RESUMO
Although two-dose mRNA vaccination provides excellent protection against SARS-CoV-2, there is little information about vaccine efficacy against variants of concern (VOC) in individuals above eighty years of age1. Here we analysed immune responses following vaccination with the BNT162b2 mRNA vaccine2 in elderly participants and younger healthcare workers. Serum neutralization and levels of binding IgG or IgA after the first vaccine dose were lower in older individuals, with a marked drop in participants over eighty years old. Sera from participants above eighty showed lower neutralization potency against the B.1.1.7 (Alpha), B.1.351 (Beta) and P.1. (Gamma) VOC than against the wild-type virus and were more likely to lack any neutralization against VOC following the first dose. However, following the second dose, neutralization against VOC was detectable regardless of age. The frequency of SARS-CoV-2 spike-specific memory B cells was higher in elderly responders (whose serum showed neutralization activity) than in non-responders after the first dose. Elderly participants showed a clear reduction in somatic hypermutation of class-switched cells. The production of interferon-γ and interleukin-2 by SARS-CoV-2 spike-specific T cells was lower in older participants, and both cytokines were secreted primarily by CD4 T cells. We conclude that the elderly are a high-risk population and that specific measures to boost vaccine responses in this population are warranted, particularly where variants of concern are circulating.
Assuntos
Envelhecimento/imunologia , Vacinas contra COVID-19/imunologia , Imunidade , SARS-CoV-2/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/sangue , Anticorpos Neutralizantes/sangue , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/sangue , Anticorpos Antivirais/imunologia , Autoanticorpos/imunologia , Linfócitos B/citologia , Linfócitos B/imunologia , Linfócitos B/metabolismo , Vacina BNT162 , Vacinas contra COVID-19/administração & dosagem , Feminino , Pessoal de Saúde , Humanos , Imunidade/genética , Imunização Secundária , Imunoglobulina A/imunologia , Switching de Imunoglobulina , Imunoglobulina G/genética , Imunoglobulina G/imunologia , Memória Imunológica/imunologia , Inflamação/sangue , Inflamação/imunologia , Interferon gama/imunologia , Interleucina-2/imunologia , Masculino , Pessoa de Meia-Idade , Hipermutação Somática de Imunoglobulina , Glicoproteína da Espícula de Coronavírus/imunologia , Linfócitos T/imunologia , Vacinação , Vacinas Sintéticas/administração & dosagem , Vacinas Sintéticas/imunologia , Vacinas de mRNARESUMO
Transmission of SARS-CoV-2 is uncontrolled in many parts of the world; control is compounded in some areas by the higher transmission potential of the B.1.1.7 variant1, which has now been reported in 94 countries. It is unclear whether the response of the virus to vaccines against SARS-CoV-2 on the basis of the prototypic strain will be affected by the mutations found in B.1.1.7. Here we assess the immune responses of individuals after vaccination with the mRNA-based vaccine BNT162b22. We measured neutralizing antibody responses after the first and second immunizations using pseudoviruses that expressed the wild-type spike protein or a mutated spike protein that contained the eight amino acid changes found in the B.1.1.7 variant. The sera from individuals who received the vaccine exhibited a broad range of neutralizing titres against the wild-type pseudoviruses that were modestly reduced against the B.1.1.7 variant. This reduction was also evident in sera from some patients who had recovered from COVID-19. Decreased neutralization of the B.1.1.7 variant was also observed for monoclonal antibodies that target the N-terminal domain (9 out of 10) and the receptor-binding motif (5 out of 31), but not for monoclonal antibodies that recognize the receptor-binding domain that bind outside the receptor-binding motif. Introduction of the mutation that encodes the E484K substitution in the B.1.1.7 background to reflect a newly emerged variant of concern (VOC 202102/02) led to a more-substantial loss of neutralizing activity by vaccine-elicited antibodies and monoclonal antibodies (19 out of 31) compared with the loss of neutralizing activity conferred by the mutations in B.1.1.7 alone. The emergence of the E484K substitution in a B.1.1.7 background represents a threat to the efficacy of the BNT162b2 vaccine.
