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1.
Child Abuse Negl ; 154: 106884, 2024 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-38875868

RESUMO

BACKGROUND: This study employed a Delphi method with a panel of experts to collaboratively design a new instrument to assess schools' readiness for school-based child sexual abuse prevention education. METHODS: An initial item pool was generated based on a review of existing empirical research and theoretical models. We invited researchers and stakeholders in the field of child sexual abuse prevention as experts to participate in a two-round online Delphi study in which they rated item importance and clarity, contributed their views on superfluous and/or missing items, gave rephrasing suggestions, and re-appraised revised items. Following the Delphi study, the instrument was pilot tested with a convenience sample of school staff. RESULTS: The initial item pool comprised 81 items in five construct sub-scales congruent with Wiener's Organizational Readiness for Change theory: contextual factors, informational assessment, change valence, change commitment, and change efficacy. In the Delphi study, 24 experts participated in round 1, and 13 participated in round 2. Based on Delphi study responses, the instrument was reduced to 56 items in the five construct subscales: contextual factors (28 items), informational assessment (13 items), change valence (6 items), change commitment (3 items), and change efficacy (6 items). The Schools' Readiness for Child Sexual Abuse Prevention Education (SR-CSAPE) was successfully pilot tested with school staff (n = 19) and minor changes to demographic items were incorporated. CONCLUSIONS: Informed by experts, the Schools' Readiness for Child Sexual Abuse Prevention Education (SR-CSAPE) is a newly-developed 56-item scale that identifies key organizational dimensions to schools' preparedness for CSA prevention education. Psychometric properties of the scale must be determined in future research.

2.
Dev Sci ; 26(5): e13358, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-36511452

RESUMO

The benefits of active music participation and training for cognitive development have been evidenced in multiple studies, with this link leveraged in music therapy approaches with clinical populations. Although music, rhythm, and movement activities are widely integrated into children's play and early education, few studies have systematically translated music therapy-based approaches to a nonclinical population to support early cognitive development. This study reports the follow-up effects of the Rhythm and Movement for Self Regulation (RAMSR) program delivered by generalist preschool teachers in low socioeconomic communities. This randomized control trial (RCT) involved 213 children across eight preschools in disadvantaged communities in Queensland, Australia. The intervention group received 16-20 sessions of RAMSR over 8 weeks, while the control group undertook usual preschool programs. Primary outcome measures included executive function (child assessment of shifting, working memory, and inhibition) and self-regulation (teacher report), with secondary outcomes of school readiness and visual-motor integration. Data were collected pre- and post-intervention, and again 6 months later once children had transitioned into school. Results demonstrated significant intervention effects across the three time points for school readiness (p = 0.038, ηp 2  = 0.09), self-regulation (p < 0.001, ηp 2  = 0.08), and inhibition (p = 0.002 ηp 2  = 0.23). Additionally, the feasibility of building capacity in teachers without any music background to successfully deliver the program was evidenced. These findings are important given that children from low socioeconomic backgrounds are more likely to need support for cognitive development yet have inequitable access to quality music and movement programs. RESEARCH HIGHLIGHTS: Initial effects of self-regulation from a rhythm and movement program were sustained following transition into school for children from disadvantaged backgrounds. Delayed effects of inhibition and school readiness from a rhythm and movement program appeared 6 months post-intervention as children entered school. Generalist teachers can successfully implement a rhythm and movement program, which boosts critical developmental cognitive skills.


Assuntos
Música , Autocontrole , Criança , Pré-Escolar , Humanos , Função Executiva , Instituições Acadêmicas , Cognição
3.
Ophthalmic Physiol Opt ; 41(5): 1134-1143, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34431543

