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Organelles form membrane contact sites between each other, allowing for the transfer of molecules and signals. Mitochondria-endoplasmic reticulum (ER) contact sites (MERCS) are cellular subdomains characterized by close apposition of mitochondria and ER membranes. They have been implicated in many diseases, including neurodegenerative, metabolic, and cardiac diseases. Although MERCS have been extensively studied, much remains to be explored. To uncover novel regulators of MERCS, we conducted a genome-wide, flow cytometry-based screen using an engineered MERCS reporter cell line. We found 410 genes whose downregulation promotes MERCS and 230 genes whose downregulation decreases MERCS. From these, 29 genes were selected from each population for arrayed screening and 25 were validated from the high population and 13 from the low population. GET4 and BAG6 were highlighted as the top 2 genes that upon suppression increased MERCS from both the pooled and arrayed screens, and these were subjected to further investigation. Multiple microscopy analyses confirmed that loss of GET4 or BAG6 increased MERCS. GET4 and BAG6 were also observed to interact with the known MERCS proteins, inositol 1,4,5-trisphosphate receptors (IP3R) and glucose-regulated protein 75 (GRP75). In addition, we found that loss of GET4 increased mitochondrial calcium uptake upon ER-Ca2+ release and mitochondrial respiration. Finally, we show that loss of GET4 rescues motor ability, improves lifespan and prevents neurodegeneration in a Drosophila model of Alzheimer's disease (Aß42Arc). Together, these results suggest that GET4 is involved in decreasing MERCS and that its loss is neuroprotective.
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Sistemas CRISPR-Cas , Membranas Associadas à Mitocôndria , Sistemas CRISPR-Cas/genética , Mitocôndrias/genética , Mitocôndrias/metabolismo , Membranas Mitocondriais/metabolismo , Retículo Endoplasmático/genética , Retículo Endoplasmático/metabolismo , Cálcio/metabolismoRESUMO
The regulation of red blood cell (RBC) homeostasis is widely assumed to rely on the control of cell production by erythropoietin (EPO) and the destruction of cells at a fixed, species-specific age. In this work, we show that such a regulatory mechanism would be a poor homeostatic solution to satisfy the changing needs of the body. Effective homeostatic control would require RBC lifespan to be variable and tightly regulated. We suggest that EPO may control RBC lifespan by determining CD47 expression in newly formed RBCs and SIRP-α expression in sinusoidal macrophages. EPO could also regulate the initiation and intensity of anti-RBC autoimmune responses that curtail RBC lifespan in some circumstances. These mechanisms would continuously modulate the rate of RBC destruction depending on oxygen availability. The control of RBC lifespan by EPO and autoimmunity emerges as a key mechanism in the homeostasis of RBCs.
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Eritropoetina , Eritropoetina/genética , Eritrócitos , Cognição , Homeostase , LongevidadeRESUMO
Accumulation of amyloid ß-peptide (Aß) is a driver of Alzheimer's disease (AD). Amyloid precursor protein (App) knock-in mouse models recapitulate AD-associated Aß pathology, allowing elucidation of downstream effects of Aß accumulation and their temporal appearance upon disease progression. Here we have investigated the sequential onset of AD-like pathologies in AppNL-F and AppNL-G-F knock-in mice by time-course transcriptome analysis of hippocampus, a region severely affected in AD. Strikingly, energy metabolism emerged as one of the most significantly altered pathways already at an early stage of pathology. Functional experiments in isolated mitochondria from hippocampus of both AppNL-F and AppNL-G-F mice confirmed an upregulation of oxidative phosphorylation driven by the activity of mitochondrial complexes I, IV and V, associated with higher susceptibility to oxidative damage and Ca2+-overload. Upon increasing pathologies, the brain shifts to a state of hypometabolism with reduced abundancy of mitochondria in presynaptic terminals. These late-stage mice also displayed enlarged presynaptic areas associated with abnormal accumulation of synaptic vesicles and autophagosomes, the latter ultimately leading to local autophagy impairment in the synapses. In summary, we report that Aß-induced pathways in App knock-in mouse models recapitulate key pathologies observed in AD brain, and our data herein adds a comprehensive understanding of the pathologies including dysregulated metabolism and synapses and their timewise appearance to find new therapeutic approaches for AD.
