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Mitochondrial aldehyde dehydrogenase (ALDH2) offers proven cardiovascular benefit although its impact in diabetes remains elusive. This study examined the effect of ALDH2 overexpression (OE) and knockout (KO) on diabetic cardiomyopathy and mechanism involved with a focus on mitochondrial integrity. ALDH2 OE and KO mice were challenged with streptozotocin (STZ, 200 mg/kg. i.p.) to establish diabetes. Diabetic patients displayed reduced plasma ALDH2 activity, cardiac remodeling and diastolic dysfunction. STZ challenge prompted reduced respiratory exchange ratio (RER), dampened fractional shortening, ejection fraction, increased LV end systolic and diastolic diameters, cardiac remodeling, cardiomyocyte contractile and intracellular Ca2+ defects (depressed peak shortening and maximal velocity of shortening/relengthening, prolonged relengthening, dampened intracellular Ca2+ rise and clearance), myocardial ultrastructural injury, oxidative stress, apoptosis and mitochondrial damage, the effects of which were overtly attenuated and accentuated by ALDH2 OE and KO, respectively. Immunoblotting revealed downregulated mitochondrial proteins PPARγ coactivator 1α (PGC-1α) and UCP-2, Ca2+ regulatory proteins including SERCA and Na+-Ca2+ exchanger, elevated phospholamban, dampened autophagy and mitophagy (LC3B ratio, TOM20, Parkin, FUNDC1 and BNIP3), disrupted phosphorylation of Akt, GSK3ß and Foxo3a, and elevated PTEN phosphorylation, the effect of which was reversed and worsened by ALDH2 OE and KO, respectively (except FUNDC1 and BNIP3). In vivo and in vitro data revealed that novel ALDH2 activator torezolid/Alda-1 protected against STZ or high glucose-induced cardiac anomalies, the effect was nullified by inhibition of Akt, GSK3ß, Parkin and mitochondrial coupling. Our data discerned a vital role for ALDH2 in diabetic cardiomyopathy possibly through regulation of Akt, GSK3ß activation, parkin mitophagy and mitochondrial function.
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Lipid nanoparticle (LNP)-coated-modified RNA(modRNA) has been developed for enhancing the stability of modRNA, but it tends to accumulate in liver. The current study aimed to optimize strategy for increasing cardiac expression efficiency of modRNA. We synthesized Luciferase (Luc)-modRNA, and also developed 122Luc modRNA, a liver silencing Luc modRNA. Intramyocardial injection of naked Luc modRNA induced high bioluminescence signal in heart, but very low in other organs including liver. Luc modRNA-LNP injection showed the signal was increased by 5 folds in the heart and by 15,000 folds in the liver, compared to naked Luc modRNA group. In comparison with Luc modRNA-LNP group, the liver signal was decreased to 0.17%, while cardiac signal showed a slight drop by intramyocardial injection of 122Luc-modRNA-LNP. Our data revealed that intramyocardial injection of naked modRNA could effectively induced cardiac-specific expression. For cardiac delivery of Luc modRNA-LNP, 122modRNA-LNP enhances specificity of cardiac expression by abolishing liver signal.
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Técnicas de Transferência de Genes , Nanopartículas , Camundongos , Animais , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , CoraçãoRESUMO
Aortic regurgitation (AR) is a common valvular heart disease that exerts volume overload on the heart and represents a global public health problem. Although mice are widely applied to shed light on the mechanisms of cardiovascular disease, mouse models of AR, especially those induced by surgery, are still paucity. Here, a mouse model of AR was described in detail which is surgically induced by disruption of the aortic valves under high-resolution echocardiography. In accordance with regurgitated blood flow, AR mouse hearts present a distinctive and clinically relevant volume overload phenotype, which is characterized by eccentric hypertrophy and cardiac dysfunction, as evidenced by echocardiographic and invasive hemodynamic evaluation. Our proposal, in a reliable and reproducible manner, provides a practical guide on the establishment and assessment of a mouse model of AR for future studies on molecular mechanisms and therapeutic targets of volume overload cardiomyopathy.
