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BACKGROUND: Removal of circulating plasma low-density lipoprotein cholesterol (LDL-C) by the liver relies on efficient endocytosis and intracellular vesicle trafficking. Increasing the availability of hepatic LDL receptors (LDLRs) remains a major clinical target for reducing LDL-C levels. Here, we describe a novel role for RNF130 (ring finger containing protein 130) in regulating plasma membrane availability of LDLR. METHODS: We performed a combination of gain-of-function and loss-of-function experiments to determine the effect of RNF130 on LDL-C and LDLR recycling. We overexpressed RNF130 and a nonfunctional mutant RNF130 in vivo and measured plasma LDL-C and hepatic LDLR protein levels. We performed in vitro ubiquitination assays and immunohistochemical staining to measure levels and cellular distribution of LDLR. We supplement these experiments with 3 separate in vivo models of RNF130 loss-of-function where we disrupted Rnf130 using either ASO (antisense oligonucleotides), germline deletion, or AAV CRISPR (adeno-associated virus clustered regularly interspaced short palindromic repeats) and measured hepatic LDLR and plasma LDL-C. RESULTS: We demonstrate that RNF130 is an E3 ubiquitin ligase that ubiquitinates LDLR resulting in redistribution of the receptor away from the plasma membrane. Overexpression of RNF130 decreases hepatic LDLR and increases plasma LDL-C levels. Further, in vitro ubiquitination assays demonstrate RNF130-dependent regulation of LDLR abundance at the plasma membrane. Finally, in vivo disruption of Rnf130 using ASO, germline deletion, or AAV CRISPR results in increased hepatic LDLR abundance and availability and decreased plasma LDL-C levels. CONCLUSIONS: Our studies identify RNF130 as a novel posttranslational regulator of LDL-C levels via modulation of LDLR availability, thus providing important insight into the complex regulation of hepatic LDLR protein levels.
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Fígado , Receptores de LDL , LDL-Colesterol/metabolismo , Receptores de LDL/genética , Receptores de LDL/metabolismo , Fígado/metabolismo , Proteínas de Transporte/metabolismo , Ubiquitinação , Lipoproteínas LDL/metabolismoRESUMO
BACKGROUND: This research aimed to investigate the associations of anthropometric measurements, physiological parameters, chronic disease comorbidities, and social and lifestyle factors with cognitive function amongst community-dwelling older adults in Taiwan. METHODS: This was an observational, cross-sectional study involving 4,578 participants at least 65 years old, recruited between January 2008 and December 2018 from the Annual Geriatric Health Examinations Program. Cognitive function was assessed using the short portable mental state questionnaire (SPMSQ). Multivariable logistic regression was done to analyze the factors associated with cognitive impairment. RESULTS: Among the 4,578 participants, 103 people (2.3%) with cognitive impairment were identified. Associated factors were age (odds ratio (OR) = 1.16, 95% confidence interval (CI) = 1.13,1.20), male gender (OR = 0.39, 95% CI = 0.21,0.72), diabetes mellitus (DM) (OR = 1.70, 95% CI = 1.03, 2.82), hyperlipidemia (OR = 0.47, 95% CI = 0.25, 0.89), exercise (OR = 0.44, 95% CI = 0.34, 0.56), albumin (OR = 0.37, 95% CI = 0.15, 0.88), and high-density lipoprotein (HDL) (OR = 0.98, 95% CI = 0.97, 1.00). Whereas waistline, alcohol intake in recent six months, and hemoglobin was not significantly associated with cognitive impairment (all p > 0.05). CONCLUSIONS: Our findings suggested that people with older age and a history of DM had a higher risk of cognitive impairment. Male gender, a history of hyperlipidemia, exercise, a high albumin level, and a high HDL level seemed to be associated with a lower risk of cognitive impairment amongst older adults.