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Doença de Alzheimer , Aplicativos Móveis , Animais , Camundongos , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/genética , Autofagia/genética , Modelos Animais de Doenças , Camundongos TransgênicosRESUMO
Idiopathic thrombocytopenic purpura is an immune-mediated disease that courses with thrombocytopenia. Eltrombopag is a thrombopoietin receptor agonist used as a second-line treatment for this disease to increase platelet count. The association of this drug with thrombotic events is known, however, with few cases of venous sinus thrombosis described in the literature. We present a 26-year-old female with idiopathic thrombocytopenic purpura diagnosed at the of age 14, splenectomized and previously treated with immunoglobulins, corticosteroids, and rituximab, with no response, who was started on oral estroprogestative and eltrombopag, with multiple dose increases, for 3 months. She was admitted to the emergency room with a 3-day history of severe frontal headache, with phono and photophobia, nausea, vomiting, and confusion. Physical examination was remarkable only for mild paraphasias, anomalous pauses, and difficulty in reading. Routine labs showed mild thrombocytopenia, leukocytosis, and elevated C-reactive Protein. She performed a brain computerized tomography and magnetic resonance that demonstrated extensive venous sinus thrombosis. She was admitted to the ward with eltrombopag suspension and enoxaparin 1mg/kg bid. Increasing thrombocytosis was observed for nine days, with a subsequent decrease to normal levels. Sequenced cerebral tomography showed hemorrhage reabsorption. At discharge, there was no improvement of neurological deficits and dabigatran 150mg bid was started for secondary prophylaxis. (AU)
La púrpura trombocitopénica idiopática es una enfermedad inmunomediada que cursa con trombocitopenia. Eltrombopag es un agonista del receptor de trombopoyetina que se utiliza como tratamiento de segunda línea de esta enfermedad para aumentar el recuento de plaquetas. Sin embargo, se conoce la asociación de este fármaco con acontecimientos trombóticos, con pocos casos de trombosis del seno venoso descritos en la literatura. Presentamos el caso de una mujer de 26 años con púrpura trombocitopénica idiopática diagnosticada a los 14 años, esplenectomizada y tratada previamente con inmunoglobulinas, corticoides y rituximab, sin respuesta, a la que se inició tratamiento con estroprogestativos orales y eltrombopag, con múltiples incrementos de dosis, durante 3 meses. Ingresó en urgencias con un cuadro de 3 días de evolución de cefalea frontal intensa, con fono y fotofobia, náuseas, vómitos y confusión. En la exploración física sólo destacaban parafasias leves,pausas anómalas y dificultad para leer. Los análisis de rutina mostraron trombocitopenia leve, leucocitosis y proteína C reactiva elevada. Se le realizó una tomografía computarizada cerebral y una resonancia magnética que demostraron una extensa trombosis del seno venoso. Fue ingresada en planta con eltrombopag en suspensión y enoxaparina 1mg/kg bid. Se observó un aumento de la trombocitosis durante nueve días, con una disminución posterior a niveles normales. La tomografía cerebral secuenciada mostró reabsorción de la hemorragia. Al alta, no hubo mejoría de los déficits neurológicos y se inició dabigatrán 150mg bid para profilaxis secundaria. (AU)
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Humanos , Feminino , Adulto , Trombose Venosa/diagnóstico , Trombose Venosa/etiologia , Púrpura Trombocitopênica Idiopática , TrombocitoseRESUMO
Eukaryotic Tribbles proteins are pseudoenzymes that regulate multiple aspects of intracellular signalling. Both Drosophila melanogaster and mammalian members of this family of pseudokinases act as negative regulators of insulin signalling. Mammalian tribbles pseudokinase (TRIB) genes have also been linked to insulin resistance and type 2 diabetes mellitus. Type 2 diabetes mellitus is associated with increased body weight, sleep problems and increased long-term mortality. Here, we investigated how manipulating the expression of Tribbles impacts body weight, sleep and mortality. We showed that the overexpression of Drosophila tribbles (trbl) in the fly fat body reduces both body weight and lifespan in adult flies without affecting food intake. Furthermore, it decreases the levels of Drosophila insulin-like peptide 2 (DILP2; ILP2) and increases night-time sleep. The three genes encoding TRIBs of mammals, TRIB1, TRIB2 and TRIB3, show both common and unique features. As the three human TRIB genes share features with Drosophila trbl, we further explored the links between TRIB genetic variants and both body weight and sleep in the human population. We identified associations between the polymorphisms and expression levels of the pseudokinases and markers of body weight and sleep duration. We conclude that Tribbles pseudokinases are involved in the control of body weight, lifespan and sleep.