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Insuficiência da Valva Aórtica , Insuficiência Cardíaca , Animais , Valva Aórtica , Insuficiência da Valva Aórtica/diagnóstico por imagem , Insuficiência da Valva Aórtica/etiologia , Insuficiência da Valva Aórtica/cirurgia , Volume Cardíaco , Modelos Animais de Doenças , Ecocardiografia , Hemodinâmica , CamundongosRESUMO
To meet the requirements of durability design for concrete suffering frost damage, several test standards have been launched. Among the various damage indexes such as deteriorated compressive strength, relative dynamic elastic modulus (RDEM), residual deformation, etc., the concept of a "Durability Factor" (DF) is proposed by many standards to define the frost resistivity of concrete against frost action based on the experimental results from standard tests. Through a review of the literature, a clear tendency of strength/RDEM decay and residual deformation increase is captured with increasing cycles of freezing and thawing. However, tests following different standards finally derive huge scattering quantitative responses of frost resistance. Based on the large database of available laboratory experiments, this study presents a statistical analysis to propose a predictable model to calculate the DF with respect to other material factors. The statistical model is believed to be more convenient for engineering applications since the time-consuming experiment is no longer needed, and it is more precise compared with that developed according to only single experimental results to cover the uncertainties and unavoidable errors in specific tests. Moreover, the formula to calculate the DF is revised into a more general form so as to be applicable for all the laboratory experiments even for those cases without fully following the standards to derive a DF value.
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BACKGROUND: Subjective cognitive decline-questionnaire 9 (SCD-Q9) was developed to detect SCD complaints at risk of mild cognitive impairment (MCI). However, our previous findings indicated that its coverage might be insufficient. To test this hypothesis, we recently translated SCD-Q21. OBJECTIVE: To examine the reliability and validity of this translated SCD-Q21 and to explore its effectiveness for discriminating MCI from controls. METHODS: Item analysis was performed to understand its item discrimination and homogeneity. The Cronbach's α and Spearman-Brown's split-half coefficients were calculated to test its reliability. The Kaiser-Meyer-Olkin (KMO) value, Bartlett's sphericity test, and exploratory factor analysis (EFA) were used to examine its construct validity. The content validity was evaluated using five-grade Likert scale. Finally, the SCD-Q21 scores in MCI and controls were compared. RESULTS: The difference of each item between the extreme groups was significant. The Cronbach's α coefficient was .913 and Spearman-Brown's split-half coefficient was .894. When performing holding one-out approach, the Cronbach's α coefficient ranged from .906 to .914. The KMO value was .929 and the difference of Bartlett's Sphericity test was significant. All experts scored 5 points when assessing its content. Finally, a significant difference of score was found between MCI and NC groups. CONCLUSIONS: The reliability and validity of the SCD-Q21 are good, which may pave a way for its application in a wider Chinese-speaking population.
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Disfunção Cognitiva , China , Disfunção Cognitiva/diagnóstico , Análise Fatorial , Humanos , Reprodutibilidade dos Testes , Inquéritos e QuestionáriosRESUMO
Background: Previous reports on APOE ε4 allele distribution in different populations have been inconclusive. The Subjective Cognitive Decline-Questionnaire 9 (SCD-Q9) was developed to identify those at risk of objective cognitive impairment [OCI; including mild cognitive impairment (MCI) and dementia groups), but its association with APOE ε4 and discriminatory powers for SCD with subtle cognitive decline (SCDs) and OCI in memory clinics are unclear. Objectives: To investigate demographic distribution of APOE ε4, its association with SCD-Q9 scores, and its ability to discriminate SCDs and OCI groups from normal control (NC). Methods: A total of 632 participants were recruited (NC = 243, SCDs = 298, OCI = 91). APOE ε4 allele distribution and association with SCD-Q9 scores were calculated and the effects on cognitive impairment were analyzed. Receiver operating characteristic (ROC) analysis was applied to identify discriminatory powers for NC, SCDs, and OCI. Results: Total APOE ε4 frequency was 13.1%. This did not vary by demography but was higher in patients with OCI. The SCD-Q9 scores were higher in APOE ε4 carriers than non-carriers in the OCI group. The area under the curve (AUC) for discriminating from OCI using APOE ε4 were 0.587 and 0.575, using SCD-Q9 scores were 0.738 and 0.571 for NC and SCDs groups, respectively. When we combined APOE ε4 and SCD-Q9 scores into the model, the AUC increased to 0.747 for discriminating OCI from NC. However, when OCI group was split into MCI and dementia groups, only total SCD-Q9 score was the independent affecting factor of MCI. Conclusion: This study demonstrated that the distribution of APOE ε4 alleles did not vary with different demographic characteristics in a large-scale cohort from a memory clinic. APOE ε4 alleles may be associated with scores of SCD-Q9 reflecting the degree of cognitive complaints but their additional contribution to SCD-Q9 scores is marginal in discriminating between NC, SCDs, and OCI.