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Disfunção Cognitiva , Vida Independente , Masculino , Humanos , Idoso , Taiwan/epidemiologia , Cognição , Disfunção Cognitiva/diagnóstico , Disfunção Cognitiva/epidemiologia , AlbuminasRESUMO
Chronic mild stress can lead to negative health outcomes. Frequency, duration, and intensity of acute stressors can affect health-related processes. We tested whether the temporal pattern of daily acute stressors (clustered or dispersed across the day) affects depression-related physiology. We used a rodent model to keep stressor frequency, duration, and intensity constant, and experimentally manipulated the temporal pattern of acute stressors delivered during the active phase of the day. Adult male Sprague-Dawley rats were exposed to one of three chronic mild stress groups: Clustered: stressors that occurred within 1 hour of each other (n = 21), Dispersed: stressors that were spread out across the active phase (n = 21), and Control: no stressors presented (n = 21). Acute mild stressors included noise, strobe lights, novel cage, cage tilt, wet bedding, and water immersion. Depression-related outcomes included: sucrose preference, body weight, circulating glucocorticoid (corticosterone) concentration after a novel acute stressor and during basal morning and evening times, and endotoxin-induced circulating interleukin-6 concentrations. Compared to control rats, those in the Clustered group gained less weight, consumed less sucrose, had a blunted acute corticosterone response, and an accentuated acute interleukin-6 response. Rats in the Dispersed group had an attenuated corticosterone decline during the active period and after an acute stressor compared to the Control group. During a chronic mild stress experience, the temporal distribution of daily acute stressors affected health-related physiologic processes. Regular exposure to daily stressors in rapid succession may predict more depression-related symptoms, whereas exposure to stressors dispersed throughout the day may predict diminished glucocorticoid negative feedback.
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Corticosterona/sangue , Estresse Fisiológico/fisiologia , Estresse Psicológico/fisiopatologia , Animais , Peso Corporal/fisiologia , Masculino , Ratos , Ratos Sprague-Dawley , Estresse Psicológico/sangue , Fatores de TempoRESUMO
This is a case report of a 16-year-old girl recently diagnosed with systemic lupus erythematosus (SLE) who presented with multiple blisters on the face, hands, arms, legs, trunk, and vaginal and oral mucosa. Skin biopsy was consistent with bullous SLE (BSLE). Dapsone is often the first-line treatment option for BSLE, but the patient's history of anemia and leukopenia and long-term immunosuppression requirement for her systemic symptoms raised concerns about dapsone and bone marrow toxicity, especially hemolytic anemia and agranulocytosis. She was started on intravenous immunoglobulin (IVIG), 2 g/kg divided over 3 days, with significant improvement in her cutaneous symptoms. IVIG is a treatment option for BSLE patients in whom agents such as dapsone are contraindicated.
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Imunoglobulinas Intravenosas/uso terapêutico , Lúpus Eritematoso Cutâneo/terapia , Pele/patologia , Adolescente , Dapsona/uso terapêutico , Feminino , Humanos , Lúpus Eritematoso Cutâneo/patologiaRESUMO
PROBLEM: The departure of physician-scientists from education and research into clinical practice is a growing challenge for the future of academic medicine. Junior faculty face competing demands for clinical productivity, teaching, research, and work-life integration, which can undermine confidence in the value of an academic career. Mentorship is important to foster career development and satisfaction in junior faculty. INTERVENTION: The goals of this academic pediatrics department were to develop, implement, and evaluate a multifaceted pediatric mentoring program to promote retention and satisfaction of junior faculty. Program elements included one-on-one mentor-mentee meetings, didactic workshops, grant review assistance, and facilitated peer-group mentoring. Program effectiveness was assessed using annual surveys of mentees and structured mentee exit interviews, as well as retention data for assistant professors. CONTEXT: The mentees were instructors and assistant professors in the department of pediatrics. OUTCOME: Seventy-nine mentees participated in the program from 2007 through 2014. The response rate from seven annual surveys was 84%. Sixty-nine percent of mentees felt more prepared to advance their careers, 81% had a better understanding of the criteria for advancement, 84% were satisfied with the program, and 95% found mentors accessible. Mentees who exited the program reported they most valued the one-on-one mentoring and viewed the experience positively regardless of promotion. Retention of assistant professors improved after initiation of the program; four of 13 hired from 2002 to 2006 left the institution, whereas 18 of 18 hired from 2007 to 2014 were retained. LESSONS LEARNED: This multifaceted mentoring program appeared to bolster satisfaction and enhance retention of junior pediatric faculty. Mentees reported increased understanding of the criteria for promotion and viewed the program as a positive experience regardless of career path. Individual mentor-mentee meetings were needed at least twice yearly to establish the mentoring relationship. Identifying "next steps" at the end of individual meetings was helpful to hold both parties accountable for progress. Mentees most valued workshops fostering development of tangible skills (such as scientific writing) and those clarifying the criteria for promotion more transparent. Facilitated peer-group mentoring for mentees at the instructor rank provided valuable peer support.
