Macrophage autophagy in atherosclerosis

Macrophages play crucial roles in atherosclerotic immune responses. Recent investigation into macrophage autophagy (AP) in atherosclerosis has demonstrated a novel pathway through which these cells contribute to vascular inflammation. AP is a cellular catabolic process involving the delivery of cytoplasmic contents to the lysosomal machinery for ultimate degradation and recycling. Basal levels of macrophage AP play an essential role in atheroprotection during early atherosclerosis. However, AP becomes dysfunctional in the more advanced stages of the pathology and its deficiency promotes vascular inflammation, oxidative stress, and plaque necrosis. In this paper, we will discuss the role of macrophages and AP in atherosclerosis and the emerging evidence demonstrating the contribution of macrophage AP to vascular pathology. Finally, we will discuss how AP could be targeted for therapeutic utility

Tailoring Cellular Function: The Contribution of the Nucleus in Mechanotransduction

Cells sense a variety of different mechanochemical stimuli and promptly react to such signals by reshaping their morphology and adapting their structural organization and tensional state. Cell reactions to mechanical stimuli arising from the local microenvironment, mechanotransduction, play a crucial role in many cellular functions in both physiological and pathological conditions. To decipher this complex process, several studies have been undertaken to develop engineered materials and devices as tools to properly control cell mechanical state and evaluate cellular responses. Recent reports highlight how the nucleus serves as an important mechanosensor organelle and governs cell mechanoresponse. In this review, we will introduce the basic mechanisms linking cytoskeleton organization to the nucleus and how this reacts to mechanical properties of the cell microenvironment. We will also discuss how perturbations of nucleus-cytoskeleton connections, affecting mechanotransduction, influence health and disease. Moreover, we will present some of the main technological tools used to characterize and perturb the nuclear mechanical state

Ultrafast hot electron dynamics in plasmonic nanostructures: Experiments, modelling, design

Metallic nanostructures exhibit localized surface plasmons (LSPs), which offer unprecedented opportunities for advanced photonic materials and devices. Following resonant photoexcitation, LSPs quickly dephase, giving rise to a distribution of energetic ‘hot’ electrons in the metal. These out-of-equilibrium carriers undergo ultrafast internal relaxation processes, nowadays pivotal in a variety of applications, from photodetection and sensing to the driving of photochemical reactions and ultrafast all-optical modulation of light. Despite the intense research activity, exploitation of hot carriers for real-world nanophotonic devices remains extremely challenging. This is due to the com- plexity inherent to hot carrier relaxation phenomena at the nanoscale, involving short-lived out-of-equilibrium electronic states over a very broad range of energies, in interaction with thermal electronic and phononic baths. These issues call for a comprehensive understanding of ultrafast hot electron dynamics in plasmonic nanostructures. This paper aims to review our contribution to the field: starting from the fundamental physics of plasmonic nanostructures, we first describe the experimental techniques used to probe hot electrons; we then introduce a numerical model of ultrafast nanoscale relaxation processes, and present examples in which experiments and modelling are combined, with the aim of designing novel optical functionalities enabled by ultrafast hot-electron dynamics

Fast transcription rates of RNA polymerase II in human cells

Averaged estimates of RNA polymerase II (RNAPII) elongation rates in mammalian cells have been shown to range between 1.3 and 4.3 kb min(-1). In this work, nascent RNAs from an integrated human immunodeficiency virus type 1-derived vector were detectable at the single living cell level by fluorescent RNA tagging. At steady state, a constant number of RNAs was measured corresponding to a minimal density of polymerases with negligible fluctuations over time. Recovery of fluorescence after photobleaching was complete within seconds, indicating a high rate of RNA biogenesis. The calculated transcription rate above 50 kb min(-1) points towards a wide dynamic range of RNAPII velocities in living cells

Photoinduced transient symmetry breaking in plasmonic structures for ultrafast nanophotonics

