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    Molecular therapies for bone regeneration: the role of non-coding RNAs in mesenchymal stem/stromal cells

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    Mestrado em Integrado em Engenharia Biol√≥gica, Ramo de Tecnologia Qu√≠mica e AlimentarOsteoporosis is a chronic skeletal disorder characterized by loss of bone mass and deterioration of the bone tissue, which leads to an increased risk of fractures. The aetiology of this disease resides on the impairment between bone resorption (conducted by osteoclasts) and formation (conducted by osteoblasts). Considering an ageing population, it is expected a steady rising number of cases over the next years, turning osteoporosis into a serious public health issue that represents a leading cause of morbidity and mortality, mainly due to the fragility fractures. Nowadays, the osteoporosis treatments consist predominantly in anti-resorptive drugs that inhibit/prevent bone resorption but are often associated with several side effects. Therefore, the need for new approaches to promote bone homeostasis and regeneration/repair of fragility fractures in patients with osteoporosis is increasing. Over the past years microRNAs (miRNAs), a class of small non-coding RNAs that coordinate virtually all cellular mechanisms through regulation of gene expression, have gained status as important post-transcriptional regulators. Recent studies revealed their pivotal role in the pathogenesis of several human diseases, including osteoporosis. In this context and following the previous results of a microRNA microarray, the main aim of this study was to investigate the role of miR-99a-5p in osteogenic differentiation and evaluate its expression during osteoclastogenesis, crucial processes required for bone formation and repair. Also, we aimed to determine its expression in fracture healing/repair process and fragility fracture samples. To achieve our aims, we first assessed miR-99a-5p expression profile during osteogenic differentiation in both MC3T3 cell line and primary human Mesenchymal Stem/Stromal Cells by reverse transcription ‚Äď real-time quantitative polymerase chain reaction (RT-qPCR). Next, to analyze the biological effect of miR-99a-5p in osteogenesis and proliferation, we performed in vitro transfections of miR-99a-5p mimics and inhibitors. In an attempt to identify relevant mechanisms and pathways of action of miR-99a-5p we further analyzed the protein expression profile of anti-miR-99a-5p transfected cells compared to control. Furthermore, the expression profile of miR-99a-5p during osteoclastogenesis of RAW 264.7 cell line and human monocytes was investigated, as well as the effect of conditioned media from MC3T3 transfected cells on osteoclastogenesis. Finally, miR-99a-5p expression during the bone repair/regeneration process and in patients that suffered an osteoporotic fracture was determined. The results showed that miR-99a-5p was significantly down-regulated during MC3T3 osteogenic differentiation and during early stages of human primary MSC osteogenic differentiation. miR-99a-5p overexpression in pre-osteoblastic cell line MC3T3 led to a decrease of osteogenic differentiation markers, whereas its inhibition enhanced osteogenesis markers, including alkaline phosphatase expression and staining. However, modulation of miR-99a-5p levels in MC3T3 cells did not show to affect proliferation. Proteomic analysis on anti-miR-99a-5p transfected cells showed that numerous proteins known to be involved in osteogenic differentiation were altered, in comparison with the control, such as plexin-A2 (PLXA2), all-trans retinoic acid-induced differentiation factor (ARAID), ARF GTPase-activating protein GIT (GIT1) and Ephrin type-A receptor 2 (EPHA2). Furthermore, inhibition of miR-99a-5p levels were predicted to impact several pathways associated with osteoporosis, including Ephrin receptor, Pl3K-Akt and canonical Wnt pathways. In contrast to osteogenesis, miR-99a-5p was upregulated during osteoclastogenesis from both RAW 264.7 cells and primary human monocytes. We also demonstrated that inhibition of miR-99a-5p in MC3T3 increased the OPG / RANKL mRNA expression ratio and that the supernatant collected from these cells inhibited RAW 264.7 differentiation into osteoclasts. Additionally, results show that miR-99a-5p was differently expressed in a time-dependent manner in the bone marrow of rats upon a bone critical defect injury. Finally, results from bone osteoporotic human samples showed increased miR-99a-5p expression levels compared with osteoarthritis samples. Taken together, our data shows that miR-99a-5p is a critical regulator of osteogenic differentiation and suggest that modulation miR-99a-5p levels might be a strategy to re-establish bone homeostasis in fragile bones.Osteoporose √© uma doen√ßa cr√≥nica do esqueleto caracterizada pela perda de massa √≥ssea e deteriora√ß√£o do tecido √≥sseo, que conduz a um aumento do risco da ocorr√™ncia de fraturas. A etiologia desta doen√ßa reside na desregula√ß√£o entre a reabsor√ß√£o (realizada pelos osteoclastos) e a forma√ß√£o (realizada pelos osteoblastos) √≥ssea. Considerando o envelhecimento da popula√ß√£o, espera-se um aumento do n√ļmero de casos nos pr√≥ximos anos, o que torna a osteoporose um grave problema de sa√ļde p√ļblica e uma das principais causas de morbidade e mortalidade, principalmente devido √†s fraturas de fragilidade √†s quais est√£o frequentemente associadas. Atualmente, os tratamentos para a osteoporose consistem predominantemente em drogas que inibem / previnem a reabsor√ß√£o √≥ssea, mas podem ter v√°rios efeitos secund√°rios associados. Portanto, a necessidade de novas abordagens que promovam a homeostasia do osso e a regenera√ß√£o de fraturas em pacientes diagnosticados com osteoporose est√° a aumentar. Nos √ļltimos anos, os microRNAs (miRNAs), uma classe de pequenos RNAs que n√£o codificam prote√≠na e que s√£o importantes reguladores da express√£o g√©nica, est√£o a ganhar cada vez mais relev√Ęncia como reguladores de mecanismos celulares. Estudos recentes t√™m vindo a revelar o seu papel na patog√©nese de v√°rias doen√ßas, entre as quais a osteoporose. Neste contexto, o principal objetivo deste estudo foi investigar o papel do miR-99a-5p na diferencia√ß√£o osteog√©nica, um processo necess√°rio e indispens√°vel para a forma√ß√£o e regenera√ß√£o √≥ssea. Al√©m disso, explorou-se o perfil de express√£o deste microRNA na osteoclastog√©nese, durante a regenera√ß√£o de fraturas √≥sseas e em pacientes com osteoporose. Para atingir estes objetivos, come√ßamos por avaliar o perfil de express√£o do miR-99a-5p durante a diferencia√ß√£o osteog√©nica, tanto na linhagem celular MC3T3, como em c√©lulas mesenquimais do estroma humanas (MSC), por transcri√ß√£o reversa - rea√ß√£o em cadeia da polimerase quantitativa em tempo real (RT-qPCR). Em seguida, para analisar o efeito biol√≥gico do miR-99a-5p na osteog√©nese e na prolifera√ß√£o, foram realizadas transfe√ß√Ķes in vitro de oligonucle√≥tidos que mimetizam ou inibem o efeito do miR-99a-5p. Com intuito de identificar quais os alvos e vias moleculares afetadas e controladas pelo miR-99a-5p, investig√°mos o perfil de prote√≠nas expressas pelas c√©lulas transfetadas com anti-miR-99a-5p em compara√ß√£o com o controlo. Para al√©m disso, o perfil de express√£o do miR-99a-5p foi tamb√©m estudado durante a osteoclastog√©nese da linha celular RAW 264.7 e de mon√≥citos humanos, bem como o efeito do meio condicionado das c√©lulas MC3T3 transfetadas na osteoclastog√©nese. Por fim, determinou-se a express√£o do miR-99a-5p durante o processo de regenera√ß√£o √≥ssea num modelo animal e em pacientes que sofreram fraturas de fragilidade/osteopor√≥ticas. Os resultados obtidos demostraram que o miR-99a-5p √© significativamente subexpresso durante a diferencia√ß√£o osteog√©nica das MC3T3 e durante as fases iniciais da diferencia√ß√£o osteog√©nica das MSCs humanas. A sobreexpress√£o do miR-99a-5p na linha celular pr√©-osteobl√°stica MC3T3 resultou numa diminui√ß√£o dos marcadores de diferencia√ß√£o osteog√©nica enquanto que a sua inibi√ß√£o aumentou a express√£o dos mesmos marcadores osteog√©nicos, entre os quais da fosfatase alcalina. Verificou-se ainda que a modula√ß√£o dos n√≠veis do miR-99a-5p na linhagem celular MC3T3 n√£o afetou a prolifera√ß√£o celular. A an√°lise prote√≥mica dos lisados celulares provenientes das MC3T3 em que a express√£o do miR-99a-5p foi inibida, comparativamente ao controlo, mostrou que diversas prote√≠nas, conhecidas por estarem envolvidas na diferencia√ß√£o osteog√©nica, se encontravam alteradas, como a plexin-A2 (PLXA2), all-trans retinoic acid-induced differentiation factor (ARAID), ARF GTPase-activating protein GIT (GIT1) and Ephrin type-A receptor 2 (EPHA2). Os resultados mostraram tamb√©m que a inibi√ß√£o dos n√≠veis do miR-99a-5p influenciam v√°rias vias descritas como estando associadas √† osteoporose, incluindo a Ephrin receptor, Pl3K-Akt e canonical Wnt. Em contraste com o perfil de express√£o verificado durante a osteog√©nese, o miR-99a-5p encontra-se sobreexpresso ao longo da osteoclastog√©nese das RAW 264.7 e dos mon√≥citos humanos. Demonstr√°mos tamb√©m que a inibi√ß√£o do miR-99a-5p nas MC3T3 fomentou o aumento de express√£o da raz√£o OPG/RANKL ao n√≠vel do mRNA e que o sobrenadante recolhido a partir dessas c√©lulas inibe a diferencia√ß√£o das RAW 264.7 em osteoclastos. Adicionalmente, os resultados mostram que a express√£o do miR-99a-5p varia ao longo do tempo na medula √≥ssea de ratos ap√≥s uma les√£o √≥ssea de defeito cr√≠tico. Finalmente, os resultados obtidos a partir de amostras humanas de pacientes com fractura de fragilidade e diagnosticados com osteoporose mostraram que estes apresentam n√≠veis mais elevados de express√£o do miR-99a-5p comparativamente ao controlo (amostras de pacientes com osteoartrite). Tendo em conta os resultados obtidos ao longo deste trabalho, conclu√≠mos que o miR-99a-5p √© um regulador cr√≠tico da diferencia√ß√£o osteog√©nica. No futuro, a modula√ß√£o dos n√≠veis do miR-99a-5p no osso pode ser utilizada como uma estrat√©gia que tem como objetivo restabelecer a homeostase √≥ssea