Assuntos
Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , Vacinas contra COVID-19/imunologia , COVID-19/imunologia , COVID-19/terapia , SARS-CoV-2/imunologia , Glicoproteína da Espícula de Coronavírus/imunologia , Vacinas Sintéticas/imunologia , Idoso , Idoso de 80 Anos ou mais , Enzima de Conversão de Angiotensina 2/metabolismo , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/isolamento & purificação , Anticorpos Neutralizantes/isolamento & purificação , Anticorpos Antivirais/isolamento & purificação , COVID-19/metabolismo , COVID-19/virologia , Feminino , Células HEK293 , Humanos , Evasão da Resposta Imune/genética , Evasão da Resposta Imune/imunologia , Imunização Passiva , Masculino , Pessoa de Meia-Idade , Modelos Moleculares , Mutação , Testes de Neutralização , SARS-CoV-2/genética , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/genética , Glicoproteína da Espícula de Coronavírus/metabolismo , Vacinas Sintéticas/administração & dosagem , Soroterapia para COVID-19 , Vacinas de mRNARESUMO
ETS proteins are a group of evolutionarily related, DNA-binding transcriptional factors. These proteins direct gene expression in diverse normal and disease states by binding to specific promoters and enhancers and facilitating assembly of other components of the transcriptional machinery. The highly conserved DNA-binding ETS domain defines the family and is responsible for specific recognition of a common sequence motif, 5'-GGA(A/T)-3'. Attaining specificity for biological regulation in such a family is thus a conundrum. We present the current knowledge of routes to functional diversity and DNA binding specificity, including divergent properties of the conserved ETS and PNT domains, the involvement of flanking structured and unstructured regions appended to these dynamic domains, posttranslational modifications, and protein partnerships with other DNA-binding proteins and coregulators. The review emphasizes recent advances from biochemical and biophysical approaches, as well as insights from genomic studies that detect ETS-factor occupancy in living cells.
Assuntos
Genoma , Proteínas Proto-Oncogênicas c-ets/genética , Proteínas Proto-Oncogênicas c-ets/metabolismo , Animais , Sequência de Bases , Sítios de Ligação , DNA/química , DNA/genética , DNA/metabolismo , Humanos , Modelos Moleculares , Dados de Sequência Molecular , Família Multigênica , Filogenia , Ligação Proteica , Conformação Proteica , Multimerização Proteica , Proteínas Proto-Oncogênicas c-ets/química , Proteínas Proto-Oncogênicas c-ets/classificação , Transdução de Sinais/fisiologia , Transcrição GênicaRESUMO
Esnault and colleagues (pp. 943-958) take a genomics approach to investigate the role of SRF (serum response factor) in the serum response of fibroblasts. The well-established dual role of SRF with alternative cofactors and responsiveness to two signaling pathways is illustrated at the genome-wide level, yet new insight comes from this global picture.
Assuntos
Actinas/metabolismo , Fibroblastos/fisiologia , Soro/metabolismo , Transdução de Sinais , Transcrição Gênica/genética , AnimaisRESUMO
ABSTRACT: Research has demonstrated the ability of evidence-based practice (EBP) to enhance quality and reliability of health care, improve health outcomes, and reduce cost and health disparities. Nursing curricula often lack best practices for teaching EBP, as well as actual EBP course content, objectives, and activities, to advance student understanding of EBP. The unfortunate results are nurse graduates who do not value or perceive that they can use EBP. This study implemented an EBP assignment assessing clinical practice guidelines as a means of improving EBP beliefs in senior-level nursing students.
Assuntos
Estudantes de Enfermagem , Currículo , Atenção à Saúde , Enfermagem Baseada em Evidências , Prática Clínica Baseada em Evidências/educação , Humanos , Reprodutibilidade dos Testes , Inquéritos e QuestionáriosRESUMO
Multiple transcription factors guide the development of mature functional natural killer (NK) cells, yet little is known about their function. We used global gene expression and genome-wide binding analyses combined with developmental and functional studies to unveil three roles for the ETS1 transcription factor in NK cells. ETS1 functions at the earliest stages of NK cell development to promote expression of critical transcriptional regulators including T-BET and ID2, NK cell receptors (NKRs) including NKp46, Ly49H, and Ly49D, and signaling molecules essential for NKR function. As a consequence, Ets1(-/-) NK cells fail to degranulate after stimulation through activating NKRs. Nonetheless, these cells are hyperresponsive to cytokines and have characteristics of chronic stimulation including increased expression of inhibitory NKRs and multiple activation-associated genes. Therefore, ETS1 regulates a broad gene expression program in NK cells that promotes target cell recognition while limiting cytokine-driven activation.