RESUMO

PURPOSE: Eye movements are integral to the reading process. This study characterised the eye movement patterns of children differentiated by their reading ability, while completing a saccadic eye movement test with irregular target spacing (Development Eye Movement (DEM) test) using a novel eye movement classification algorithm. METHODS: Participants included 196 Grade 2 Australian schoolchildren (mean age: 7.9 ± 0.3 years) who completed a computerised version of the DEM test, while their eye movements were recorded (Tobii TX300 eye-tracker). Children also completed a standardised reading comprehension test, which categorised them into below average and average or above reading ability groups. A novel eye movement classification algorithm was developed that considered the vertical and horizontal eye movements of each child. RESULTS: Compared to children with average or above reading ability, the below average reading group displayed poor vertical eye movement control, demonstrated by a significantly greater proportion of interline eye movements (vertical eye movements away from the current line) (p < 0.001). Differences in horizontal eye movements were also observed, with below average readers demonstrating a smaller proportion of expected forward saccades (p < 0.001) (within-line forward saccades with horizontal amplitude between the minimum and maximum horizontal spacing between digits), while this group also displayed longer fixation durations (p = 0.001). The below average reading group demonstrated significantly poorer results on all standard DEM metrics than the average or above reading ability group: horizontal subtest time (p < 0.001), vertical subtest time (p = 0.004) and ratio (p = 0.004). CONCLUSIONS: Children exhibiting below average reading ability were poorer at maintaining control of vertical (interline), as well as horizontal, eye movements compared to children with average or above reading ability. Future studies should explore the mechanisms underlying these differences, particularly in vertical eye movements, given that reading paragraphs (involving multiple lines of text) requires accurate eye movements in both the vertical and horizontal direction.


Assuntos
Movimentos Oculares , Leitura , Austrália , Criança , Fixação Ocular , Humanos , Movimentos Sacádicos
4.
Health Promot Pract ; 21(4): 591-600, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-30458648

RESUMO

Chronic diseases, like diabetes and heart disease, disproportionately impact women of color as compared to White women. Community-engaged and participatory approaches are proposed as a means to address chronic disease health disparities in minority communities, as they allow for tailoring and customization of strategies that align with community needs, interests, and priorities. While community-based participatory research (CBPR) is a framework that offers a clear set of principles to guide intervention design and development, the complexity and diversity of community contexts make it challenging to anticipate all of the possible pathways to implementation. This article describes the application of CBPR principles in the design and development of SHE Tribe (She's Healthy and Empowered), a social network-based healthy lifestyle intervention intended to promote the adoption of sustainable health behaviors in underserved communities. Practical and specific strategies are described to aid practitioners, researchers, and community partners as they engage in community-academic partnerships. These strategies uncover some of the inner workings of this partnership to promote trust and collaboration and maximize partner strengths, with the aim to aid others with key elements and practical steps in the application of participatory methods.


Assuntos
Pesquisa Participativa Baseada na Comunidade , Estilo de Vida Saudável , Grupos Minoritários , Relações Comunidade-Instituição , Feminino , Comportamentos Relacionados com a Saúde , Humanos , Confiança
5.
Acta Ophthalmol ; 97(8): e1141-e1148, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31228337

RESUMO

PURPOSE: This study evaluated the association between performance on visual information processing tests and academic performance in school children. METHODS: Visual-motor integration (VMI), the Developmental Eye Movement (DEM) test, visual acuity and stereoacuity were assessed in 222 Grade 2 children (mean age: 7.90 ± 0.33 years). Academic performance was assessed using standardized tests of reading and mathematics (PAT-R and PAT-M). Linear regression analyses examined associations between visual information processing (VMI and DEM) and academic measures, adjusting for school socio-economic background and age. Receiver operating characteristic (ROC) analysis was used to assess the ability of the tests to identify children with below average academic performance. RESULTS: Visual-motor integration (VMI) and DEM (horizontal time) were most strongly associated with PAT-R and PAT-M. Linear regression models explained 28.6% of variance in PAT-R (VMI: standardized regression coefficient = 0.31, p < 0.01; DEM horizontal time: -0.28, p < 0.01) and 24.1% of variance in PAT-M (VMI: standardized regression coefficient = 0.29, p < 0.01; DEM horizontal time: -0.16, p = 0.02). Receiver operating characteristic (ROC) curve analysis indicated that VMI was most strongly associated with below average PAT-R (area under curve [AUC] of 0.74 [95% CI: 0.67-0.81]) and PAT-M (AUC of 0.73 [95% CI: 0.66-0.81]). CONCLUSION: Visual-motor integration (VMI) was most strongly associated with reading and mathematics scores in school children. A child's academic performance can be an important factor in their optometric management. The ability of clinical tests to identify children at risk of underachieving academically provides additional support to clinicians in managing their patients.