    Rehabilitation Exercise Repetition Segmentation and Counting using Skeletal Body Joints

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    Physical exercise is an essential component of rehabilitation programs that improve quality of life and reduce mortality and re-hospitalization rates. In AI-driven virtual rehabilitation programs, patients complete their exercises independently at home, while AI algorithms analyze the exercise data to provide feedback to patients and report their progress to clinicians. To analyze exercise data, the first step is to segment it into consecutive repetitions. There has been a significant amount of research performed on segmenting and counting the repetitive activities of healthy individuals using raw video data, which raises concerns regarding privacy and is computationally intensive. Previous research on patients' rehabilitation exercise segmentation relied on data collected by multiple wearable sensors, which are difficult to use at home by rehabilitation patients. Compared to healthy individuals, segmenting and counting exercise repetitions in patients is more challenging because of the irregular repetition duration and the variation between repetitions. This paper presents a novel approach for segmenting and counting the repetitions of rehabilitation exercises performed by patients, based on their skeletal body joints. Skeletal body joints can be acquired through depth cameras or computer vision techniques applied to RGB videos of patients. Various sequential neural networks are designed to analyze the sequences of skeletal body joints and perform repetition segmentation and counting. Extensive experiments on three publicly available rehabilitation exercise datasets, KIMORE, UI-PRMD, and IntelliRehabDS, demonstrate the superiority of the proposed method compared to previous methods. The proposed method enables accurate exercise analysis while preserving privacy, facilitating the effective delivery of virtual rehabilitation programs.Comment: 8 pages, 1 figure, 2 table

    Effect of intermittent fasting on circulating inflammatory markers in obesity: A review of human trials

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    Obesity is associated with low-grade inflammation. Weight loss, by means of dietary restriction, has been shown to reduce systemic inflammation. Intermittent fasting has recently gained popularity as a weight loss diet, but its effects on inflammatory markers in individuals with obesity have yet to be summarized. Accordingly, this review examined how the two main forms of intermittent fasting, i.e., time restricted eating (TRE) and alternate day fasting (ADF), impact body weight and key circulating inflammatory markers (i.e., C-reactive protein (CRP), tumor necrosis factor-alpha (TNF-alpha), and interleukin-6 (IL-6)), in adults with obesity. Results from this review reveal that TRE with various eating window durations (4‚Äď10‚ÄČh per day) has no effect on circulating levels of CRP, TNF-alpha or IL-6, with 1‚Äď5% weight loss. As for ADF, reductions in CRP concentrations were noted when >6% weight loss was achieved. However, ADF had no effect on TNF-alpha or IL-6 concentrations, with this degree of weight loss. Thus, intermittent fasting has little or no effect on key inflammatory markers, but more research is warranted to confirm these preliminary findings

