Mikhail Menshikov

Differential effects of the autophagy inhibitors 3-methyladenine and chloroquine on spontaneous and TNF-α-induced neutrophil apoptosis

Autophagy and apoptosis cooperate to modulate cell survival. Neutrophils are short-lived cells and apoptosis is considered to be the major mechanism of their death. In the present study, we addressed whether autophagy regulates neutrophil apoptosis and investigated the effects of autophagy inhibition on apoptosis of human neutrophils. We first showed that the established autophagy inhibitors 3-methyladenine (MA) and chloroquine (CQ) markedly accelerated spontaneous neutrophil apoptosis as was evidenced by phosphatidylserine exposure, DNA fragmentation and caspase-3 activation. Apoptosis induced by the autophagy inhibitors was completely abrogated by a pan-caspase inhibitor Q-VD-OPh. Unexpectedly, both MA and CQ significantly delayed neutrophil apoptosis induced by TNF-α, although the inhibitors did attenuate late pro-survival effect of the cytokine. The effect was specific for TNF-α because it was not observed in the presence of other inflammation-associated cytokines (IL-1β or IL-8). The autophagy inhibitors did not modulate surface expression of TNF-α receptors in the absence or presence of TNF-α. Both MA and CQ induced a marked down-regulation of a key anti-apoptotic protein Mcl-1 but did not affect significantly the levels of another anti-apoptotic protein Bcl-XL. Finally, to confirm the effects of the pharmacological inhibition of autophagy by a genetic approach, we evaluated the consequences of siRNA-mediated autophagy suppression in neutrophil-like differentiated HL60 cells. Knockdown of ATG5 in the cells resulted in accelerated spontaneous apoptosis but attenuated TNF-α-induced apoptosis. Together, these data suggest that autophagy regulates neutrophil apoptosis in an inflammatory context-dependent manner and mediates the early pro-apoptotic effect of TNF-α in neutrophils.

Asymptotic behaviour of randomly reflecting billiards in unbounded tubular domains

We study stochastic billiards in infinite planar domains with curvilinear boundaries: that is, piecewise deterministic motion with randomness introduced via random reflections at the domain boundary. Physical motivation for the process originates with ideal gas models in the Knudsen regime, with particles reflecting off microscopically rough surfaces. We classify the process into recurrent and transient cases. We also give almost-sure results on the long-term behaviour of the location of the particle, including a super-diffusive rate of escape in the transient case. A key step in obtaining our results is to relate our process to an instance of a one-dimensional stochastic process with asymptotically zero drift, for which we prove some new almost-sure bounds of independent interest. We obtain some of these bounds via an application of general semimartingale criteria, also of some independent interest.

A Note on Transience Versus Recurrence for a Branching Random Walk in Random Environment

We consider a branching random walk in random environment on ℤd where particles perform independent simple random walks and branch, according to a given offspring distribution, at a random subset of sites whose density tends to zero at infinity. Given that initially one particle starts at the origin, we identify the critical rate of decay of the density of the branching sites separating transience from recurrence, i.e., the progeny hits the origin with probability <1 resp. =1. We show that for d≥3 there is a dichotomy in the critical rate of decay, depending on whether the mean offspring at a branching site is above or below a certain value related to the return probability of the simple random walk. The dichotomy marks a transition from local to global behavior in the progeny that hits the origin. We also consider the situation where the branching sites occur in two or more types, with different offspring distributions, and show that the classification is more subtle due to a possible interplay between the types. This note is part of a series of papers by the second author and various co-authors investigating the problem of transience versus recurrence for random motions in random media.

On the connectivity properties of the complementary set in fractal percolation models

Abstract. We study the connectivity properties of the complementary set in Poisson multiscale percolation model and in Mandelbrots percolation model in arbitrary dimension. By using a result about majorizing dependent random fields by Bernoulli fields, we prove that if the selection parameter is less than certain critical value, then, by choosing the scaling parameter large enough, we can assure that there is no percolation in the complementary set.

On a general many-dimensional excited random walk

In this paper we study a substantial generalization of the model of excited random walk introduced in [Electron. Commun. Probab. 8 (2003) 86–92] by Benjamini and Wilson. We consider a discrete-time stochastic process (Xn,n=0,1,2,…) taking values on Zd, d≥2, described as follows: when the particle visits a site for the first time, it has a uniformly-positive drift in a given direction l; when the particle is at a site which was already visited before, it has zero drift. Assuming uniform ellipticity and that the jumps of the process are uniformly bounded, we prove that the process is ballistic in the direction l so that lim infn→∞Xn⋅ln>0. A key ingredient in the proof of this result is an estimate on the probability that the process visits less than n1/2+α distinct sites by time n, where α is some positive number depending on the parameters of the model. This approach completely avoids the use of tan points and coupling methods specific to the excited random walk. Furthermore, we apply this technique to prove that the excited random walk in an i.i.d. random environment satisfies a ballistic law of large numbers and a central limit theorem.

A mixture of the exclusion process and the voter model

We consider a one-dimensional nearest-neighbour interacting particle system, which is a mixture of the simple exclusion process and the voter model. The state space is taken to be the countable set of the configurations that have a finite number of particles to the right of the origin and a finite number of empty sites to the left of it. We obtain criteria for the ergodicity and some other properties of this system using the method of Lyapunov functions.

A Markov chain model of a polling system with parameter regeneration

We study a model of a polling system i.e.\ a collection of

Explosion, implosion, and moments of passage times for continuous-time Markov chains: a semimartingale approach

d

Extracellular acidosis promotes neutrophil transdifferentiation to MHC class II-expressing cells

queues with a single server that switches from queue to queue. The service time distribution and arrival rates change randomly every time a queue is emptied. This model is mapped to a mathematically equivalent model of a random walk with random choice of transition probabilities, a model which is of independent interest. All our results are obtained using methods from the constructive theory of Markov chains. We determine conditions for the existence of polynomial moments of hitting times for the random walk. An unusual phenomenon of thickness of the region of null recurrence for both the random walk and the queueing model is also proved.

Periodicity in the transient regime of exhaustive polling systems

We establish general theorems quantifying the notion of recurrence–through an estimation of the moments of passage times–for irreducible continuous-time Markov chains on countably infinite state spaces. Sharp conditions of occurrence of the phenomenon of explosion are also obtained. A new phenomenon of implosion is introduced and sharp conditions for its occurrence are proven. The general results are illustrated by treating models having a difficult behaviour even in discrete time.