Cell Senescence, Multiple Organelle Dysfunction and Atherosclerosis

Our research is supported by national funds through FCT- Fundação para a Ciência e Tecnologia and by PROGRAMAS DE ATIVIDADES CONJUNTAS (PAC) grant numbers PTDC/MED-PAT/29395/2017 and N◦3/SAICT/2015. ARAM is supported by the CEECIND/01006/2017, funded by FCT.Atherosclerosis is an age-related disorder associated with long-term exposure to cardiovascular risk factors. The asymptomatic progression of atherosclerotic plaques leads to major cardiovascular diseases (CVD), including acute myocardial infarctions or cerebral ischemic strokes in some cases. Senescence, a biological process associated with progressive structural and functional deterioration of cells, tissues and organs, is intricately linked to age-related diseases. Cell senescence involves coordinated modifications in cellular compartments and has been demonstrated to contribute to different stages of atheroma development. Senescence-based therapeutic strategies are currently being pursued to treat and prevent CVD in humans in the near-future. In addition, distinct experimental settings allowed researchers to unravel potential approaches to regulate anti-apoptotic pathways, facilitate excessive senescent cell clearance and eventually reverse atherogenesis to improve cardiovascular function. However, a deeper knowledge is required to fully understand cellular senescence, to clarify senescence and atherogenesis intertwining, allowing researchers to establish more effective treatments and to reduce the cardiovascular disorders' burden. Here, we present an objective review of the key senescence-related alterations of the major intracellular organelles and analyze the role of relevant cell types for senescence and atherogenesis. In this context, we provide an updated analysis of therapeutic approaches, including clinically relevant experiments using senolytic drugs to counteract atherosclerosis.publishersversionpublishe

Lysosome (Dys)function in Atherosclerosis—A Big Weight on the Shoulders of a Small Organelle

Funding: This research was supported by the research project PTDC/MEDPAT/29395/2017, financed by national funds through the Fundação para a Ciência e Tecnologia (FCT) and by PROGRAMAS DE ATIVIDADES CONJUNTAS (PAC), Reference: No. 03/SAICT/2015. AM was supported by the CEECIND/01006/2017, funded by FCT. This manuscript was supported by the LYSOCIL project, which has received funding from the European Union’s Horizon 2020 Research and Innovation Programme under grant agreement no. 811087.Atherosclerosis is a progressive insidious chronic disease that underlies most of the cardiovascular pathologies, including myocardial infarction and ischemic stroke. The malfunctioning of the lysosomal compartment has a central role in the etiology and pathogenesis of atherosclerosis. Lysosomes are the degradative organelles of mammalian cells and process endogenous and exogenous substrates in a very efficient manner. Dysfunction of these organelles and consequent inefficient degradation of modified low-density lipoproteins (LDL) and apoptotic cells in atherosclerotic lesions have, therefore, numerous deleterious consequences for cellular homeostasis and disease progression. Lysosome dysfunction has been mostly studied in the context of the inherited lysosomal storage disorders (LSDs). However, over the last years it has become increasingly evident that the consequences of this phenomenon are more far-reaching, also influencing the progression of multiple acquired human pathologies, such as neurodegenerative diseases, cancer, and cardiovascular diseases (CVDs). During the formation of atherosclerotic plaques, the lysosomal compartment of the various cells constituting the arterial wall is under severe stress, due to the tremendous amounts of lipoproteins being processed by these cells. The uncontrolled uptake of modified lipoproteins by arterial phagocytic cells, namely macrophages and vascular smooth muscle cells (VSMCs), is the initial step that triggers the pathogenic cascade culminating in the formation of atheroma. These cells become pathogenic “foam cells,” which are characterized by dysfunctional lipid-laden lysosomes. Here, we summarize the current knowledge regarding the origin and impact of the malfunctioning of the lysosomal compartment in plaque cells. We further analyze how the field of LSD research may contribute with some insights to the study of CVDs, particularly how therapeutic approaches that target the lysosomes in LSDs could be applied to hamper atherosclerosis progression and associated mortality.publishersversionpublishe

