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1.
EMBO J ; 40(23): e108271, 2021 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-34605059

RESUMO

Mutations in the gene encoding the CDKL5 kinase are among the most common genetic causes of childhood epilepsy and can also give rise to the severe neurodevelopmental condition CDD (CDKL5 deficiency disorder). Despite its importance for human health, the phosphorylation targets and cellular roles of CDKL5 are poorly understood, especially in the cell nucleus. Here, we report that CDKL5 is recruited to sites of DNA damage in actively transcribed regions of the nucleus. A quantitative phosphoproteomic screen for nuclear CDKL5 substrates reveals a network of transcriptional regulators including Elongin A (ELOA), phosphorylated on a specific CDKL5 consensus motif. Recruitment of CDKL5 and ELOA to damaged DNA, and subsequent phosphorylation of ELOA, requires both active transcription and the synthesis of poly(ADP-ribose) (PAR), to which CDKL5 can bind. Critically, CDKL5 kinase activity is essential for the transcriptional silencing of genes induced by DNA double-strand breaks. Thus, CDKL5 is a DNA damage-sensing, PAR-controlled transcriptional modulator, a finding with implications for understanding the molecular basis of CDKL5-related diseases.


Assuntos
Quebras de DNA de Cadeia Dupla , Dano ao DNA , Elonguina/metabolismo , Neurônios/patologia , Fosfoproteínas/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Ativação Transcricional , Elonguina/genética , Síndromes Epilépticas/genética , Síndromes Epilépticas/metabolismo , Síndromes Epilépticas/patologia , Humanos , Mutação , Neurônios/metabolismo , Fosfoproteínas/genética , Fosforilação , Poli Adenosina Difosfato Ribose/metabolismo , Proteínas Serina-Treonina Quinases/genética , Espasmos Infantis/genética , Espasmos Infantis/metabolismo , Espasmos Infantis/patologia
2.
Mol Cell ; 66(5): 610-621.e4, 2017 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-28575657

RESUMO

Defects in the repair of DNA interstrand crosslinks (ICLs) are associated with the genome instability syndrome Fanconi anemia (FA). Here we report that cells with mutations in RFWD3, an E3 ubiquitin ligase that interacts with and ubiquitylates replication protein A (RPA), show profound defects in ICL repair. An amino acid substitution in the WD40 repeats of RFWD3 (I639K) found in a new FA subtype abolishes interaction of RFWD3 with RPA, thereby preventing RFWD3 recruitment to sites of ICL-induced replication fork stalling. Moreover, single point mutations in the RPA32 subunit of RPA that abolish interaction with RFWD3 also inhibit ICL repair, demonstrating that RPA-mediated RFWD3 recruitment to stalled replication forks is important for ICL repair. We also report that unloading of RPA from sites of ICL induction is perturbed in RFWD3-deficient cells. These data reveal important roles for RFWD3 localization in protecting genome stability and preserving human health.


Assuntos
Dano ao DNA , Anemia de Fanconi/enzimologia , Reparo de DNA por Recombinação , Origem de Replicação , Proteína de Replicação A/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Sítios de Ligação , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Endonucleases/genética , Endonucleases/metabolismo , Anemia de Fanconi/genética , Células HeLa , Humanos , Mutação , Ligação Proteica , Interferência de RNA , Proteína de Replicação A/genética , Transfecção , Ubiquitina-Proteína Ligases/genética
3.
Scand J Med Sci Sports ; 34(4): e14616, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38553779

RESUMO

PURPOSE: The purpose of this prospective cohort study was to investigate the influence of types of motivation, basic psychological needs satisfaction and of a coach-created motivational climate on continued participation in youth sports across types of sport, competitive levels, ages, and gender. METHODS: Participants were 7110 adolescent (age 12-20 years) members of leisure time club organized in basketball, handball, football, badminton, and gymnastics in Denmark. Motivational regulation was measured with BRSQ-6, basic psychological needs satisfaction and frustration were measured with PNSS-S, and coach-created climate was measured with the EDMCQ-C. The participants' continuation or dropout was measured at the beginning of the following season with a short electronic questionnaire. RESULTS: Intrinsic motivation, identified behavior regulation, experiences of competence, relatedness, and autonomy, as well as a coach-created empowering motivational climate, were associated with continuation both in the sport and in the club the following season across different sports, genders, age groups, and competitive levels. Introjected and external behavior regulation, frustrations with the need to experience competence, relatedness, and autonomy, as well as a disempowering coach-created climate, were associated with dropout. CONCLUSION: In Danish youth sports, autonomous motivation, satisfaction of basic psychological needs, and an empowering coach-created motivational climate have a positive impact on the continuation of the sport and the club the following season. In contrast, controlled types of motivation, needs frustration, and a disempowering coach-created climate are associated with dropout. This is the case at both elite and recreational levels, for boys and girls, adolescents, and youth.