    Alterations to cerebral perfusion, metabolite profiles, and neuronal morphology in the hippocampus and cortex of male and female mice during chronic exposure to a high-salt diet

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    Excess dietary salt reduces resting cerebral blood flow (CBF) and vascular reactivity, which can limit the fueling of neuronal metabolism. It is hitherto unknown whether metabolic derangements induced by high-salt-diet (HSD) exposure during adulthood are reversed by reducing salt intake. In this study, male and female mice were fed an HSD from 9 to 16 months of age, followed by a normal-salt diet (ND) thereafter until 23 months of age. Controls were continuously fed either ND or HSD. CBF and metabolite profiles were determined longitudinally by arterial spin labeling magnetic resonance imaging and magnetic resonance spectroscopy, respectively. HSD reduced cortical and hippocampal CBF, which recovered after dietary salt normalization, and affected hippocampal but not cortical metabolite profiles. Compared to ND, HSD increased hippocampal glutamine and phosphocreatine levels and decreased creatine and choline levels. Dietary reversal only allowed recovery of glutamine levels. Histology analyses revealed that HSD reduced the dendritic arborization and spine density of cortical and hippocampal neurons, which were not recovered after dietary salt normalization. We conclude that sustained HSD exposure throughout adulthood causes permanent structural and metabolic alterations to the mouse brain that are not fully normalized by lowering dietary salt during aging

    A Multi-Scale Examination Of Skeletal Muscle’s Contribution To Local And Systemic Immunomodulation

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    The innate immune system requires input from a myriad of tissues and cell types to adequately prepare, locate, and neutralize infections. Skeletal muscle‚Äôs widespread distribution throughout the body and its potent ability to secrete cytokines makes it a vital signaling organ to alert the immune system during both localized and systemic injuries and illnesses. This dissertation first deciphers the crosstalk between skeletal muscle myocytes and macrophages during acute lung injury, reporting the macrophage-derived cytokine, tumor necrosis factor őĪ, to be necessary for eliciting the full potential of the skeletal muscle inflammatory milieu. Next, the total contribution of skeletal muscle mediators is quantified using muscle specific knockouts for toll-like receptor 4, interleukin-6, and C-C motif chemokine ligand 2. These novel mouse strains allow for targeted ablation of the receptor and effector molecules involved in endotoxemia specifically in myocytes, providing insight on the proportion of inflammatory cytokines derived from these muscle cells. Finally, to improve skeletal muscle and exercise research, a novel, open-source mouse exercise wheel is presented that allows for controllable and trackable experimentation. This device improves upon existing methods by allowing researchers to limit animals based on time- and distance- milestones. Together, these data provide a comprehensive examination spanning from molecular signaling to animal modeling of the mechanisms and magnitude to which skeletal muscle regulates immune homeostasis

    Post-Mortem Assessment and Evolutionary Role of the Autopsy

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    The Chapter is dedicated to the evolutionary role of autopsy, reporting the historical profiles, the state of the art, and prospects for future development of the main related techniques and methods of the ancillary disciplines (like Radiology), involved in historic synergy in the post-mortem assessment, together with the mother discipline Forensic Pathology. A task sustainable through the utilization of the so-called advanced molecular autopsy, a convergence of different skills jointly makes use of the high dimensionality of data generated by new technologies requiring a data mining approach governed by improved bioinformatics and computational biology tools. The evolution of the scientific research and the increased accuracy of the various disciplines will be able to weigh the value of evidence, placed at the disposal of the justice system as truth and proof

    Physiological Adaptions to Acute Hypoxia

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    When tissues are insufficiently supplied with oxygen, the environment is said to be hypoxic. Acute (exposures to) hypoxia can occur occupationally, within the scope of training and competitions or under pathological conditions. The increasing interest in acute exposure to altitude for training and research purposes makes it more important than ever to understand the physiological processes that occur under hypoxic conditions. Therefore, the scope of this chapter is to describe the main types of hypoxia on the oxygen cascade, to summarize the physiological consequences of acute hypoxia on the three main areas and to highlight the clinical consequences of acute hypoxia exposures for healthcare practitioners