Assuntos
Desempenho Acadêmico , Desenvolvimento Infantil , Desempenho Psicomotor/fisiologia , Estudantes/psicologia , Visão Binocular/fisiologia , Acuidade Visual , Percepção Visual/fisiologia , Criança , Movimentos Oculares/fisiologia , Feminino , Humanos , Masculino , Matemática , Queensland , Curva ROC , Leitura , Instituições Acadêmicas
6.
Ophthalmic Physiol Opt ; 39(3): 141-147, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30994200

RESUMO

PURPOSE: Screening for uncorrected hyperopia in school children is important given its association with poorer visual function and academic performance. However, standard distance visual acuity screening may not detect low to moderate hyperopia. The plus lens test is used to screen for hyperopia in many school screening protocols, but has not been well validated. The current study investigated the effectiveness of the plus lens test to identify hyperopia in school children. METHODS: Participants included Grade 2 school children. Monocular distance visual acuity (logMAR letter chart) was measured unaided, and then through a +1.50D lens, known as the plus lens test. Cycloplegic refraction was undertaken to classify moderate hyperopia (≥+2.00D). Sensitivity, specificity, positive predictive values (PPV) and negative predictive values (NPV) were calculated for commonly used cut-offs for the plus lens test: 6/6, 6/9 and less than two lines difference between unaided acuity and acuity through the plus lens test. RESULTS: The sample included 59 children (mean age 7.2 ± 0.4 years). Fourteen (24%) children were classified as having uncorrected hyperopia. The sensitivity and specificity of the +1.50 plus lens test for identifying hyperopia were 0% and 98% respectively for a 6/6 cut-off, 29% and 91% for 6/9 cut-off, and 50% and 76% for a <2 line reduction between unaided acuity and acuity through the plus lens test. Receiver Operating Curve (ROC) analysis revealed area under curves of 0.69 based on acuity through the plus lens test, and 0.65 for a reduction in acuity through the plus lens test. CONCLUSIONS: The plus lens test has low sensitivity for detecting uncorrected hyperopia using traditional cut-offs of 6/9 or better. This raises questions about the role of the plus lens test in school screening batteries.


Assuntos
Hiperopia/diagnóstico , Lentes , Óptica e Fotônica/métodos , Refração Ocular/fisiologia , Seleção Visual/métodos , Acuidade Visual/fisiologia , Criança , Feminino , Humanos , Masculino
7.
Ophthalmic Physiol Opt ; 38(5): 516-524, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30221376

RESUMO

PURPOSE: Vision is considered important for academic performance in children; however, the evidence in this area tends to be inconsistent and inconclusive. This study explored the association between vision function and visual information processing measures and standardised academic achievement scores in Grade 3 Australian children. METHODS: Participants included 108 Grade 3 primary school children (M = 8.82 ± 0.32 years) from three state primary schools in South-East Queensland. All participants underwent a standard vision screening, including distance visual acuity (VA), binocular vision testing and stereoacuity (SA). A computer-based battery of visual information processing tests including the Development Eye Movement (DEM) test, Visual Sequential Memory (VSM) and Symbol Search (SS) was also administered. Australian National Assessment Program for Literacy and Numeracy (NAPLAN) scores across five subtests of academic performance were obtained for each child: Reading, Writing, Spelling, Grammar/Punctuation and Numeracy. RESULTS: The DEM adjusted horizontal and vertical times were most strongly associated with all of the NAPLAN subtest scores (p < 0.01), adjusted for age and the socio-economic status of the school; the DEM ratio was not significantly associated with any of the NAPLAN subtests. VSM and SS scores were significantly associated with one or more NAPLAN subtests, as were worse and better eye VA; SA showed no significant association with any of the NAPLAN subtests. CONCLUSIONS: Performance on the horizontal and vertical DEM subtests was most strongly associated with academic performance. These data, in conjunction with other clinical data, can provide useful information to clinicians regarding their prescribing and management philosophy for children with lower levels of uncorrected refractive error and binocular vision anomalies.