Assuntos
Futebol Americano , Motivação , Adolescente , Humanos , Masculino , Feminino , Criança , Adulto Jovem , Adulto , Estudos Prospectivos , Dinamarca , Satisfação Pessoal , Autonomia Pessoal
4.
Int Orthop ; 48(1): 37-47, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38078940

RESUMO

PURPOSE: Low-velocity gunshot fractures (LVGFs) are a common type of gunshot-induced trauma with the potential for complications such as infection and osteomyelitis. The effectiveness of antibiotic therapy in LVGFs remains uncertain, leading to ongoing debate about the appropriate treatment. In this review, we evaluate recent updates on the current understanding of antibiotic therapy in LVGFs, how previous studies have investigated the use of antibiotics in LVGFs, and the current state of institutional policies and protocols for treating LVGFs with antibiotics. METHODS: We conducted a review of PubMed, Embase, and Web of Science databases to identify studies that investigated the use of antibiotics in LVGFs after the last review in 2013. Due to the lack of quantitative clinical trial studies, we employed a narrative synthesis approach to analyze and present the findings from the included primary studies. We categorized the outcomes based on the anatomical location of the LVGFs. RESULTS: After evaluating 67 publications with the necessary qualifications out of 578 abstracts, 17 articles were included. The sample size of the studies ranged from 22 to 252 patients. The antibiotics used in the studies varied, and the follow-up period ranged from three months to ten years. The included studies investigated the use of antibiotics in treating LVGFs at various anatomic locations, including the humerus, forearm, hand and wrist, hip, femur, tibia, and foot and ankle. CONCLUSION: Our study provides updated evidence for the use of antibiotics in LVGFs and highlights the need for further research to establish evidence-based guidelines. We also highlight the lack of institutional policies for treating LVGFs and the heterogeneity in treatments among institutions with established protocols. A single-dose antibiotic approach could be cost-effective for patients with non-operatively treated LVGFs. We suggest that a national or international registry for gunshot injuries, antibiotics, and infections could serve as a valuable resource for collecting and analyzing data related to these important healthcare issues.


Assuntos
Fraturas Ósseas , Osteomielite , Ferimentos por Arma de Fogo , Humanos , Antibioticoprofilaxia/efeitos adversos , Antibacterianos/uso terapêutico , Fraturas Ósseas/complicações , Tíbia , Osteomielite/tratamento farmacológico , Ferimentos por Arma de Fogo/complicações
5.
BMC Musculoskelet Disord ; 24(1): 263, 2023 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-37016368

RESUMO

BACKGROUND: The incidence of periprosthetic femur fracture (PPFF) in the setting of total hip arthroplasty (THA) is steadily increasing. We seek to address whether there is a difference in outcomes between Vancouver B fracture types managed with ORIF when the original stem was a press-fit stem versus a cemented stem. METHODS: In this retrospective cohort study at a level 1 trauma center, we identified 136 patients over 65 years-of-age with Vancouver B-type fractures sustained between 2005 and 2019. Patients were treated by ORIF and had either cemented or press-fit stems prior to their injury. Outcomes were subsidence of the femoral implant, time to full weight bearing, rate of the hip implant revision, estimated blood loss (EBL), postoperative complications, and the one-year mortality rate. RESULTS: A total of 103 (75.7%) press-fit and 33 (24.3%) cemented patients were reviewed. Patient baseline characteristics, Vancouver fracture sub-types, and implant characteristics were not found to be significantly different between groups. The difference in subsidence rates, postoperative complications, and time to weight bearing were not significantly different between groups. EBL and one-year mortality rate were significantly higher in the cemented group. CONCLUSIONS: In geriatric patients with Vancouver B type periprosthetic fractures managed with ORIF, patients with an originally press fit stem may have lower mortality, lower estimated blood loss, and similar subsidence and hospital length of stays when compared to those with a cemented stem.


