Targeting BAFF and APRIL in systemic lupus erythematosus and other antibody-associated diseases.

The B cell-stimulating molecules, BAFF (B cell activating factor) and APRIL (a proliferation-inducing ligand), are critical factors in the maintenance of the B cell pool and humoral immunity. In addition, BAFF and APRIL are involved in the pathogenesis of a number of human autoimmune diseases, with elevated levels of these cytokines detected in the sera of patients with systemic lupus erythematosus (SLE), IgA nephropathy, Sjögren's syndrome, and rheumatoid arthritis. As such, both molecules are rational targets for new therapies in B cell-driven autoimmune diseases, and several inhibitors of BAFF or BAFF and APRIL together have been investigated in clinical trials. These include the BAFF/APRIL dual inhibitor, atacicept, and the BAFF inhibitor, belimumab, which is approved as an add-on therapy for patients with active SLE. Post hoc analyses of these trials indicate that baseline serum levels of BAFF and BAFF/APRIL correlate with treatment response to belimumab and atacicept, respectively, suggesting a role for the two molecules as predictive biomarkers. It will, however, be important to refine future testing to identify active forms of BAFF and APRIL in the circulation, as well as to distinguish between homotrimer and heteromer configurations. In this review, we discuss the rationale for dual BAFF/APRIL inhibition versus single BAFF inhibition in autoimmune disease, by focusing on the similarities and differences between the physiological and pathogenic roles of the two molecules. A summary of the preclinical and clinical data currently available is also presented

The Excursion Set Theory of Halo Mass Functions, Halo Clustering, and Halo Growth

I review the excursion set theory (EST) of dark matter halo formation and clustering. I recount the Press-Schechter argument for the mass function of bound objects and review the derivation of the Press-Schechter mass function in EST. The EST formalism is powerful and can be applied to numerous problems. I review the EST of halo bias and the properties of void regions. I spend considerable time reviewing halo growth in the EST. This section culminates with descriptions of two Monte Carlo methods for generating halo mass accretion histories. In the final section, I emphasize that the standard EST approach is the result of several simplifying assumptions. Dropping these assumptions can lead to more faithful predictions and a more versatile formalism. One such assumption is the constant height of the barrier for nonlinear collapse. I review implementations of the excursion set approach with arbitrary barrier shapes. An application of this is the now well-known improvement to standard EST that follows from the ellipsoidal-collapse barrier. Additionally, I emphasize that the statement that halo accretion histories are independent of halo environments is a simplifying assumption, rather than a prediction of the theory. I review the method for constructing correlated random walks of the density field in more general cases. I construct a simple toy model with correlated walks and I show that excursion set theory makes a qualitatively simple and general prediction for the relation between halo accretion histories and halo environments: regions of high density preferentially contain late-forming halos and conversely for regions of low density. I conclude with a brief discussion of this prediction in the context of recent numerical studies of the environmental dependence of halo properties. (Abridged)Comment: 62 pages, 19 figures. Review article based on lectures given at the Sixth Summer School of the Helmholtz Institute for Supercomputational Physics. Accepted for Publication in IJMPD. Comments Welcom

Penetration depth of low-coherence enhanced backscattered light in sub-diffusion regime

The mechanisms of photon propagation in random media in the diffusive multiple scattering regime have been previously studied using diffusion approximation. However, similar understanding in the low-order (sub-diffusion) scattering regime is not complete due to difficulties in tracking photons that undergo very few scatterings events. Recent developments in low-coherence enhanced backscattering (LEBS) overcome these difficulties and enable probing photons that travel very short distances and undergo only a few scattering events. In LEBS, enhanced backscattering is observed under illumination with spatial coherence length L_sc less than the scattering mean free path l_s. In order to understand the mechanisms of photon propagation in LEBS in the subdiffusion regime, it is imperative to develop analytical and numerical models that describe the statistical properties of photon trajectories. Here we derive the probability distribution of penetration depth of LEBS photons and report Monte Carlo numerical simulations to support our analytical results. Our results demonstrate that, surprisingly, the transport of photons that undergo low-order scattering events has only weak dependence on the optical properties of the medium (l_s and anisotropy factor g) and strong dependence on the spatial coherence length of illumination, L_sc, relative to those in the diffusion regime. More importantly, these low order scattering photons typically penetrate less than l_s into the medium due to low spatial coherence length of illumination and their penetration depth is proportional to the one-third power of the coherence volume (i.e. [l_s \pi L_sc^2 ]^1/3).Comment: 32 pages(including 7 figures), modified version to appear in Phys. Rev.

An exact analytical solution for generalized growth models driven by a Markovian dichotomic noise

Logistic growth models are recurrent in biology, epidemiology, market models, and neural and social networks. They find important applications in many other fields including laser modelling. In numerous realistic cases the growth rate undergoes stochastic fluctuations and we consider a growth model with a stochastic growth rate modelled via an asymmetric Markovian dichotomic noise. We find an exact analytical solution for the probability distribution providing a powerful tool with applications ranging from biology to astrophysics and laser physics