Assuntos
Células Matadoras Naturais/imunologia , Proteína Proto-Oncogênica c-ets-1/deficiência , Motivos de Aminoácidos , Animais , Sítios de Ligação , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Células Cultivadas/efeitos dos fármacos , Células Cultivadas/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/imunologia , Proteína 2 Inibidora de Diferenciação/biossíntese , Proteína 2 Inibidora de Diferenciação/genética , Interleucina-15/farmacologia , Interleucina-15/fisiologia , Peptídeos e Proteínas de Sinalização Intracelular/genética , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/metabolismo , Ativação Linfocitária/efeitos dos fármacos , Ativação Linfocitária/genética , Ativação Linfocitária/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Dados de Sequência Molecular , Proteína Proto-Oncogênica c-ets-1/genética , Proteína Proto-Oncogênica c-ets-1/fisiologia , Quimera por Radiação , Receptores de Células Matadoras Naturais/biossíntese , Receptores de Células Matadoras Naturais/genética , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Proteínas com Domínio T/biossíntese , Proteínas com Domínio T/genética , Fatores de Transcrição/biossíntese , Fatores de Transcrição/genética , Transcrição Gênica/efeitos dos fármacos , Transcrição Gênica/imunologiaRESUMO
Many different transcription factors (TFs) regulate gene expression in a combinatorial fashion, often by binding in close proximity to each other on composite cis-regulatory DNA elements. Here, we investigated how ETS TFs bind with the AP1 TFs JUN-FOS at composite DNA-binding sites. DNA-binding ability with JUN-FOS correlated with the phenotype of ETS proteins in prostate cancer. We found that the oncogenic ETS-related gene (ERG) and ETS variant (ETV) 1/4/5 subfamilies co-occupy ETS-AP1 sites with JUN-FOS in vitro, whereas JUN-FOS robustly inhibited DNA binding by the tumor suppressors ETS homologous factor (EHF) and SAM pointed domain-containing ETS TF (SPDEF). EHF bound ETS-AP1 DNA with tighter affinity than ERG in the absence of JUN-FOS, possibly enabling EHF to compete with ERG and JUN-FOS for binding to ETS-AP1 sites. Genome-wide mapping of EHF- and ERG-binding sites in prostate epithelial cells revealed that EHF is preferentially excluded from closely spaced ETS-AP1 DNA sequences. Structural modeling and mutational analyses indicated that adjacent positively charged surfaces from EHF and JUN-FOS use electrostatic repulsion to disfavor simultaneous DNA binding. Conservation of positive residues on the JUN-FOS interface identified E74-like ETS TF 1 (ELF1) as an additional ETS TF exhibiting anticooperative DNA binding with JUN-FOS, and we found that ELF1 is frequently down-regulated in prostate cancer. In summary, divergent electrostatic features of ETS TFs at their JUN-FOS interface enable distinct binding events at ETS-AP1 DNA sites, which may drive specific targeting of ETS TFs to facilitate distinct transcriptional programs.
Assuntos
DNA/metabolismo , Proteínas Proto-Oncogênicas c-ets/metabolismo , Proteínas Proto-Oncogênicas c-fos/metabolismo , Proteínas Proto-Oncogênicas c-jun/metabolismo , Eletricidade Estática , Sítios de Ligação , Humanos , Ligação Proteica , Fatores de Transcrição/metabolismo , Regulador Transcricional ERG/metabolismoRESUMO
Autoinhibition enables spatial and temporal regulation of cellular processes by coupling protein activity to surrounding conditions, often via protein partnerships or signaling pathways. We report the molecular basis of DNA-binding autoinhibition of ETS transcription factors ETV1, ETV4 and ETV5, which are often overexpressed in prostate cancer. Inhibitory elements that cooperate to repress DNA binding were identified in regions N- and C-terminal of the ETS domain. Crystal structures of these three factors revealed an α-helix in the C-terminal inhibitory domain that packs against the ETS domain and perturbs the conformation of its DNA-recognition helix. Nuclear magnetic resonance spectroscopy demonstrated that the N-terminal inhibitory domain (NID) is intrinsically disordered, yet utilizes transient intramolecular interactions with the DNA-recognition helix of the ETS domain to mediate autoinhibition. Acetylation of selected lysines within the NID activates DNA binding. This investigation revealed a distinctive mechanism for DNA-binding autoinhibition in the ETV1/4/5 subfamily involving a network of intramolecular interactions not present in other ETS factors. These distinguishing inhibitory elements provide a platform through which cellular triggers, such as protein-protein interactions or post-translational modifications, may specifically regulate the function of these oncogenic proteins.