Assuntos
Artroplastia de Quadril , Fraturas do Fêmur , Prótese de Quadril , Fraturas Periprotéticas , Humanos , Idoso , Fraturas Periprotéticas/epidemiologia , Fraturas Periprotéticas/etiologia , Fraturas Periprotéticas/cirurgia , Estudos Retrospectivos , Reoperação/efeitos adversos , Artroplastia de Quadril/efeitos adversos , Prótese de Quadril/efeitos adversos , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/cirurgia , Fraturas do Fêmur/diagnóstico por imagem , Fraturas do Fêmur/etiologia , Fraturas do Fêmur/cirurgia
6.
J Sports Sci ; 41(8): 715-726, 2023 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-37486014

RESUMO

PURPOSE: The purpose of this study was to translate and validate a Danish version of the coach-created Empowering and Disempowering Motivational Climate Questionnaire (EDMCQ-C), retest the factor structure and provide further investigation into the psychometric properties in terms of measurement invariance across gender, age and competitive level, reliability and predictive validity. METHODS: The participants were 1719 male and 551 female Danish football players 12-20 years of age (M = 14.81) playing at recreational, medium and elite levels. Participants filled in EDMCQ-C as well as questionnaires measuring psychological needs (BPNESS) and behaviour regulation (BRSQ). Factor structure of the EDMCQ-C was tested using Exploratory Structural Equation Modelling. To test whether the factor structure differed across gender, age group and competitive level, an invariance analysis comparing configurational, metric and scalar models was conducted. RESULTS: EDMCQ-C showed good psychometric properties and measurement invariance across age, gender and competitive level. Both dimensions of EDMCQ-C were associated to needs satisfaction and behaviour regulation in expected directions and had high internal consistency. CONCLUSION: This study provides evidence for the reliability of the two dimensions of EDMCQ-C, their predictive validity and for measurement invariance across age, gender and competitive level and provides a Danish version of the EDMCQ with sound psychometric properties.


Assuntos
Motivação , Poder Psicológico , Humanos , Masculino , Feminino , Reprodutibilidade dos Testes , Inquéritos e Questionários , Psicometria/métodos , Dinamarca
7.
Med Probl Perform Art ; 36(3): 187-198, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34464964

RESUMO

OBJECTIVE: Sports science has identified the trainer-athlete relationship in the etiology of injuries. We aimed to investigate: 1) the association between empowering (EMC) and disempowering (DMC) motivational-climate and musculoskeletal injuries in ballet, and 2) if EMC moderates the association between DMC and injuries. METHODS: A cross-sectional cohort survey-study was conducted online among ballet dancers (>18 yrs old) reporting acute and overuse injuries of the previous 2 years. Motivational climate was assessed with the Empowering-and-Disempowering Motivational Climate Questionnaire (5-point Likert scale). The Oslo Sports Trauma Research Centre Overuse Injury Questionnaire assessed severity of overuse injuries. Linear regression was performed adjusted for the confounders age, sex, expertise, experience, and initiation-age with an interaction term between EMC and DMC to assess effect modification. RESULTS: An international sample of 189 dancers (26.7±7.9 yrs; 130 professionals) reported 197 acute and 465 overuse injuries (in the previous 2 years). Mean EMC was 3.1±1.07, DMC 3.3±1.08. EMC was associated with less acute (b=-0.22; 95%CI -0.40 to -0.04) and overuse injuries (b=-0.74; 95%CI -0.99 to -0.50), while DMC was associated with more injuries (acute: b=0.30; 95%CI 0.13 to 0.47; overuse: b=0.74; 95%CI 0.50 to 0.98). When tested together and adjusted for confounders, EMC lost its protective effect (acute: b=-0.15; 95%CI -0.19 to 0.49; overuse: b=-0.34; 95%CI -0.81 to 0.13). DMC was positively associated with injuries throughout all settings (acute: b=0.43; 95%CI 0.10 to 0.76; overuse: b=0.46; 95%CI 0.00 to 0.91). EMC showed no moderating effects on DMC in the adjusted models. CONCLUSION: To avoid injuries, it is not enough to create an EMC, because any disempowering nuances may negatively affect empowering climates. Teachers should avoid DMC altogether to prevent injuries in dancers.


