949 research outputs found

    A simple histone code opens many paths to epigenetics

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    Nucleosomes can be covalently modified by addition of various chemical groups on several of their exposed histone amino acids. These modifications are added and removed by enzymes (writers) and can be recognized by nucleosome-binding proteins (readers). Linking a reader domain and a writer domain that recognize and create the same modification state should allow nucleosomes in a particular modification state to recruit enzymes that create that modification state on nearby nucleosomes. This positive feedback has the potential to provide the alternative stable and heritable states required for epigenetic memory. However, analysis of simple histone codes involving interconversions between only two or three types of modified nucleosomes has revealed only a few circuit designs that allow heritable bistability. Here we show by computer simulations that a histone code involving alternative modifications at two histone positions, producing four modification states, combined with reader-writer proteins able to distinguish these states, allows for hundreds of different circuits capable of heritable bistability. These expanded possibilities result from multiple ways of generating two-step cooperativity in the positive feedback - through alternative pathways and an additional, novel cooperativity motif. Our analysis reveals other properties of such epigenetic circuits. They are most robust when the dominant nucleosome types are different at both modification positions and are not the type inserted after DNA replication. The dominant nucleosome types often recruit enzymes that create their own type or destroy the opposing type, but never catalyze their own destruction. The circuits appear to be evolutionary accessible; most circuits can be changed stepwise into almost any other circuit without losing heritable bistability. Thus, our analysis indicates that systems that utilize an expanded histone code have huge potential for generating stable and heritable nucleosome modification states and identifies the critical features of such systems.Kim Sneppen and Ian B. Dod

    Implementation fidelity of a computer-assisted intervention for children with speech sound disorders

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    © 2017 The Speech Pathology Association of Australia Limited Published by Informa UK Limited, trading as Taylor & Francis Group. Background: Implementation fidelity refers to the degree to which an intervention or programme adheres to its original design. This paper examines implementation fidelity in the Sound Start Study, a clustered randomised controlled trial of computer-assisted support for children with speech sound disorders (SSD). Method: Sixty-three children with SSD in 19 early childhood centres received computer-assisted support (Phoneme Factory Sound Sorter [PFSS]–Australian version). Educators facilitated the delivery of PFSS targeting phonological error patterns identified by a speech-language pathologist. Implementation data were gathered via (1) the computer software, which recorded when and how much intervention was completed over 9 weeks; (2) educators’ records of practice sessions; and (3) scoring of fidelity (intervention procedure, competence and quality of delivery) from videos of intervention sessions. Result: Less than one-third of children received the prescribed number of days of intervention, while approximately one-half participated in the prescribed number of intervention plays. Computer data differed from educators’ data for total number of days and plays in which children participated; the degree of match was lower as data became more specific. Fidelity to intervention procedures, competency and quality of delivery was high. Conclusion: Implementation fidelity may impact intervention outcomes and so needs to be measured in intervention research; however, the way in which it is measured may impact on data

    Основные подходы к разработке проекта рекультивации месторождения бокситов «Белинское»

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    © 2017 American Speech-Language-Hearing Association. Purpose: The aim was to evaluate the effectiveness of computer-assisted input-based intervention for children with speech sound disorders (SSD). Method: The Sound Start Study was a cluster-randomized controlled trial. Seventy-nine early childhood centers were invited to participate, 45 were recruited, and 1,205 parents and educators of 4- and 5-year-old children returned questionnaires. Children whose parents and educators had concerns about speech were assessed (n =275); 132 children who were identified with phonological patternbased errors underwent additional assessment. Children with SSD and no difficulties with receptive language or hearing, typical nonverbal intelligence, and English as their primary language were eligible; 123 were randomized into two groups (intervention n = 65; control n = 58), and 3 withdrew. The intervention group involved Phoneme Factory Sound Sorter software (Wren & Roulstone, 2013) administered by educators over 9 weeks; the control group involved typical classroom practices. Participants were reassessed twice by a speech-language pathologist who was unaware of the initial assessment and intervention conditions. Results: For the primary outcome variable (percentage of consonants correct), the significant mean change from pre- to postintervention for the intervention group (mean change = +6.15,