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Docentes de Medicina , Tutoria , Pediatria/educação , Desenvolvimento de Pessoal , Adulto , California , Mobilidade Ocupacional , Feminino , Humanos , Masculino , Grupo Associado , Satisfação Pessoal , Avaliação de Programas e Projetos de SaúdeRESUMO
The molecular mechanisms that regulate and coordinate signaling between the extracellular matrix (ECM) and cells contributing to the developing vasculature are complex and poorly understood. Myocardin-like protein 2 (MKL2) is a transcriptional co-activator that in response to RhoA and cytoskeletal actin signals physically associates with serum response factor (SRF), activating a subset of SRF-regulated genes. We now report the discovery of a previously undescribed MKL2/TGFß signaling pathway in embryonic stem (ES) cells that is required for maturation and stabilization of the embryonic vasculature. Mkl2(-/-) null embryos exhibit profound derangements in the tunica media of select arteries and arterial beds, which leads to aneurysmal dilation, dissection and hemorrhage. Remarkably, TGFß expression, TGFß signaling and TGFß-regulated genes encoding ECM are downregulated in Mkl2(-/-) ES cells and the vasculature of Mkl2(-/-) embryos. The gene encoding TGFß2, the predominant TGFß isoform expressed in vascular smooth muscle cells and embryonic vasculature, is activated directly via binding of an MKL2/SRF protein complex to a conserved CArG box in the TGFß2 promoter. Moreover, Mkl2(-/-) ES cells exhibit derangements in cytoskeletal organization, cell adhesion and expression of ECM that are rescued by forced expression of TGFß2. Taken together, these data demonstrate that MKL2 regulates a conserved TGF-ß signaling pathway that is required for angiogenesis and ultimately embryonic survival.
Assuntos
Vasos Sanguíneos/embriologia , Células-Tronco Embrionárias/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Fatores de Transcrição/fisiologia , Fator de Crescimento Transformador beta2/genética , Animais , Fístula Arteriovenosa/embriologia , Fístula Arteriovenosa/genética , Vasos Sanguíneos/metabolismo , Células Cultivadas , Embrião de Mamíferos , Células-Tronco Embrionárias/fisiologia , Viabilidade Fetal/genética , Hemorragia/embriologia , Hemorragia/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neovascularização Fisiológica/genética , Neovascularização Fisiológica/fisiologia , Transdução de Sinais/genética , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Fator de Crescimento Transformador beta2/metabolismoRESUMO
Neck pain is an extremely common symptom with many possible etiologies. A substantial number of patients are turning to complementary and alternative medicine (CAM). Low-quality evidence supports the beneficial effects of CAM. Feldenkrais, massage therapy, and spinal manipulation are discussed in detail. Complications are generally benign and self-limited, although occasional catastrophic consequences have been documented. Despite the favorable opinion many rheumatologists have of some CAM therapy, many patients are not disclosing CAM use to their medical providers. By expressing interest, asking questions, and taking a shared-decision-making approach, providers can encourage disclosure and provide valuable input.
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Manipulações Musculoesqueléticas/métodos , Cervicalgia/reabilitação , Humanos , Manipulação Quiroprática/métodos , Massagem/métodos , Propriocepção/fisiologiaRESUMO
This is dataset describing the levels of Food, Drug, & Cosmetic (FD&C) dye in juice drinks, breakfast cereals, frozen desserts, ice cream cones, fruit flavored soft drinks, frostings & icings, fruit snacks/candy, decoration chips for baking, water enhancers, and flavored fruit drink powder. Data values are organized by absolute values, averages, SDs and % RSD. High performance liquid chromatography with a photometric diode array detector (HPLC-PDA) was used to measure dye levels and generate the data. These values can be used to calculate levels of dyes consumed within various populations, such as children, and compare them to accepted daily intake (ADIs) values established by the United States Food & Drug Administration (US FDA). The data are interpreted in "Survey of Certified Food Dye Levels in Food Samples Consumed by Children for Updated Exposure Levels" in the Journal of Food Additives and Contaminants: Part B.1.