Assuntos
Proteínas E1A de Adenovirus/química , Proteínas de Ligação a DNA/química , DNA/química , Proteínas Intrinsicamente Desordenadas/química , Processamento de Proteína Pós-Traducional , Proteínas Proto-Oncogênicas/química , Fatores de Transcrição/química , Acetilação , Proteínas E1A de Adenovirus/genética , Proteínas E1A de Adenovirus/metabolismo , Sítios de Ligação , Clonagem Molecular , Cristalografia por Raios X , DNA/metabolismo , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Escherichia coli/genética , Escherichia coli/metabolismo , Expressão Gênica , Proteínas Intrinsicamente Desordenadas/genética , Proteínas Intrinsicamente Desordenadas/metabolismo , Cinética , Lisina/química , Lisina/metabolismo , Ligação Proteica , Conformação Proteica em alfa-Hélice , Domínios e Motivos de Interação entre Proteínas , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas c-ets , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismoRESUMO
The aberrant expression of an oncogenic ETS transcription factor is implicated in the progression of the majority of prostate cancers, 40% of melanomas, and most cases of gastrointestinal stromal tumor and Ewing's sarcoma. Chromosomal rearrangements in prostate cancer result in overexpression of any one of four ETS transcription factors. How these four oncogenic ETS genes differ from the numerous other ETS genes expressed in normal prostate and contribute to tumor progression is not understood. We report that these oncogenic ETS proteins, but not other ETS factors, enhance prostate cell migration. Genome-wide binding analysis matched this specific biological function to occupancy of a unique set of genomic sites highlighted by the presence of ETS- and AP-1-binding sequences. ETS/AP-1-binding sequences are prototypical RAS-responsive elements, but oncogenic ETS proteins activated a RAS/MAPK transcriptional program in the absence of MAPK activation. Thus, overexpression of oncogenic ETS proteins can replace RAS/MAPK pathway activation in prostate cells. The genomic description of this ETS/AP-1-regulated, RAS-responsive, gene expression program provides a resource for understanding the role of these ETS factors in both an oncogenic setting and the developmental processes where these genes normally function.
Assuntos
Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Transdução de Sinais , Proteínas ras/metabolismo , Sequência de Bases , Linhagem Celular Tumoral , Movimento Celular , Regulação Neoplásica da Expressão Gênica , Genoma , Humanos , Masculino , Neoplasias da Próstata/genética , Neoplasias da Próstata/fisiopatologia , Ligação Proteica , Proteínas Proto-Oncogênicas/genética , Fator de Transcrição AP-1/metabolismoRESUMO
BACKGROUND: Diabetes is a major health concern in the United States. Poor quality diabetes care leads to negative outcomes affecting patients and healthcare systems. Research shows evidence-based clinical practice guidelines from the American Diabetes Association, Standards of Medical Care in Diabetes-2017, have improved outcomes in management of diabetes. AIMS: The aim of this improvement project was to improve diabetes care and outcomes in a primary care clinic serving a Hispanic community in Miami-Dade, Florida. Specific objectives of the project were to improve primary care provider attitudes and knowledge of American Diabetes Association guidelines and outcomes in patients with diabetes. METHODS: This two-phase quality improvement project used a pre- and post-test study design. In Phase I, the Diabetes Attitude Survey was administered to determine primary care provider attitudes and knowledge of guidelines. Based on survey results, a 2-hr educational intervention was developed to inform providers regarding the American Diabetes Association clinical practice guidelines. In Phase II, data were collected for 19 clinical quality diabetes outcome measures from agency reports. Guidelines were implemented into practice, and intervention effectiveness was evaluated. RESULTS: Statistical analysis (paired-sample t-test) revealed postintervention improvement in provider knowledge and attitudes, and patient outcomes. Findings suggest the intervention led to improvements in the quality of diabetes care in this Hispanic clinic. LINKING EVIDENCE TO ACTION: Project success supports the importance of evidence-based clinical practice guideline use to achieve better diabetes outcomes. Implementation of the American Diabetes Association Standards of Medical Care in Diabetes to improve patient outcomes is strongly recommended. It is equally important that clinical agencies educate and update primary care providers to achieve best practice and best patient diabetes outcomes. Other healthcare professionals can use this project design to provide culturally competent care to patients with diabetes.