Assuntos
Traumatismos em Atletas , Transtornos Traumáticos Cumulativos , Dança , Doenças Musculoesqueléticas , Traumatismos em Atletas/epidemiologia , Estudos Transversais , Transtornos Traumáticos Cumulativos/epidemiologia , Humanos , Percepção
8.
J Cell Sci ; 130(22): 3862-3877, 2017 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-28982714

RESUMO

Homeostasis of renewing tissues requires balanced proliferation, differentiation and movement. This is particularly important in the intestinal epithelium where lineage tracing suggests that stochastic differentiation choices are intricately coupled to the position of a cell relative to a niche. To determine how position is achieved, we followed proliferating cells in intestinal organoids and discovered that the behaviour of mitotic sisters predicted long-term positioning. We found that, normally, 70% of sisters remain neighbours, while 30% lose contact and separate after cytokinesis. These post-mitotic placements predict longer term differences in positions assumed by sisters: adjacent sisters reach similar positions over time; in a pair of separating sisters, one remains close to its birthplace while the other is displaced upward. Computationally modelling crypt dynamics confirmed that post-mitotic separation leads to sisters reaching different compartments. We show that interkinetic nuclear migration, cell size and asymmetric tethering by a process extending from the basal side of cells contribute to separations. These processes are altered in adenomatous polyposis coli (Apc) mutant epithelia where separation is lost. We conclude that post-mitotic placement contributes to stochastic niche exit and, when defective, supports the clonal expansion of Apc mutant cells.


Assuntos
Núcleo Celular/fisiologia , Mucosa Intestinal/citologia , Animais , Transporte Biológico , Adesão Celular , Humanos , Cinética , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Mitose , Organoides/citologia , Técnicas de Cultura de Tecidos
9.
Chem Res Toxicol ; 32(3): 500-512, 2019 03 18.
Artigo em Inglês | MEDLINE | ID: mdl-30793592

RESUMO

Transcription factor NF-E2 p45-related factor 2 (Nrf2) and its principal negative regulator, Kelch-like ECH-associated protein 1 (Keap1), comprise a molecular effector and sensor system that robustly responds to perturbations of the cellular redox homeostasis by orchestrating a comprehensive cytoprotective program. Under homeostatic conditions, Nrf2 is a short-lived protein, which is targeted for ubiquitination and proteasomal degradation. Upon encounter of electrophiles, oxidants, or pro-inflammatory stimuli, the cysteine sensors in Keap1 are chemically modified, rendering Keap1 unable to target Nrf2 for degradation, and consequently leading to accumulation of the transcription factor and enhanced transcription of cytoprotective genes. A detailed understanding of the protein-protein interactions between Nrf2 and Keap1 has been achieved by use of various in vitro systems, but few assays are available to assess these interactions in the context of the living cell. We previously developed an imaging-based FLIM/FRET methodology to visualize and measure the interaction between Nrf2 and Keap1 in single cells. Here, our goal was to improve this methodology in order to increase throughput and precision, and decrease cell-to-cell variability. To eliminate the possibility of orientation bias, we incorporated a flexible linker between Keap1 and the FRET acceptor fluorescent protein tag. To ensure the correct image capture of Nrf2 fused to the FRET donor fluorescent protein tag, we matched the maturation time of the fluorescent tag to the half-life of the endogenous Nrf2, by using sfGFP as the FRET donor. Using a global binning approach increased the assay throughput, whereas including the measured instrument response function in the analysis improved precision. The application of this methodology revealed a strong covariation of the results with the expression level of the acceptor. Taking the acceptor level into account circumvented cell-to-cell variability and enhanced sensitivity of the measurements of the Keap1-Nrf2 interaction in live cells.


Assuntos
Transferência Ressonante de Energia de Fluorescência , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Microscopia de Fluorescência por Excitação Multifotônica , Fator 2 Relacionado a NF-E2/metabolismo , Análise de Célula Única , Sobrevivência Celular , Células HEK293 , Células HeLa , Humanos , Proteína 1 Associada a ECH Semelhante a Kelch/química , Fator 2 Relacionado a NF-E2/química , Imagem Óptica
10.
PLoS Biol ; 14(6): e1002491, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-27348469

RESUMO

The crypts of the intestinal epithelium house the stem cells that ensure the continual renewal of the epithelial cells that line the intestinal tract. Crypt number increases by a process called crypt fission, the division of a single crypt into two daughter crypts. Fission drives normal tissue growth and maintenance. Correspondingly, it becomes less frequent in adulthood. Importantly, fission is reactivated to drive adenoma growth. The mechanisms governing fission are poorly understood. However, only by knowing how normal fission operates can cancer-associated changes be elucidated. We studied normal fission in tissue in three dimensions using high-resolution imaging and used intestinal organoids to identify underlying mechanisms. We discovered that both the number and relative position of Paneth cells and Lgr5+ cells are important for fission. Furthermore, the higher stiffness and increased adhesion of Paneth cells are involved in determining the site of fission. Formation of a cluster of Lgr5+ cells between at least two Paneth-cell-rich domains establishes the site for the upward invagination that initiates fission.