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Diabetes Mellitus Tipo 2 , Neuropeptídeos , Animais , Humanos , Peso Corporal , Proteínas Quinases Dependentes de Cálcio-Calmodulina/genética , Proteínas Quinases Dependentes de Cálcio-Calmodulina/metabolismo , Proteínas de Ciclo Celular/genética , Drosophila melanogaster/genética , Drosophila melanogaster/metabolismo , Insulina/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Mamíferos/metabolismo , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Duração do Sono , Regulação para Cima/genéticaRESUMO
Parkinson's disease (PD) is characterised by selective death of dopaminergic (DA) neurons in the midbrain and motor function impairment. Gastrointestinal issues often precede motor deficits in PD, indicating that the gut-brain axis is involved in the pathogenesis of this disease. The features of PD include both mitochondrial dysfunction and activation of the unfolded protein response (UPR) in the endoplasmic reticulum (ER). PINK1 is a mitochondrial kinase involved in the recycling of defective mitochondria, and PINK1 mutations cause early-onset PD. Like PD patients, pink1 mutant Drosophila show degeneration of DA neurons and intestinal dysfunction. These mutant flies also lack vital proteins due to sustained activation of the kinase R-like endoplasmic reticulum kinase (dPerk), a kinase that induces the UPR. Here, we investigated the role of dPerk in intestinal dysfunction. We showed that intestinal expression of dPerk impairs mitochondrial function, induces cell death, and decreases lifespan. We found that suppressing dPerk in the intestine of pink1-mutant flies rescues intestinal cell death and is neuroprotective. We conclude that in a fly model of PD, blocking gut-brain transmission of UPR-mediated toxicity, is neuroprotective.
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Proteínas de Drosophila , Doença de Parkinson , Animais , Drosophila/metabolismo , Drosophila melanogaster/genética , Drosophila melanogaster/metabolismo , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Doença de Parkinson/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Resposta a Proteínas não DobradasRESUMO
BACKGROUND: Alzheimer's disease (AD) research has relied on mouse models overexpressing human mutant A ßPP; however, newer generation knock-in models allow for physiological expression of amyloid-ß protein precursor (AßPP) containing familial AD mutations where murine AßPP is edited with a humanized amyloid-ß (Aß) sequence. The AppNL-F mouse model has shown substantial similarities to AD brains developing late onset cognitive impairment. OBJECTIVE: In this study, we aimed to characterize mature primary cortical neurons derived from homozygous AppNL-F embryos, especially to identify early mitochondrial alterations in this model. METHODS: Primary cultures of AppNL-F neurons kept in culture for 12-15 days were used to measure Aß levels, secretase activity, mitochondrial functions, mitochondrial-ER contacts, synaptic function, and cell death. RESULTS: We detected higher levels of Aß42 released from AppNL-F neurons as compared to wild-type neurons. AppNL-F neurons, also displayed an increased Aß42/Aß40 ratio, similar to adult AppNL-F mouse brain. Interestingly, we found an upregulation in mitochondrial oxygen consumption with concomitant downregulation in glycolytic reserve. Furthermore, AppNL-F neurons were more susceptible to cell death triggered by mitochondrial electron transport chain inhibition. Juxtaposition between ER and mitochondria was found to be substantially upregulated, which may account for upregulated mitochondrial-derived ATP production. However, anterograde mitochondrial movement was severely impaired in this model along with loss in synaptic vesicle protein and impairment in pre- and post-synaptic function. CONCLUSION: We show that widespread mitochondrial alterations can be detected in AppNL-F neurons in vitro, where amyloid plaque deposition does not occur, suggesting soluble and oligomeric Aß-species being responsible for these alterations.