Assuntos
Diabetes Mellitus/terapia , Guias como Assunto , Desenvolvimento de Programas/métodos , Hispânico ou Latino/psicologia , Humanos , Atenção Primária à Saúde/métodos , Saúde Pública/métodos , Saúde Pública/tendências , Melhoria de Qualidade , Estados UnidosRESUMO
This column shares the best evidence-based strategies and innovative ideas on how to facilitate the learning and implementation of EBP principles and processes by clinicians as well as nursing and interprofessional students. Guidelines for submission are available at https://onlinelibrary.wiley.com/journal/10.1111/(ISSN)1741-6787.
Assuntos
Educação em Enfermagem/métodos , Prática Clínica Baseada em Evidências/métodos , Educação em Enfermagem/normas , Prática Clínica Baseada em Evidências/normas , Docentes de Enfermagem/tendências , Humanos , Avaliação de Processos e Resultados em Cuidados de Saúde/métodosRESUMO
The E26 transformation-specific (Ets-1) transcription factor is autoinhibited by a conformationally disordered serine-rich region (SRR) that transiently interacts with its DNA-binding ETS domain. In response to calcium signaling, autoinhibition is reinforced by calmodulin-dependent kinase II phosphorylation of serines within the SRR. Using mutagenesis and quantitative DNA-binding measurements, we demonstrate that phosphorylation-enhanced autoinhibition requires the presence of phenylalanine or tyrosine (Ï) residues adjacent to the SRR phosphoacceptor serines. The introduction of additional phosphorylated Ser-Ï-Asp, but not Ser-Ala-Asp, repeats within the SRR dramatically reinforces autoinhibition. NMR spectroscopic studies of phosphorylated and mutated SRR variants, both within their native context and as separate trans-acting peptides, confirmed that the aromatic residues and phosphoserines contribute to the formation of a dynamic complex with the ETS domain. Complementary NMR studies also identified the SRR-interacting surface of the ETS domain, which encompasses its positively charged DNA-recognition interface and an adjacent region of neutral polar and nonpolar residues. Collectively, these studies highlight the role of aromatic residues and their synergy with phosphoserines in an intrinsically disordered regulatory sequence that integrates cellular signaling and gene expression.
Assuntos
Fosfosserina/química , Proteína Proto-Oncogênica c-ets-1/química , Humanos , Ressonância Magnética Nuclear Biomolecular , Peptídeos , Fosfosserina/metabolismo , Estrutura Terciária de Proteína , Proteína Proto-Oncogênica c-ets-1/genética , Proteína Proto-Oncogênica c-ets-1/metabolismo , Sequências Repetitivas de AminoácidosRESUMO
The affinity of the Ets-1 transcription factor for DNA is autoinhibited by an intrinsically disordered serine-rich region (SRR) and a helical inhibitory module (IM) appended to its winged helix-turn-helix ETS domain. Using NMR spectroscopy, we investigated how Ets-1 recognizes specific versus nonspecific DNA, with a focus on the roles of protein dynamics and autoinhibition in these processes. Upon binding either DNA, the two marginally stable N-terminal helices of the IM predominantly unfold, but still sample partially ordered conformations. Also, on the basis of amide chemical shift perturbation mapping, Ets-1 associates with both specific and nonspecific DNA through the same canonical ETS domain interface. These interactions are structurally independent of the SRR, and thus autoinhibition does not impart DNA-binding specificity. However, relative to the pronounced NMR spectroscopic changes in Ets-1 resulting from specific DNA binding, the spectra of the nonspecific DNA complexes showed conformational exchange broadening and lacked several diagnostic amide and indole signals attributable to hydrogen bonding interactions seen in reported X-ray crystallographic structures of this transcription factor with its cognate DNA sequences. Such differences are highlighted by the chemical shift and relaxation properties of several interfacial lysine and arginine side chains. Collectively, these data support a general model in which Ets-1 interacts with nonspecific DNA via dynamic electrostatic interactions, whereas hydrogen bonding drives the formation of well-ordered complexes with specific DNA.