    Acute Effects of Velocity-Based Resistance Training on the Physical Functional Performance of Older Adults

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    International Journal of Exercise Science 15(3): 399-413, 2022. The aim of this study was to analyse the acute effects of velocity-based resistance training on the physical and functional performance of older adults. Twenty participants (70.4 ¬Ī 7.4 years) performed the deadlift exercise, in two different resistance training protocols. The moderate-velocity protocol (MV) predicted maximum loads so that the movement velocity during the concentric phase remained in the range of 0.5 to 0.7 m/s and the high-velocity protocol (HV) predicted maximum loads so that the movement velocity remained between 0.8 and 1.0 m/s. The jump height (cm), handgrip strength (kg), and time (s) to complete the functional tests were assessed before (baseline), and immediately (post), 24-h, and 48-h after the MV and HV protocols. Compared to baseline, both training protocols acutely led to a gradual reduction in walking velocity, with significant values 24 hours after training (p = 0.044), on the other hand, both protocols improved performance in the timed up and go test at post (p \u3c 0.001) and in the sit-to-stand test at 48-h (p = 0.024), although there were no significant differences between them for any times analysed (p \u3e 0.05). No other outcomes exhibited significant changes. Results indicate that neither of the protocols (MV and HV) led to significant impairments in physical function of the older adults, and can be recommended with the safety criterion of at least 48-h of rest between sessions

    Sanfilippo syndrome: molecular basis, disease models and therapeutic approaches

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    Sanfilippo syndrome or mucopolysaccharidosis III is a lysosomal storage disorder caused by mutations in genes responsible for the degradation of heparan sulfate, a glycosaminoglycan located in the extracellular membrane. Undegraded heparan sulfate molecules accumulate within lysosomes leading to cellular dysfunction and pathology in several organs, with severe central nervous system degeneration as the main phenotypical feature. The exact molecular and cellular mechanisms by which impaired degradation and storage lead to cellular dysfunction and neuronal degeneration are still not fully understood. Here, we compile the knowledge on this issue and review all available animal and cellular models that can be used to contribute to increase our understanding of Sanfilippo syndrome disease mechanisms. Moreover, we provide an update in advances regarding the different and most successful therapeutic approaches that are currently under study to treat Sanfilippo syndrome patients and discuss the potential of new tools such as induced pluripotent stem cells to be used for disease modeling and therapy development

    Estudo da remodelagem reversa miocárdica através da análise proteómica do miocárdio e do líquido pericárdico