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Doença de Alzheimer , Animais , Camundongos , Humanos , Doença de Alzheimer/metabolismo , Camundongos Transgênicos , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Neurônios/metabolismo , Placa Amiloide/metabolismo , Modelos Animais de DoençasRESUMO
Hepatocellular Adenomas (HA) are rare benign tumors of the liver which occur predominantly in young women. Although benign, HA may have complications such as hemorrhage and malignant transformation. So, sometimes conservative management is not enough. We report a case of a 26-year-old woman on oral contraceptives who presented with acute abdominal pain and signs of hemodynamic shock. She underwent transarterial embolization due to the presence of multiple HA with rupture and active hemorrhage. This minimally invasive treatment failed to control the disease. The patient presented a progressive increase in the size of the masses with signs of recent hemorrhage, and the HA became unresectable, so she underwent liver transplantation. Liver transplantation is rarely indicated for the treatment of HA; however, in unresectable masses, it should be considered to prevent potential rupture with hemorrhage or malignant transformation.
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As the productivity and quality of tomato fruits are responsive to Mg applications, without surpassing the threshold of toxicity, the assessment of potential levels of Mg accumulation in tissues, as well as the interactions with Ca and physicochemical properties, prompt this study. An agronomic workflow for Mg enrichment, consisting of six foliar applications of MgSO4 with four concentrations (0%, 0.25%, 1% and 4%), equivalent to 0, 43.9, 175.5 and 702 g ha-1, was applied on two tomato (Lycopersicum esculentum L.) genotypes (Heinz1534 and Heinz9205). During fruit development, leaf gas exchange was screened, with only minor physiological deviations being found. At harvest, Mg contents among tissues and the interactions with Ca were analyzed, and it was found that in both varieties a higher Mg/Ca ratio prevailed in the most external part of the fruit sprayed with 4% MgSO4. However, Mg distribution prevailed relatively near the epidermis in H1534, while in H9205 the higher contents of this nutrient occurred in the core of the fruit, which indicated a decrease of the relative proportion of Ca. The morphologic (height and diameter), physical (dry weight and density) and colorimetric parameters, and the total soluble solids of fruits, did not reveal significant changes in both tomato varieties. It was further concluded that foliar application until 4% MgSO4 does not have physiological impacts in the fruit's quality of both varieties, but in spite of the different patterns of Mg accumulation in tissues, if the mean value in the whole fruit is considered, this nutrient prevails in H1534. This study thus suggests that variety H1534 can be used to attain tomato fruits with added value, providing an option of further processing to achieve food products with functional properties, ultimately proving a beneficial option to producers, the food processing industry and consumers. Moreover, the study reinforces the importance of variety choice when designing enrichment workflows.
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Calcium is essential for plants, yet as its mobility is limited, the understanding of the rate of Ca2+ accumulation and deposition in tissues of tubers, as well as the interactions with other critical nutrients prompted this study. To assess the interactions and differential accumulation of micro and macronutrients in the tissues of tubers, Solanum tuberosum L. varieties Agria and Rossi were cultivated and, after the beginning of tuberization, four foliar sprayings (at 8-10 day intervals) with CaCl2 (3 and 6 kg ha-1) or Ca(NO3)2 (2 and 4 kg ha-1) solutions were performed. It was found that both fertilizers increased Ca accumulation in tubers (mostly in the parenchyma tissues located in the center of the equatorial region). The functioning of the photosynthetic apparatus was not affected until the 3rd application but was somewhat affected when approaching the end of the crop cycle (after the 4th application), although the lower dose of CaCl2 seemed to improve the photochemical use of energy, particularly when compared with the greater dose of Ca(NO3)2. Still, none of these impacts modified tuber height and diameter. Following the increased accumulation of Ca, in the tubers of both varieties, the mean contents of P, K, Na, Fe, and Zn revealed different accumulation patterns. Moreover, accumulation of K, Fe, Mn, and Zn prevailed in the epidermis, displaying a contrasting pattern relative to Ca. Therefore, Ca accumulation revealed a heterogeneous trend in the different regions analyzed, and Ca enrichment of tubers altered the accumulation of other nutrients.