Assuntos
Proteína Proto-Oncogênica c-ets-1/química , Proteína Proto-Oncogênica c-ets-1/metabolismo , Animais , Arginina/química , Sequência de Bases , DNA/química , DNA/metabolismo , Lisina/química , Camundongos , Modelos Moleculares , Simulação de Dinâmica Molecular , Ressonância Magnética Nuclear Biomolecular , Ligação Proteica , Conformação Proteica , Estrutura Secundária de Proteína , Proteína Proto-Oncogênica c-ets-1/antagonistas & inibidores , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Eletricidade EstáticaRESUMO
Histone H3 lysine 4 (H3K4) methylation is a dynamic modification. In budding yeast, H3K4 methylation is catalyzed by the Set1-COMPASS methyltransferase complex and is removed by Jhd2, a JMJC domain family demethylase. The catalytic JmjC and JmjN domains of Jhd2 have the ability to remove all three degrees (mono-, di-, and tri-) of H3K4 methylation. Jhd2 also contains a plant homeodomain (PHD) finger required for its chromatin association and H3K4 demethylase functions. The Jhd2 PHD finger associates with chromatin independent of H3K4 methylation and the H3 N-terminal tail. Therefore, how Jhd2 associates with chromatin to perform H3K4 demethylation has remained unknown. We report a novel interaction between the Jhd2 PHD finger and histone H2A. Two residues in H2A (Phe-26 and Glu-57) serve as a binding site for Jhd2 in vitro and mediate its chromatin association and H3K4 demethylase functions in vivo. Using RNA sequencing, we have identified the functional target genes for Jhd2 and the H2A Phe-26 and Glu-57 residues. We demonstrate that H2A Phe-26 and Glu-57 residues control chromatin association and H3K4 demethylase functions of Jhd2 during positive or negative regulation of transcription at target genes. Importantly, we show that H2B Lys-123 ubiquitination blocks Jhd2 from accessing its binding site on chromatin, and thereby, we have uncovered a second mechanism by which H2B ubiquitination contributes to the trans-histone regulation of H3K4 methylation. Overall, our study provides novel insights into the chromatin binding dynamics and H3K4 demethylase functions of Jhd2.
Assuntos
Cromatina/metabolismo , Histonas/metabolismo , Histona Desmetilases com o Domínio Jumonji/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/metabolismo , Transcrição Gênica/fisiologia , Ubiquitinação/fisiologia , Cromatina/genética , Histonas/genética , Histona Desmetilases com o Domínio Jumonji/genética , Metilação , Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/genéticaRESUMO
Concussion in football athletes is certainly more prevalent and has potentially serious outcomes. With current concerns and increasing return-to-play issues, additional assessment focus is needed. Division 1 college football athletes, from 18 to 20.9 years (n = 177; age, 19.7 ± 1.2 years; height, 182.3 ± 4.5 cm; weight, 97.3 ± 10.6 kg), before fall practice, over a period of 3 years, underwent baseline postural stability testing (sensory organization test [SOT], NeuroCom). Individuals, who were diagnosed with a concussion (headache, dizziness, fatigue, confusion, or loss of consciousness) during practice or actual competition (n = 15; age, 18.9 ± 0.9 years; height, 181.8 ± 2.5 cm; weight, 86.6 ± 3.6 kg), underwent serial evaluation after injury and 24 hours after concussion. As soon as the player was considered asymptomatic, the test was completed on the first and 14th day. A control group of noninjured male athletes (n = 15; age, 19.1 ± 0.4 years; height, 178.2 ± 3.2 cm; weight, 78.6 ± 2.1 kg) were tested for the same time frame. This particular study was only one part of the total evaluation conducted for the concussed athlete's return to play. Results indicated that the concussion group had a statistically significant (p = 0.037) change from their baseline SOT score and the control group (p = 0.025). This change remained significant until day 14 of posttesting. These data indicate that the SOT, when available, may be a positive additional assessment of concussed college-aged football players. Professionals, when dealing with concussion in competitive sports, do need to continue to work together, but awareness of SOT assessments may also contribute to the return-to-play decisions.
