Selective miRNA disruption in T reg cells leads to uncontrolled autoimmunity

A new regulatory T (T reg) cell–specific, FoxP3-GFP-hCre bacterial artificial chromosome transgenic mouse was crossed to a conditional Dicer knockout (KO) mouse strain to analyze the role of microRNAs (miRNAs) in the development and function of T reg cells. Although thymic T reg cells developed normally in this setting, the cells showed evidence of altered differentiation and dysfunction in the periphery. Dicer-deficient T reg lineage cells failed to remain stable, as a subset of cells down-regulated the T reg cell–specific transcription factor FoxP3, whereas the majority expressed altered levels of multiple genes and proteins (including Neuropilin 1, glucocorticoid-induced tumor necrosis factor receptor, and cytotoxic T lymphocyte antigen 4) associated with the T reg cell fingerprint. In fact, a significant percentage of the T reg lineage cells took on a T helper cell memory phenotype including increased levels of CD127, interleukin 4, and interferon γ. Importantly, Dicer-deficient T reg cells lost suppression activity in vivo; the mice rapidly developed fatal systemic autoimmune disease resembling the FoxP3 KO phenotype. These results support a central role for miRNAs in maintaining the stability of differentiated T reg cell function in vivo and homeostasis of the adaptive immune system

Soft and hard wall in a stochastic reaction diffusion equation

We consider a stochastically perturbed reaction diffusion equation in a bounded interval, with boundary conditions imposing the two stable phases at the endpoints. We investigate the asymptotic behavior of the front separating the two stable phases, as the intensity of the noise vanishes and the size of the interval diverges. In particular, we prove that, in a suitable scaling limit, the front evolves according to a one-dimensional diffusion process with a non-linear drift accounting for a "soft" repulsion from the boundary. We finally show how a "hard" repulsion can be obtained by an extra diffusive scaling.Comment: 33 page

Finite to infinite steady state solutions, bifurcations of an integro-differential equation

We consider a bistable integral equation which governs the stationary solutions of a convolution model of solid--solid phase transitions on a circle. We study the bifurcations of the set of the stationary solutions as the diffusion coefficient is varied to examine the transition from an infinite number of steady states to three for the continuum limit of the semi--discretised system. We show how the symmetry of the problem is responsible for the generation and stabilisation of equilibria and comment on the puzzling connection between continuity and stability that exists in this problem

Avalanche of Bifurcations and Hysteresis in a Model of Cellular Differentiation

Cellular differentiation in a developping organism is studied via a discrete bistable reaction-diffusion model. A system of undifferentiated cells is allowed to receive an inductive signal emenating from its environment. Depending on the form of the nonlinear reaction kinetics, this signal can trigger a series of bifurcations in the system. Differentiation starts at the surface where the signal is received, and cells change type up to a given distance, or under other conditions, the differentiation process propagates through the whole domain. When the signal diminishes hysteresis is observed

Practice Parameter: Therapies for Benign Paroxysmal Positional Vertigo (An Evidence-Based Review): Report of the Quality Standards Subcommittee of the American Academy of Neurologysymbol Symbol

American Academy of Neurology; BPPV = benign paroxysmal positional vertigo; CONSORT = Consolidated Standards of Reporting Trials; CRP = canalith repositioning procedure; NNT = number needed to treat

Domain Walls in Non-Equilibrium Systems and the Emergence of Persistent Patterns

Domain walls in equilibrium phase transitions propagate in a preferred direction so as to minimize the free energy of the system. As a result, initial spatio-temporal patterns ultimately decay toward uniform states. The absence of a variational principle far from equilibrium allows the coexistence of domain walls propagating in any direction. As a consequence, *persistent* patterns may emerge. We study this mechanism of pattern formation using a non-variational extension of Landau's model for second order phase transitions. PACS numbers: 05.70.Fh, 42.65.Pc, 47.20.Ky, 82.20MjComment: 12 pages LaTeX, 5 postscript figures To appear in Phys. Rev.

A Decision Analysis Evaluating Screening for Kidney Cancer Using Focused Renal Ultrasound

Background Screening for renal cell carcinoma (RCC) has been identified as a key research priority; however, no randomised control trials have been performed. Value of information analysis can determine whether further research on this topic is of value. Objective To determine (1) whether current evidence suggests that screening is potentially cost effective and, if so, (2) in which age/sex groups, (3) identify evidence gaps, and (4) estimate the value of further research to close those gaps. Design, setting, and participants A decision model was developed evaluating screening in asymptomatic individuals in the UK. A National Health Service perspective was adopted. Intervention A single focused renal ultrasound scan compared with standard of care (no screening). Outcome measurements and statistical analysis Expected lifetime costs, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratio (ICER), discounted at 3.5% per annum. Results and limitations Given a prevalence of RCC of 0.34% (0.18–0.54%), screening 60-yr-old men resulted in an ICER of £18 092/QALY (€22 843/QALY). Given a prevalence of RCC of 0.16% (0.08–0.25%), screening 60-yr-old women resulted in an ICER of £37 327/QALY (€47 129/QALY). In the one-way sensitivity analysis, the ICER was <£30 000/QALY as long as the prevalence of RCC was ≥0.25% for men and ≥0.2% for women at age 60 yr. Given the willingness to pay a threshold of £30 000/QALY (€37 878/QALY), the population-expected values of perfect information were £194 million (€244 million) and £97 million (€123 million) for 60-yr-old men and women, respectively. The expected value of perfect parameter information suggests that the prevalence of RCC and stage shift associated with screening are key research priorities. Conclusions Current evidence suggests that one-off screening of 60-yr-old men is potentially cost effective and that further research into this topic would be of value to society. Patient summary Economic modelling suggests that screening 60-yr-old men for kidney cancer using ultrasound may be a good use of resources and that further research on this topic should be performed

Phase-Field Formulation for Quantitative Modeling of Alloy Solidification

A phase-field formulation is introduced to simulate quantitatively microstructural pattern formation in alloys. The thin-interface limit of this formulation yields a much less stringent restriction on the choice of interface thickness than previous formulations and permits to eliminate non-equilibrium effects at the interface. Dendrite growth simulations with vanishing solid diffusivity show that both the interface evolution and the solute profile in the solid are well resolved

Application of elastostatic Green function tensor technique to electrostriction in cubic, hexagonal and orthorhombic crystals

The elastostatic Green function tensor approach, which was recently used to treat electrostriction in numerical simulation of domain structure formation in cubic ferroelectrics, is reviewed and extended to the crystals of hexagonal and orthorhombic symmetry. The tensorial kernels appearing in the expressions for effective nonlocal interaction of electrostrictive origin are derived explicitly and their physical meaning is illustrated on simple examples. It is argued that the bilinear coupling between the polarization gradients and elastic strain should be systematically included in the Ginzburg-Landau free energy expansion of electrostrictive materials.Comment: 4 page