Assuntos
Mucosa Intestinal/citologia , Celulas de Paneth/citologia , Receptores Acoplados a Proteínas G/metabolismo , Nicho de Células-Tronco , Células-Tronco/citologia , Fatores Etários , Animais , Adesão Celular , Contagem de Células , Divisão Celular , Proliferação de Células , Integrina beta4/metabolismo , Mucosa Intestinal/metabolismo , Intestino Delgado/citologia , Intestino Delgado/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Microscopia Confocal , Modelos Biológicos , Organoides/citologia , Organoides/metabolismo , Celulas de Paneth/metabolismo , Receptores Acoplados a Proteínas G/genética , Células-Tronco/metabolismo
11.
Lab Invest ; 98(3): 380-390, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29251735

RESUMO

Photonics, especially optical coherence elastography (OCE) and second harmonic generation (SHG) imaging are novel high-resolution imaging modalities for characterization of biological tissues. Following our preliminary experience, we hypothesized that OCE and SHG imaging would delineate the microstructure of prostate tissue and aid in distinguishing cancer from the normal benign prostatic tissue. Furthermore, these approaches may assist in characterization of the grade of cancer, as well. In this study, we confirmed a high diagnostic accuracy of OCE and SHG imaging in the detection and characterization of prostate cancer for a large set of biopsy tissues obtained from men suspected to have prostate cancer using transrectal ultrasound (TRUS). The two techniques and methods described here are complementary, one depicts the stiffness of tissues and the other illustrates the orientation of collagen structure around the cancerous lesions. The results showed that stiffness of cancer tissue was ~57.63% higher than that of benign tissue (Young's modulus of 698.43±125.29 kPa for cancerous tissue vs 443.07±88.95 kPa for benign tissue with OCE. Using histology as a reference standard and 600 kPa as a cut-off threshold, the data analysis showed sensitivity and specificity of 89.6 and 99.8%, respectively. Corresponding positive and negative predictive values were 99.5 and 94.6%, respectively. There was a significant difference noticed in terms of Young's modulus for different Gleason scores estimated by OCE (P-value<0.05). For SHG, distinct patterns of collagen distribution were seen for different Gleason grade disease with computed quantification employing a ratio of anisotropic to isotropic (A:I ratio) and this correlated with disease aggressiveness.


Assuntos
Técnicas de Imagem por Elasticidade , Imagem Óptica , Próstata/diagnóstico por imagem , Neoplasias da Próstata/diagnóstico por imagem , Microscopia de Geração do Segundo Harmônico , Idoso , Idoso de 80 Anos ou mais , Colágeno/análise , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Próstata/patologia , Prostatectomia , Neoplasias da Próstata/patologia , Neoplasias da Próstata/cirurgia
12.
Skeletal Radiol ; 47(6): 771-777, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29247259

RESUMO

PURPOSE: To investigate the relationship between sarcopenia with short-term surgical outcome in elderly patients with proximal femur fractures. METHODS AND MATERIALS: Following Institutional Review Board approval, a database of patients receiving a pelvis CT scan for acute trauma between January 2000-August 2016 was screened for an isolated proximal femur fracture. Patients were excluded if they were: < 50 years old, had conditions predisposing to sarcopenia (renal failure, congestive heart failure, muscular dystrophies), had undergone no surgical treatment, had other major traumatic injuries, or had a pathologic femur fracture. The paraspinal muscle density (PSD) at the L4 level was measured in Hounsfield units. The skeletal muscle index (SMI) was measured as the total skeletal muscle area at L4 divided by patient height.2 PSD and SMI were tested for association with surgical outcome measures: length of hospital stay, perioperative mortality, medical complications, in-hospital blood transfusion volume, and 90-day readmission rate, using multiple variable regression analysis. Pearson correlation of PSD and SMI was performed. RESULTS: Controlling for age, gender, body mass index (BMI), and fracture type, low PSD and SMI were both independently associated with longer length of hospitalization (p = 0.008 and p = 0.032, respectively). Low PSD was associated with a higher amount of blood transfusion volume during the perioperative period (p = 0.004). Pearson correlation revealed moderate positive correlation between the SMI and PSD (r = 0.579, p < 0.001). CONCLUSION: In proximal femur fractures, elderly patients with sarcopenia are more likely to have prolonged hospitalization following surgery and require more blood transfusion volume during the perioperative period.


