Targeting Serotonin Transporters in the Treatment of Juvenile and Adolescent Depression

Depression is a serious public health concern. Many patients are not effectively treated, but in children and adolescents this problem is compounded by limited pharmaceutical options. Currently, the Food and Drug Administration approves only two antidepressants for use in these young populations. Both are selective serotonin reuptake inhibitors (SSRIs). Compounding matters further, they are therapeutically less efficacious in children and adolescents than in adults. Here, we review clinical and preclinical literature describing the antidepressant efficacy of SSRIs in juveniles and adolescents. Since the high-affinity serotonin transporter (SERT) is the primary target of SSRIs, we then synthesize these reports with studies of SERT expression/function during juvenile and adolescent periods. Preclinical literature reveals some striking parallels with clinical studies, primary among them is that, like humans, juvenile and adolescent rodents show reduced antidepressant-like responses to SSRIs. These findings underscore the utility of preclinical assays designed to screen drugs for antidepressant efficacy across ages. There is general agreement that SERT expression/function is lower in juveniles and adolescents than in adults. It is well established that chronic SSRI treatment decreases SERT expression/function in adults, but strikingly, SERT expression/function in adolescents is increased following chronic treatment with SSRIs. Finally, we discuss a putative role for organic cation transporters and/or plasma membrane monoamine transporter in serotonergic homeostasis in juveniles and adolescents. Taken together, fundamental differences in SERT, and putatively in other transporters capable of serotonin clearance, may provide a mechanistic basis for the relative inefficiency of SSRIs to treat pediatric depression, relative to adults

Shift invariant preduals of ℓ₁(ℤ)

The Banach space ℓ<sub>1</sub>(ℤ) admits many non-isomorphic preduals, for example, C(K) for any compact countable space K, along with many more exotic Banach spaces. In this paper, we impose an extra condition: the predual must make the bilateral shift on ℓ<sub>1</sub>(ℤ) weak<sup>*</sup>-continuous. This is equivalent to making the natural convolution multiplication on ℓ<sub>1</sub>(ℤ) separately weak*-continuous and so turning ℓ<sub>1</sub>(ℤ) into a dual Banach algebra. We call such preduals <i>shift-invariant</i>. It is known that the only shift-invariant predual arising from the standard duality between C<sub>0</sub>(K) (for countable locally compact K) and ℓ<sub>1</sub>(ℤ) is c<sub>0</sub>(ℤ). We provide an explicit construction of an uncountable family of distinct preduals which do make the bilateral shift weak<sup>*</sup>-continuous. Using Szlenk index arguments, we show that merely as Banach spaces, these are all isomorphic to c<sub>0</sub>. We then build some theory to study such preduals, showing that they arise from certain semigroup compactifications of ℤ. This allows us to produce a large number of other examples, including non-isometric preduals, and preduals which are not Banach space isomorphic to c<sub>0</sub>

{VeSTA} : a Tool to Verify the Correct Integration of a Component in a Composite Timed System

International audienceVesta is a push-button tool for checking the correct integration of a component in an environment, for component-based timed systems. By correct integration, we mean that the local properties of the component are preserved when this component is merged into an environment. This correctness is checked by means of a so-called divergencesensitive and stability-respecting timed tau-simulation, ensuring the preservation of all linear timed properties expressed in the logical formalism Mitl (Metric Interval Temporal Logic), as well as strong non-zenoness and deadlock-freedom. The development of the tool was guided by the architecture of the Open-Kronos tool. This allows, as additional feature, an easy connection of the models considered in Vesta to the Open- Caesar verification platform, and to the Open-Kronos tool

Parametric LTL on Markov Chains

This paper is concerned with the verification of finite Markov chains against parametrized LTL (pLTL) formulas. In pLTL, the until-modality is equipped with a bound that contains variables; e.g., $\Diamond_{\le x}\ \varphi$ asserts that $\varphi$ holds within $x$ time steps, where $x$ is a variable on natural numbers. The central problem studied in this paper is to determine the set of parameter valuations $V_{\prec p} (\varphi)$ for which the probability to satisfy pLTL-formula $\varphi$ in a Markov chain meets a given threshold $\prec p$, where $\prec$ is a comparison on reals and $p$ a probability. As for pLTL determining the emptiness of $V_{> 0}(\varphi)$ is undecidable, we consider several logic fragments. We consider parametric reachability properties, a sub-logic of pLTL restricted to next and $\Diamond_{\le x}$, parametric B\"uchi properties and finally, a maximal subclass of pLTL for which emptiness of $V_{> 0}(\varphi)$ is decidable.Comment: TCS Track B 201

Ontogeny of NET expression and antidepressant-like response to desipramine in wild-type and SERT mutant mice

