS category of measured laminations

In the author's Ph.D., a version of the tangential LS category for foliated spaces depending on a transverse invariant measure, called the measured category, was introduced. Unfortunately, the measured category vanishes easily. When it is zero, the rate of convergence to zero of the quantity involved in the definition, by taking arbitrarily large homotopies, gives a new invariant, called the secondary measured category. Several versions of classical results are proved for the secondary measured category. It is also shown that the secondary measured category is a transverse invariant related to the growth of (pseudo)groups. The equality between secondary category and the growth of a group is done in the case of free suspensions by Rohlin groups.Comment: 14 pages. arXiv admin note: substantial text overlap with arXiv:1112.500

Measurement of islet cell antibodies in the Type 1 Diabetes Genetics Consortium: efforts to harmonize procedures among the laboratories

Background and Purpose Three network laboratories measured antibodies to islet autoantigens. Antibodies to glutamic acid decarboxylase (GAD65 [GADA]) and the intracellular portion of protein tyrosine phosphatase (IA-2ic [IA-2A]) were measured by similar, but not identical, methods in samples from participants in the Type 1 Diabetes Genetics Consortium (T1DGC)

Synthesis and Detection of Oxygen-18 Labeled Phosphate

Phosphorus (P) has only one stable isotope and therefore tracking P dynamics in ecosystems and inferring sources of P loading to water bodies have been difficult. Researchers have recently employed the natural abundance of the ratio of 18O/16O of phosphate to elucidate P dynamics. In addition, phosphate highly enriched in oxygen-18 also has potential to be an effective tool for tracking specific sources of P in the environment, but has so far been used sparingly, possibly due to unavailability of oxygen-18 labeled phosphate (OLP) and uncertainty in synthesis and detection. One objective of this research was to develop a simple procedure to synthesize highly enriched OLP. Synthesized OLP is made up of a collection of species that contain between zero and four oxygen-18 atoms and, as a result, the second objective of this research was to develop a method to detect and quantify each OLP species. OLP was synthesized by reacting either PCl5 or POCl3 with water enriched with 97 atom % oxygen-18 in ambient atmosphere under a fume hood. Unlike previous reports, we observed no loss of oxygen-18 enrichment during synthesis. Electrospray ionization mass spectrometertry (ESI-MS) was used to detect and quantify each species present in OLP. OLP synthesized from POCl3 contained 1.2% P18O16O3, 18.2% P18O216O2, 67.7% P18O316O, and 12.9% P18O4, and OLP synthesized from PCl5 contained 0.7% P16O4, 9.3% P18O316O, and 90.0% P18O4. We found that OLP can be synthesized using a simple procedure in ambient atmosphere without the loss of oxygen-18 enrichment and ESI-MS is an effective tool to detect and quantify OLP that sheds light on the dynamics of synthesis in ways that standard detection methods cannot