Invasive Allele Spread under Preemptive Competition

We study a discrete spatial model for invasive allele spread in which two alleles compete preemptively, initially only the "residents" (weaker competitors) being present. We find that the spread of the advantageous mutation is well described by homogeneous nucleation; in particular, in large systems the time-dependent global density of the resident allele is well approximated by Avrami's law.Comment: Computer Simulation Studies in Condensed Matter Physics XVIII, edited by D.P. Landau, S.P. Lewis, and H.-B. Schuttler, (Springer, Heidelberg, Berlin, in press

Simulations of metastable decay in two- and three-dimensional models with microscopic dynamics

We present a brief analysis of the crossover phase diagram for the decay of a metastable phase in a simple dynamic lattice-gas model of a two-phase system. We illustrate the nucleation-theoretical analysis with dynamic Monte Carlo simulations of a kinetic Ising lattice gas on square and cubic lattices. We predict several regimes in which the metastable lifetime has different functional forms, and provide estimates for the crossovers between the different regimes. In the multidroplet regime, the Kolmogorov-Johnson-Mehl-Avrami theory for the time dependence of the order-parameter decay and the two-point density correlation function allows extraction of both the order parameter in the metastable phase and the interfacial velocity from the simulation data.Comment: 14 pages, 4 figures, submitted to J. Non-Crystalline Solids, conference proceeding for IXth International Conference on the Physics of Non-Crystalline Solids, October, 199

Microstructure and velocity of field-driven Ising interfaces moving under a soft stochastic dynamic

We present theoretical and dynamic Monte Carlo simulation results for the mobility and microscopic structure of 1+1-dimensional Ising interfaces moving far from equilibrium in an applied field under a single-spin-flip ``soft'' stochastic dynamic. The soft dynamic is characterized by the property that the effects of changes in field energy and interaction energy factorize in the transition rate, in contrast to the nonfactorizing nature of the traditional Glauber and Metropolis rates (``hard'' dynamics). This work extends our previous studies of the Ising model with a hard dynamic and the unrestricted SOS model with soft and hard dynamics. [P.A. Rikvold and M. Kolesik, J. Stat. Phys. 100, 377 (2000); J. Phys. A 35, L117 (2002); Phys. Rev. E 66, 066116 (2002).] The Ising model with soft dynamics is found to have closely similar properties to the SOS model with the same dynamic. In particular, the local interface width does not diverge with increasing field, as it does for hard dynamics. The skewness of the interface at nonzero field is very weak and has the opposite sign of that obtained with hard dynamics.Comment: 19 pages LaTex with 7 imbedded figure

Photoluminescence and charge transfer in the prototypical 2D/3D semiconductor heterostructure MoS₂/GaAs

The new generation of two-dimensional (2D) materials has shown a broad range of applications for optical and electronic devices. Understanding the properties of these materials when integrated with the more traditional three-dimensional (3D) semiconductors is an important challenge for the implementation of ultra-thin electronic devices. Recent observations have shown that by combining MoS$_2$ with GaAs it is possible to develop high quality photodetectors and solar cells. Here, we present a study of the effects of intrinsic GaAs, p-doped GaAs, and n-doped GaAs substrates on the photoluminescence of monolayer MoS$_2$. We observe a decrease of an order of magnitude in the emission intensity of MoS$_2$ in all MoS$_2$/GaAs heterojunctions, when compared to a control sample consisting of a MoS$_2$ monolayer isolated from GaAs by a few layers of hexagonal boron nitride. We also see a dependence of the trion to A-exciton emission ratio in the photoluminescence spectra on the type of substrate, a dependence that we relate to the static charge exchange between MoS$_2$ and the substrates when the junction is formed. Scanning Kelvin probe microscopy measurements of the heterojunctions suggest type-I band alignments, so that excitons generated on the MoS$_2$ monolayer will be transferred to the GaAs substrate. Our results shed light on the charge exchange leading to band offsets in 2D/3D heterojunctions which play a central role in the understanding and further improvement of electronic devices.Comment: Accepted in Applied Physics Letter

Young users and the digital divide: readers, participants or creators on Internet?