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[This corrects the article DOI: 10.7150/thno.22177.].
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To explore the mechanism by which rosuvastatin prevents coronary microembolism (CME)-induced cardiac injury and cardiomyocyte apoptosis. Animal and cell models of CME were established and treated with different doses of rosuvastatin. Echocardiography and histological staining were applied to assess left ventricular function and cardiac injury. Masson trichrome staining was used to evaluate fibrin deposition in the myocardium. The activity of lactate dehydrogenase (LDH) in serum and cell culture supernatant was detected. TUNEL staining and flow cytometry were used to evaluate apoptosis in myocardium and cardiomyocytes, respectively. The activity of ROS was revealed by DHE staining. The expression levels of Nox2, cleaved caspase-3, cytochrome C, p53, Bax and Bcl-2 were also detected. Rosuvastatin pretreatment improved the left ventricular function of CME mice and reduced inflammatory cell infiltration and fibrin deposition in the myocardium. Rosuvastatin reduced the production of ROS by inhibiting the expression of Nox2. Rosuvastatin also downregulated pro-apoptotic proteins cleaved caspase-3, cytochrome C, p53 and Bax, and upregulated anti-apoptotic Bcl-2. Rosuvastatin mitigates CME-induced cardiac injury by inhibiting Nox2-induced ROS overproduction and alleviating p53/Bax/Bcl-2-dependent cardiomyocyte apoptosis.
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Citocromos c , Proteína Supressora de Tumor p53 , Animais , Apoptose , Caspase 3/metabolismo , Citocromos c/metabolismo , Fibrina/metabolismo , Camundongos , Miocárdio/patologia , Miócitos Cardíacos/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Rosuvastatina Cálcica/metabolismo , Rosuvastatina Cálcica/farmacologia , Transdução de Sinais , Proteína Supressora de Tumor p53/metabolismo , Proteína X Associada a bcl-2/metabolismoRESUMO
BACKGROUND AND OBJECTIVE: Myocardial infarction (MI) leads to pathological cardiac remodeling and heart failure. Sodium tanshinone IIA sulfonate (STS) shows to possess therapeutic potential. The present study aimed to explore the potential role of STS in ventricular remodeling post-MI. METHODS: Mice were randomly divided into sham, MI + normal saline (NS) and MI + STS (20.8 mg/kg/day intraperitoneally) groups. MI was established following left anterior descending artery ligation. Cardiac function was evaluated using echocardiography. Scar size and myocardial fibrosis-associated markers were detected using Masson's trichrome staining and western blot analysis (WB). Necrosis and inflammation were assessed using H&E staining, lactate dehydrogenase (LDH) detection, ELISA, immunohistochemical staining, and WB. Furthermore, angiogenesis markers and associated proteins were detected using immunohistochemical staining and WB. RESULTS: Mice treated with STS exhibited significant improvements in cardiac function, smaller scar size, and low expression levels of α-smooth muscle actin and collagen I and III at 28 days following surgery, compared with the NS-treated group. Moreover, treatment with STS reduced eosinophil necrosis, the infiltration of inflammatory cells, plasma levels of LDH, high mobility group protein B1, interleukin-1ß and tumor necrosis factor- α, and protein expression of these cytokines at 3 days. Macrophage infiltration was also decreased in the STS group in the early phase. Additionally, CD31+ vascular density, protein levels of hypoxia-inducible factor- 1α, and vascular endothelial growth factor were elevated in the STS-treated mice at 28 days. CONCLUSION: STS improved pathological remodeling post-MI, and the associated therapeutic effects may be a result of a decrease in myocardial necrosis, modulation of inflammation, and an increase in angiogenesis.