Assuntos
Desempenho Acadêmico/normas , Leitura , Erros de Refração/fisiopatologia , Instituições Acadêmicas , Seleção Visual/métodos , Visão Binocular/fisiologia , Acuidade Visual/fisiologia , Criança , Feminino , Humanos , Incidência , Masculino , Queensland/epidemiologia , Erros de Refração/diagnóstico , Erros de Refração/epidemiologia
8.
Front Psychol ; 8: 903, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28626440

RESUMO

Executive functions are important higher-order cognitive skills for goal-directed thought and action. These capacities contribute to successful school achievement and lifelong wellbeing. The importance of executive functions to children's education begins in early childhood and continues throughout development. This study explores contributions of child and family factors in early childhood to the development of executive function in adolescence. Analyses draw on data from the nationally representative study, Growing up in Australia: The Longitudinal Study of Australian Children. Participants are 4819 children in the Kindergarten Cohort who were recruited at age 4-5 years. Path analyses were employed to examine contributions of early childhood factors, including family socio-economic position (SEP), parenting behaviors, maternal mental health, and a child behavioral risk index, to the development of executive function in adolescence. The influence of children's early self-regulatory behaviors (attentional regulation at 4-5 years and approaches to learning at 6-7 years) were also taken into account. A composite score for the outcome measure of executive function was constructed from scores on three Cogstate computerized tasks for assessing cognition and measured visual attention, visual working memory, and spatial problem-solving. Covariates included child gender, age at assessment of executive function, Aboriginal and Torres Strait Islander status, speaking a language other than English at home, and child's receptive vocabulary skills. There were significant indirect effects involving child and family risk factors measured at 4-5 years on executive function at age 14-15 years, mediated by measures of self-regulatory behavior. Child behavioral risk, family SEP and parenting behaviors (anger, warmth, and consistency) were associated with attentional regulation at 4-5 years which, in turn, was significantly associated with approaches to learning at 6-7 years. Both attentional regulation and approaches to learning were directly associated with executive functioning at 14-15 years. These findings suggest that children's early self-regulatory capacities are the basis for later development of executive function in adolescence when capabilities for planning and problem-solving are important to achieving educational goals.

9.
PLoS One ; 8(10): e76608, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24204644

RESUMO

Oscillatory entrainment to the speech signal is important for language processing, but has not yet been studied in developmental disorders of language. Developmental dyslexia, a difficulty in acquiring efficient reading skills linked to difficulties with phonology (the sound structure of language), has been associated with behavioural entrainment deficits. It has been proposed that the phonological 'deficit' that characterises dyslexia across languages is related to impaired auditory entrainment to speech at lower frequencies via neuroelectric oscillations (<10 Hz, 'temporal sampling theory'). Impaired entrainment to temporal modulations at lower frequencies would affect the recovery of the prosodic and syllabic structure of speech. Here we investigated event-related oscillatory EEG activity and contingent negative variation (CNV) to auditory rhythmic tone streams delivered at frequencies within the delta band (2 Hz, 1.5 Hz), relevant to sampling stressed syllables in speech. Given prior behavioural entrainment findings at these rates, we predicted functionally atypical entrainment of delta oscillations in dyslexia. Participants performed a rhythmic expectancy task, detecting occasional white noise targets interspersed with tones occurring regularly at rates of 2 Hz or 1.5 Hz. Both groups showed significant entrainment of delta oscillations to the rhythmic stimulus stream, however the strength of inter-trial delta phase coherence (ITC, 'phase locking') and the CNV were both significantly weaker in dyslexics, suggestive of weaker entrainment and less preparatory brain activity. Both ITC strength and CNV amplitude were significantly related to individual differences in language processing and reading. Additionally, the instantaneous phase of prestimulus delta oscillation predicted behavioural responding (response time) for control participants only.


Assuntos
Ritmo Delta , Dislexia/fisiopatologia , Adulto , Estudos de Casos e Controles , Potenciais Evocados , Feminino , Lateralidade Funcional , Humanos , Masculino , Desempenho Psicomotor , Tempo de Reação , Adulto Jovem
11.
J Transl Med ; 10: 138, 2012 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-22747748

RESUMO

This manuscript summarizes current thinking on the value and promise of evolving circulating tumor cell (CTC) technologies for cancer patient diagnosis, prognosis, and response to therapy, as well as accelerating oncologic drug development. Moving forward requires the application of the classic steps in biomarker development-analytical and clinical validation and clinical qualification for specific contexts of use. To that end, this review describes methods for interactive comparisons of proprietary new technologies, clinical trial designs, a clinical validation qualification strategy, and an approach for effectively carrying out this work through a public-private partnership that includes test developers, drug developers, clinical trialists, the US Food & Drug Administration (FDA) and the US National Cancer Institute (NCI).