Abstract word count: 250 Introduction word count: 74

LTL Parameter Synthesis of Parametric Timed Automata

The parameter synthesis problem for parametric timed automata is undecidable in general even for very simple reachability properties. In this paper we introduce restrictions on parameter valuations under which the parameter synthesis problem is decidable for LTL properties. The investigated bounded integer parameter synthesis problem could be solved using an explicit enumeration of all possible parameter valuations. We propose an alternative symbolic zone-based method for this problem which results in a faster computation. Our technique extends the ideas of the automata-based approach to LTL model checking of timed automata. To justify the usefulness of our approach, we provide experimental evaluation and compare our method with explicit enumeration technique.Comment: 23 pages, extended versio

The Mechanism of Tuning of The Mole Cricket Singing Burrow

1. Experimental and theoretical studies on the acoustics of the singing burrow of the mole cricket Gryllotalpa australis are reported. 2. The burrow typically consists of a bulb about 26 mm long and 20 mm in diameter, connected through a constriction of diameter about 10 mm to a flaring horn with length about 40 mm and equivalent mouth diameter about 34 mm. The mouth geometry of the burrow differs from one species to another, and the aperture may be either single, double or even multiple. The end of the bulb opposite the horn connects to a narrow exit tunnei of diameter about 8 mm and length up to 1 m. The singing cricket positions itself close to the constriction between the bulb and the horn and produces a song with a frequency around 2.5 kHz. 3. Measurements of sound pressure within the burrow when it is excited by an external sound source at the song frequency show a pressure minimum at the constriction and an amplitude and phase distribution that is consistent with resonance of the burrow at its second modal frequency. The burrow is approximately three-quarters of a wavelength long at this frequency. The same result is obtained when the burrow is excited by a dipole source located near the constriction. 4. Non-parametric model calculations confirm this conclusion and also give broad agreement with the measured response curves over a frequency range from about 1.5 to 5 kHz. The calculated curves indicate an additional resonance at about 1.2 kHz associated with the first mode of the burrow—the Helmholtz or Klipsch resonance—which is apparently not utilised by the insect. This detail is consistent with earlier measurements, and is also supported by measured responses reported here that show an increase in sound pressure with decreasing frequency below 2 kHz as predicted by the model. 5. The measured performance of the burrow is broadly consistent with the model. According to the model, the burrow geometry is close to optimal for maximal sound power radiation

Parameter-Independent Strategies for pMDPs via POMDPs

Markov Decision Processes (MDPs) are a popular class of models suitable for solving control decision problems in probabilistic reactive systems. We consider parametric MDPs (pMDPs) that include parameters in some of the transition probabilities to account for stochastic uncertainties of the environment such as noise or input disturbances. We study pMDPs with reachability objectives where the parameter values are unknown and impossible to measure directly during execution, but there is a probability distribution known over the parameter values. We study for the first time computing parameter-independent strategies that are expectation optimal, i.e., optimize the expected reachability probability under the probability distribution over the parameters. We present an encoding of our problem to partially observable MDPs (POMDPs), i.e., a reduction of our problem to computing optimal strategies in POMDPs. We evaluate our method experimentally on several benchmarks: a motivating (repeated) learner model; a series of benchmarks of varying configurations of a robot moving on a grid; and a consensus protocol.Comment: Extended version of a QEST 2018 pape

Probabilistic Verification at Runtime for Self-Adaptive Systems

An effective design of effective and efficient self-adaptive systems may rely on several existing approaches. Software models and model checking techniques at run time represent one of them since they support automatic reasoning about such changes, detect harmful configurations, and potentially enable appropriate (self-)reactions. However, traditional model checking techniques and tools may not be applied as they are at run time, since they hardly meet the constraints imposed by on-the-fly analysis, in terms of execution time and memory occupation. For this reason, efficient run-time model checking represents a crucial research challenge. This paper precisely addresses this issue and focuses on probabilistic run-time model checking in which reliability models are given in terms of Discrete Time Markov Chains which are verified at run-time against a set of requirements expressed as logical formulae. In particular, the paper discusses the use of probabilistic model checking at run-time for self-adaptive systems by surveying and comparing the existing approaches divided in two categories: state-elimination algorithms and algebra-based algorithms. The discussion is supported by a realistic example and by empirical experiments

Noncommutative Figa-Talamanca-Herz algebras for Schur multipliers

We introduce a noncommutative analogue of the Fig\'a-Talamanca-Herz algebra $A_p(G)$ on the natural predual of the operator space $\frak{M}_{p,cb}$ of completely bounded Schur multipliers on Schatten space $S_p$. We determine the isometric Schur multipliers and prove that the space $\frak{M}_{p}$ of bounded Schur multipliers on Schatten space $S_p$ is the closure in the weak operator topology of the span of isometric multipliers.Comment: 24 pages; corrected typo