The end of HIV: Still a very long way to go, but progress continues.

In an Editorial accompanying PLOS Medicine's Special Issue on Advances in Prevention, Treatment and Cure of HIV/AIDS, Guest Editors Steven Deeks, Sharon Lewin, and Linda-Gail Bekker discuss priorities in the field and the content of the issue

Digging into Lipid Membrane Permeation for Cardiac Ion Channel Blocker d-Sotalol with All-Atom Simulations.

Interactions of drug molecules with lipid membranes play crucial role in their accessibility of cellular targets and can be an important predictor of their therapeutic and safety profiles. Very little is known about spatial localization of various drugs in the lipid bilayers, their active form (ionization state) or translocation rates and therefore potency to bind to different sites in membrane proteins. All-atom molecular simulations may help to map drug partitioning kinetics and thermodynamics, thus providing in-depth assessment of drug lipophilicity. As a proof of principle, we evaluated extensively lipid membrane partitioning of d-sotalol, well-known blocker of a cardiac potassium channel Kv11.1 encoded by the hERG gene, with reported substantial proclivity for arrhythmogenesis. We developed the positively charged (cationic) and neutral d-sotalol models, compatible with the biomolecular CHARMM force field, and subjected them to all-atom molecular dynamics (MD) simulations of drug partitioning through hydrated lipid membranes, aiming to elucidate thermodynamics and kinetics of their translocation and thus putative propensities for hydrophobic and aqueous hERG access. We found that only a neutral form of d-sotalol accumulates in the membrane interior and can move across the bilayer within millisecond time scale, and can be relevant to a lipophilic channel access. The computed water-membrane partitioning coefficient for this form is in good agreement with experiment. There is a large energetic barrier for a cationic form of the drug, dominant in water, to cross the membrane, resulting in slow membrane translocation kinetics. However, this form of the drug can be important for an aqueous access pathway through the intracellular gate of hERG. This route will likely occur after a neutral form of a drug crosses the membrane and subsequently re-protonates. Our study serves to demonstrate a first step toward a framework for multi-scale in silico safety pharmacology, and identifies some of the challenges that lie therein

A L\'evy input fluid queue with input and workload regulation

We consider a queuing model with the workload evolving between consecutive i.i.d.\ exponential timers $\{e_q^{(i)}\}_{i=1,2,...}$ according to a spectrally positive L\'evy process $Y_i(t)$ that is reflected at zero, and where the environment $i$ equals 0 or 1. When the exponential clock $e_q^{(i)}$ ends, the workload, as well as the L\'evy input process, are modified; this modification may depend on the current value of the workload, the maximum and the minimum workload observed during the previous cycle, and the environment $i$ of the L\'evy input process itself during the previous cycle. We analyse the steady-state workload distribution for this model. The main theme of the analysis is the systematic application of non-trivial functionals, derived within the framework of fluctuation theory of L\'evy processes, to workload and queuing models

Queues with delays in two-state strategies and Lévy input

We consider a reflected Lévy process without negative jumps, starting at the origin. When the reflected process first upcrosses level K, a timer is activated. After D time units, the timer expires and the Lévy exponent of the Lévy process is changed. As soon as the process hits zero again, the Lévy exponent reverses to the original function. If the process has reached the origin before the timer expires then the Lévy exponent does not change. Using martingale techniques, we analyze the steady-state distribution of the resulting process, reflected at the origin. We pay special attention to the cases of deterministic and exponential timers, and to the following three special Lévy processes: (i) a compound Poisson process plus negative drift (corresponding to an M/G/1 queue), (ii) Brownian motion, and (iii) a Lévy process that is a subordinator until the timer expires. © Applied Probability Trust 2008

A fluid model for a relay node in an ad-hoc network: the case of heavy-tailed input

Relay nodes in an ad-hoc network can be modelled as fluid queues, in which the available service capacity is shared by the input and output. In this paper such a relay node is considered; jobs arrive according to a Poisson process and bring along a random amount of work. The total transmission capacity is fairly shared, meaning that, when n jobs are present, each job transmits traffic into the queue at rate 1/(n+1) while the queue is drained at the same rate of 1/(n + 1). Where previous studies mainly concentrated on the case of exponentially distributed job sizes, the present paper addresses regularly varying jobs. The focus lies on the tail asymptotics of the sojourn time S. Using sample-path arguments, it is proven that P {S > x} behaves roughly as the residual job size, i.e., if the job sizes are regularly varying of index –v, the tail of S is regularly varying of index 1 – v. In addition, we address the tail asymptotics of other performance metrics, such as the workload in the queue, the flow transfer time and the queueing delay