Assuntos
Células Neoplásicas Circulantes , Biomarcadores Tumorais , Humanos
12.
Behav Brain Funct ; 8: 1, 2012 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-22217191

RESUMO

BACKGROUND: The objective of this study was to scrutinize number line estimation behaviors displayed by children in mathematics classrooms during the first three years of schooling. We extend existing research by not only mapping potential logarithmic-linear shifts but also provide a new perspective by studying in detail the estimation strategies of individual target digits within a number range familiar to children. METHODS: Typically developing children (n = 67) from Years 1-3 completed a number-to-position numerical estimation task (0-20 number line). Estimation behaviors were first analyzed via logarithmic and linear regression modeling. Subsequently, using an analysis of variance we compared the estimation accuracy of each digit, thus identifying target digits that were estimated with the assistance of arithmetic strategy. RESULTS: Our results further confirm a developmental logarithmic-linear shift when utilizing regression modeling; however, uniquely we have identified that children employ variable strategies when completing numerical estimation, with levels of strategy advancing with development. CONCLUSION: In terms of the existing cognitive research, this strategy factor highlights the limitations of any regression modeling approach, or alternatively, it could underpin the developmental time course of the logarithmic-linear shift. Future studies need to systematically investigate this relationship and also consider the implications for educational practice.


Assuntos
Matemática/educação , Processos Mentais/fisiologia , Algoritmos , Análise de Variância , Criança , Desenvolvimento Infantil , Formação de Conceito , Interpretação Estatística de Dados , Feminino , Humanos , Modelos Lineares , Masculino , Testes Neuropsicológicos , Desempenho Psicomotor/fisiologia , Análise de Regressão , Instituições Acadêmicas , Escalas de Wechsler
13.
Dev Neuropsychol ; 36(6): 682-701, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21761993

RESUMO

In this study we set out to dissociate the developmental time course of automatic symbolic number processing and cognitive control functions in grade 1-3 British primary school children. Event-related potential (ERP) and behavioral data were collected in a physical size discrimination numerical Stroop task. Task-irrelevant numerical information was processed automatically already in grade 1. Weakening interference and strengthening facilitation indicated the parallel development of general cognitive control and automatic number processing. Relationships among ERP and behavioral effects suggest that control functions play a larger role in younger children and that automaticity of number processing increases from grade 1 to 3.


Assuntos
Desenvolvimento Infantil/fisiologia , Cognição/fisiologia , Discriminação Psicológica/fisiologia , Função Executiva/fisiologia , Conceitos Matemáticos , Automatismo/psicologia , Mapeamento Encefálico , Criança , Eletroencefalografia/psicologia , Potenciais Evocados/fisiologia , Feminino , Humanos , Masculino , Teste de Stroop , Reino Unido , Percepção Visual/fisiologia
14.
Front Psychol ; 2: 392, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-22291671

RESUMO

The process of learning symbolic Arabic digits in early childhood requires that magnitude and spatial information integrates with the concept of symbolic digits. Previous research has separately investigated the development of automatic access to magnitude and spatial information from symbolic digits. However, developmental trajectories of symbolic number knowledge cannot be fully understood when considering components in isolation. In view of this, we have synthesized the existing lines of research and tested the use of both magnitude and spatial information with the same sample of British children in Years 1, 2, and 3 (6-8 years of age). The physical judgment task of the numerical Stroop paradigm demonstrated that automatic access to magnitude was present from Year 1 and the distance effect signaled that a refined processing of numerical information had developed. Additionally, a parity judgment task showed that the onset of the spatial-numerical association of response codes effect occurs in Year 2. These findings uncover the developmental timeline of how magnitude and spatial representations integrate with symbolic number knowledge during early learning of Arabic digits and resolve inconsistencies between previous developmental and experimental research lines.

