Phosphoinositide 3-Kinaseγ Controls the Intracellular Localization of CpG to Limit DNA-PKcs-Dependent IL-10 Production in Macrophages

Synthetic oligodeoxynucleotides containing unmethylated CpG motifs (CpG) stimulate innate immune responses. Phosphoinositide 3-kinase (PI3K) has been implicated in CpG-induced immune activation; however, its precise role has not yet been clarified. CpG-induced production of IL-10 was dramatically increased in macrophages deficient in PI3Kγ (p110γ−/−). By contrast, LPS-induced production of IL-10 was unchanged in the cells. CpG-induced, but not LPS-induced, IL-10 production was almost completely abolished in SCID mice having mutations in DNA-dependent protein kinase catalytic subunit (DNA-PKcs). Furthermore, wortmannin, an inhibitor of DNA-PKcs, completely inhibited CpG-induced IL-10 production, both in wild type and p110γ−/− cells. Microscopic analyses revealed that CpG preferentially localized with DNA-PKcs in p110γ−/− cells than in wild type cells. In addition, CpG was preferentially co-localized with the acidic lysosomal marker, LysoTracker, in p110γ−/− cells, and with an early endosome marker, EEA1, in wild type cells. Over-expression of p110γ in Cos7 cells resulted in decreased acidification of CpG containing endosome. A similar effect was reproduced using kinase-dead mutants, but not with a ras-binding site mutant, of p110γ. Thus, it is likely that p110γ, in a manner independent of its kinase activity, inhibits the acidification of CpG-containing endosomes. It is considered that increased acidification of CpG-containing endosomes in p110γ−/− cells enforces endosomal escape of CpG, which results in increased association of CpG with DNA-PKcs to up-regulate IL-10 production in macrophages

Systematic Review of Mucosal Immunity Induced by Oral and Inactivated Poliovirus Vaccines against Virus Shedding following Oral Poliovirus Challenge

Inactivated poliovirus vaccine (IPV) may be used in mass vaccination campaigns during the final stages of polio eradication. It is also likely to be adopted by many countries following the coordinated global cessation of vaccination with oral poliovirus vaccine (OPV) after eradication. The success of IPV in the control of poliomyelitis outbreaks will depend on the degree of nasopharyngeal and intestinal mucosal immunity induced against poliovirus infection. We performed a systematic review of studies published through May 2011 that recorded the prevalence of poliovirus shedding in stool samples or nasopharyngeal secretions collected 5–30 days after a “challenge” dose of OPV. Studies were combined in a meta-analysis of the odds of shedding among children vaccinated according to IPV, OPV, and combination schedules. We identified 31 studies of shedding in stool and four in nasopharyngeal samples that met the inclusion criteria. Individuals vaccinated with OPV were protected against infection and shedding of poliovirus in stool samples collected after challenge compared with unvaccinated individuals (summary odds ratio [OR] for shedding 0.13 (95% confidence interval [CI] 0.08–0.24)). In contrast, IPV provided no protection against shedding compared with unvaccinated individuals (summary OR 0.81 [95% CI 0.59–1.11]) or when given in addition to OPV, compared with individuals given OPV alone (summary OR 1.14 [95% CI 0.82–1.58]). There were insufficient studies of nasopharyngeal shedding to draw a conclusion. IPV does not induce sufficient intestinal mucosal immunity to reduce the prevalence of fecal poliovirus shedding after challenge, although there was some evidence that it can reduce the quantity of virus shed. The impact of IPV on poliovirus transmission in countries where fecal-oral spread is common is unknown but is likely to be limited compared with OPV

Search games with multiple hidden objects

We consider a class of zero-sum search games in which a Searcher seeks to minimize the expected time to find several objects hidden by a Hider. We begin by analyzing a game in which the Searcher wishes to find $k$ balls hidden among $n>k$ boxes. There is a known cost of searching each box, and the Searcher seeks to minimize the total expected cost of finding all the objects in the worst case. We show that it is optimal for the Searcher to begin by searching a $k$-subset $H$ of boxes with probability $\nu(H)$, which is proportional to the product of the search costs of the boxes in $H$. The Searcher should then search the $n-k$ remaining boxes in a random order. A worst-case Hider distribution is the distribution $\nu$. We distinguish between the case of a smart Searcher who can change his search plan as he goes along and a normal Searcher who has to set out his plan from the beginning. We show that a smart Searcher has no advantage. We then show how the game can be formulated in terms of a more general network search game, and we give upper and lower bounds for the value of the game on an arbitrary network. For $2$-arc connected networks (networks that cannot be disconnected by the removal of fewer than two arcs), we solve the game for a smart Searcher and give an upper bound on the value for a normal Searcher. This bound is tight if the network is a circle

A graph patrol problem with random attack times

This paper presents a patrol problem, where a patroller traverses a graph through edges to detect potential attacks at nodes. To design a patrol policy, the patroller needs to take into account not only the graph structure, but also the different attack time distributions, as well as different costs incurred due to successful attacks, at different nodes. We consider both random attackers and strategic attackers. A random attacker chooses which node to attack according to a probability distribution known to the patroller. A strategic attacker plays a two-person zero-sum game with the patroller. For each case, we give an exact linear program to compute the optimal solution. Because the linear programs quickly become computationally intractable as the problem size grows, we develop index-based heuristics. In the random-attacker case, our heuristic is optimal when there are two nodes, and in a suitably chosen asymptotic regime. In the strategic-attacker case, our heuristic is optimal when there are two nodes if the attack times are deterministic taking integer values. In our numerical experiments, our heuristic typically achieves within 1% of optimality with computation time orders of magnitude less than what is required to compute the optimal policy

Ambush frequency should increase over time during optimal predator search for prey

We advance and apply the mathematical theory of search games to model the problem faced by a predator searching for prey. Two search modes are available: ambush and cruising search. Some species can adopt either mode, with their choice at a given time traditionally explained in terms of varying habitat and physiological conditions. We present an additional explanation of the observed predator alternation between these search modes, which is based on the dynamical nature of the search game they are playing: the possibility of ambush decreases the propensity of the prey to frequently change locations and thereby renders it more susceptible to the systematic cruising search portion of the strategy. This heuristic explanation is supported by showing that in a new idealized search game where the predator is allowed to ambush or search at any time, and the prey can change locations at intermittent times, optimal predator play requires an alternation (or mixture) over time of ambush and cruise search. Thus, our game is an extension of the well-studied 'Princess and Monster'search game. Search games are zero sum games, where the pay-off is the capture time and neither the Searcher nor the Hider knows the location of the other. We are able to determine the optimal mixture of the search modes when the predator uses a mixture which is constant over time, and also to determine how the mode mixture changes over time when dynamic strategies are allowed (the ambush probability increases over time). In particular, we establish the 'square root law of search predation': the optimal proportion of active search equals the square root of the fraction of the region that has not yet been explored. © 2011 The Royal Society

Pták's characterization of reflexivity in tensor products

summary:We characterize the reflexivity of the completed projective tensor products $X{\widetilde{\otimes }_\pi } Y$ of Banach spaces in terms of certain approximative biorthogonal systems