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Infarto do Miocárdio , Remodelação Ventricular , Animais , Cicatriz/patologia , Modelos Animais de Doenças , Humanos , Inflamação/metabolismo , Camundongos , Infarto do Miocárdio/tratamento farmacológico , Miocárdio/metabolismo , Neovascularização Patológica/metabolismo , Fenantrenos , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
Objective: Subjective cognitive decline (SCD) complaints as the early manifestation of mild cognitive impairment (MCI) may be harbingers of objective cognitive decline. SCD-questinnaire9 (SCD-Q9) is developed to investigate the early sign for MCI. However, few studies have reported its power for discriminating MCI from healthy controls (HCs). Therefore, this study aims to investigate the discrimination power of SCD-Q9 as a brief screening tool for early detection of SCD in MCI.Methods: 84 HCs and 205 people with MCI were recruited. Their demographic information and scores of SCD-Q9 were compared. A binary logistic regression model was used to analyze the potential affecting factors of MCI, and the Receiver Operating Characteristic analysis was applied to test the discrimination powers of those factors, including SCD-Q9.Results: (1) Single and total scores of SCD-Q9 were all lower in the MCI group than those in the HC group. (2) Ageing, lower education and higher total scores of SCD-Q9 were associated with MCI. (3) Area Under the Curves (AUC) of SCD-Q9 for discriminating MCI from HC group was 0.815 and when integrating age and education, the AUC improved slightly and reached 0.839. Additionally, the sensitivity and specificity were 68.8% and 85.7%, respectively when a cut-off value of 3 was applied. Conclusions: SCD-Q9 may be able to detect the subjective cognitive decline in MCI early, but it may be used together with other screening questionnaires to improve its sensitivity and further verification of its power is needed.
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Disfunção Cognitiva , Disfunção Cognitiva/diagnóstico , Disfunção Cognitiva/psicologia , Diagnóstico Precoce , Humanos , Programas de Rastreamento , Testes Neuropsicológicos , Sensibilidade e EspecificidadeRESUMO
Progressive cardiac fibrosis accelerates the development of heart failure. Here, we aimed to explore serum Wnt5a and Wnt11 levels in hypertension patients, the roles of Wnt5a and Wnt11 in cardiac fibrosis and potential mechanisms under pressure overload. The pressure overload mouse model was built by transverse aortic constriction (TAC). Cardiac fibrosis was analyzed by Masson's staining. Serum Wnt5a or Wnt11 was elevated and associated with diastolic dysfunction in hypertension patients. TAC enhanced the expression and secretion of Wnt5a or Wnt11 from cardiomyocytes (CMs), cardiac fibroblasts (CFs), and cardiac microvascular endothelial cells (CMECs). Knockdown of Wnt5a and Wnt11 greatly improved cardiac fibrosis and function at 4 weeks after TAC. In vitro, shWnt5a or shWnt11 lentivirus transfection inhibited pro-fibrotic effects in CFs under mechanical stretch (MS). Similarly, conditional medium from stretched-CMs transfected with shWnt5a or shWnt11 lentivirus significantly suppressed the pro-fibrotic effects induced by conditional medium from stretched-CMs. These data suggested that CMs- or CFs-derived Wnt5a or Wnt11 showed a pro-fibrotic effect under pressure overload. In vitro, exogenous Wnt5a or Wnt11 activated ERK and p38 (fibrotic-related signaling) pathway, promoted the phosphorylation of EGFR, and increased the expression of Frizzled 5 (FZD5) in CFs. Inhibition or knockdown of EGFR greatly attenuated the increased FZD5, p-p38, and p-ERK levels, and the pro-fibrotic effect induced by Wnt5a or Wnt11 in CFs. Si-FZD5 transfection suppressed the increased p-EGFR level, and the fibrotic-related effects in CFs treated with Wnt5a or Wnt11. In conclusion, pressure overload enhances the secretion of Wnt5a or Wnt11 from CMs and CFs which promotes cardiac fibrosis by activation the crosstalk of FZD5 and EGFR. Thus, Wnt5a or Wnt11 may be a novel therapeutic target for the prevention of cardiac fibrosis under pressure overload.