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    Valve replacement remains as the standard therapeutic option for aortic stenosis patients, aiming at abolishing pressure overload and triggering myocardial reverse remodeling. However, despite the instant hemodynamic benefit, not all patients show complete regression of myocardial hypertrophy, being at higher risk for adverse outcomes, such as heart failure. The current comprehension of the biological mechanisms underlying an incomplete reverse remodeling is far from complete. Furthermore, definitive prognostic tools and ancillary therapies to improve the outcome of the patients undergoing valve replacement are missing. To help abridge these gaps, a combined myocardial (phospho)proteomics and pericardial fluid proteomics approach was followed, taking advantage of human biopsies and pericardial fluid collected during surgery and whose origin anticipated a wealth of molecular information contained therein. From over 1800 and 750 proteins identified, respectively, in the myocardium and in the pericardial fluid of aortic stenosis patients, a total of 90 dysregulated proteins were detected. Gene annotation and pathway enrichment analyses, together with discriminant analysis, are compatible with a scenario of increased pro-hypertrophic gene expression and protein synthesis, defective ubiquitinproteasome system activity, proclivity to cell death (potentially fed by complement activity and other extrinsic factors, such as death receptor activators), acute-phase response, immune system activation and fibrosis. Specific validation of some targets through immunoblot techniques and correlation with clinical data pointed to complement C3 ő≤ chain, Muscle Ring Finger protein 1 (MuRF1) and the dual-specificity Tyr-phosphorylation regulated kinase 1A (DYRK1A) as potential markers of an incomplete response. In addition, kinase prediction from phosphoproteome data suggests that the modulation of casein kinase 2, the family of IőļB kinases, glycogen synthase kinase 3 and DYRK1A may help improve the outcome of patients undergoing valve replacement. Particularly, functional studies with DYRK1A+/- cardiomyocytes show that this kinase may be an important target to treat cardiac dysfunction, provided that mutant cells presented a different response to stretch and reduced ability to develop force (active tension). This study opens many avenues in post-aortic valve replacement reverse remodeling research. In the future, gain-of-function and/or loss-of-function studies with isolated cardiomyocytes or with animal models of aortic bandingdebanding will help disclose the efficacy of targeting the surrogate therapeutic targets. Besides, clinical studies in larger cohorts will bring definitive proof of complement C3, MuRF1 and DYRK1A prognostic value.A substitui√ß√£o da v√°lvula a√≥rtica continua a ser a op√ß√£o terap√™utica de refer√™ncia para doentes com estenose a√≥rtica e visa a elimina√ß√£o da sobrecarga de press√£o, desencadeando a remodelagem reversa mioc√°rdica. Contudo, apesar do benef√≠cio hemodin√Ęmico imediato, nem todos os pacientes apresentam regress√£o completa da hipertrofia do mioc√°rdio, ficando com maior risco de eventos adversos, como a insufici√™ncia card√≠aca. Atualmente, os mecanismos biol√≥gicos subjacentes a uma remodelagem reversa incompleta ainda n√£o s√£o claros. Al√©m disso, n√£o dispomos de ferramentas de progn√≥stico definitivos nem de terapias auxiliares para melhorar a condi√ß√£o dos pacientes indicados para substitui√ß√£o da v√°lvula. Para ajudar a resolver estas lacunas, uma abordagem combinada de (fosfo)prote√≥mica e prote√≥mica para a caracteriza√ß√£o, respetivamente, do mioc√°rdio e do l√≠quido peric√°rdico foi seguida, tomando partido de bi√≥psias e l√≠quidos peric√°rdicos recolhidos em ambiente cir√ļrgico. Das mais de 1800 e 750 prote√≠nas identificadas, respetivamente, no mioc√°rdio e no l√≠quido peric√°rdico dos pacientes com estenose a√≥rtica, um total de 90 prote√≠nas desreguladas foram detetadas. As an√°lises de anota√ß√£o de genes, de enriquecimento de vias celulares e discriminativa corroboram um cen√°rio de aumento da express√£o de genes pro-hipertr√≥ficos e de s√≠ntese proteica, um sistema ubiquitina-proteassoma ineficiente, uma tend√™ncia para morte celular (potencialmente acelerada pela atividade do complemento e por outros fatores extr√≠nsecos que ativam death receptors), com ativa√ß√£o da resposta de fase aguda e do sistema imune, assim como da fibrose. A valida√ß√£o de alguns alvos espec√≠ficos atrav√©s de immunoblot e correla√ß√£o com dados cl√≠nicos apontou para a cadeia ő≤ do complemento C3, a Muscle Ring Finger protein 1 (MuRF1) e a dual-specificity Tyr-phosphoylation regulated kinase 1A (DYRK1A) como potenciais marcadores de uma resposta incompleta. Por outro lado, a predi√ß√£o de cinases a partir do fosfoproteoma, sugere que a modula√ß√£o da case√≠na cinase 2, a fam√≠lia de cinases do IőļB, a glicog√©nio sintase cinase 3 e da DYRK1A pode ajudar a melhorar a condi√ß√£o dos pacientes indicados para interven√ß√£o. Em particular, a avalia√ß√£o funcional de cardiomi√≥citos DYRK1A+/- mostraram que esta cinase pode ser um alvo importante para tratar a disfun√ß√£o card√≠aca, uma vez que os mi√≥citos mutantes responderam de forma diferente ao estiramento e mostraram uma menor capacidade para desenvolver for√ßa (tens√£o ativa). Este estudo levanta v√°rias hip√≥teses na investiga√ß√£o da remodelagem reversa. No futuro, estudos de ganho e/ou perda de fun√ß√£o realizados em cardiomi√≥citos isolados ou em modelos animais de banding-debanding da aorta ajudar√£o a testar a efic√°cia de modular os potenciais alvos terap√™uticos encontrados. Al√©m disso, estudos cl√≠nicos em coortes de maior dimens√£o trar√£o conclus√Ķes definitivas quanto ao valor de progn√≥stico do complemento C3, MuRF1 e DYRK1A.Programa Doutoral em Biomedicin
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