Polarised epithelial monolayers of the gastric mucosa reveal insights into mucosal homeostasis and defence against infection

Objective Helicobacter pylori causes life-long colonisation of the gastric mucosa, leading to chronic inflammation with increased risk of gastric cancer. Research on the pathogenesis of this infection would strongly benefit from an authentic human in vitro model. Design Antrum-derived gastric glands from surgery specimens served to establish polarised epithelial monolayers via a transient air–liquid interface culture stage to study cross-talk with H. pylori and the adjacent stroma. Results The resulting ‘mucosoid cultures’, so named because they recapitulate key characteristics of the gastric mucosa, represent normal stem cell-driven cultures that can be passaged for months. These highly polarised columnar epithelial layers encompass the various gastric antral cell types and secrete mucus at the apical surface. By default, they differentiate towards a foveolar, MUC5AC-producing phenotype, whereas Wnt signalling stimulates proliferation of MUC6-producing cells and preserves stemness—reminiscent of the gland base. Stromal cells from the lamina propria secrete Wnt inhibitors, antagonising stem-cell niche signalling and inducing differentiation. On infection with H. pylori, a strong inflammatory response is induced preferentially in the undifferentiated basal cell phenotype. Infection of cultures for several weeks produces foci of viable bacteria and a persistent inflammatory condition, while the secreted mucus establishes a barrier that only few bacteria manage to overcome. Conclusion Gastric mucosoid cultures faithfully reproduce the features of normal human gastric epithelium, enabling new approaches for investigating the interaction of H. pylori with the epithelial surface and the cross-talk with the basolateral stromal compartment. Our observations provide striking insights in the regulatory circuits of inflammation and defence.</p

Implementation of higher-order absorbing boundary conditions for the Einstein equations

We present an implementation of absorbing boundary conditions for the Einstein equations based on the recent work of Buchman and Sarbach. In this paper, we assume that spacetime may be linearized about Minkowski space close to the outer boundary, which is taken to be a coordinate sphere. We reformulate the boundary conditions as conditions on the gauge-invariant Regge-Wheeler-Zerilli scalars. Higher-order radial derivatives are eliminated by rewriting the boundary conditions as a system of ODEs for a set of auxiliary variables intrinsic to the boundary. From these we construct boundary data for a set of well-posed constraint-preserving boundary conditions for the Einstein equations in a first-order generalized harmonic formulation. This construction has direct applications to outer boundary conditions in simulations of isolated systems (e.g., binary black holes) as well as to the problem of Cauchy-perturbative matching. As a test problem for our numerical implementation, we consider linearized multipolar gravitational waves in TT gauge, with angular momentum numbers l=2 (Teukolsky waves), 3 and 4. We demonstrate that the perfectly absorbing boundary condition B_L of order L=l yields no spurious reflections to linear order in perturbation theory. This is in contrast to the lower-order absorbing boundary conditions B_L with L<l, which include the widely used freezing-Psi_0 boundary condition that imposes the vanishing of the Newman-Penrose scalar Psi_0.Comment: 25 pages, 9 figures. Minor clarifications. Final version to appear in Class. Quantum Grav

Internal states of model isotropic granular packings. III. Elastic properties

In this third and final paper of a series, elastic properties of numerically simulated isotropic packings of spherical beads assembled by different procedures and subjected to a varying confining pressure P are investigated. In addition P, which determines the stiffness of contacts by Hertz's law, elastic moduli are chiefly sensitive to the coordination number, the possible values of which are not necessarily correlated with the density. Comparisons of numerical and experimental results for glass beads in the 10kPa-10MPa range reveal similar differences between dry samples compacted by vibrations and lubricated packings. The greater stiffness of the latter, in spite of their lower density, can hence be attributed to a larger coordination number. Voigt and Reuss bounds bracket bulk modulus B accurately, but simple estimation schemes fail for shear modulus G, especially in poorly coordinated configurations under low P. Tenuous, fragile networks respond differently to changes in load direction, as compared to load intensity. The shear modulus, in poorly coordinated packings, tends to vary proportionally to the degree of force indeterminacy per unit volume. The elastic range extends to small strain intervals, in agreement with experimental observations. The origins of nonelastic response are discussed. We conclude that elastic moduli provide access to mechanically important information about coordination numbers, which escape direct measurement techniques, and indicate further perspectives.Comment: Published in Physical Review E 25 page