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Receptores ErbB/metabolismo , Receptores Frizzled/metabolismo , Miocárdio/metabolismo , Transdução de Sinais , Proteínas Wnt/metabolismo , Proteína Wnt-5a/metabolismo , Idoso , Idoso de 80 Anos ou mais , Animais , Animais Recém-Nascidos , Cardiomiopatias/metabolismo , Fibroblastos/metabolismo , Fibrose , Humanos , Hipertensão/sangue , Masculino , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Miocárdio/patologia , Pressão , Ratos Sprague-Dawley , Estresse Mecânico , Proteínas Wnt/sangue , Proteína Wnt-5a/sangueRESUMO
OBJECTIVES: Movement restriction policies (MRPs) are effective in preventing/delaying COVID-19 transmission but are associated with high societal cost. This study aims to estimate the health burden of the first wave of COVID-19 in China and the cost-effectiveness of early versus late implementation of MRPs to inform preparation for future waves. METHODS: The SEIR (susceptible, exposed, infectious, and recovered) modeling framework was adapted to simulate the health and cost outcomes of initiating MRPs at different times: rapid implementation (January 23, the real-world scenario), delayed by 1 week, delayed by 2 weeks, and delayed by 4 weeks. The end point was set as the day when newly confirmed cases reached zero. Two costing perspectives were adopted: healthcare and societal. Input data were obtained from official statistics and published literature. The primary outcomes were disability-adjusted life-years, cost, and net monetary benefit. Costs were reported in both Chinese renminbi (RMB) and US dollars (USD) at 2019 values. RESULTS: The first wave of COVID-19 in China resulted in 38 348 disability adjusted life-years lost (95% CI 19 417-64 130) and 2639 billion RMB losses (95% CI 1347-4688). The rapid implementation strategy dominated all other delayed strategies. This conclusion was robust to all scenarios tested. At a willingness-to-pay threshold of 70 892 RMB (the national annual GDP per capita) per disability-adjusted life-year saved, the probability for the rapid implementation to be the optimal strategy was 96%. CONCLUSIONS: Early implementation of MRPs in response to COVID-19 reduced both the health burden and societal cost and thus should be used for future waves of COVID-19.
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COVID-19/complicações , Efeitos Psicossociais da Doença , Distanciamento Físico , Fatores de Tempo , COVID-19/economia , COVID-19/epidemiologia , China , Análise Custo-Benefício , Humanos , Saúde Pública/métodos , Saúde Pública/normas , Saúde Pública/estatística & dados numéricosRESUMO
Curcumin (1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione) is a potent anticancer drug with versatile biological activities, while the clinical translation of curcumin is severely limited due to its hydrophobicity, rapid elimination, and metabolism in the blood circulation. Herein, we aim to unravel the potential of curcumin as a synergistic agent with immunotherapy in the treatment of cancers. In an effort to minimize premature release and improve the systemic bioavailability, a superior blood stable and reduction sensitive curcumin micellar formulation, of which the release can be triggered by cancer cells, is rationally designed. We have synthesized a telodendrimer (mPEG-PLA-(LA)4) capable of forming reversible disulfide crosslinked micelles (DCMs). The curcumin loaded DCMs (Cur/DCMs) are spherical with a uniform size of 24.6 nm. The in vitro release profile demonstrates that curcumin releases significantly slower from DCMs than that from non-crosslinked micelles (NCMs), while the release can be accelerated with the increasing concentration of reducing agent glutathione (GSH). Intravenous administration of Cur/DCMs stably retains curcumin in the bloodstream and efficiently improves the systemic bioavailability. Furthermore, Cur/DCMs exhibit synergistic anticancer efficacy when combined with the anti-PD-1 antibody in an MC-38 colon cancer xenograft model. Our results potentiate the integration of blood stable curcumin nanoformulation and immunotherapy for cancer treatment.