RESUMO
Polymers have the potential to replace metallic or bioprosthetic heart valve components due to superior durability and inertness while allowing for native tissue-like flexibility. Despite these appealing properties, certain polymers such as polyetheretherketone (PEEK) have issues with hemocompatibility, which have previously been addressed through assorted complex processes. In this paper, we explore the enhancement of PEEK hemocompatibility with polymer crystallinity. Amorphous, semi-crystalline and crystalline PEEK are investigated in addition to a highly crystalline carbon fiber (CF)/PEEK composite material (CFPEEK). The functional group density of the PEEK samples is determined, showing that higher crystallinity results in increased amount of surface carbonyl functional groups. The increase of crystallinity (and negatively charged groups) appears to cause significant reductions in platelet adhesion (33 vs. 1.5 % surface coverage), hemolysis (1.55 vs. 0.75 %âcm-2), and thrombin generation rate (4840 vs. 1585 mU/mL/min/cm2). In combination with the hemocompatibility study, mechanical characterization demonstrates that tailoring crystallinity is a simple and effective method to control both hemocompatibility and mechanical performance of PEEK. Furthermore, the results display that CFPEEK composite performed very well in all categories due to its enhanced crystallinity and complete carbon encapsulation, allowing the unique properties of CFPEEK to empower new concepts in cardiovascular device design.
Assuntos
Polietilenoglicóis , Polímeros , Benzofenonas , Cetonas/química , Teste de Materiais , Polietilenoglicóis/química , Polímeros/uso terapêutico , Vasos Sanguíneos/transplanteRESUMO
Low nephron endowment at birth is a risk factor for chronic kidney disease. The prevalence of this condition is increasing due to higher survival rates of preterm infants and children with multi- organ birth defect syndromes that affect the kidney and urinary tract. We created a mouse model of congenital low nephron number due to deletion of Mta2 in nephron progenitor cells. Mta2 is a core component of the Nucleosome Remodeling and Deacetylase (NuRD) chromatin remodeling complex. These mice developed albuminuria at 4 weeks of age followed by focal segmental glomerulosclerosis (FSGS) at 8 weeks, with progressive kidney injury and fibrosis. Our studies reveal that altered mitochondrial metabolism in the post-natal period leads to accumulation of neutral lipids in glomeruli at 4 weeks of age followed by reduced mitochondrial oxygen consumption. We found that NuRD cooperated with Zbtb7a/7b to regulate a large number of metabolic genes required for fatty acid oxidation and oxidative phosphorylation. Analysis of human kidney tissue also supported a role for reduced mitochondrial lipid metabolism and ZBTB7A/7B in FSGS and CKD. We propose that an inability to meet the physiological and metabolic demands of post-natal somatic growth of the kidney promotes the transition to CKD in the setting of glomerular hypertrophy due to low nephron endowment.
RESUMO
Despite intense investigation over the past century, the molecular mechanisms that regulate maintenance and adaptation of the heart during postnatal development are poorly understood. Myocardin is a remarkably potent transcriptional coactivator expressed exclusively in cardiac myocytes and smooth muscle cells during postnatal development. Here we show that myocardin is required for maintenance of cardiomyocyte structure and sarcomeric organization and that cell-autonomous loss of myocardin in cardiac myocytes triggers programmed cell death. Mice harboring a cardiomyocyte-restricted null mutation in the myocardin gene (Myocd) develop dilated cardiomyopathy and succumb from heart failure within a year. Remarkably, ablation of the Myocd gene in the adult heart leads to the rapid-onset of heart failure, dilated cardiomyopathy, and death within a week. Myocd gene ablation is accompanied by dissolution of sarcomeric organization, disruption of the intercalated disc, and cell-autonomous loss of cardiomyocytes via apoptosis. Expression of myocardin/serum response factor-regulated myofibrillar genes is extinguished, or profoundly attenuated, in myocardin-deficient hearts. Conversely, proapoptotic factors are induced and activated in myocardin-deficient hearts. We conclude that the transcriptional coactivator myocardin is required for maintenance of heart function and ultimately cardiomyocyte survival.