The UN in the lab

We consider two alternatives to inaction for governments combating terrorism, which we term Defense and Prevention. Defense consists of investing in resources that reduce the impact of an attack, and generates a negative externality to other governments, making their countries a more attractive objective for terrorists. In contrast, Prevention, which consists of investing in resources that reduce the ability of the terrorist organization to mount an attack, creates a positive externality by reducing the overall threat of terrorism for all. This interaction is captured using a simple 3×3 “Nested Prisoner’s Dilemma” game, with a single Nash equilibrium where both countries choose Defense. Due to the structure of this interaction, countries can benefit from coordination of policy choices, and international institutions (such as the UN) can be utilized to facilitate coordination by implementing agreements to share the burden of Prevention. We introduce an institution that implements a burden-sharing policy for Prevention, and investigate experimentally whether subjects coordinate on a cooperative strategy more frequently under different levels of cost sharing. In all treatments, burden sharing leaves the Prisoner’s Dilemma structure and Nash equilibrium of the game unchanged. We compare three levels of burden sharing to a baseline in a between-subjects design, and find that burden sharing generates a non-linear effect on the choice of the efficient Prevention strategy and overall performance. Only an institution supporting a high level of mandatory burden sharing generates a significant improvement in the use of the Prevention strategy

Edoxaban: an update on the new oral direct factor Xa inhibitor.

Edoxaban is a once-daily oral anticoagulant that rapidly and selectively inhibits factor Xa in a concentration-dependent manner. This review describes the extensive clinical development program of edoxaban, including phase III studies in patients with non-valvular atrial fibrillation (NVAF) and symptomatic venous thromboembolism (VTE). The ENGAGE AF-TIMI 48 study (N = 21,105; mean CHADS2 score 2.8) compared edoxaban 60 mg once daily (high-dose regimen) and edoxaban 30 mg once daily (low-dose regimen) with dose-adjusted warfarin [international normalized ratio (INR) 2.0-3.0] and found that both regimens were non-inferior to warfarin in the prevention of stroke and systemic embolism in patients with NVAF. Both edoxaban regimens also provided significant reductions in the risk of hemorrhagic stroke, cardiovascular mortality, major bleeding and intracranial bleeding. The Hokusai-VTE study (N = 8,292) in patients with symptomatic VTE had a flexible treatment duration of 3-12 months and found that following initial heparin, edoxaban 60 mg once daily was non-inferior to dose-adjusted warfarin (INR 2.0-3.0) for the prevention of recurrent VTE, and also had a significantly lower risk of bleeding events. Both studies randomized patients at moderate-to-high risk of thromboembolic events and were further designed to simulate routine clinical practice as much as possible, with edoxaban dose reduction (halving dose) at randomisation or during the study if required, a frequently monitored and well-controlled warfarin group, a well-monitored transition period at study end and a flexible treatment duration in Hokusai-VTE. Given the phase III results obtained, once-daily edoxaban may soon be a key addition to the range of antithrombotic treatment options

Hamiltonian 2-forms in Kahler geometry, III Extremal metrics and stability

This paper concerns the explicit construction of extremal Kaehler metrics on total spaces of projective bundles, which have been studied in many places. We present a unified approach, motivated by the theory of hamiltonian 2-forms (as introduced and studied in previous papers in the series) but this paper is largely independent of that theory. We obtain a characterization, on a large family of projective bundles, of those `admissible' Kaehler classes (i.e., the ones compatible with the bundle structure in a way we make precise) which contain an extremal Kaehler metric. In many cases, such as on geometrically ruled surfaces, every Kaehler class is admissible. In particular, our results complete the classification of extremal Kaehler metrics on geometrically ruled surfaces, answering several long-standing questions. We also find that our characterization agrees with a notion of K-stability for admissible Kaehler classes. Our examples and nonexistence results therefore provide a fertile testing ground for the rapidly developing theory of stability for projective varieties, and we discuss some of the ramifications. In particular we obtain examples of projective varieties which are destabilized by a non-algebraic degeneration.Comment: 40 pages, sequel to math.DG/0401320 and math.DG/0202280, but largely self-contained; partially replaces and extends math.DG/050151