15.
Neuroimage ; 47(4): 1960-73, 2009 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-19481157

RESUMO

Several brain imaging studies have assumed that response conflict is present in Stroop tasks. However, this has not been demonstrated directly. We examined the time-course of stimulus and response conflict resolution in a numerical Stroop task by combining single-trial electro-myography (EMG) and event-related brain potentials (ERP). EMG enabled the direct tracking of response conflict and the peak latency of the P300 ERP wave was used to index stimulus conflict. In correctly responded trials of the incongruent condition EMG detected robust incorrect response hand activation which appeared consistently in single trials. In 50-80% of the trials correct and incorrect response hand activation coincided temporally, while in 20-50% of the trials incorrect hand activation preceded correct hand activation. EMG data provides robust direct evidence for response conflict. However, congruency effects also appeared in the peak latency of the P300 wave which suggests that stimulus conflict also played a role in the Stroop paradigm. Findings are explained by the continuous flow model of information processing: Partially processed task-irrelevant stimulus information can result in stimulus conflict and can prepare incorrect response activity. A robust congruency effect appeared in the amplitude of incongruent vs. congruent ERPs between 330-400 ms, this effect may be related to the activity of the anterior cingulate cortex.


Assuntos
Conflito Psicológico , Tomada de Decisões/fisiologia , Eletroencefalografia/métodos , Eletromiografia/métodos , Potencial Evocado Motor/fisiologia , Córtex Motor/fisiologia , Movimento/fisiologia , Desempenho Psicomotor/fisiologia , Adulto , Feminino , Humanos , Masculino
16.
Mol Cell Biol ; 25(24): 10731-44, 2005 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-16314499

RESUMO

Transforming growth factor beta (TGF-beta) was originally identified by virtue of its ability to induce transformation of the AKR-2B and NRK fibroblasts but was later found to be a potent inhibitor of the growth of epithelial, endothelial, and lymphoid cells. Although the growth-inhibitory pathway of TGF-beta mediated by the Smad proteins is well studied, the signaling pathway leading to the transforming activity of TGF-beta in fibroblasts is not well understood. Here we show that SnoN, a member of the Ski family of oncoproteins, is required for TGF-beta-induced proliferation and transformation of AKR-2B and NRK fibroblasts. TGF-beta induces upregulation of snoN expression in both epithelial cells and fibroblasts through a common Smad-dependent mechanism. However, a strong and prolonged activation of snoN transcription that lasts for 8 to 24 h is detected only in these two fibroblast lines. This prolonged induction is mediated by Smad2 and appears to play an important role in the transformation of both AKR-2B and NRK cells. Reduction of snoN expression by small interfering RNA or shortening of the duration of snoN induction by a pharmacological inhibitor impaired TGF-beta-induced anchorage-independent growth of AKR-2B cells. Interestingly, Smad2 and Smad3 play opposite roles in regulating snoN expression in both fibroblasts and epithelial cells. The Smad2/Smad4 complex activates snoN transcription by direct binding to the TGF-beta-responsive element in the snoN promoter, while the Smad3/Smad4 complex inhibits it through a novel Smad inhibitory site. Mutations of Smad4 that render it defective in heterodimerization with Smad3, which are found in many human cancers, convert the activity of Smad3 on the snoN promoter from inhibitory to stimulatory, resulting in increased snoN expression in cancer cells. Thus, we demonstrate a novel role of SnoN in the transforming activity of TGF-beta in fibroblasts and also uncovered a mechanism for the elevated SnoN expression in some human cancer cells.


Assuntos
Transformação Celular Neoplásica/genética , Regulação Neoplásica da Expressão Gênica , Proteínas Proto-Oncogênicas/genética , Fator de Crescimento Transformador beta/farmacologia , Animais , Sequência de Bases , Linhagem Celular , Transformação Celular Neoplásica/metabolismo , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Camundongos , Dados de Sequência Molecular , Mutação , Fosforilação , Proteínas/farmacologia , Proteínas Proto-Oncogênicas/metabolismo , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/farmacologia , Elementos de Resposta/genética , Proteína Smad2/genética , Proteína Smad2/metabolismo , Proteína Smad3/genética , Proteína Smad3/metabolismo , Proteína Smad4/genética , Proteína Smad4/metabolismo , Transcrição Gênica
17.
J Biol Chem ; 280(44): 36865-72, 2005 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-16093248