Assuntos
Concussão Encefálica/diagnóstico , Futebol Americano/lesões , Equilíbrio Postural/fisiologia , Volta ao Esporte/fisiologia , Adolescente , Concussão Encefálica/etiologia , Concussão Encefálica/fisiopatologia , Estudos de Casos e Controles , Futebol Americano/fisiologia , Humanos , Masculino , Universidades , Adulto JovemRESUMO
BACKGROUND: Identifying risk factors for cardiovascular disease (CVD) early in life gives advanced practice nurses an opportunity to educate parents about choices that promote long-term heart health. The addition of universal lipid screening to 9- to 11-year-old well-child examinations opens a time interval that is adequate for conversations related to cardiovascular health. OBJECTIVE: The objective of this study was to determine if the use of a 10-minute health promotion plan that includes identification of child modifiable CVD risk factors would have an effect on parental intent to engage in lifestyle changes that promote heart health in 9- to 11-year-old children. METHODS: The quasi-experimental pilot study involved 26 English-speaking parents of 9- to 11-year-old children during routine well-child examinations. Participants completed questionnaires before and after receiving a health promotion plan and the child's modifiable CVD risk screening results. The advanced practice nurse-researcher analyzed the questionnaires to evaluate parental intent to promote lifestyle changes. RESULTS: Increases were seen in concern for the child's future heart health and in awareness of diet and exercise recommendations. Participants were likely to encourage more fruits and vegetables (100%), limit "screen time" (96%), encourage physical activity (92%), and limit sugar-sweetened beverage intake (96%). Factors identified as most influential on participant decision to encourage change were the child's body mass index (38.46%), lipid screening results (23.08%), and "other"-tobacco smoke exposure (15.38%), which closely approximate national prevalence for each risk category. CONCLUSIONS: The American Academy of Pediatrics recommends lipid screening once for all children between 9 and 11 years of age. In this study, outlining recommendations for good health and identifying modifiable CVD risk factors showed a positive effect on parental intent to encourage lifestyle changes. Further research is needed to advance the science of CVD prevention and risk reduction in children.
Assuntos
Doenças Cardiovasculares/prevenção & controle , Proteção da Criança , Promoção da Saúde , Estilo de Vida , Pais , Comportamento de Redução do Risco , Criança , Dieta , Exercício Físico , Feminino , Humanos , Lipídeos/sangue , Masculino , Motivação , Projetos Piloto , Inquéritos e QuestionáriosRESUMO
Aging is a complex phenotype responsive to a plethora of environmental inputs; yet only a limited number of transcriptional regulators are known to influence life span. How the downstream expression programs mediated by these factors (or others) are coordinated into common or distinct set of aging effectors is an addressable question in model organisms, such as C. elegans. Here, we establish the transcription factor ETS-4, an ortholog of vertebrate SPDEF, as a longevity determinant. Adult worms with ets-4 mutations had a significant extension of mean life span. Restoring ETS-4 activity in the intestine, but not neurons, of ets-4 mutant worms rescued life span to wild-type levels. Using RNAi, we demonstrated that ets-4 is required post-developmentally to regulate adult life span; thus uncoupling the role of ETS-4 in aging from potential functions in worm intestinal development. Seventy ETS-4-regulated genes, identified by gene expression profiling of two distinct ets-4 alleles and analyzed by bioinformatics, were enriched for known longevity effectors that function in lipid transport, lipid metabolism, and innate immunity. Putative target genes were enriched for ones that change expression during normal aging, the majority of which are controlled by the GATA factors. Also, some ETS-4-regulated genes function downstream of the FOXO factor, DAF-16 and the insulin/IGF-1 signaling pathway. However, epistasis and phenotypic analyses indicate that ets-4 functioned in parallel to the insulin/IGF-1 receptor, daf-2 and akt-1/2 kinases. Furthermore, ets-4 required daf-16 to modulate aging, suggesting overlap in function at the level of common targets that affect life span. In conclusion, ETS-4 is a new transcriptional regulator of aging, which shares transcriptional targets with GATA and FOXO factors, suggesting that overlapping pathways direct common sets of lifespan-related genes.
