RESUMO
OBJECTIVES: Cognitive and functional skills training improves skills and cognitive test performance, but the true test of efficacy is real-world transfer. We trained participants with mild cognitive impairment (MCI) or normal cognition (NC) for up to 12 weeks on six technology-related skills using remote computerized functional skills assessment and training (FUNSAT) software. Using ecological momentary assessment (EMA), we measured real-world performance of the technology-related skills over 6 months and related EMA-identified changes in performance to training gains. DESIGN: Randomized clinical trial with post-training follow-up. SETTING: A total of 14 Community centers in New York City and Miami. PARTICIPANTS: Older adults with normal cognition (n = 72) or well-defined MCI (n = 92), ranging in age from 60 to 90, primarily female, and racially and ethnically diverse. INTERVENTION: Computerized cognitive and skills training. MEASUREMENTS: EMA surveys measuring trained and untrained functional skills 3 or more days per week for 6 months and training gains from baseline to end of training. RESULTS: Training gains in completion times across all 6 tasks were significant (p <0.001) for both samples, with effect sizes more than 1.0 SD for all tasks. EMA surveys detected increases in performance for both trained (p <0.03) and untrained (p <0.001) technology-related skills for both samples. Training gains in completion times predicted increases in performance of both trained and untrained technology-related skills (all p <0.001). CONCLUSIONS: Computerized training produces increases in real-world performance of important technology-related skills. These gains continued after the end of training, with greater gains in MCI participants.
Assuntos
Disfunção Cognitiva , Avaliação Momentânea Ecológica , Humanos , Feminino , Idoso , Disfunção Cognitiva/terapia , Cognição , Atividades Cotidianas , Testes NeuropsicológicosRESUMO
Coactivator-associated arginine methyltransferase 1 (CARM1) is a methyltransferase whose function has been highly studied in the context of nuclear receptor signaling. However, CARM1 is known to epigenetically regulate expression of several myogenic genes involved in differentiation such as Myog and MEF2C. CARM1 also acts to regulate myogenesis through its influence on various cellular processes from embryonic to adult myogenesis. First, CARM1 has a crucial role in establishing polarity-regulated gene expression during an asymmetric satellite cell division by methylating PAX7, leading to the expression of Myf5. Second, satellite cells express the CARM1-FL and CARM1-ΔE15 isoforms. The former has been shown to promote pre-mRNA splicing through its interaction with CA150 and U1C, leading to their methylation and increased activity, while the latter displays a reduction in both metrics, thus, modulating alternative pre-mRNA splice forms in muscle cells. Third, CARM1 is a regulator of autophagy through its positive reinforcement of AMPK activity and gene expression. Autophagy already has known implications in ageing and disease, and CARM1 could follow suite. Thus, CARM1 is a central regulator of several important processes impacting muscle stem cell function and myogenesis.
Assuntos
Proteína-Arginina N-Metiltransferases , Precursores de RNA , Precursores de RNA/metabolismo , Proteína-Arginina N-Metiltransferases/genética , Proteína-Arginina N-Metiltransferases/metabolismo , Células-Tronco/metabolismo , Epigênese GenéticaRESUMO
We used ecological momentary assessment (EMA) to track symptoms during a clinical trial. Thirty-six participants with major depressive disorder (MDD) and MADRS scores ≥20 were enrolled in a nonrandomized 6-week open-label trial of commercially available antidepressants. Twice daily, a mobile device prompted participants to self-report the 6 items of the HamD6 sub-scale derived from the Hamilton rating scale for depression (HamD17). Morning EMA reports asked "how do you feel now" whereas evening reports gathered a full-day impression. Clinicians who were blinded to the EMA data rated the MADRS, HamD17 and HamD6 at screen, baseline and weeks 2,4, and 6. Hierarchical linear modeling (HLM) examined the course of the EMA assessments and convergence between EMA scores and clinician ratings. HLM analyses revealed strong correlations between AM and PM EMA derived HamD6 scores and revealed significant improvements over time. EMA improvements were significantly correlated with the clinician rated HamD6 scores at endpoint and predicted clinician rated HamD6 score changes from baseline to endpoint (p < .001). There was a large correlation between EMA and clinician derived HamD6 scores at each in-person assessment after baseline. Treatment response defined by EMA matched the clinician rated HamD6 treatment responses in 33 of 36 cases (91.7%). EMA derived symptom scores appear to be efficient and valid measures to track daily symptomatic change in clinical trials and may provide more accurate measures of symptom severity than the episodic "snapshots" that are currently used as clinical outcomes. These findings support further investigation of EMA for assessment in clinical trials.