This article analyses how young people, parents and teachers perceive the uses of digital tools and environments made by those known as digital natives. The research combines analysis of an extensive bibliography on the subject with the results of field research based on 30 focus groups, involving 120 youngsters and 60 adults in five Spanish cities, within the framework of a national study. The results show that while adults consider that young people use technological tools in complex ways directed towards content creation, teenagers perceive themselves as mainly readers and participants on the Net

Clinical outcomes of patients with acute myeloid leukemia: evaluation of genetic and molecular findings in a real-life setting

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Microstructure and Velocity of Field-Driven SOS Interfaces: Analytic Approximations and Numerical Results

The local structure of a solid-on-solid (SOS) interface in a two-dimensional kinetic Ising ferromagnet with single-spin-flip Glauber dynamics, which is driven far from equilibrium by an applied field, is studied by an analytic mean-field, nonlinear-response theory [P.A. Rikvold and M. Kolesik, J. Stat. Phys. 100, 377 (2000)] and by dynamic Monte Carlo simulations. The probability density of the height of an individual step in the surface is obtained, both analytically and by simulation. The width of the probability density is found to increase dramatically with the magnitude of the applied field, with close agreement between the theoretical predictions and the simulation results. Excellent agreement between theory and simulations is also found for the field-dependence and anisotropy of the interface velocity. The joint distribution of nearest-neighbor step heights is obtained by simulation. It shows increasing correlations with increasing field, similar to the skewness observed in other examples of growing surfaces.Comment: 18 pages RevTex4 with imbedded figure

Warm molecular and ionized gas kinematics in the type-2 quasar J0945+1737

We analyse Near-Infrared Integral Field Spectrograph (NIFS) observations of the type-2 quasar (QSO2) SDSS J094521.33+173753.2 to investigate its warm molecular and ionized gas kinematics. This QSO2 has a bolometric luminosity of 1045.7 erg s−1 and a redshift of z = 0.128. The K-band spectra provided by NIFS cover a range of 1.99–2.40 μm where low ionization (Paα and Brδ), high ionization ([S XI]λ1.920 μm and [Si VI]λ1.963 μm), and warm molecular lines (from H21-0S(5) to 1-0S(1)) are detected, allowing us to study the multi-phase gas kinematics. Our analysis reveals gas in ordinary rotation in all the emission lines detected and also outflowing gas in the case of the low and high ionization emission lines. In the case of the nuclear spectrum, which corresponds to a circular aperture of 0.3″ (686 pc) in diameter, the warm molecular lines can be characterized using a single Gaussian component of full width at half maximum (FWHM) = 350 − 400 km s−1, while Paα, Brδ, and [Si VI] are best fitted with two blue-shifted Gaussian components of FWHM ∼ 800 and 1700 km s−1, in addition to a narrow component of ∼300 km s−1. We interpret the blue-shifted broad components as outflowing gas, which reaches the highest velocities, of up to −840 km s−1, in the south-east direction (PA ∼ 125°), extending up to a distance of ∼3.4 kpc from the nucleus. The ionized outflow has a maximum mass outflow rate of Ṁout,max = 42–51 M⊙ yr−1, and its kinetic power represents 0.1% of the quasar bolometric luminosity. Very Large Array (VLA) data of J0945 show extended radio emission (PA ∼ 100°) that is aligned with the clumpy emission traced by the narrow component of the ionized lines up to scales of several kiloparsecs, and with the innermost part of the outflow (central ∼0.4″ = 915 pc). Beyond that radius, at the edge of the radio jet, the high velocity gas shows a different PA of ∼125°. This might be an indication that the line-emitting gas is being compressed and accelerated by the shocks generated by the radio jet