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Antineoplásicos/farmacocinética , Neoplasias do Colo/tratamento farmacológico , Curcumina/farmacocinética , Micelas , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos Imunológicos , Linhagem Celular , Linhagem Celular Tumoral , Química Farmacêutica , Curcumina/administração & dosagem , Preparações de Ação Retardada , Portadores de Fármacos , Liberação Controlada de Fármacos , Estabilidade de Medicamentos , Sinergismo Farmacológico , Feminino , Hemólise , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Nanopartículas , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Cardiac fibrosis is a reparative process after myocardial infarction (MI), which leads to cardiac remodeling and finally heart failure. Endothelial-to-mesenchymal transition (EndMT) is induced after MI and contributes to cardiac fibrosis after MI. Orphan nuclear receptor Nur77 is a key regulator of inflammation, angiogenesis, proliferation, and apoptosis in vascular endothelial cells. Here, we investigated the role of orphan nuclear receptor Nur77 in EndMT and cardiac fibrosis after MI. Cardiac fibrosis was induced through MI by ligation of the left anterior descending coronary artery. We demonstrated that Nur77 knockout aggravated cardiac dysfunction and cardiac fibrosis 30 days after MI. Moreover, Nur77 deficiency resulted in enhanced EndMT as shown by increased expression of FSP-1, SM22α, Snail, and decreased expression of PECAM-1 and eNOS compared with wild-type mice after MI. Then, we found overexpression Nur77 in human coronary artery endothelial cells significantly inhibited interleukin 1ß and transforming growth factor ß2-induced EndMT, as shown by a reduced transition to a fibroblast-like phenotype and preserved angiogenesis potential. Mechanistically, we demonstrated that Nur77 downregulated EndMT by inhibiting the nuclear factor-κB-dependent pathway. In conclusion, Nur77 is involved in cardiac fibrosis by inhibiting EndMT and may be a promising target for therapy of cardiac fibrosis after MI.
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Transição Epitelial-Mesenquimal/fisiologia , Fibrose/metabolismo , Infarto do Miocárdio/metabolismo , Miocárdio/metabolismo , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/deficiência , Animais , Células Cultivadas , Vasos Coronários/metabolismo , Vasos Coronários/patologia , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Endotélio/metabolismo , Endotélio/patologia , Fibrose/patologia , Coração/fisiologia , Humanos , Interleucina-1beta/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Miocárdio/patologia , NF-kappa B/metabolismo , Neovascularização Patológica/metabolismo , Neovascularização Patológica/patologia , Transdução de Sinais/fisiologia , Fator de Crescimento Transformador beta/metabolismoRESUMO
PURPOSE: It is unclear how and to what extent various infection prevention and control (IPC) policies affect the spread of an epidemic during work resumption. In order to assess the impact of IPC policies, this research addresses the results of a policy simulation in Shanghai, China, which estimates the transmission dynamics of COVID-19 under various IPC policies and offers evidence-based outcomes of work resumption policies for the world. MATERIALS AND METHODS: This simulation research is based on a system dynamics (SD) model that integrates IPC work resumption policies implemented in Shanghai into the classical susceptible-exposed-infected-removed (SEIR) epidemiological model. Input data were obtained from official websites, the Baidu migration index and published literature. The SD model was validated by comparing results with real-world data. RESULTS: The simulations show that a non-quarantined and non-staged approach to work resumption (Policy 1) would bring a small secondary outbreak of COVID-19. The quarantined but non-staged approach (Policy 2) and the non-quarantined but staged approach (Policy 3) would not bring a secondary outbreak of COVID-19. However, they both would generate more newly confirmed cases than the staged and quarantined approach (Policy 4). Moreover, the 14-day quarantine policy alone appears to be more effective in reducing transmission risk than the staged work resumption policy alone. The combined staged and quarantined IPC policy led to the fewest confirmed cases caused by work resumption in Shanghai, and the spread of COVID-19 stopped (ie, the number of newly confirmed cases reduced to zero) at the earliest date. CONCLUSION: Conservative IPC policies can prevent a second outbreak of COVID-19 during work resumption. The dynamic systems model designed in this study can serve as a tool to test various IPC work resumption policies, facilitating decision-making in responses to combating the COVID-19 pandemic.
