The role of the histone methyltransferase SET domain bifurcated 1 during palatal development.

The histone methyltransferase SET domain bifurcated 1 (SETDB1) catalyzes the trimethylation of lysine 9 of histone H3, thereby regulating gene expression. In this study, we used conditional knockout mice, where Setdb1 was deleted only in neural crest cells (Setdb1fl/fl,Wnt1-Cre + mice), to clarify the role of SETDB1 in palatal development. Setdb1fl/fl,Wnt1-Cre + mice died shortly after birth due to a cleft palate with full penetration. Reduced palatal mesenchyme proliferation was seen in Setdb1fl/fl,Wnt1-Cre + mice, which might be a possible mechanism of cleft palate development. Quantitative RT-PCR and in situ hybridization showed that expression of the Pax9, Bmp4, Bmpr1a, Wnt5a, and Fgf10 genes, known to be important for palatal development, were markedly decreased in the palatal mesenchyme of Setdb1fl/fl,Wnt1-Cre + mice. Along with these phenomena, SMAD1/5/9 phosphorylation was decreased by the loss of Setdb1. Our results demonstrated that SETDB1 is indispensable for palatal development partially through its proliferative effect. Taken together with previous reports that PAX9 regulates BMP signaling during palatal development which implies that loss of Setdb1 may be involved in the cleft palate development by decreasing SMAD-dependent BMP signaling through Pax9.

Framework for Supporting Adolescent Peer Leaders: A Pilot Using Text Messaging in a School-Based Substance Use Prevention Program.

Training peer leaders (PLs) as implementation agents is a state-of-the-art approach in prevention, but the field lacks frameworks for providing support. Text messaging, a powerful tool for direct intervention, may be useful in this regard. We introduce a conceptual framework for engaging, retaining, and educating adolescent PLs and conduct a pilot test of this framework using text messages for delivery to middle school PLs in a new, peer-led substance use prevention program. Fifty eighth-graders were recruited as PLs. We used a newly-developed framework to create text messages to strengthen peer leaders': (a) mission, agency, and team identity; (b) connection to adult mentors; (c) content knowledge and application to their own lives; and (d) preparation for prevention activities. Thirty-four texts were sent to PLs over 4 months. PL replies and participation were recorded to track engagement. Forty-one PLs (71%) received texts and completed baseline and post-program surveys. Parents and school staff completed post-program questionnaires. Eighty-five percent of PLs responded to at least one text message. Response rates for specific messages varied from 22 to 56%. Students were most likely to reply to texts about preparation for their own prevention activities in the school. Ninety-five percent of PLs said they read messages even when they did not reply. Eighty-three percent of PLs said the messages helped them accomplish their mission. PLs reported that they wanted to receive messages in the future. PL attendance had very little variability in two of the three schools, but replies to texts were associated with better attendance in one school. Our study provides a framework for supporting adolescent peer leaders in a network intervention. Automated text messaging supporting middle school PLs was feasible, engaging, and well-received. Texting activity was associated with participation in school-based activities. Future priorities include systematically varying text support to determine its true effect on implementation and on involvement by less engaged PLs.

Early initiation of remdesivir and its effect on oxygen desaturation: A clinical review study among high-risk COVID-19 patients in Myanmar.

Background: Although Remdesivir has been evaluated for the treatment of coronavirus disease 2019 (COVID-19), few study has yet shown effective mortality reduction. It might be because, in almost all those studies, remdesivir therapy was started beyond 7th days from the onset of symptoms when the active viral replications have already gone. Methods: This study reviewed the effectiveness of early remdesivir therapy during viral phase of COVID-19 and safety of its administration at home or community care during the outbreak of COVID-19 from July to September 2021 in Myanmar. We retrospectively reviewed clinical records of 204 high risk COVID-19 patients who had received remdesivir therapy within 7 days from the onset of illness and before oxygen desaturation. Findings: All patients received remdesivir therapy according to standard five days course of 200 mg loading dose on day 1, followed by 100 mg daily for up to 4 additional days. Out of 204 patients, 60.75% (124/204) were aged 60 years and above with comorbidity; 21.1% (43/204) aged under 60 years with comorbidity and 18.1% (37/204) were aged more than 60 years old without comorbidity. The patients who received RDSV therapy within 1-4 days and within 5-7 days were 50.5% (103/204) and 49.5% (101/204) respectively. All patients survived to 21 days without ICU admission or mechanical ventilation. Eighty six percent of patients had no hypoxia and only five percent had moderate to severe hypoxia, requiring oxygen. Those who received RDSV therapy within 1 to 4 days from the onset of symptoms had significantly lower rate of hypoxia compared to those who received remdesivir therapy on 5 to 7 days. After RDSV therapy, increased lymphocyte count and decreased CPR were observed in 74.5% (152/204) and 52.9% (108/204) of the patients respectively. There was no report of major adverse events. Conclusion: Remdesivir, if given within first 4 days from the onset of symptoms, is the most effective strategy for prevention of oxygen desaturation, further progression of COVID-19 and death although it is still beneficial if given later, days 5 to 7. It is a safe drug to be prescribed in hospital at home care. It may be cost-benefit if high-risk group of patients with COVID-19 were selected for early remdesivir therapy in the community.