Assuntos
Testes de Função Cardíaca , Coração/fisiologia , Miócitos Cardíacos/citologia , Proteínas Nucleares/metabolismo , Transativadores/metabolismo , Envelhecimento/patologia , Animais , Apoptose , Cardiomiopatia Dilatada/patologia , Cardiomiopatia Dilatada/fisiopatologia , Sobrevivência Celular , Deleção de Genes , Coração/fisiopatologia , Integrases/metabolismo , Camundongos , Camundongos Mutantes , Contração Miocárdica/fisiologia , Miocárdio/metabolismo , Miocárdio/patologia , Miocárdio/ultraestrutura , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/ultraestrutura , Cadeias Pesadas de Miosina/metabolismo , Proteínas Nucleares/genética , Especificidade de Órgãos , Transativadores/genéticaRESUMO
In this backstory, researchers from Swiss Federal Institute of Technology (ETH Zurich) who initiated an interdisciplinary program to generate innovative solutions for different cardiovascular diseases, such as myocardial infarction, valvular replacement, and movement-based rehabilitation therapy, discuss the benefits and challenges of interdisciplinary research.
RESUMO
Myocardin (Myocd) is a potent transcriptional coactivator that has been implicated in cardiovascular development and adaptation of the cardiovascular system to hemodynamic stress. To determine the function of myocardin in the developing cardiovascular system, Myocd(F/F)/Wnt1-Cre(+) and Myocd(F/F)/Pax3-Cre(+) mice were generated in which the myocardin gene was selectively ablated in neural crest-derived SMCs populating the cardiac outflow tract and great arteries. Both Myocd(F/F)/Wnt1-Cre(+) and Myocd(F/F)/Pax3-Cre(+) mutant mice survived to birth, but died prior to postnatal day 3 from patent ductus arteriosus (PDA). Neural crest-derived SMCs populating the ductus arteriosus (DA) and great arteries exhibited a cell autonomous block in expression of myocardin-regulated genes encoding SMC-restricted contractile proteins. Moreover, Myocd-deficient vascular SMCs populating the DA exhibited ultrastructural features generally associated with the SMC synthetic, rather than contractile, phenotype. Consistent with these findings, ablation of the Myocd gene in primary aortic SMCs harvested from Myocd conditional mutant mice caused a dramatic decrease in SMC contractile protein expression. Taken together, these data demonstrate that myocardin regulates expression of genes required for the contractile phenotype in neural crest-derived SMCs and provide new insights into the molecular and genetic programs that may underlie PDA.
Assuntos
Permeabilidade do Canal Arterial/genética , Regulação da Expressão Gênica no Desenvolvimento , Contração Muscular/genética , Miócitos de Músculo Liso/metabolismo , Proteínas Nucleares/fisiologia , Transativadores/fisiologia , Animais , Camundongos , Camundongos Transgênicos , Mutação , Crista Neural/citologia , Crista Neural/crescimento & desenvolvimento , Crista Neural/metabolismo , Proteínas Nucleares/genética , Deleção de Sequência , Transativadores/genéticaRESUMO
Bruton's tyrosine kinase (BTK) is a target for treatment of hematologic malignancies and autoimmune diseases. TAK-020 is a highly selective covalent BTK inhibitor that inhibits both B cell receptor and fragment crystallizable receptor signaling. We assessed the safety/tolerability and pharmacokinetics/pharmacodynamics (PDs) of TAK-020 in healthy subjects. Each cohort of the single-rising dose (n = 72; 9 cohorts) and the multiple-rising dose (n = 48; 6 cohorts) portions of the study comprised six TAK-020-treated and two placebo-treated, subjects aged 18-55 years (inclusive). The PD effects were assessed by measuring BTK occupancy and the inhibition of fragment crystallizable epsilon receptor 1 (FcεRI)-mediated activation of basophils. Overall, treatment-emergent adverse events (TEAEs) were similar to placebo; there were no serious TEAEs or no TEAEs leading to discontinuation. TAK-020 was rapidly absorbed (median time to maximum plasma concentration (Tmax ) 45-60 minutes) with a half-life of ~ 3-9 hours at doses ≥ 2.5 mg. TAK-020 exposure was generally dose proportional for single doses ≤ 70 mg and after multiple doses of ≤ 60 mg once daily. Target occupancy was dose dependent, with doses ≥ 2.5 mg yielding maximum and sustained occupancy > 70% for > 96 hours. Single doses ≥ 4.4 mg reduced FcεRI-mediated activation of basophils by > 80% and comparable inhibition was observed with daily dosing ≥3.75 mg for 9 days. Inhibition persisted for 24-72 hours postdose and the duration generally increased with dose. TAK-020 was generally well-tolerated in healthy subjects after single and multiple doses and demonstrated target engagement and pathway modulation. The PD effects outlasted drug exposures, as expected for covalent inhibition of BTK.