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Low density lipoprotein receptor-related protein 6 (LRP6), a Wnt co-receptor, induces multiple functions in various organs. We recently reported cardiac specific LRP6 deficiency caused cardiac dysfunction in mice. Whether cardiomyocyte-expressed LRP6 protects hearts against ischemic stress is largely unknown. Here, we investigated the effects of cardiac LRP6 in response to ischemic reperfusion (I/R) injury. Tamoxifen inducible cardiac specific LRP6 overexpression mice were generated to build I/R model by occlusion of the left anterior descending (LAD) coronary artery for 40 min and subsequent release of specific time. Cardiac specific LRP6 overexpression significantly ameliorated myocardial I/R injury as characterized by the improved cardiac function, strain pattern and infarct area at 24 h after reperfusion. I/R induced-apoptosis and endoplasmic reticulum (ER) stress were greatly inhibited by LRP6 overexpression in cardiomyocytes. LRP6 overexpression enhanced the expression of heat shock transcription factor-1(HSF1) and heat shock proteins (HSPs), the level of p-glycogen synthase kinase 3ß(GSK3ß)(S9) and p-AMPK under I/R. HSF1 inhibitor deteriorated the apoptosis and decreased p-GSK3ß(S9) level in LRP6 overexpressed -cardiomyocytes treated with H2O2. Si-HSF1 or overexpression of active GSK3ß significantly attenuated the increased expression of HSF1 and p-AMPK, and the inhibition of apoptosis and ER stress induced by LRP6 overexpression in H2O2-treated cardiomyocytes. AMPK inhibitor suppressed the increase in p-GSK3ß (S9) level but didn't alter HSF1 nucleus expression in LRP6 overexpressed-cardiomyocytes treated with H2O2. Active GSK3ß, but not AMPK inhibitor, attenuated the inhibition of ubiquitination of HSF1 induced by LRP6-overexpressed-cardiomyocytes treated with H2O2. LRP6 overexpression increased interaction of HSF1 and GSK3ß which may be involved in the reciprocal regulation under oxidative stress. In conclusion, cardiac LRP6 overexpression significantly inhibits cardiomyocyte apoptosis and ameliorates myocardial I/R injury by the crosstalk of HSF1 and GSK3ß signaling.
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Glicogênio Sintase Quinase 3 beta , Fatores de Transcrição de Choque Térmico/metabolismo , Peróxido de Hidrogênio , Proteína-6 Relacionada a Receptor de Lipoproteína de Baixa Densidade , Animais , Apoptose , Glicogênio Sintase Quinase 3 beta/genética , Proteína-6 Relacionada a Receptor de Lipoproteína de Baixa Densidade/genética , Proteína-6 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo , Camundongos , Estresse OxidativoRESUMO
OBJECTIVE: To evaluate the protective effect of pravastatin on atherosclerotic development and inflammatory monocyte subset in atherosclerotic apolipoprotein E (ApoE)-/- mice after myocardial infarction (MI). METHODS: Male ApoE-/- mice (8 weeks old) were fed a high-fat diet for 14 weeks throughout the experiment. A MI model was produced using 18-week-old ApoE-/- mice. They were randomly divided into three groups: sham group, MI group, and MI+Pra group (40 mg/kg/day pravastatin). After 4 weeks (at the end of the study period), the mice were sacrificed and cardiac function was evaluated by echocardiography. Aortic lesion areas were evaluated using oil red O staining. Plaque macrophage in aortic sinus was analyzed by immunofluorescence staining. Flow cytometry was used to explore the proportions of monocyte subsets in the blood, spleen, and bone marrowï¼. RESULTS: Pravastatin improved cardiac function and reduced lesion areas. It also attenuated the supply of monocytes in spleen, especially the inflammatory Ly6Chigh monocyte subset. Pravastatin also subsequently reduced macrophage accumulation in atherosclerotic lesions. CONCLUSIONS: MI accelerated chronic atherosclerosis progress. Pravastatin suppressed atherosclerotic development and inhibited inflammatory monocytosis after MI in ApoE-/- mice.