Assuntos
Fraturas do Fêmur/diagnóstico por imagem , Fraturas do Fêmur/cirurgia , Sarcopenia/complicações , Sarcopenia/diagnóstico por imagem , Idoso , Idoso de 80 Anos ou mais , Transfusão de Componentes Sanguíneos/estatística & dados numéricos , Feminino , Humanos , Tempo de Internação/estatística & dados numéricos , Masculino , Estudos Retrospectivos , Tomografia Computadorizada por Raios X , Resultado do Tratamento
13.
Development ; 141(24): 4806-16, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25468943

RESUMO

During somitogenesis, epithelial somites form from the pre-somitic mesoderm (PSM) in a periodic manner. This periodicity is regulated by a molecular oscillator, known as the 'segmentation clock', that is characterised by an oscillatory pattern of gene expression that sweeps the PSM in a caudal-rostral direction. Key components of the segmentation clock are intracellular components of the Notch, Wnt and FGF pathways, and it is widely accepted that intracellular negative-feedback loops regulate oscillatory gene expression. However, an open question in the field is how intracellular oscillations are coordinated, in the form of spatiotemporal waves of expression, across the PSM. In this study, we provide a potential mechanism for this process. We show at the mRNA level that the Notch1 receptor and Delta-like 1 (Dll1) ligand vary dynamically across the PSM of both chick and mouse. Remarkably, we also demonstrate similar dynamics at the protein level; hence, the pathway components that mediate intercellular coupling themselves exhibit oscillatory dynamics. Moreover, we quantify the dynamic expression patterns of Dll1 and Notch1, and show they are highly correlated with the expression patterns of two known clock components [Lfng mRNA and the activated form of the Notch receptor (cleaved Notch intracellular domain, NICD)]. Lastly, we show that Notch1 is a target of Notch signalling, whereas Dll1 is Wnt regulated. Regulation of Dll1 and Notch1 expression thus links the activity of Wnt and Notch, the two main signalling pathways driving the clock.


Assuntos
Relógios Biológicos/fisiologia , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Mesoderma/embriologia , Receptor Notch1/metabolismo , Transdução de Sinais/fisiologia , Somitos/embriologia , Algoritmos , Animais , Western Blotting , Proteínas de Ligação ao Cálcio , Embrião de Galinha , Glicosiltransferases/metabolismo , Processamento de Imagem Assistida por Computador , Imuno-Histoquímica , Hibridização In Situ , Hibridização in Situ Fluorescente , Mesoderma/metabolismo , Camundongos , Reação em Cadeia da Polimerase em Tempo Real , Receptores Notch/metabolismo
14.
J Sports Sci ; 40(1): 1-2, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34861801
15.
J Sports Sci ; 35(2): 149-158, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-27055568

RESUMO

Adopting an integrated achievement goal (Nicholls, J. G. (1989). The competitive ethos and democratic education. Cambridge, MA: Harvard University Press.) and self-determination theory (Deci, E. L., & Ryan, R. M. (2000). The "what" and "why" of goal pursuits: Human needs and the self-determination of behavior. Psychological Inquiry, 11, 227-268. doi:10.1207/S15327965PLI1104_01) perspective as proffered by Duda, J. L. (2013). (The conceptual and empirical foundations of empowering coachingTM: Setting the stage for the PAPA project. International Journal of Sport and Exercise Psychology, 11, 311-318. doi:10.1080/1612197X.2013.839414), the aim of the current study was to observe empowering and disempowering features of the multidimensional motivational coaching environment in training and competition in youth sport. Seventeen grass-roots soccer coaches were observed and rated in training and competitive settings using the multidimensional motivational climate observation system (MMCOS; Smith, N., Tessier, D., Tzioumakis, Y., Quested, E., Appleton, P., Sarrazin, P., … Duda, J. L. (2015). Development and validation of the multidimensional motivational climate observation system (MMCOS). Journal of Sport and Exercise Psychology, 37, 4-22. doi:10.1123/jsep.2014-0059). In line with our hypotheses, coaches created different motivational environments in the two contexts. More specifically, coaches were observed to create a less empowering and more disempowering environment in competition compared to in training. The observed differences were underpinned by distinctive motivational strategies used by coaches in the two contexts. Findings have implications for the assessment of the coach-created motivational environment and the promotion of quality motivation for young athletes taking part in grass-roots-level sport.