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Humanos , Masculino , Adulto , Sarcoma de Kaposi/diagnóstico , Sarcoma de Kaposi/terapia , Infecções por HIV , BiópsiaRESUMO
The innate immune response mounts a defense against foreign invaders and declines with age. An inappropriate induction of this response can cause diseases. Previous studies showed that mitochondria can be repurposed to promote inflammatory signaling. Damaged mitochondria can also trigger inflammation and promote diseases. Mutations in pink1, a gene required for mitochondrial health, cause Parkinson's disease, and Drosophila melanogaster pink1 mutants accumulate damaged mitochondria. Here, we show that defective mitochondria in pink1 mutants activate Relish targets and demonstrate that inflammatory signaling causes age-dependent intestinal dysfunction in pink1-mutant flies. These effects result in the death of intestinal cells, metabolic reprogramming and neurotoxicity. We found that Relish signaling is activated downstream of a pathway stimulated by cytosolic DNA. Suppression of Relish in the intestinal midgut of pink1-mutant flies restores mitochondrial function and is neuroprotective. We thus conclude that gut-brain communication modulates neurotoxicity in a fly model of Parkinson's disease through a mechanism involving mitochondrial dysfunction.
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Proteínas de Drosophila , Gastroenteropatias , Enteropatias , Doença de Parkinson , Animais , Drosophila/metabolismo , Drosophila melanogaster/genética , Proteínas de Drosophila/genética , Proteínas Serina-Treonina Quinases/genética , Doença de Parkinson/genéticaRESUMO
Cutaneous findings should be actively sought in suspected cases of sepsis, as some of them (such as ecthyma gangrenosum) may provide clues about the infectious agent involved and the patient's immunosuppression status.
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BACKGROUND: Mitochondrial dysfunction is a common feature of aging, neurodegeneration, and metabolic diseases. Hence, mitotherapeutics may be valuable disease modifiers for a large number of conditions. In this study, we have set up a large-scale screening platform for mitochondrial-based modulators with promising therapeutic potential. RESULTS: Using differentiated human neuroblastoma cells, we screened 1200 FDA-approved compounds and identified 61 molecules that significantly increased cellular ATP without any cytotoxic effect. Following dose response curve-dependent selection, we identified the flavonoid luteolin as a primary hit. Further validation in neuronal models indicated that luteolin increased mitochondrial respiration in primary neurons, despite not affecting mitochondrial mass, structure, or mitochondria-derived reactive oxygen species. However, we found that luteolin increased contacts between mitochondria and endoplasmic reticulum (ER), contributing to increased mitochondrial calcium (Ca2+) and Ca2+-dependent pyruvate dehydrogenase activity. This signaling pathway likely contributed to the observed effect of luteolin on enhanced mitochondrial complexes I and II activities. Importantly, we observed that increased mitochondrial functions were dependent on the activity of ER Ca2+-releasing channels inositol 1,4,5-trisphosphate receptors (IP3Rs) both in neurons and in isolated synaptosomes. Additionally, luteolin treatment improved mitochondrial and locomotory activities in primary neurons and Caenorhabditis elegans expressing an expanded polyglutamine tract of the huntingtin protein. CONCLUSION: We provide a new screening platform for drug discovery validated in vitro and ex vivo. In addition, we describe a novel mechanism through which luteolin modulates mitochondrial activity in neuronal models with potential therapeutic validity for treatment of a variety of human diseases.
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Retículo Endoplasmático/efeitos dos fármacos , Luteolina/farmacologia , Mitocôndrias/efeitos dos fármacos , Neurônios/metabolismo , Animais , Linhagem Celular Tumoral , Avaliação Pré-Clínica de Medicamentos , Retículo Endoplasmático/metabolismo , Ensaios de Triagem em Larga Escala , Humanos , Camundongos , Mitocôndrias/metabolismo , Neurônios/efeitos dos fármacos , Transdução de SinaisRESUMO
The way organelles are viewed by cell biologists is quickly changing. For many years, these cellular entities were thought to be unique and singular structures that performed specific roles. However, in recent decades, researchers have discovered that organelles are dynamic and form physical contacts. In addition, organelle interactions modulate several vital biological functions, and the dysregulation of these contacts is involved in cell dysfunction and different pathologies, including neurodegenerative diseases. Mitochondria-ER contact sites (MERCS) are among the most extensively studied and understood juxtapositioned interorganelle structures. In this review, we summarise the major biological and ultrastructural dysfunctions of MERCS in neurodegeneration, with a particular focus on Alzheimer's disease as well as Parkinson's disease, amyotrophic lateral sclerosis and frontotemporal dementia. We also propose an updated version of the MERCS hypothesis in Alzheimer's disease based on new findings. Finally, we discuss the possibility of MERCS being used as possible drug targets to halt cell death and neurodegeneration.