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Aterosclerose , Infarto do Miocárdio , Placa Aterosclerótica , Animais , Apolipoproteínas E/genética , Aterosclerose/tratamento farmacológico , Aterosclerose/genética , Modelos Animais de Doenças , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Infarto do Miocárdio/tratamento farmacológico , Pravastatina/farmacologia , Pravastatina/uso terapêuticoRESUMO
BACKGROUND: Since SCD (plus) was standardized, little is known about its demographic characteristics and its outcomes of neuropsychological assessments, including the SCD questionnaire 9 (SCD-Q9). OBJECTIVE: To characterize SCD (plus) by comparing the neuropsychological features among its subgroups and with normal controls (NC). Also, to explore its demographics and to understand the relation of the chief complaints and the scores of SCD-Q9. METHODS: Multistage stratified cluster random sampling was conducted to select participants. As a result, 84 NC and 517 SCD (plus) were included. SCD (plus) was further classified into several subgroups (SCD-C: concerned cognitive decline; SCD-F: complaints about SCD within the past five years; SCD-P: feeling performance being not as good as their peers; SCD+: presented> 3 of SCD (plus) features; SCD-: presented ≤ 3 of SCD (plus) features (see the diagnostic criteria for the details)) and between-group comparisons of neuropsychological scores were conducted. Point-biserial correlation and binary logistic regression analyses were performed to investigate the demographic characteristics of its subgroups. Finally, Spearman correlation was used to better understand the relation of SCD (plus) to SCD-Q9. RESULTS: (1) Scores of AVLT-LR (AVLT-LR: Auditory Verbal Learning Test-Long Delayed Recall) and MoCA-B (MoCA: Montreal Cognitive Assessment-Basic) were lower in the SCD-P group than those in the NC group, and the SCD+ group scored lower in the MoCA-B and CDT(CDT: Clock Drawing Test) than the SCD- group. (2) Females were more concerned than male participants. Individuals with lower education level felt that their cognitive performance were worse than their peers. Also, younger people might express concerns more than the more elderly. People who had complaints of SCD-P might be more likely to report SCD-C, but less likely to report SCD-F. (3) Positive correlations were found between the chief complaints of SCD (plus) and some items of SCD-Q9. CONCLUSIONS: SCD (plus) may be related to demographic factors. Individuals with SCD (plus) already exhibited cognitive impairment, which can be detected by SCD-Q9.
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Envelhecimento/fisiologia , Disfunção Cognitiva/diagnóstico , Disfunção Cognitiva/fisiopatologia , Testes Neuropsicológicos , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Autoavaliação Diagnóstica , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores SexuaisRESUMO
Nap1l1 gene encodes a tissue specific nucleosome assembly protein and is essential for tissue development. Here, we report the generation and characterization of a nap1l1 transgenic reporter in zebrafish model. We showed that a 5-kilobase (kb) genomic fragment immediately upstream of the nap1l1 gene transcription initiation site is capable of targeting the nucleic enhanced green fluorescence protein (EGFP) expression initially to central nervous system and subsequently to lateral line neuromasts, cardiomyocytes, and paraxial vessels, where the endogenous nap1l1 normally expresses with only a few exception. In adulthood, zebrafish nap1l1 promoter-driving nEGFP is predominantly expressed in lateral line system, liver, and ovary, but not in heart. Therefore, this novel transgenic reporter line, Tg(nap1l1:nEGFP)zs102, would be a valuable tool for studying the development and regeneration of lateral line system and also for investigating cardiac development.