Assuntos
Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Basófilos/efeitos dos fármacos , Inibidores de Proteínas Quinases/efeitos adversos , Administração Oral , Adolescente , Adulto , Tirosina Quinase da Agamaglobulinemia/metabolismo , Basófilos/imunologia , Basófilos/metabolismo , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Miastenia Gravis/tratamento farmacológico , Miastenia Gravis/imunologia , Placebos/administração & dosagem , Placebos/efeitos adversos , Inibidores de Proteínas Quinases/administração & dosagem , Púrpura Trombocitopênica Idiopática/tratamento farmacológico , Púrpura Trombocitopênica Idiopática/imunologia , Adulto JovemRESUMO
Introduction: Anxiety disorders result inhigh patient burden and utilization of healthcare resources. Evidence-based treatments for pathological anxiety include targeted psychotherapy and use of serotonin-augmenting agents. Limitations in access to cognitive behavioral therapy and potential disadvantages to the use of psychotropics make the need for novel approaches to therapeutics for pathological anxiety salient.Areas Covered: Neuroplasticity mechanisms, as well as managing oxidative stress and inflammatory cellular allostatic loads can decrease anxiety. The gasotransmitter hydrogen sulfide (H2S) can impact these mechanisms through a) maintaining intracellular reduced glutathione in the CNS to decrease oxidative stress; b) facilitating neuroplasticity in amygdalar regions via the 2B subunit of n-methyl-d-aspartate (NMDA) receptors, in conjunction with the cAMP messenger system and a CNS kinase, PKC-γ; and c) regulating intracellular Ca2+ homeostasis in neurons and glial cells, among others.Expert Opinion: Given the mounting evidence for the role of H2S in neuronal health and its potential to decrease pathological anxiety, the current challenge in H2S therapeutics remains finding an efficient delivery system of this gasotransmitter in a reliable, safe and nontoxic form to engage in clinical trials. Current efforts include H2S-delivering moieties attached to known drugs, natural sulfide-releasing compounds such as garlic, and the regulation of dysfunctional breathing through breathing retraining.
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Transtornos de Ansiedade/tratamento farmacológico , Gasotransmissores/uso terapêutico , Sulfeto de Hidrogênio/uso terapêutico , Plasticidade Neuronal/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Animais , Gasotransmissores/administração & dosagem , Humanos , Sulfeto de Hidrogênio/administração & dosagemRESUMO
Studies have shown significant cardiovascular effects of exogenous apelin administration, including the potent activation of cardiac contraction. However, the role of the endogenous apelin-APJ pathway is less clear. To study the loss of endogenous apelin-APJ signaling, we generated mice lacking either the ligand (apelin) or the receptor (APJ). Apelin-deficient mice were viable, fertile, and showed normal development. In contrast, APJ-deficient mice were not born in the expected Mendelian ratio, and many showed cardiovascular developmental defects. Under basal conditions, both apelin and APJ null mice that survived to adulthood manifested modest decrements in contractile function. However, with exercise stress both mutant lines demonstrated consistent and striking decreases in exercise capacity. To explain these findings, we explored the role of autocrine signaling in vitro using field stimulation of isolated left ventricular cardiomyocytes lacking either apelin or APJ. Both groups manifested less sarcomeric shortening and impaired velocity of contraction and relaxation with no difference in calcium transient. Taken together, these results demonstrate that endogenous apelin-APJ signaling plays a modest role in maintaining basal cardiac function in adult mice with a more substantive role during conditions of stress. In addition, an autocrine pathway seems to exist in myocardial cells, the ablation of which reduces cellular contraction without change in calcium transient. Finally, differences in the developmental phenotype between apelin and APJ null mice suggest the possibility of undiscovered APJ ligands or ligand-independent effects of APJ.
