Rab11-mediated trafficking and human cancers: An updated review

Many disorders block and subvert basic cellular processes in order to boost their pro-gression. One protein family that is prone to be altered in human cancers is the small GTPase RAB11 family, the master regulator of vesicular trafficking. RAB11 isoforms function as membrane organizers connecting the transport of cargoes towards the plasma membrane with the assembly of autophagic precursors and the generation of cellular protrusions. These processes dramatically impact normal cell physiology and their alteration significantly affects the survival, progression and metastatization as well as the accumulation of toxic materials of cancer cells. In this review, we dis-cuss biological mechanisms ensuring cargo recognition and sorting through a RAB11-dependent pathway, a prerequisite to understand the effect of RAB11 alterations in human cancers

Modelling Competing Endogenous RNA Networks

MicroRNAs (miRNAs) are small RNA molecules, about 22 nucleotide long, which post-transcriptionally regulate their target messenger RNAs (mRNAs). They accomplish key roles in gene regulatory networks, ranging from signaling pathways to tissue morphogenesis, and their aberrant behavior is often associated with the development of various diseases. Recently it has been experimentally shown that the way miRNAs interact with their targets can be described in terms of a titration mechanism. From a theoretical point of view titration mechanisms are characterized by threshold effect at near-equimolarity of the different chemical species, hypersensitivity of the system around the threshold, and cross-talk among targets. The latter characteristic has been lately identified as competing endogenous RNA (ceRNA) effect to mark those indirect interactions among targets of a common pool of miRNAs they are in competition for. Here we propose a stochastic model to analyze the equilibrium and out-of-equilibrium properties of a network of miRNAs interacting with mRNA targets. In particular we are able to describe in detail the peculiar equilibrium and non-equilibrium phenomena that the system displays in proximity to the threshold: (i) maximal cross-talk and correlation between targets, (ii) robustness of ceRNA effect with respect to the model's parameters and in particular to the catalyticity of the miRNA-mRNA interaction, and (iii) anomalous response-time to external perturbations

From Endogenous to Synthetic microRNA-Mediated Regulatory Circuits: An Overview

MicroRNAs are short non-coding RNAs that are evolutionarily conserved and are pivotal post-transcriptional mediators of gene regulation. Together with transcription factors and epigenetic regulators, they form a highly interconnected network whose building blocks can be classified depending on the number of molecular species involved and the type of interactions amongst them. Depending on their topology, these molecular circuits may carry out specific functions that years of studies have related to the processing of gene expression noise. In this review, we first present the different over-represented network motifs involving microRNAs and their specific role in implementing relevant biological functions, reviewing both theoretical and experimental studies. We then illustrate the recent advances in synthetic biology, such as the construction of artificially synthesised circuits, which provide a controlled tool to test experimentally the possible microRNA regulatory tasks and constitute a starting point for clinical applications

Nucleation dynamics in 2d cylindrical Ising models and chemotaxis

The aim of our work is to study the effect of geometry variation on nucleation times and to address its role in the context of eukaryotic chemotaxis (i.e. the process which allows cells to identify and follow a gradient of chemical attractant). As a first step in this direction we study the nucleation dynamics of the 2d Ising model defined on a cylindrical lattice whose radius changes as a function of time. Geometry variation is obtained by changing the relative value of the couplings between spins in the compactified (vertical) direction with respect to the horizontal one. This allows us to keep the lattice size unchanged and study in a single simulation the values of the compactification radius which change in time. We show, both with theoretical arguments and numerical simulations that squeezing the geometry allows the system to speed up nucleation times even in presence of a very small energy gap between the stable and the metastable states. We then address the implications of our analysis for directional chemotaxis. The initial steps of chemotaxis can be modelled as a nucleation process occurring on the cell membrane as a consequence of the external chemical gradient (which plays the role of energy gap between the stable and metastable phases). In nature most of the cells modify their geometry by extending quasi-onedimensional protrusions (filopodia) so as to enhance their sensitivity to chemoattractant. Our results show that this geometry variation has indeed the effect of greatly decreasing the timescale of the nucleation process even in presence of very small amounts of chemoattractants.Comment: 27 pages, 6 figures and 2 table