Assuntos
Tutoria , Motivação , Poder Psicológico , Futebol/psicologia , Esportes Juvenis/psicologia , Adolescente , Adulto , Criança , Comportamento Competitivo , Feminino , Humanos , Masculino , Autonomia Pessoal , Condicionamento Físico Humano/psicologia
16.
Lancet ; 386(10000): 1299-1310, 2015 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-26460664

RESUMO

Acute compartment syndrome of the extremities is well known, but diagnosis can be challenging. Ineffective treatment can have devastating consequences, such as permanent dysaesthesia, ischaemic contractures, muscle dysfunction, loss of limb, and even loss of life. Despite many studies, there is no consensus about the way in which acute extremity compartment syndromes should be diagnosed. Many surgeons suggest continuous monitoring of intracompartmental pressure for all patients who have high-risk extremity injuries, whereas others suggest aggressive surgical intervention if acute compartment syndrome is even suspected. Although surgical fasciotomy might reduce intracompartmental pressure, this procedure also carries the risk of long-term complications. In this paper in The Lancet Series about emergency surgery we summarise the available data on acute extremity compartment syndrome of the upper and lower extremities in adults and children, discuss the underlying pathophysiology, and propose a clinical guideline based on the available data.


Assuntos
Braço , Síndromes Compartimentais/diagnóstico , Perna (Membro) , Doença Aguda , Adulto , Braço/irrigação sanguínea , Braço/cirurgia , Criança , Síndromes Compartimentais/cirurgia , Humanos , Perna (Membro)/irrigação sanguínea , Perna (Membro)/cirurgia
17.
J Sport Exerc Psychol ; 37(1): 4-22, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25730888

RESUMO

This article outlines the development and validation of the Multidimensional Motivational Climate Observation System (MMCOS). Drawing from an integration of the dimensions of the social environment emphasized within achievement goal theory and self-determination theory (as assumed within Duda's [2013] conceptualization of "empowering" and "disempowering" climates), the MMCOS was developed to enable an objective assessment of the coach-created motivational environment in sport. Study 1 supported the initial validity and reliability of the newly developed observation system. Study 2 further examined the interobserver reliability and factorial structure of the MMCOS. Study 3 explored the predictive validity of the observational system in relation to athletes' reported basic psychological need satisfaction. Overall, the results of these studies provide preliminary support for the inter- and intraobserver reliability, as well as factorial and predictive validity of the MMCOS. Suggestions for the use of this observational system in future research in sport are provided.


Assuntos
Atletas/psicologia , Motivação , Observação/métodos , Adolescente , Adulto , Criança , Europa (Continente) , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Psicológicos , Futebol , Inquéritos e Questionários
18.
J Cell Sci ; 125(Pt 4): 887-95, 2012 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-22399804

RESUMO

Colorectal cancers commonly carry truncation mutations in the adenomatous polyposis coli (APC) gene. The APC protein contributes to the stabilization of microtubules. Consistently, microtubules in cells lacking APC depolymerize more readily in response to microtubule-destabilizing drugs. This raises the possibility that such agents are suitable for treatment of APC-deficient cancers. However, APC-deficient cells have a compromised spindle assembly checkpoint, which renders them less sensitive to killing by microtubule poisons whose toxicity relies on the induction of prolonged mitotic arrest. Here, we describe the novel discovery that the clinically used microtubule-depolymerizing drug vinorelbine (Navelbine) kills APC-deficient cells in culture and in intestinal tissue more effectively than it kills wild-type cells. This is due to the ability of vinorelbine to kill cells in interphase independently of mitotic arrest. Consistent with a role for p53 in cell death in interphase, depletion of p53 renders cells less sensitive to vinorelbine, but only in the presence of wild-type APC. The pro-apoptotic protein BIM (also known as BCL2L11) is recruited to mitochondria in response to vinorelbine, where it can inhibit the anti-apoptotic protein BCL2, suggesting that BIM mediates vinorelbine-induced cell death. This recruitment of BIM is enhanced in cells lacking APC. Consistently, BIM depletion dampens the selective effect of vinorelbine on these cells. Our findings reveal that vinorelbine is a potential therapeutic agent for colorectal cancer, but they also illustrate the importance of the APC tumour suppressor status when predicting therapeutic efficacy.