    Lexicality and frequency in specific language impairment: accuracy and error data from two nonword repetition tests

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    Purpose: Deficits in phonological working memory and deficits in phonological processing have both been considered potential explanatory factors in Specific Language Impairment (SLI). Manipulations of the lexicality and phonotactic frequency of nonwords enable contrasting predictions to be derived from these hypotheses. Method: 18 typically developing (TD) children and 18 children with SLI completed an assessment battery that included tests of language ability, non-verbal intelligence, and two nonword repetition tests that varied in lexicality and frequency. Results: Repetition accuracy showed that children with SLI were unimpaired for short and simple high lexicality nonwords, whereas clear impairments were shown for all low lexicality nonwords. For low lexicality nonwords, greater repetition accuracy was seen for nonwords constructed from high over low frequency phoneme sequences. Children with SLI made the same proportion of errors that substituted a nonsense syllable for a lexical item as TD children, and this was stable across nonword length. Conclusions: The data show support for a phonological processing deficit in children with SLI, where long-term lexical and sub-lexical phonological knowledge mediate the interpretation of nonwords. However, the data also suggest that while phonological processing may provide a key explanation of SLI, a full account is likely to be multi-faceted

    Integration of light and circadian signals that regulate chloroplast transcription by a nuclear-encoded sigma factor

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    We investigated the signalling pathways that regulate chloroplast transcription in response to environmental signals. One mechanism controlling plastid transcription involves nuclear‐encoded sigma subunits of plastid‐encoded plastid RNA polymerase. Transcripts encoding the sigma factor SIG5 are regulated by light and the circadian clock. However, the extent to which a chloroplast target of SIG5 is regulated by light‐induced changes in SIG5 expression is unknown. Moreover, the photoreceptor signalling pathways underlying the circadian regulation of chloroplast transcription by SIG5 are unidentified. We monitored the regulation of chloroplast transcription in photoreceptor and sigma factor mutants under controlled light regimes in Arabidopsis thaliana. We established that a chloroplast transcriptional response to light intensity was mediated by SIG5; a chloroplast transcriptional response to the relative proportions of red and far red light was regulated by SIG5 through phytochrome and photosynthetic signals; and the circadian regulation of chloroplast transcription by SIG5 was predominantly dependent on blue light and cryptochrome. Our experiments reveal the extensive integration of signals concerning the light environment by a single sigma factor to regulate chloroplast transcription. This may originate from an evolutionarily ancient mechanism that protects photosynthetic bacteria from high light stress, which subsequently became integrated with higher plant phototransduction networks

    The Special Sauce of the Cancer Prevention and Control Research Network: 20 Years of Lessons Learned in Developing the Evidence Base, Building Community Capacity, and Translating Research into Practice

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    PURPOSE: The Cancer Prevention and Control Research Network (CPCRN) is a national network focused on accelerating the translation of cancer prevention and control research evidence into practice through collaborative, multicenter projects in partnership with diverse communities. From 2003 to 2022, the CPCRN included 613 members. METHODS: We: (1) characterize the extent and nature of collaborations through a bibliometric analysis of 20 years of Network publications; and (2) describe key features and functions of the CPCRN as related to organizational structure, productivity, impact, and focus on health equity, partnership development, and capacity building through analysis of 22 in-depth interviews and review of Network documentation. RESULTS: Searching Scopus for multicenter publications among the CPCRN members from their time of Network engagement yielded 1,074 collaborative publications involving two or more members. Both the overall number and content breadth of multicenter publications increased over time as the Network matured. Since 2004, members submitted 123 multicenter grant applications, of which 72 were funded (59%), totaling more than $77 million secured. Thematic analysis of interviews revealed that the CPCRN\u27s success-in terms of publication and grant productivity, as well as the breadth and depth of partnerships, subject matter expertise, and content area foci-is attributable to: (1) its people-the inclusion of members representing diverse content-area interests, multidisciplinary perspectives, and geographic contexts; (2) dedicated centralized structures and processes to enable and evaluate collaboration; and (3) focused attention to strategically adapting to change. CONCLUSION: CPCRN\u27s history highlights organizational, strategic, and practical lessons learned over two decades to optimize Network collaboration for enhanced collective impact in cancer prevention and control. These insights may be useful to others seeking to leverage collaborative networks to address public health problems