Histone methyltransferase SET domain bifurcated 1 negatively regulates parathyroid hormone/parathyroid hormone-related peptide receptor to control chondrocyte proliferation in Meckel's cartilage.

OBJECTIVE: The aim of this study is to show that the proliferation of chondrocytes is regulated by SET domain bifurcated 1 (SETDB1) along with the downregulation of parathyroid hormone (PTH)/parathyroid hormone-related peptide (PTHrP) receptor in Meckel's cartilage. DESIGN: Setdb1 was knocked down or overexpressed in a mouse chondrogenic ATDC5 cells, by transfecting the cells with short interfering RNA against Setdb1 or wild-type Setdb1 expression vector, respectively. Cell proliferation was detected by bromodeoxyuridine incorporation. Setdb1 was conditionally deleted in neural crest cells with Wnt1-Cre (Setdb1 conditional knockout mice). Immunofluorescence staining of paraffin sections of embryonic days 13.5 and 14.5 Setdb1 conditional knockout mice or transfected ATDC5 cells was performed to detect PTH/PTHrP receptor. Protein kinase B (AKT) phosphorylation inhibitor was added to both siRNA-transfected ATDC5 cultures to determine whether AKT activation induces PTH/PTHrP receptor expression after Setdb1 knockdown or vice versa. RESULTS: Setdb1 knockdown in ATDC5 cells showed increased cell proliferation and parathyroid hormone receptor 1 expression. Contrasting results were observed in the Setdb1-overexpressed wild-type cells. Immunofluorescence staining showed the highly expressed PTH/PTHrP receptor in Setdb1-knocked down ATDC5 cells and in the chondrocytes of Setdb1 conditional knockout embryonic Meckel's cartilage, indicating the negative regulation of SETDB1 on PTH/PTHrP receptor. Strong staining of phosphorylated AKT was observed in Setdb1-knocked down ATDC5 cells. However, the inhibition of AKT phosphorylation significantly reduced both the PTH/PTHrP receptor staining and the Setdb1-knockdown-induced increase in ATDC5 cell proliferation. CONCLUSIONS: Our findings contribute new insights on SETDB1 function in relation with AKT and PTH/PTHrP receptor during chondrocyte proliferation.

Efficacy of Web-Based Collection of Strength-Based Testimonials for Text Message Extension of Youth Suicide Prevention Program: Randomized Controlled Experiment.

BACKGROUND: Equipping members of a target population to deliver effective public health messaging to peers is an established approach in health promotion. The Sources of Strength program has demonstrated the promise of this approach for "upstream" youth suicide prevention. Text messaging is a well-established medium for promoting behavior change and is the dominant communication medium for youth. In order for peer 'opinion leader' programs like Sources of Strength to use scalable, wide-reaching media such as text messaging to spread peer-to-peer messages, they need techniques for assisting peer opinion leaders in creating effective testimonials to engage peers and match program goals. We developed a Web interface, called Stories of Personal Resilience in Managing Emotions (StoryPRIME), which helps peer opinion leaders write effective, short-form messages that can be delivered to the target population in youth suicide prevention program like Sources of Strength. OBJECTIVE: To determine the efficacy of StoryPRIME, a Web-based interface for remotely eliciting high school peer leaders, and helping them produce high-quality, personal testimonials for use in a text messaging extension of an evidence-based, peer-led suicide prevention program. METHODS: In a double-blind randomized controlled experiment, 36 high school students wrote testimonials with or without eliciting from the StoryPRIME interface. The interface was created in the context of Sources of Strength-an evidence-based youth suicide prevention program-and 24 ninth graders rated these testimonials on relatability, usefulness/relevance, intrigue, and likability. RESULTS: Testimonials written with the StoryPRIME interface were rated as more relatable, useful/relevant, intriguing, and likable than testimonials written without StoryPRIME, P=.054. CONCLUSIONS: StoryPRIME is a promising way to elicit high-quality, personal testimonials from youth for prevention programs that draw on members of a target population to spread public health messages.