Assuntos
Proteínas de Transporte/metabolismo , Tolerância ao Exercício , Cardiopatias Congênitas/metabolismo , Contração Miocárdica , Miócitos Cardíacos/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Adipocinas , Animais , Apelina , Receptores de Apelina , Comunicação Autócrina , Sinalização do Cálcio , Proteínas de Transporte/genética , Ecocardiografia , Tolerância ao Exercício/genética , Feminino , Genótipo , Cardiopatias Congênitas/genética , Cardiopatias Congênitas/patologia , Cardiopatias Congênitas/fisiopatologia , Peptídeos e Proteínas de Sinalização Intercelular , Imageamento por Ressonância Magnética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Contração Miocárdica/genética , Miócitos Cardíacos/patologia , Fenótipo , Receptores Acoplados a Proteínas G/deficiência , Receptores Acoplados a Proteínas G/genética , Sarcômeros/metabolismo , Volume Sistólico , Função Ventricular , Pressão VentricularRESUMO
BACKGROUND: Breast cancer is Asian American women's most frequently occurring cancer. METHODS: Asian American women completed breast cancer-related baseline surveys for 2 studies 5 years apart. RESULTS: Statistically significant and rapid improvements in knowledge and screening practices were seen between the 948 participants in the first study (1995) and the 1540 participants in the second study. This increase paralleled the reported climb in early detection rates among Asian American women. CONCLUSIONS: The data document the achievement of a tipping point in breast cancer screening rates with culturally and linguistically focused education programs and increased access to screening among disadvantaged women.
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Asiático/estatística & dados numéricos , Neoplasias da Mama/diagnóstico , Educação em Saúde/métodos , Conhecimentos, Atitudes e Prática em Saúde , Programas de Rastreamento/estatística & dados numéricos , Saúde da Mulher , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/etnologia , Autoexame de Mama , California/epidemiologia , Estudos de Viabilidade , Feminino , Humanos , Incidência , Pessoa de Meia-Idade , Aceitação pelo Paciente de Cuidados de Saúde/etnologia , Aceitação pelo Paciente de Cuidados de Saúde/estatística & dados numéricos , Fatores de Tempo , Saúde da Mulher/etnologia , Adulto JovemRESUMO
The time course and functional significance of the structural changes associated with long-term facilitation of Aplysia sensory to motor neuron synaptic connections in culture were examined by time-lapse confocal imaging of individual sensory neuron varicosities labeled with three different fluorescent markers: the whole-cell marker Alexa-594 and two presynaptic marker proteins-synaptophysin-eGFP to monitor changes in synaptic vesicle distribution and synapto-PHluorin to monitor active transmitter release sites. Repeated pulses of serotonin induce two temporally, morphologically, and molecularly distinct presynaptic changes: (1) a rapid activation of silent presynaptic terminals by filling of preexisting empty varicosities with synaptic vesicles, which parallels intermediate-term facilitation, is completed within 3-6 hr and requires translation but not transcription and (2) a slower generation of new functional varicosities which occurs between 12-18 hr and requires transcription and translation. Enrichment of empty varicosities with synaptophysin accounts for 32% of the newly activated synapses at 24 hr, whereas newly formed varicosities account for 68%.