    Core outcome measurement instruments for use in clinical and research settings for adults with post-COVID-19 condition: an international Delphi consensus study.

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    Post-COVID-19 condition (also known as long COVID) is a new, complex, and poorly understood disorder. A core outcome set (COS) for post-COVID-19 condition in adults has been developed and agreement is now required on the most appropriate measurement instruments for these core outcomes. We conducted an international consensus study involving multidisciplinary experts and people with lived experience of long COVID. The study comprised a literature review to identify measurement instruments for the core outcomes, a three-round online modified Delphi process, and an online consensus meeting to generate a core outcome measurement set (COMS). 594 individuals from 58 countries participated. The number of potential instruments for the 12 core outcomes was reduced from 319 to 19. Consensus was reached for inclusion of the modified Medical Research Council Dyspnoea Scale for respiratory outcomes. Measures for two relevant outcomes from a previously published COS for acute COVID-19 were also included: time until death, for survival, and the Recovery Scale for COVID-19, for recovery. Instruments were suggested for consideration for the remaining nine core outcomes: fatigue or exhaustion, pain, post-exertion symptoms, work or occupational and study changes, and cardiovascular, nervous system, cognitive, mental health, and physical outcomes; however, consensus was not achieved for instruments for these outcomes. The recommended COMS and instruments for consideration provide a foundation for the evaluation of post-COVID-19 condition in adults, which should help to optimise clinical care and accelerate research worldwide. Further assessment of this COMS is warranted as new data emerge on existing and novel measurement instruments

    Genome wide association study of Preserved Ratio Impaired Spirometry (PRISm)

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    Background: Preserved Ratio Impaired Spirometry (PRISm) is defined as FEV1 &lt;80% predicted, FEV1/FVC ≥0.70. PRISm is associated with respiratory symptoms and co-morbidities. Our objective was to discover novel genetic signals for PRISm and see if they provide insight into the pathogenesis of PRISm and associated co-morbidities.Methods: We undertook a genome-wide association study (GWAS) of PRISm in UK Biobank participants (Stage 1), and selected SNPs reaching genome-wide significance for replication in 13 cohorts (Stage 2). A combined meta-analysis of Stage 1 and Stage 2 was done to determine top SNPs. We used cross-trait Linkage Disequilibrium score regression to estimate genome-wide genetic correlation between PRISM and pulmonary and extra-pulmonary traits. Phenome-wide association studies of top SNPs was performed. Results: 22 signals reached significance in the joint meta-analysis, including four signals novel for lung function. A strong genome-wide genetic correlation (rg) between PRISm and spirometric COPD (rg = 0.62, p-value &lt;0.001) was observed, and genetic correlation with type II diabetes (rg = 0.12, p-value 0.007). PheWAS showed that 18 of 22 signals were associated with diabetic traits and 7 with blood pressure traits.Discussion: This is the first GWAS to successfully identify SNPs associated with PRISm. Four of the signals; rs7652391 (nearest gene MECOM), rs9431040 (HLX), rs62018863 (TMEM114) and rs185937162 (HLA-B) have not been described in association with lung function before, demonstrating the utility of using different lung function phenotypes in GWAS. Genetic factors associated with PRISm are strongly correlated with risk of both other lung diseases and extra-pulmonary co-morbidity.<br/
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