Assuntos
Proteínas de Caenorhabditis elegans/genética , Caenorhabditis elegans/genética , Caenorhabditis elegans/fisiologia , Longevidade/genética , Fatores de Transcrição/metabolismo , Transcrição Gênica , Animais , Sequência de Bases , Proteínas de Caenorhabditis elegans/metabolismo , DNA de Helmintos/metabolismo , Fatores de Transcrição Forkhead , Deleção de Genes , Regulação da Expressão Gênica no Desenvolvimento , Genes de Helmintos/genética , Insulina/metabolismo , Fator de Crescimento Insulin-Like I/metabolismo , Mucosa Intestinal/metabolismo , Larva/crescimento & desenvolvimento , Larva/metabolismo , Modelos Genéticos , Mutação/genética , Especificidade de Órgãos/genética , Oviposição/genética , Ligação Proteica , Transdução de Sinais/genética , Fatores de Transcrição/genéticaRESUMO
Ras/MAPK signaling is often aberrantly activated in human cancers. The downstream effectors are transcription factors, including those encoded by the ETS gene family. Using cell-based assays and biophysical measurements, we have determined the mechanism by which Ras/MAPK signaling affects the function of Ets1 via phosphorylation of Thr38 and Ser41. These ERK2 phosphoacceptors lie within the unstructured N-terminal region of Ets1, immediately adjacent to the PNT domain. NMR spectroscopic analyses demonstrated that the PNT domain is a four-helix bundle (H2-H5), resembling the SAM domain, appended with two additional helices (H0-H1). Phosphorylation shifted a conformational equilibrium, displacing the dynamic helix H0 from the core bundle. The affinity of Ets1 for the TAZ1 (or CH1) domain of the coactivator CBP was enhanced 34-fold by phosphorylation, and this binding was sensitive to ionic strength. NMR-monitored titration experiments mapped the interaction surfaces of the TAZ1 domain and Ets1, the latter encompassing both the phosphoacceptors and PNT domain. Charge complementarity of these surfaces indicate that electrostatic forces act in concert with a conformational equilibrium to mediate phosphorylation effects. We conclude that the dynamic helical elements of Ets1, appended to a conserved structural core, constitute a phospho-switch that directs Ras/MAPK signaling to downstream changes in gene expression. This detailed structural and mechanistic information will guide strategies for targeting ETS proteins in human disease.
Assuntos
Proteína de Ligação a CREB/metabolismo , Proteína Proto-Oncogênica c-ets-1/metabolismo , Proteínas ras/metabolismo , Sequência de Aminoácidos , Animais , Proteína de Ligação a CREB/química , Sequência Conservada , Humanos , Sistema de Sinalização das MAP Quinases , Camundongos , Modelos Moleculares , Simulação de Dinâmica Molecular , Dados de Sequência Molecular , Células NIH 3T3 , Ressonância Magnética Nuclear Biomolecular , Fosforilação , Ligação Proteica , Conformação Proteica , Domínios e Motivos de Interação entre Proteínas , Proteína Proto-Oncogênica c-ets-1/química , Proteína Proto-Oncogênica c-ets-1/genética , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Homologia de Sequência de Aminoácidos , Transdução de Sinais , Eletricidade EstáticaRESUMO
The nursing faculty shortage is directly related to the ongoing shortage of nurses. As a result of many nursing faculty retiring, the discipline of nursing is losing its most experienced educators. The need is great for programs that will increase access and prepare nurse educators. Doctorate degrees for nurses have evolved in myriad ways. Discussions over the nature of doctoral education for the preparation of nurse educators are at the forefront of debates in nursing education. In response to National League for Nursing (2007; Core competencies of nurse educators, http://www.nln.org/profdev/corecompletter.htm) and Institute of Medicine (2010; The future of nursing: Leading change, advancing health. Washington, DC: National Academies Press, http://thefutureofnursing.org/IOM-Report) calls to increase the number of nursing faculty, the colleges of nursing and education at a major university have combined to establish a collaborative doctoral program. This article describes the historical evolution of the nursing doctorate degrees and the development and implementation of the EdD in Instructional Leadership for Nurse Educators.