Development of a mobile application to improve exercise accuracy and quality of life in knee osteoarthritis patients: a randomized controlled trial.

INTRODUCTION: Knee Osteoarthritis (OA) is a degenerative joint disease that needs consistent exercise and an accurate understanding of the condition for long-term maintenance. While the accessibility of outpatient care is essential for disease management, many patients lack the resources to receive adequate healthcare. To address this challenge, we developed a not-for-profit interactive mobile application that provides a disease-specific educational background and a structured exercise regimen to patients. MATERIAL AND METHODS: "Rak Kao" (English translation: Love-Your-Knee) mobile application was designed to analyze the questionnaire data to assess the stage of knee OA and generate a personalized recommendation of treatment and exercise type using rule-based and Artificial Intelligence (AI) techniques. A single-blinded study was conducted with patients (n = 82) who were randomly assigned to the mobile application group (M-group) and the handout group (H-group). Patient groups were controlled for age, gender, BMI, onset of pain, grade of disease, education level, and occupation. Accuracy in performance of three prescribed knee exercises (catch-bend-down, stretch-touch-feet, and sit-stretch-hold) was evaluated. Clinical outcomes were evaluated before and after the 4-weeks program to assess the range of motion, symptoms, pain, physical activity, and quality of life via the KOOS and KSS scores. RESULTS: Completion of the study led to significantly more overall exercise accuracy in the M-group (76.2%) than the H-group (52.5%). Activities of daily life, quality of life, ability to do sports and recreational activities were significantly more improved in the M-group than the H-group (p < .01). No difference in the range of motion between groups. Satisfaction of patients' experience was higher in the M-group than the H-group (p = .001) after the 4-week regimen. CONCLUSIONS: With the better accuracy and outcomes for rehabilitation in the M-group than the H-group, we strongly recommend using our mobile application as a better alternative than handouts for exercises and information for patients with knee OA. TRIAL REGISTRATION: ClinicalTrials.gov: NCT03666585.

Integrated Analysis of the microRNA-mRNA Network Predicts Potential Regulators of Atrial Fibrillation in Humans.

Atrial fibrillation (AF) is a form of sustained cardiac arrhythmia and microRNAs (miRs) play crucial roles in the pathophysiology of AF. To identify novel miR-mRNA pairs, we performed RNA-seq from atrial biopsies of persistent AF patients and non-AF patients with normal sinus rhythm (SR). Differentially expressed miRs (11 down and 9 up) and mRNAs (95 up and 82 down) were identified and hierarchically clustered in a heat map. Subsequently, GO, KEGG, and GSEA analyses were run to identify deregulated pathways. Then, miR targets were predicted in the miRDB database, and a regulatory network of negatively correlated miR-mRNA pairs was constructed using Cytoscape. To select potential candidate genes from GSEA analysis, the top-50 enriched genes in GSEA were overlaid with predicted targets of differentially deregulated miRs. Further, the protein-protein interaction (PPI) network of enriched genes in GSEA was constructed, and subsequently, GO and canonical pathway analyses were run for genes in the PPI network. Our analyses showed that TNF-α, p53, EMT, and SYDECAN1 signaling were among the highly affected pathways in AF samples. SDC-1 (SYNDECAN-1) was the top-enriched gene in p53, EMT, and SYDECAN1 signaling. Consistently, SDC-1 mRNA and protein levels were significantly higher in atrial samples of AF patients. Among negatively correlated miRs, miR-302b-3p was experimentally validated to suppress SDC-1 transcript levels. Overall, our results suggested that the miR-302b-3p/SDC-1 axis may be involved in the pathogenesis of AF.

Inhibition of CREB-CBP Signaling Improves Fibroblast Plasticity for Direct Cardiac Reprogramming.

Direct cardiac reprogramming of fibroblasts into induced cardiomyocytes (iCMs) is a promising approach but remains a challenge in heart regeneration. Efforts have focused on improving the efficiency by understanding fundamental mechanisms. One major challenge is that the plasticity of cultured fibroblast varies batch to batch with unknown mechanisms. Here, we noticed a portion of in vitro cultured fibroblasts have been activated to differentiate into myofibroblasts, marked by the expression of αSMA, even in primary cell cultures. Both forskolin, which increases cAMP levels, and TGFß inhibitor SB431542 can efficiently suppress myofibroblast differentiation of cultured fibroblasts. However, SB431542 improved but forskolin blocked iCM reprogramming of fibroblasts that were infected with retroviruses of Gata4, Mef2c, and Tbx5 (GMT). Moreover, inhibitors of cAMP downstream signaling pathways, PKA or CREB-CBP, significantly improved the efficiency of reprogramming. Consistently, inhibition of p38/MAPK, another upstream regulator of CREB-CBP, also improved reprogramming efficiency. We then investigated if inhibition of these signaling pathways in primary cultured fibroblasts could improve their plasticity for reprogramming and found that preconditioning of cultured fibroblasts with CREB-CBP inhibitor significantly improved the cellular plasticity of fibroblasts to be reprogrammed, yielding ~2-fold more iCMs than untreated control cells. In conclusion, suppression of CREB-CBP signaling improves fibroblast plasticity for direct cardiac reprogramming.

Transcription factor competition at the γ-globin promoters controls hemoglobin switching.

BCL11A, the major regulator of fetal hemoglobin (HbF, α2γ2) level, represses γ-globin expression through direct promoter binding in adult erythroid cells in a switch to adult hemoglobin (HbA, α2ß2). To uncover how BCL11A initiates repression, we used CRISPR-Cas9, dCas9, dCas9-KRAB and dCas9-VP64 screens to dissect the γ-globin promoters and identified an activator element near the BCL11A-binding site. Using CUT&RUN and base editing, we demonstrate that a proximal CCAAT box is occupied by the activator NF-Y. BCL11A competes with NF-Y binding through steric hindrance to initiate repression. Occupancy of NF-Y is rapidly established following BCL11A depletion, and precedes γ-globin derepression and locus control region (LCR)-globin loop formation. Our findings reveal that the switch from fetal to adult globin gene expression within the >50-kb ß-globin gene cluster is initiated by competition between a stage-selective repressor and a ubiquitous activating factor within a remarkably discrete region of the γ-globin promoters.