Assuntos
Proteína da Polipose Adenomatosa do Colo/deficiência , Microtúbulos/efeitos dos fármacos , Mitose/efeitos dos fármacos , Vimblastina/análogos & derivados , Adenoma/tratamento farmacológico , Adenoma/genética , Proteína da Polipose Adenomatosa do Colo/genética , Antineoplásicos Fitogênicos/farmacologia , Apoptose/efeitos dos fármacos , Proteínas Reguladoras de Apoptose/deficiência , Proteínas Reguladoras de Apoptose/metabolismo , Proteína 11 Semelhante a Bcl-2 , Ciclo Celular/fisiologia , Linhagem Celular Tumoral , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Humanos , Interfase/efeitos dos fármacos , Proteínas de Membrana/deficiência , Proteínas de Membrana/metabolismo , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Proteínas Proto-Oncogênicas/deficiência , Proteínas Proto-Oncogênicas/metabolismo , Proteína Supressora de Tumor p53/deficiência , Vimblastina/farmacologia , Vinorelbina
19.
Emerg Radiol ; 21(4): 359-65, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24557456

RESUMO

This study aims (1) to evaluate the spectrum of musculoskeletal (MSK) findings detected on trauma-related torso CT exams performed in the emergency department and (2) to identify the findings of high clinical importance that are underreported. Following IRB approval, two fellowship-trained MSK radiologists independently reviewed 200 consecutive trauma CT torso examinations performed at a level 1 trauma center, focusing on MSK findings. Discrepancies were resolved by consensus. Findings were categorized as of high, moderate, or low clinical importance based on criteria established with an orthopedic trauma surgeon. Findings evident on only one series (scout, axial, or sagittal/coronal reformations) were documented. The consensus reading was compared to the final report. Unreported findings of high clinical importance were entered into our departmental QA system. Eighty-two percent (164/200) of the studies had at least one MSK finding. There were 433 total findings of varying importance and the overall detection rate was 61 % (266/433). The detection rate for high importance findings was 80 % (177/221) with the majority representing acute fractures (99 %). For findings of high clinical importance, the lowest detection rates were for fractures of the sternum, proximal humerus, and forearm. Of the high severity findings, 6.3 % (14/221) were detected only on sagittal or coronal reformatted or scout images. Twenty percent of musculoskeletal findings of high clinical importance on trauma-related CT torso exams were not reported. Fractures of the sternum, proximal humerus, and forearm were the most commonly missed fractures and review of scout and multiplanar reformations can increase detection.


Assuntos
Sistema Musculoesquelético/diagnóstico por imagem , Traumatismos Torácicos/diagnóstico por imagem , Tomografia Computadorizada por Raios X/métodos , Ferimentos e Lesões/diagnóstico por imagem , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Meios de Contraste , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Centros de Traumatologia , Índices de Gravidade do Trauma , Ácidos Tri-Iodobenzoicos
20.
J Sport Exerc Psychol ; 36(3): 303-15, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24918313

RESUMO

Perfectionism is a personality characteristic that has been found to predict sports performance in athletes. To date, however, research has exclusively examined this relationship at an individual level (i.e., athletes' perfectionism predicting their personal performance). The current study extends this research to team sports by examining whether, when manifested at the team level, perfectionism predicts team performance. A sample of 231 competitive rowers from 36 boats completed measures of self-oriented, team-oriented, and team-prescribed perfectionism before competing against one another in a 4-day rowing competition. Strong within-boat similarities in the levels of team members' team-oriented perfectionism supported the existence of collective team-oriented perfectionism at the boat level. Two-level latent growth curve modeling of day-by-day boat performance showed that team-oriented perfectionism positively predicted the position of the boat in midcompetition and the linear improvement in position. The findings suggest that imposing perfectionistic standards on team members may drive teams to greater levels of performance.


Assuntos
Desempenho Atlético/psicologia , Esportes/psicologia , Adolescente , Adulto , Atletas/psicologia , Comportamento Competitivo , Feminino , Humanos , Masculino , Estudos Prospectivos , Testes Psicológicos , Esportes/normas , Adulto Jovem
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