First passage statistics for diffusing diffusivity

A rapidly increasing number of systems is identified in which the stochastic motion of tracer particles follows the Brownian law $\langle\mathbf{r}^2(t) \rangle\simeq Dt$ yet the distribution of particle displacements is strongly non-Gaussian. A central approach to describe this effect is the diffusing diffusivity (DD) model in which the diffusion coefficient itself is a stochastic quantity, mimicking heterogeneities of the environment encountered by the tracer particle on its path. We here quantify in terms of analytical and numerical approaches the first passage behaviour of the DD model. We observe significant modifications compared to Brownian-Gaussian diffusion, in particular that the DD model may have a more efficient first passage dynamics. Moreover we find a universal crossover point of the survival probability independent of the initial condition.Comment: 11 pages, 2 figures, IOP LaTe

Identification of transmembrane domains that regulate spatial arrangements and activity of prokineticin receptor 2 dimers

The chemokine prokineticin 2 (PK2) activates its cognate G protein-coupled receptor (GPCR) PKR2 to elicit various downstream signaling pathways involved in diverse biological processes. Many GPCRs undergo dimerization that can modulate a number of functions including membrane delivery and signal transduction. The aim of this study was to elucidate the interface of PKR2 protomers within dimers by analyzing the ability of PKR2 transmembrane (TM) deletion mutants to associate with wild type (WT) PKR2 in yeast using co-immunoprecipitation and mammalian cells using bioluminescence resonance energy transfer. Deletion of TMs 5-7 resulted in a lack of detectable association with WT PKR2, but could associate with a truncated mutant lacking TMs 6-7 (TM1-5). Interestingly, TM1-5 modulated the distance, or organization, between protomers and positively regulated Gαs signaling and surface expression of WT PKR2. We propose that PKR2 protomers form type II dimers involving TMs 4 and 5, with a role for TM5 in modulation of PKR2 function

The random diffusivity approach for diffusion in heterogeneous systems

The two hallmark features of Brownian motion are the linear growth $\langle x^2(t) \rangle = 2 D d t$ of the mean squared displacement (MSD) with diffusion coefficient $D$ in $d$ spatial dimensions, and the Gaussian distribution of displacements. With the increasing complexity of the studied systems deviations from these two central properties have been unveiled over the years. Recently, a large variety of systems have been reported in which the MSD exhibits the linear growth in time of Brownian (Fickian) transport, however, the distribution of displacements is pronouncedly non-Gaussian (Brownian yet non-Gaussian, BNG). A similar behaviour is also observed for viscoelastic-type motion where an anomalous trend of the MSD, i.e., $\langle x^2(t) \rangle \sim t^\alpha$, is combined with a priori unexpected non-Gaussian distributions (anomalous yet non-Gaussian, ANG). This kind of behaviour observed in BNG and ANG diffusions has been related to the presence of heterogeneities in the systems and a common approach has been established to address it, that is, the random diffusivity approach. This dissertation explores extensively the field of random diffusivity models. Starting from a chronological description of all the main approaches used as an attempt of describing BNG and ANG diffusion, different mathematical methodologies are defined for the resolution and study of these models. The processes that are reported in this work can be classified in three subcategories, i) randomly-scaled Gaussian processes, ii) superstatistical models and iii) diffusing diffusivity models, all belonging to the more general class of random diffusivity models. Eventually, the study focuses more on BNG diffusion, which is by now well-established and relatively well-understood. Nevertheless, many examples are discussed for the description of ANG diffusion, in order to highlight the possible scenarios which are known so far for the study of this class of processes. The second part of the dissertation deals with the statistical analysis of ran- dom diffusivity processes. A general description based on the concept of moment- generating function is initially provided to obtain standard statistical properties of the models. Then, the discussion moves to the study of the power spectral analysis and the first passage statistics for some particular random diffusivity models. A comparison between the results coming from the random diffusivity approach and the ones for standard Brownian motion is discussed. In this way, a deeper physical understanding of the systems described by random diffusivity models is also outlined. To conclude, a discussion based on the possible origins of the heterogeneity is sketched, with the main goal of inferring which kind of systems can actually be described by the random diffusivity approach.BERC.2018-202