RESUMO

Immunotherapeutic drugs that mimic sphingosine 1-phosphate (S1P) disrupt lymphocyte trafficking and cause T helper and T effector cells to be retained in secondary lymphoid tissue and away from sites of inflammation. The prototypical therapeutic agent, 2-alkyl-2-amino-1,3-propanediol (FTY720), stimulates S1P signaling pathways only after it is phosphorylated by one or more unknown kinases. We generated sphingosine kinase 2 (SPHK2) null mice to demonstrate that this kinase is responsible for FTY720 phosphorylation and thereby its subsequent actions on the immune system. Both systemic and lymphocyte-localized sources of SPHK2 contributed to FTY720 induced lymphopenia. Although FTY720 was selectively activated in vivo by SPHK2, other S1P pro-drugs can be phosphorylated to cause lymphopenia through the action of additional sphingosine kinases. Our results emphasize the importance of SPHK2 expression in both lymphocytes and other tissues for immune modulation and drug metabolism.


Assuntos
Imunossupressores/toxicidade , Linfócitos/efeitos dos fármacos , Linfócitos/enzimologia , Linfopenia , Fosfotransferases (Aceptor do Grupo Álcool)/fisiologia , Propilenoglicóis/toxicidade , Animais , Cloridrato de Fingolimode , Citometria de Fluxo , Homozigoto , Imunossupressores/metabolismo , Linfopenia/induzido quimicamente , Linfopenia/enzimologia , Lisofosfolipídeos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fosforilação/efeitos dos fármacos , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Pró-Fármacos/metabolismo , Pró-Fármacos/toxicidade , Propilenoglicóis/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Esfingosina/análogos & derivados , Esfingosina/metabolismo
18.
Neuromuscul Disord ; 12(4): 366-70, 2002 May.
Artigo em Inglês | MEDLINE | ID: mdl-12062254

RESUMO

We devised non-radioactive PCR assays for the DMD(mdx3Cv) and DMD(mdx4Cv) mouse dystrophin point mutations, in which mutant and wild type reactions electrophoresed separately diagnose whether the DNA carries the mutant, wild type, or both alleles. This simple and reliable assay facilitates the use of these mutant mouse models, which have an extended inflammatory phase (DMD(mdx3Cv)), less reversion to wild type (DMD(mdx4Cv)), and reduced expression of dystrophin mRNAs arising from internal promoter usage than the DMD(mdx) mouse. The PCR assays described facilitate the use of the DMD(mdx3Cv) and DMD(mdx4Cv) mutant mouse models, when maintaining the mutations as heterozygotes, backcrossing into different inbred genetic backgrounds, or when crossing targeted mutations into these dystrophic backgrounds.


Assuntos
Distrofina/genética , Distrofia Muscular Animal/genética , Mutação Puntual , Reação em Cadeia da Polimerase/métodos , Animais , Modelos Animais de Doenças , Genótipo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos mdx , Distrofia Muscular de Duchenne/genética
19.
J Clin Invest ; 109(7): 939-50, 2002 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-11927621

RESUMO

P-selectin glycoprotein ligand-1 (PSGL-1) mediates rolling of leukocytes on P-selectin under flow. The glycoproteins that enable leukocyte tethering to or rolling on E-selectin are not known. We used gene targeting to prepare PSGL-1-deficient (PSGL-1-/-) mice, which were healthy but had moderately elevated total blood leukocytes. Fluid-phase E-selectin bound to approximately 70% fewer sites on PSGL-1-/- than PSGL-1+/+ neutrophils. Compared with PSGL-1+/+ leukocytes, significantly fewer PSGL-1-/- leukocytes rolled on E-selectin in vitro, because their initial tethering to E-selectin was impaired. The residual cells that tethered rolled with the same shear resistance and velocities as PSGL-1+/+ leukocytes. Compared with PSGL-1+/+ mice, significantly fewer PSGL-1-/- leukocytes rolled on E-selectin in TNF-alpha-treated venules of cremaster muscle in which P-selectin function was blocked by an mAb. The residual PSGL-1-/- leukocytes that tethered rolled with slow velocities equivalent to those of PSGL-1+/+ leukocytes. These results reveal a novel function for PSGL-1 in tethering leukocytes to E-selectin under flow.


Assuntos
Quimiotaxia de Leucócito/imunologia , Selectina E/imunologia , Glicoproteínas de Membrana/imunologia , Neutrófilos/imunologia , Selectina-P/imunologia , Animais , Feminino , Imunoglobulina M/imunologia , Ligantes , Masculino , Glicoproteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fator de Necrose Tumoral alfa/imunologia
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