Assuntos
Aplysia/metabolismo , Potenciação de Longa Duração/fisiologia , Terminações Pré-Sinápticas/metabolismo , Terminações Pré-Sinápticas/fisiologia , Animais , Aplysia/efeitos dos fármacos , Aplysia/fisiologia , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Potenciais Pós-Sinápticos Excitadores/fisiologia , Potenciação de Longa Duração/efeitos dos fármacos , Neurônios Aferentes/efeitos dos fármacos , Neurônios Aferentes/metabolismo , Neurônios Aferentes/fisiologia , Terminações Pré-Sinápticas/efeitos dos fármacos , Sinapses/efeitos dos fármacos , Sinapses/metabolismo , Sinapses/fisiologia , Vesículas Sinápticas/efeitos dos fármacos , Vesículas Sinápticas/metabolismo , Vesículas Sinápticas/fisiologiaRESUMO
The SAP family transcription factor myocardin functionally synergizes with serum response factor (SRF) and plays an important role in cardiac development. To determine the function of myocardin in the smooth muscle cell (SMC) lineage, we mapped the pattern of myocardin gene expression and examined the molecular mechanisms underlying transcriptional activity of myocardin in SMCs and embryonic stem (ES) cells. The human and murine myocardin genes were expressed in vascular and visceral SMCs at levels equivalent to or exceeding those observed in the heart. During embryonic development, the myocardin gene was expressed abundantly in a precise, developmentally regulated pattern in SMCs. Forced expression of myocardin transactivated multiple SMC-specific transcriptional regulatory elements in non-SMCs. By contrast, myocardin-induced transactivation was not observed in SRF(-/-) ES cells but could be rescued by forced expression of SRF or the SRF DNA-binding domain. Furthermore, expression of a dominant-negative myocardin mutant protein or small-interfering-RNA-induced myocardin knockdown significantly reduced SM22 alpha promoter activity in SMCs. Most importantly, forced expression of myocardin activated expression of the SM22 alpha, smooth muscle alpha-actin, and calponin-h1 genes in undifferentiated mouse ES cells. Taken together, these data demonstrate that myocardin plays an important role in the SRF-dependent transcriptional program that regulates SMC development and differentiation.
Assuntos
Diferenciação Celular/fisiologia , Músculo Liso Vascular/metabolismo , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Fator de Resposta Sérica/metabolismo , Transativadores/genética , Transativadores/metabolismo , Sequência de Aminoácidos , Animais , Células COS , Células Cultivadas , DNA Complementar/genética , DNA Complementar/isolamento & purificação , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Humanos , Camundongos , Proteínas dos Microfilamentos/genética , Dados de Sequência Molecular , Proteínas Musculares/genética , Músculo Liso/metabolismo , Músculo Liso Vascular/citologia , Miocárdio/metabolismo , Especificidade de Órgãos , Regiões Promotoras Genéticas/efeitos dos fármacos , Regiões Promotoras Genéticas/fisiologia , RNA Interferente Pequeno/farmacologia , Ratos , Alinhamento de Sequência , Fator de Resposta Sérica/deficiência , Fator de Resposta Sérica/genética , Células-Tronco/citologia , Células-Tronco/metabolismo , Ativação TranscricionalRESUMO
BACKGROUND: The mammalian target of rapamycin (mTOR) pathway is a driver of breast tumorigenesis. The mTOR inhibitor everolimus reverses antihormonal therapy resistance and is an approved therapy for metastatic breast cancer. A synergistic effect with fluoropyrimidine has been suggested. The present study evaluated the safety and tolerability of an all-oral combination of everolimus and capecitabine for metastatic breast cancer (MBC). PATIENTS AND METHODS: MBC patients naive to capecitabine and mTOR inhibitors who had received ≤ 3 previous chemotherapy regimens in the metastatic setting were eligible for the present study. The patients were scheduled to receive capecitabine 825 mg/m2 twice daily for 14 days in a 21-day cycle, combined with everolimus in 5 separate dose cohorts: 2.5 mg every other day, 2.5 mg daily, 5 mg daily, 7.5 mg daily, and 10 mg daily. A 3+3 design was used. The maximum tolerated dose was based on the dose-limiting toxicity of everolimus plus capecitabine. RESULTS: A total of 18 patients were enrolled in the present trial. The median age was 58 years. Most had received previous anthracycline (83%) and taxane (94%) therapy. The maximum tolerated dose was everolimus 7.5 mg daily and capecitabine 825 mg/m2. The incidence of grade 3 events was low and mainly hematologic in nature. One incident each of grade 4 neutropenia, thrombocytopenia, hyperglycemia, and mucositis occurred. No grade 5 events occurred. The clinical benefit rate was 50%. The median progression-free survival was 196 days, and the median overall survival was 569 days. CONCLUSION: The all-oral regimen of everolimus with capecitabine is active and well tolerated, with encouraging results for progression-free survival, overall survival, and clinical benefit rate in patients with MBC.