Characterisation of the molecular mechanisms regulating luteinizing hormone receptor

G protein coupled receptors (GPCRs) are the major family of membrane proteins transducing extracellular stimuli into intracellular signals. The luteinizing hormone receptor (LHR) is a GPCR expressed in gonadal and extragonadal tissues where it plays pivotal roles in reproduction and pregnancy. Endocytic trafficking of GPCRs represents a key mechanism in defining cellular responses by controlling signalling at both temporal and spatial level. After ligand activation, LHR is internalised into very early endosomes (VEEs), small vesicles (~400nm in diameter) close to the plasma membrane and distinct from the classic early endosome. Our laboratory identified the Adaptor Protein containing pleckstrin homology (PH) domain, PTB domain and Leucine zipper motif 1 (APPL1) as a marker of ~50% of VEEs where LHR is internalised to. My aims were to characterise the VEE by identifying the mechanisms dictating LHR post-endocytic sorting from this novel compartment, the role of APPL1 and how this impacts receptor signalling. Imaging LHR recycling in real time at single event resolution, enabled me to identify the kinetics and the machinery involved. While APPL1 was not required for LHR localisation in VEEs, it is essential for receptor recycling and negative regulation of cAMP production; two functions never ascribed before to APPL1 for any membrane cargo. These two functions of APPL1 are regulated in an opposing manner by phosphorylation of Ser410 of APPL1, achieved by activation of the Gαs-cAMP-PKA pathway, highlighting the mutual regulation of GPCR trafficking and signalling. I also demonstrated that both Gαs-cAMP and Gαq/11-calcium signalling require LHR internalisation, that endosomal signalling and recycling involves distinct adenylate cyclases and that Gαs activation is restricted to microdomains of the VEE. Finally, LHR recycling and cAMP signalling are also regulated by APPL1 in primary human endometrial stromal cells, where LHR trafficking and signalling could be perturbed in pathological conditions such as PCOS.Open Acces

Impact of New Technologies on Economic Behavior and Consumer Freedom of Choice: from Neuromarketing to Neuro-Rights

Objective: to identify the possibilities for an adequate response of the existing legal regime to the various challenges posed to European law by artificial intelligence systems underlying neuromarketing techniques.Methods: the study is based on the risk-oriented approach, formal-logical, formal-legal and comparative-legal methods, as well as on the method of legal forecasting, in order to identify the problems of legislation caused by the emerging technologies capable of recognizing human emotions and using them to control consumer behavior, and to propose ways to solve them.Results: the conducted research provides a brief overview of the most widely used neuromarketing techniques used by algorithms and machine learning. These allow identifying points of cognitive and emotional vulnerability, collecting and processing data, and then building the most effective marketing techniques that push a consumer to choose a certain product or service. Ethical problems are analyzed which arise from the use of neuromarketing techniques in relation to some basic values such as individual independence, human dignity, and freedom of choice. The subtle line is shown between techniques that manipulate consumer behavior (manipulation technique) and those that, on the contrary, have a persuasive effect, which in itself does not make them illegal (persuasion technique). An overview of the existing legal framework is presented, as well as case law from both the European Court of Justice and national courts of member states with a particular focus on the Unfair Commercial Practices Directive, the EU General Regulation on the Protection of Personal Data (hard law), and codes of ethics (soft law).Scientific novelty: the paper points out the transformation of traditional legal categories and important problem points of the existing regulation due to the growing recognition of the potential of neuromarketing as a tool capable of explaining and predicting consumer behavior, as well as influencing the economic behavior of the subjects of relations.Practical significance: the obtained conclusions and proposals can be taken into account in improving the regulation of artificial intelligence in terms of its safety and reliability, increasing trust in the system, given the need to protect ethical principles and maintain fundamental values