From traumatic childhood to cocaine abuse: the critical function of the immune system

Background: Experiencing traumatic childhood is a risk factor for developing substance use disorder (SUD), but the mechanisms that underlie this relationship have not been determined. Adverse childhood experiences affect the immune system and the immune system mediates the effects of psychostimulants. However, whether this system is involved in the etiology of SUD in individuals who have experience early life stress is unknown. Methods:In this study, we performed a series of ex vivo and in vivo experiments in mice and humans to define the function of the immune system in the early-life stress-induced susceptibility to the neurobehavioral effects of cocaine. Results: We provide evidence that exposure to social-stress (S-S) at an early age permanently sensitizes the peripheral (splenocytes) and brain (microglia) immune responses to cocaine in mice. In the brain, microglial activation in the ventral tegmental area (VTA) of S-S mice was associated with functional alterations in dopaminergic neurotransmission, as measured by whole-cell voltage clamp recordings in dopamine (DA) neurons. Notably, preventing immune activation during the S-S exposure reverted the effects of DA in the VTA and the cocaine-induced behavioral phenotype to control levels. In humans, cocaine modulated Toll-like receptor 4-mediated innate immunity, an effect that was enhanced in cocaine addicts who had experienced a difficult childhood. Conclusions Collectively, our findings demonstrate that sensitization to cocaine in early-life-stressed individuals involves brain and peripheral immune responses and that this mechanism is shared between mice and humans

Characterising Probabilistic Processes Logically

In this paper we work on (bi)simulation semantics of processes that exhibit both nondeterministic and probabilistic behaviour. We propose a probabilistic extension of the modal mu-calculus and show how to derive characteristic formulae for various simulation-like preorders over finite-state processes without divergence. In addition, we show that even without the fixpoint operators this probabilistic mu-calculus can be used to characterise these behavioural relations in the sense that two states are equivalent if and only if they satisfy the same set of formulae.Comment: 18 page

Distributed Synthesis in Continuous Time

We introduce a formalism modelling communication of distributed agents strictly in continuous-time. Within this framework, we study the problem of synthesising local strategies for individual agents such that a specified set of goal states is reached, or reached with at least a given probability. The flow of time is modelled explicitly based on continuous-time randomness, with two natural implications: First, the non-determinism stemming from interleaving disappears. Second, when we restrict to a subclass of non-urgent models, the quantitative value problem for two players can be solved in EXPTIME. Indeed, the explicit continuous time enables players to communicate their states by delaying synchronisation (which is unrestricted for non-urgent models). In general, the problems are undecidable already for two players in the quantitative case and three players in the qualitative case. The qualitative undecidability is shown by a reduction to decentralized POMDPs for which we provide the strongest (and rather surprising) undecidability result so far

Embedding real-time in stochastic process algebras

We present a stochastic process algebra including immediate actions, deadlock and termination, and explicit stochastic delays, in the setting of weak choice between immediate actions and passage of time. The operational semantics is a spent time semantics, avoiding explicit clocks. We discuss the embedding of weak-choice real-time process theories and analyze the behavior of parallel composition in the weak choice framework

A Geological Itinerary Through the Southern Apennine Thrust-Belt (Basilicata—Southern Italy)

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Dimerisation induced formation of the active site and the identification of three metal sites in EAL-phosphodiesterases

The bacterial second messenger cyclic di-3′,5′-guanosine monophosphate (c-di-GMP) is a key regulator of bacterial motility and virulence. As high levels of c-di-GMP are associated with the biofilm lifestyle, c-di-GMP hydrolysing phosphodiesterases (PDEs) have been identified as key targets to aid development of novel strategies to treat chronic infection by exploiting biofilm dispersal. We have studied the EAL signature motif-containing phosphodiesterase domains from the Pseudomonas aeruginosa proteins PA3825 (PA3825EAL) and PA1727 (MucREAL). Different dimerisation interfaces allow us to identify interface independent principles of enzyme regulation. Unlike previously characterised two-metal binding EAL-phosphodiesterases, PA3825EAL in complex with pGpG provides a model for a third metal site. The third metal is positioned to stabilise the negative charge of the 5′-phosphate, and thus three metals could be required for catalysis in analogy to other nucleases. This newly uncovered variation in metal coordination may provide a further level of bacterial PDE regulation

Optimised chronic infection models demonstrate that siderophore ‘cheating’ in Pseudomonas aeruginosa is context specific

The potential for siderophore mutants of Pseudomonas aeruginosa to attenuate virulence during infection, and the possibility of exploiting this for clinical ends, have attracted much discussion. This has largely been based on the results of in vitro experiments conducted in iron-limited growth medium, in which siderophore mutants act as social ‘cheats:’ increasing in frequency at the expense of the wild type to result in low-productivity, low-virulence populations dominated by mutants. We show that insights from in vitro experiments cannot necessarily be transferred to infection contexts. First, most published experiments use an undefined siderophore mutant. Whole-genome sequencing of this strain revealed a range of mutations affecting phenotypes other than siderophore production. Second, iron-limited medium provides a very different environment from that encountered in chronic infections. We conducted cheating assays using defined siderophore deletion mutants, in conditions designed to model infected fluids and tissue in cystic fibrosis lung infection and non-healing wounds. Depending on the environment, siderophore loss led to cheating, simple fitness defects, or no fitness effect at all. Our results show that it is crucial to develop defined in vitro models in order to predict whether siderophores are social, cheatable and suitable for clinical exploitation in specific infection contexts

Bounded Model Checking of GSMP Models of Stochastic Real-Time Systems

Model checking is a popular algorithmic verification technique for checking temporal requirements of mathematical models of systems. In this paper, we consider the problem of verifying bounded reachability properties of stochastic real-time systems modeled as generalized semi-Markov processes (GSMP). While GSMPs is a rich model for stochastic systems widely used in performance evaluation, existing model checking algorithms are applicable only to subclasses such as discrete-time or continuous-time Markov chains. The main contribution of the paper is an algorithm to compute the probability that a given GSMP satisfies a property of the form “can the system reach a target before time T within k discrete events, while staying within a set of safe states”. For this, we show that the probability density function for the remaining firing times of different events in a GSMP after k discrete events can be effectively partitioned into finitely many regions and represented by exponentials and polynomials. We report on illustrative examples and their analysis using our techniques

Conformance-based doping detection for cyber-physical systems

We present a novel and generalised notion of doping cleanness for cyber-physical systems that allows for perturbing the inputs and observing the perturbed outputs both in the time– and value–domains. We instantiate our definition using existing notions of conformance for cyber-physical systems. We show that our generalised definitions are essential in a data-driven method for doping detection and apply our definitions to a case study concerning diesel emission tests