Assuntos
Transtorno Depressivo Maior , Avaliação Momentânea Ecológica , Antidepressivos/uso terapêutico , Depressão , Transtorno Depressivo Maior/diagnóstico , Transtorno Depressivo Maior/tratamento farmacológico , Humanos , AutorrelatoRESUMO
Muscle stem cell function has been suggested to be regulated by Acetyl-CoA and NAD+ availability, but the mechanisms remain unclear. Here we report the identification of two acetylation sites on PAX7 that positively regulate its transcriptional activity. Lack of PAX7 acetylation reduces DNA binding, specifically to the homeobox motif. The acetyltransferase MYST1 stimulated by Acetyl-CoA, and the deacetylase SIRT2 stimulated by NAD +, are identified as direct regulators of PAX7 acetylation and asymmetric division in muscle stem cells. Abolishing PAX7 acetylation in mice using CRISPR/Cas9 mutagenesis leads to an expansion of the satellite stem cell pool, reduced numbers of asymmetric stem cell divisions, and increased numbers of oxidative IIA myofibers. Gene expression analysis confirms that lack of PAX7 acetylation preferentially affects the expression of target genes regulated by homeodomain binding motifs. Therefore, PAX7 acetylation status regulates muscle stem cell function and differentiation potential to facilitate metabolic adaptation of muscle tissue.
Assuntos
Autorrenovação Celular/genética , Músculo Esquelético/lesões , Fator de Transcrição PAX7/metabolismo , Regeneração/genética , Células Satélites de Músculo Esquelético/fisiologia , Acetilação , Animais , Células COS , Sistemas CRISPR-Cas , Cardiotoxinas/administração & dosagem , Cardiotoxinas/toxicidade , Diferenciação Celular/genética , Chlorocebus aethiops , Modelos Animais de Doenças , Técnicas de Silenciamento de Genes , Histona Acetiltransferases/genética , Histona Acetiltransferases/metabolismo , Humanos , Camundongos , Camundongos Transgênicos , Músculo Esquelético/citologia , Músculo Esquelético/efeitos dos fármacos , Mutagênese , Cultura Primária de Células , Regiões Promotoras Genéticas , Células Sf9 , Sirtuína 2/genética , Sirtuína 2/metabolismo , Spodoptera , Ativação TranscricionalRESUMO
Satellite cells are the main muscle-resident cells responsible for muscle regeneration. Much research has described this population as being heterogeneous, but little is known about the different roles each subpopulation plays. Recent advances in the field have utilized the power of single-cell analysis to better describe and functionally characterize subpopulations of satellite cells as well as other cell groups comprising the muscle tissue. Furthermore, emerging technologies are opening the door to answering as-yet-unresolved questions pertaining to satellite cell heterogeneity and cell fate decisions.
Assuntos
Músculo Esquelético/citologia , Células Satélites de Músculo Esquelético/citologia , Análise de Célula Única , Diferenciação Celular , Humanos , Desenvolvimento MuscularRESUMO
PAX7 is a paired-homeobox transcription factor that specifies the myogenic identity of muscle stem cells and acts as a nodal factor by stimulating proliferation while inhibiting differentiation. We previously found that PAX7 recruits the H3K4 methyltransferases MLL1/2 to epigenetically activate target genes. Here we report that in the absence of Mll1, myoblasts exhibit reduced H3K4me3 at both Pax7 and Myf5 promoters and reduced Pax7 and Myf5 expression. Mll1-deficient myoblasts fail to proliferate but retain their differentiation potential, while deletion of Mll2 had no discernable effect. Re-expression of PAX7 in committed Mll1 cKO myoblasts restored H3K4me3 enrichment at the Myf5 promoter and Myf5 expression. Deletion of Mll1 in satellite cells reduced satellite cell proliferation and self-renewal, and significantly impaired skeletal muscle regeneration. Pax7 expression was unaffected in quiescent satellite cells but was markedly downregulated following satellite cell activation. Therefore, MLL1 is required for PAX7 expression and satellite cell function in vivo. Furthermore, PAX7, but not MLL1, is required for Myf5 transcriptional activation in committed myoblasts.