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

Amplification and generation of ultra-intense twisted laser pulses via stimulated Raman scattering

Twisted Laguerre–Gaussian lasers, with orbital angular momentum and characterized by doughnut-shaped intensity profiles, provide a transformative set of tools and research directions in a growing range of fields and applications, from super-resolution microcopy and ultra-fast optical communications to quantum computing and astrophysics. The impact of twisted light is widening as recent numerical calculations provided solutions to long-standing challenges in plasma-based acceleration by allowing for high-gradient positron acceleration. The production of ultra-high-intensity twisted laser pulses could then also have a broad influence on relativistic laser–matter interactions. Here we show theoretically and with ab initio three-dimensional particle-in-cell simulations that stimulated Raman backscattering can generate and amplify twisted lasers to petawatt intensities in plasmas. This work may open new research directions in nonlinear optics and high–energy-density science, compact plasma-based accelerators and light sources

Cross-cultural adaptation and psychometric properties of the Brazilian coach-athlete relationship questionnaire (CART-Q), athlete Version

The aim of this study was to test the psychometric properties of the Brazilian version of the Coach-Athlete Relationship Questionnaire (CART-Q)-Athlete Version. For this, three studies were performed. In the first, four translators and five experts in Sport Psychology adapted the CART-Q contents to the Brazilian context. In the second, 364 athletes of individual and collective sports answered the adapted version of CART-Q. In the third, an independent sample of 185 athletes answered the CART-Q and the Task and Ego Orientation in Sport Questionnaire (TEOSQ) to analyze the external validity of the instrument; and 50 athletes answered the CART-Q in two distinct moments for the analysis of the temporal stability. Study 1 showed that the Portuguese version contains clear and relevant questions (CVC> 0.80). Study 2 showed that the CART-Q presents satisfactory internal consistency (a> 0.70/CC> 0.70). The confirmatory factor analysis showed that the model with 11 items showed good fit [X2/gl = 3.03; CFI = 0.96, GFI =0 94; TLI = 0.94; RMSEA = 0.08] and also the existence of the second-order model. Study 3 showed the external (r> 0.40 with variable task orientation) and internal validity (CFA with an independent sample) and temporal stability (ICC> 0.70). It was concluded that the Brazilian version for of CART-Q proved to be valid to evaluate the perception of athletes about their relationship with the coach in the Brazilian sports context

Beneficial effects of the activation of the Angiotensin-(1-7) MAS receptor in a murine model of adriamycin-induced nephropathy

Angiotensin-(1-7) [Ang-(1-7)] is a biologically active heptapeptide that may counterbalance the physiological actions of angiotensin II (Ang II) within the renin-angiotensin system (RAS). Here, we evaluated whether activation of the Mas receptor with the oral agonist, AVE 0991, would have renoprotective effects in a model of adriamycin (ADR)-induced nephropathy. We also evaluated whether the Mas receptor contributed for the protective effects of treatment with AT1 receptor blockers. ADR (10 mg/kg) induced significant renal injury and dysfunction that was maximal at day 14 after injection. Treatment with the Mas receptor agonist AVE 0991 improved renal function parameters, reduced urinary protein loss and attenuated histological changes. Renoprotection was associated with reduction in urinary levels of TGF-{beta}. Similar renoprotection was observed after treatment with the AT1 receptor antagonist, Losartan. AT1 and Mas receptor mRNA levels dropped after ADR administration and treatment with losartan reestablished the expression of Mas receptor and increased the expression of ACE2. ADR-induced nephropathy was similar in wild type (Mas(+/+)) and Mas knockout (Mas (-/-)) mice, suggesting there was no endogenous role for Mas receptor activation. However, treatment with Losartan was able to reduce renal injury only in Mas(+/+) , but not in Mas (-/-) mice. Therefore, these findings suggest that exogenous activation of the Mas receptor protects from ADR-induced nephropathy and contributes to the beneficial effects of AT1 receptor blockade. Medications which target specifically the ACE2/Ang-(1-7)/Mas axis may offer new therapeutic opportunities to treat human nephropathies

Very Low Temperature Tunnelling Spectroscopy in the heavy fermion superconductor PrOs4_4Sb12_{12}

We present scanning tunnelling spectroscopy measurements on the heavy fermion superconductor PrOs$_4$Sb$_{12}$. Our results show that the superconducting gap opens over a large part of the Fermi surface. The deviations from isotropic BCS s-wave behavior are discussed in terms of a finite distribution of values of the superconducting gap.Comment: 4 pages, 4 figure

Cardiopulmonary exercise test in patients with refractory angina: functional and ischemic evaluation

Objectives: Refractory angina (RA) is a chronic condition clinically characterized by low effort tolerance; therefore, physical stress testing is not usually requested for these patients. Cardiopulmonary exercise testing (CPET) is considered a gold standard examination for functional capacity evaluation, even in submaximal tests, and it has gained great prominence in detecting ischemia. The authors aimed to determine cardiorespiratory capacity by using the oxygen consumption efficiency slope (OUES) in patients with refractory angina. The authors also studied the O2 pulse response by CPET and the association of ischemic changes with contractile modifications by exercise stress echocardiography (ESE). Methods: Thirty-one patients of both sexes, aged 45 to 75 years, with symptomatic (Canadian Cardiovascular Society class II to IV) angina who underwent CPET on a treadmill and exercise stress echocardiography on a lower limb cycle ergometer were studied. ClinicalTrials.gov: NCT03218891. Results: The patients had low cardiorespiratory capacity (OUES of 1.74 ± 0.4 L/min; 63.9±14.7% of predicted), and 77% of patients had a flattening or drop in O2 pulse response. There was a direct association between Heart Rate (HR) at the onset of myocardial ischemia detected by ESE and HR at the onset of flattening or drop in oxygen pulse response detected by CPET (R = 0.48; p = 0.019). Conclusion: Patients with refractory angina demonstrate low cardiorespiratory capacity. CPET shows good sensitivity for detecting abnormal cardiovascular response in these patients with a significant relationship between flattening O2 pulse response during CEPT and contractile alterations detected by exercise stress echocardiography

All-Optical Steering Of Laser-Wakefield-Accelerated Electron Beams

We investigate the influence of a tilted laser-pulse-intensity front on laser-wakefield acceleration. Such asymmetric light pulses may be exploited to obtain control over the electron-bunch-pointing direction and in our case allowed for reproducible electron-beam steering in an all-optical way within an 8 mrad opening window with respect to the initial laser axis. We also discovered evidence of collective electron-betatron oscillations due to odd-axis electron injection into the wakefield induced by a pulse-front tilt. These findings are supported by 3D particle-in-cell simulations