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In December 2019, a coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), began infecting humans, causing a novel disease, coronavirus disease 19 (COVID-19). This was first described in the Wuhan province of the People's Republic of China. SARS-CoV-2 has spread throughout the world, causing a global pandemic. To date, thousands of cases of COVID-19 have been reported in the United Kingdom, and over 45,000 patients have died. Some progress has been achieved in managing this disease, but the biological determinants of health, in addition to age, that affect SARS-CoV-2 infectivity and mortality are under scrutiny. Recent studies show that several medical conditions, including diabetes and hypertension, increase the risk of COVID-19 and death. The increased vulnerability of elderly individuals and those with comorbidities, together with the prevalence of neurodegenerative diseases with advanced age, led us to investigate the links between neurodegeneration and COVID-19. We analysed the primary health records of 13,338 UK individuals tested for COVID-19 between March and July 2020. We show that a pre-existing diagnosis of Alzheimer's disease predicts the highest risk of COVID-19 and mortality among elderly individuals. In contrast, Parkinson's disease patients were found to have a higher risk of SARS-CoV-2 infection but not mortality from COVID-19. We conclude that there are disease-specific differences in COVID-19 susceptibility among patients affected by neurodegenerative disorders.
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We report the case of a 32-year-old woman presenting to the emergency department with ankle edema and arthralgia. Only later in the follow-up period, she developed erythema nodosum. The study revealed bilateral hilar and mediastinal lymphadenopathy and biopsy demonstrated non-caseating granulomas consistent with a diagnosis of Lofgren's syndrome. Patients often do not present with all signs and symptoms, which delays the correct diagnosis. This case reinforces the need to use diagnostic methods, particularly non-invasive ones, such as ultrasound (US), in such cases. US of the lower extremity swelling could have helped the diagnosis, even without demonstrating effusion.
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In December 2019, a novel disease, coronavirus disease 19 (COVID-19), emerged in Wuhan, People's Republic of China. COVID-19 is caused by a novel coronavirus (SARS-CoV-2) presumed to have jumped species from another mammal to humans. This virus has caused a rapidly spreading global pandemic. To date, over 300,000 cases of COVID-19 have been reported in England and over 40,000 patients have died. While progress has been achieved in managing this disease, the factors in addition to age that affect the severity and mortality of COVID-19 have not been clearly identified. Recent studies of COVID-19 in several countries identified links between air pollution and death rates. Here, we explored potential links between major fossil fuel-related air pollutants and SARS-CoV-2 mortality in England. We compared current SARS-CoV-2 cases and deaths from public databases to both regional and subregional air pollution data monitored at multiple sites across England. After controlling for population density, age and median income, we show positive relationships between air pollutant concentrations, particularly nitrogen oxides, and COVID-19 mortality and infectivity. Using detailed UK Biobank data, we further show that PM2.5 was a major contributor to COVID-19 cases in England, as an increase of 1 m3 in the long-term average of PM2.5 was associated with a 12% increase in COVID-19 cases. The relationship between air pollution and COVID-19 withstands variations in the temporal scale of assessments (single-year vs 5-year average) and remains significant after adjusting for socioeconomic, demographic and health-related variables. We conclude that a small increase in air pollution leads to a large increase in the COVID-19 infectivity and mortality rate in England. This study provides a framework to guide both health and emissions policies in countries affected by this pandemic.