We study the spatio-temporal evolution of hot electrons generated in plasmonic nanostructures under resonant excitation with fs-laser pulses. A spatially inhomogeneous version of the Three-Temperature Model for hot-electrons dynamics, coupled to semiclassical calculations of third-order optical nonlinearity in gold, enabled us to engineer a transient symmetry breaking of the optical properties at the nanoscale. This effect is exploited to achieve all-optical control of light with unprecedented speed. For instance, a photoinduced broadband dichroism, fully reversible and transiently vanishing in less than 1 picoseconds (overcoming the speed bottleneck caused by slower, electron-phonon and phonon-phonon relaxation processes), has been experimentally demonstrated in plasmonic metasurfaces with nanocross metaatoms. Also, we designed a nonlinear plasmonic metagrating (based on cross-polarized gold nanostrip dimer metaatoms), where the nanoscale symmetry breaking enables ultrafast reconfiguration of diffraction orders via control laser pulses. The photoinduced power imbalance between symmetrical diffraction orders is calculated to exceed 20% under moderate (similar to 2 mJ/cm(2)) laser fluence, and returns to the balanced diffraction in about 2 ps. Our design has been developed for gold nanomaterials, but the concept of ultrafast all-optical symmetry breaking can be exploited beyond plasmonics (e.g. in semiconductor nanostructures), with potential impact on a broad range of applications in nanophotonics

The Role of Tricellulin in Epithelial Jamming and Unjamming via Segmentation of Tricellular Junctions

Collective cellular behavior in confluent monolayers supports physiological and pathological processes of epithelial development, regeneration, and carcinogenesis. Here, the attainment of a mature and static tissue configuration or the local reactivation of cell motility involve a dynamic regulation of the junctions established between neighboring cells. Tricellular junctions (tTJs), established at vertexes where three cells meet, are ideally located to control cellular shape and coordinate multicellular movements. However, their function in epithelial tissue dynamic remains poorly defined. To investigate the role of tTJs establishment and maturation in the jamming and unjamming transitions of epithelial monolayers, a semi-automatic image-processing pipeline is developed and validated enabling the unbiased and spatially resolved determination of the tTJ maturity state based on the localization of fluorescent reporters. The software resolves the variation of tTJ maturity accompanying collective transitions during tissue maturation, wound healing, and upon the adaptation to osmolarity changes. Altogether, this work establishes junctional maturity at tricellular contacts as a novel biological descriptor of collective responses in epithelial monolayers

Disease-relevant proteostasis regulation of cystic fibrosis transmembrane conductance regulator

Mismanaged protein trafficking by the proteostasis network contributes to several conformational diseases, including cystic fibrosis, the most frequent lethal inherited disease in Caucasians. Proteostasis regulators, as cystamine, enable the beneficial action of cystic fibrosis transmembrane conductance regulator (CFTR) potentiators in \u394F508-CFTR airways beyond drug washout. Here we tested the hypothesis that functional CFTR protein can sustain its own plasma membrane (PM) stability. Depletion or inhibition of wild-type CFTR present in bronchial epithelial cells reduced the availability of the small GTPase Rab5 by causing Rab5 sequestration within the detergent-insoluble protein fraction together with its accumulation in aggresomes. CFTR depletion decreased the recruitment of the Rab5 effector early endosome antigen 1 to endosomes, thus reducing the local generation of phosphatidylinositol-3-phosphate. This diverts recycling of surface proteins, including transferrin receptor and CFTR itself. Inhibiting CFTR function also resulted in its ubiquitination and interaction with SQSTM1/p62 at the PM, favoring its disposal. Addition of cystamine prevented the recycling defect of CFTR by enhancing BECN1 expression and reducing SQSTM1 accumulation. Our results unravel an unexpected link between CFTR protein and function, the latter regulating the levels of CFTR surface expression in a positive feed-forward loop, and highlight CFTR as a pivot of proteostasis in bronchial epithelial cells