Brownian Simulations and Uni-Directional Flux in Diffusion

Brownian dynamics simulations require the connection of a small discrete simulation volume to large baths that are maintained at fixed concentrations and voltages. The continuum baths are connected to the simulation through interfaces, located in the baths sufficiently far from the channel. Average boundary concentrations have to be maintained at their values in the baths by injecting and removing particles at the interfaces. The particles injected into the simulation volume represent a unidirectional diffusion flux, while the outgoing particles represent the unidirectional flux in the opposite direction. The classical diffusion equation defines net diffusion flux, but not unidirectional fluxes. The stochastic formulation of classical diffusion in terms of the Wiener process leads to a Wiener path integral, which can split the net flux into unidirectional fluxes. These unidirectional fluxes are infinite, though the net flux is finite and agrees with classical theory. We find that the infinite unidirectional flux is an artifact caused by replacing the Langevin dynamics with its Smoluchowski approximation, which is classical diffusion. The Smoluchowski approximation fails on time scales shorter than the relaxation time $1/\gamma$ of the Langevin equation. We find the unidirectional flux (source strength) needed to maintain average boundary concentrations in a manner consistent with the physics of Brownian particles. This unidirectional flux is proportional to the concentration and inversely proportional to $\sqrt{\Delta t}$ to leading order. We develop a BD simulation that maintains fixed average boundary concentrations in a manner consistent with the actual physics of the interface and without creating spurious boundary layers

Random paths and current fluctuations in nonequilibrium statistical mechanics

An overview is given of recent advances in nonequilibrium statistical mechanics about the statistics of random paths and current fluctuations. Although statistics is carried out in space for equilibrium statistical mechanics, statistics is considered in time or spacetime for nonequilibrium systems. In this approach, relationships have been established between nonequilibrium properties such as the transport coefficients, the thermodynamic entropy production, or the affinities, and quantities characterizing the microscopic Hamiltonian dynamics and the chaos or fluctuations it may generate. This overview presents results for classical systems in the escape-rate formalism, stochastic processes, and open quantum systems

Algorithm for normal random numbers

We propose a simple algorithm for generating normally distributed pseudo random numbers. The algorithm simulates N molecules that exchange energy among themselves following a simple stochastic rule. We prove that the system is ergodic, and that a Maxwell like distribution that may be used as a source of normally distributed random deviates follows when N tends to infinity. The algorithm passes various performance tests, including Monte Carlo simulation of a finite 2D Ising model using Wolff's algorithm. It only requires four simple lines of computer code, and is approximately ten times faster than the Box-Muller algorithm.Comment: 5 pages, 3 encapsulated Postscript Figures. Submitted to Phys.Rev.Letters. For related work, see http://pipe.unizar.es/~jf

Theory of Adiabatic fluctuations : third-order noise

We consider the response of a dynamical system driven by external adiabatic fluctuations. Based on the `adiabatic following approximation' we have made a systematic separation of time-scales to carry out an expansion in $\alpha |\mu|^{-1}$, where $\alpha$ is the strength of fluctuations and $|\mu|$ is the damping rate. We show that probability distribution functions obey the differential equations of motion which contain third order terms (beyond the usual Fokker-Planck terms) leading to non-Gaussian noise. The problem of adiabatic fluctuations in velocity space which is the counterpart of Brownian motion for fast fluctuations, has been solved exactly. The characteristic function and the associated probability distribution function are shown to be of stable form. The linear dissipation leads to a steady state which is stable and the variances and higher moments are shown to be finite.Comment: Plain Latex, no figures, 28 pages; to appear in J. Phys.

Probing Ion-Ion and Electron-Ion Correlations in Liquid Metals within the Quantum Hypernetted Chain Approximation

We use the Quantum Hypernetted Chain Approximation (QHNC) to calculate the ion-ion and electron-ion correlations for liquid metallic Li, Be, Na, Mg, Al, K, Ca, and Ga. We discuss trends in electron-ion structure factors and radial distribution functions, and also calculate the free-atom and metallic-atom form-factors, focusing on how bonding effects affect the interpretation of X-ray scattering experiments, especially experimental measurements of the ion-ion structure factor in the liquid metallic phase.Comment: RevTeX, 19 pages, 7 figure

"Engaging with birth stories in pregnancy: a hermeneutic phenomenological study of women's experiences across two generations"

BACKGROUND: The birth story has been widely understood as a crucial source of knowledge about childbirth. What has not been reported is the effect that birth stories may have on primigravid women's understandings of birth. Findings are presented from a qualitative study exploring how two generations of women came to understand birth in the milieu of other's stories. The prior assumption was that birth stories must surely have a positive or negative influence on listeners, steering them towards either medical or midwifery-led models of care. METHODS: A Heideggerian hermeneutic phenomenological approach was used. Twenty UK participants were purposively selected and interviewed. Findings from the initial sample of 10 women who were pregnant in 2012 indicated that virtual media was a primary source of birth stories. This led to recruitment of a second sample of 10 women who gave birth in the 1970s-1980s, to determine whether they were more able to translate information into knowledge via stories told through personal contact and not through virtual technologies RESULTS: Findings revealed the experience of 'being-in-the-world' of birth and of stories in that world. From a Heideggerian perspective, the birth story was constructed through 'idle talk' (the taken for granted assumptions of things, which come into being through language). Both oral stories and those told through technology were described as the 'modern birth story'. The first theme 'Stories are difficult like that', examines the birth story as problematic and considers how stories shape meaning. The second 'It's a generational thing', considers how women from two generations came to understand what their experience might be. The third 'Birth in the twilight of certainty,' examines women's experience of Being in a system of birth as constructed, portrayed and sustained in the stories being shared. CONCLUSIONS: The women pregnant in 2012 framed their expectations in the language of choice, whilst the women who birthed in the 1970s-1980s framed their experience in the language of safety. For both, however, the world of birth was the same; saturated with, and only legitimised by the birth of a healthy baby. Rather than creating meaningful understanding, the 'idle talk' of birth made both cohorts fearful of leaving the relative comfort of the 'system', and of claiming an alternative birth