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Poluentes Atmosféricos , Poluição do Ar , COVID-19 , Poluentes Atmosféricos/análise , Poluição do Ar/análise , China , Inglaterra , Humanos , Material Particulado/análise , SARS-CoV-2RESUMO
Recent findings have shown that the connectivity and crosstalk between mitochondria and the endoplasmic reticulum (ER) at mitochondria-ER contact sites (MERCS) are altered in Alzheimer's disease (AD) and in AD-related models. MERCS have been related to the initial steps of autophagosome formation as well as regulation of mitochondrial function. Here, the interplay between MERCS, mitochondria ultrastructure and function and autophagy were evaluated in different AD animal models with increased levels of Aß as well as in primary neurons derived from these animals. We start by showing that the levels of Mitofusin 1, Mitofusin 2 and mitochondrial import receptor subunit TOM70 are decreased in post-mortem brain tissue derived from familial AD. We also show that Aß increases the juxtaposition between ER and mitochondria both in adult brain of different AD mouse models as well as in primary cultures derived from these animals. In addition, the connectivity between ER and mitochondria are also increased in wild-type neurons exposed to Aß. This alteration in MERCS affects autophagosome formation, mitochondrial function and ATP formation during starvation. Interestingly, the increment in ER-mitochondria connectivity occurs simultaneously with an increase in mitochondrial activity and is followed by upregulation of autophagosome formation in a clear chronological sequence of events. In summary, we report that Aß can affect cell homeostasis by modulating MERCS and, consequently, altering mitochondrial activity and autophagosome formation. Our data suggests that MERCS is a potential target for drug discovery in AD.
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Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Autofagossomos/metabolismo , Retículo Endoplasmático/metabolismo , Mitocôndrias/metabolismo , Mitocôndrias/fisiologia , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/fisiopatologia , Animais , Autofagossomos/fisiologia , Encéfalo/metabolismo , Encéfalo/fisiopatologia , Modelos Animais de Doenças , Retículo Endoplasmático/fisiologia , Feminino , Homeostase/fisiologia , Humanos , Masculino , Camundongos , Camundongos Transgênicos , Pessoa de Meia-Idade , Proteínas de Transporte da Membrana Mitocondrial/metabolismo , Membranas Mitocondriais/metabolismo , Neurônios/metabolismo , Neurônios/fisiologia , Regulação para Cima/fisiologiaRESUMO
RESUMO: A área de investigação do turismo acessível (TA) apresenta uma tendência de crescimento. Contudo, a maioria dos estudos foca-se na acessibilidade física, havendo poucos que analisem as atitudes dos estudantes e profissionais desse setor relativamente às pessoas com deficiência (PcD). Assim sendo, esta revisão tem como objetivo analisar os trabalhos efetuados em outras áreas científicas sobre as atitudes relativamente às PcD. Pretende-se mapear metodologias, instrumentos de medição e principais variáveis e fatores associados às atitudes, para promover a sua inclusão na sociedade. Realizaram-se pesquisas na Scopus, tendo-se obtido 492 registos. Destes, foram selecionados 96 artigos para análise. Os resultados evidenciam que a avaliação das atitudes relativamente às PcD é uma temática de grande relevância em várias áreas científicas. Os estudos utilizam diversos instrumentos para medir essas atitudes. As experiências anteriores, qualidade e frequência do contato com PcD e conhecimento acerca da deficiência têm influência nas atitudes. Contudo, os resultados divergem na influência do perfil sociodemográfico nas atitudes face às PcD. Existe tendência para o recurso a metodologias quantitativas utilizando, como instrumento de recolha de dados, o questionário. O artigo termina identificando áreas de investigação relevantes para o aumento do conhecimento dos fatores que influenciam essas atitudes e, consequentemente, para o desenvolvimento do TA.
ABSTRACT: The investigation area of accessible tourism (AT) has a growing trend. However, most studies focus on physical accessibility, and only a few analyse the attitudes of students and professionals in this sector towards people with disabilities (PwD). This review aims to analyse the work carried out in other scientific areas on attitudes towards PwD. It is intended to map methodologies, measurement instruments and main variables and factors related with attitudes, to promote their inclusion in society. Research was carried out at Scopus and 492 records were obtained. Of these, 96 articles were selected for analysis. Results show that the assessment of attitudes towards PwD is a topic of great relevance in several scientific areas. Studies use several instruments to measure these attitudes. Previous experiences, quality, and frequency of contact with PwD and knowledge about disability have an influence on attitudes. However, results differ in the influence of the sociodemographic profile on attitudes towards PwD. There is a trend towards the use of quantitative methodologies, using the questionnaire as a tool for data collection. The article ends by identifying areas of research relevant to the increasing knowledge of the factors that influence these attitudes and, consequently, to the development of AT.