MIRELLA: a mathematical model explains the effect of microRNA-mediated synthetic genes regulation on intracellular resource allocation

Competition for intracellular resources, also known as gene expression burden, induces coupling between independently co-expressed genes, a detrimental effect on predictability and reliability of gene circuits in mammalian cells. We recently showed that microRNA (miRNA)-mediated target downregulation correlates with the upregulation of a co-expressed gene, and by exploiting miRNAs-based incoherent-feed-forward loops (iFFLs) we stabilise a gene of interest against burden. Considering these findings, we speculate that miRNA-mediated gene downregulation causes cellular resource redistribution. Despite the extensive use of miRNA in synthetic circuits regulation, this indirect effect was never reported before. Here we developed a synthetic genetic system that embeds miRNA regulation, and a mathematical model, MIRELLA, to unravel the miRNA (MI) RolE on intracellular resource aLLocAtion. We report that the link between miRNA-gene downregulation and independent genes upregulation is a result of the concerted action of ribosome redistribution and ‘queueing-effect’ on the RNA degradation pathway. Taken together, our results provide for the first time insights into the hidden regulatory interaction of miRNA-based synthetic networks, potentially relevant also in endogenous gene regulation. Our observations allow to define rules for complexity- and context-aware design of genetic circuits, in which transgenes co-expression can be modulated by tuning resource availability via number and location of miRNA target sites

Micro-beam and pulsed laser beam techniques for the micro-fabrication of diamond surface and bulk structures

Micro-fabrication in diamond is involved in a wide set of emerging technologies, exploiting the exceptional characteristics of diamond for application in bio-physics, photonics, radiation detection. Micro ion-beam irradiation and pulsed laser irradiation are complementary techniques, which permit the implementation of complex geometries, by modification and functionalization of surface and/or bulk material, modifying the optical, electrical and mechanical characteristics of the material. In this article we summarize the work done in Florence (Italy) concerning ion beam and pulsed laser beam micro-fabrication in diamond.Comment: 14 pages, 5 figure

Atorvastatin modulates anti-proliferative and pro-proliferative signals in Her2/neu-positive mammary cancer

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Non-Pharmacological Treatments

In clinical psychiatry, we dispose of different non-pharmacological approaches, such as somatic treatments, chronobiological treatments, cognitive remediation, and psychotherapy. Somatic treatments include transcranial direct current stimulation (tDCS), transcranial magnetic stimulation (TMS), and electroconvulsive therapy (ECT). These techniques, which exert their function through the modulation of cortical excitability, find an application in many psychiatric disorders, but mainly in resistant depression. Chronotherapies, a group of non-pharmacological therapeutic approaches to mood disorder treatment, are rooted in the hypothesis of chronobiology aetiopathogenesis of psychiatric disorders (mainly mood disorders). Chrono-biological treatments include light therapy (LT), sleep deprivation (SD), and dark therapy (DT). While LT and SD are mainly used in depression, DT finds a clinical application in mania. Cognitive remediation (CR) is a set of interventions based on behavioural training whose goal is to enhance neurocognitive abilities. This technique finds its main application in schizophrenia. Psychotherapy approaches have a proved effectiveness for the treatment of various psychiatric conditions when combined to psychopharmacological treatment. The two main approaches are cognitive-behavioural therapy and psychodynamic therapy

Hierarchical large-scale elastic metamaterials for passive seismic wave mitigation

Large scale elastic metamaterials have recently attracted increasing interest in the scientific community for their potential as passive isolation structures for seismic waves. In particular, so-called "seismic shields"have been proposed for the protection of large areas where other isolation strategies (e.g. dampers) are not workable solutions. In this work, we investigate the feasibility of an innovative design based on hierarchical design of the unit cell, i.e. a structure with a self-similar geometry repeated at different scales. Results show how the introduction of hierarchy allows the conception of unit cells exhibiting reduced size with respect to the wavelength while maintaining the same or improved isolation efficiency at frequencies of interest for earthquake engineering. This allows to move closer to the practical realization of such seismic shields, where low-frequency operation and acceptable size are both essential characteristics for feasibility