Elucidating the Molecular Mechanism of Cis-Regulation by the Long Noncoding RNA LincRNA-p21

Pervasive transcription is a hallmark of mammalian genomes. Although protein-coding genes span only a small fraction of the genome, more than two-thirds is transcribed, yielding thousands of noncoding transcripts whose expression exhibits a tight correlation with cell type, disease state, and other biological phenomena. A subset of these transcripts, termed long noncoding RNAs (lncRNAs) on account of their length (\u3e200 nucleotides) and lack of apparent coding potential, have been shown to play functional roles in processes ranging from immune signaling to organogenesis. In contrast to trans-acting lncRNAs, which may operate in either the nucleus or cytoplasm, cis-acting lncRNAs remain at their site of transcription and regulate the expression of nearby protein-coding genes. These lncRNAs have been proposed to act through three main mechanisms: (1) the RNA molecule may interact with protein factors to enact transcriptional activation or repression; (2) the act of lncRNA transcription may increase the local concentration of RNA polymerase II or chromatin-modifying factors; or (3) DNA elements within a lncRNA locus may directly regulate the expression of both the lncRNA and its neighboring gene. Deconvolving these interlinked mechanisms has proven challenging and necessitates the development and implementation of new experimental techniques. In this work, we used a suite of independent molecular and genetic approaches, including a novel ribozyme-based tool for targeted transcript degradation, to expand our understanding of the molecular “logic” through which cis-acting lncRNAs enact gene regulation. We focused on the p53-inducible lncRNA LincRNA-p21, which acts in cis to reinforce the expression of the nearby protein-coding gene and key p53 target p21/Cdkn1a. To identify the functional element of cis-regulation at this locus, we generated four mouse strains harboring complementary LincRNA-p21 loss-of-function mutations that allowed us to separately examine the importance of the LincRNA-p21 transcriptional process and the underlying DNA sequence. This parallel genetic approach demonstrated that full-length LincRNA-p21 transcription, processing, and accumulation are dispensable for cis-regulation and revealed a requirement for a conserved sequence element within exon 1. Further experiments with molecular tools suggested that active transcription through this conserved region promotes p21 expression, implicating a dual role for the transcriptional process and sequence elements within the locus. This comprehensive functional dissection of a single lncRNA locus attests to the regulatory potential of lncRNA loci and further reveals the biological significance of pervasive genomic transcription

The Effects of Education on Cardiovascular Disease Knowledge

Cardiovascular disease (CVD) is the leading cause of morbidity and mortality for adults in the United States. The three main risk factors for the development of CVD include hypertension, high cholesterol, and tobacco use; these factors are largely prevented or reduced through lifestyle modifications. Researchers indicate that knowledge of CVD mortality has been linked with individual action to reduce one’s CVD risk. Researchers have also indicated that segments of our underserved society, particularly those with the highest CVD mortality rates, are also the least knowledgeable about CVD and their own personal risk. These risk factors were a concern within the targeted population for this EBP project: adult patients at a rural Midwest outpatient health center. Using the Stetler Model and Kotter’s Eight Stages of Change as guides, this EBP project was implemented with the objective of evaluating the effectiveness of video plus written education materials on CVD knowledge levels among adults with one or more risk factors for the development of CVD. Over an 8-week period, a total of 100 adult patients were asked to watch a 3-minute NHLBI video and provided a CDC written handout on CVD risk factors before their regularly scheduled appointments. Pre- and post-test knowledge tests were collected on 57 adults who completed the entire project. A paired sample t-test demonstrated that the educational intervention significantly increased patient’s CVD knowledge (p \u3c .001). Sixty-eight percent of patients reported they would change their lifestyle habits to reduce their CVD risk factors as a result of this education. The findings suggest this educational strategy resulted in overall favorable effects on patients with CVD risk factors

Optimizing sustainment logistics for a U.S. Army infantry brigade combat team with integer programming

Proceedings of the 49th Annual Meeting of Western Decision Sciences Institute. The article of record as published may be found at http://wdsinet.org/Annual_Meetings/2020_Proceedings/ProceedingsPapers.htmlThe U.S. Army has directed the manning and equipping Brigade Support Battalions to fulfill the organic sustainment needs of brigades, as An Army Infantry Brigade Combat Team cannot organically transport all of its assigned assets. We formulated an integer programming model to optimize sustainment outcomes of supported units and analyze risk associated with shortfalls that may arise. We developed a scenario reflecting the steady resupply of an Infantry BCT during combat operations and a system for prioritizing competing resupply needs. Our mathematical modeling framework provides a foundation on which more advanced applications and analysis can be developed in the future

The impact of behavioural screening on intervention outcomes in a randomised, controlled multiple behaviour intervention trial

Background: With an increasing research focus on multiple health behaviour change interventions, a methodological issue requiring further investigation is whether or not to employ pre-trial behavioural screening to exclude participants who are achieving a pre-specified level of one or more behaviours. Behavioural screening can be used to direct limited resources to participants most in need of a behaviour change intervention; but may reduce the representativeness of the sample and limit comparability with trials that do not employ pre-trial behavioural screening. Furthermore, the impact of this type of screening on intervention participation and intervention effects is unknown

Awareness and bispectral index (BIS) monitoring in mechanically ventilated patients in the emergency department and intensive care unit: A systematic review protocol

INTRODUCTION: Accidental awareness with recall is one of the most feared complications for patients undergoing general anaesthesia and can lead to post-traumatic stress disorder in up to 70% of patients experiencing it. To reduce the incidence of awareness with recall, the bispectral index monitor is recommended for patients receiving total intravenous anaesthetics, especially those receiving neuromuscular blockers. While extensive investigation into awareness and bispectral index monitoring has occurred for operating room patients, this has not extended to other clinical arenas where sedated and mechanically ventilated patients are cared for, namely the intensive care unit and emergency department. The purpose of this systematic review is to assess the world\u27s literature to determine the incidence of awareness with paralysis in mechanically ventilated patients and the impact of bispectral index monitoring for reducing this complication. METHODS AND ANALYSIS: Randomised trials and non-randomised studies are eligible for inclusion. With aid from a medical librarian, an electronic search will include Ovid Medline, Embase.com, Scopus, Cochrane Database of Systematic Reviews and Cochrane Central Register of Controlled Trials. To find data published in abstract form, literature from professional society conferences (2010-2019) will be manually searched. Two authors will independently review search results and consensus will be reached with assistance from a third author, as needed. Heterogeneity and publication bias will be assessed and reported. If possible and appropriate, a meta-analysis of the data will be conducted for quantitative data analysis. ETHICS AND DISSEMINATION: The proposed systematic review does not require ethical approval, as it is conducted at the study level and does not involve individual patient-level data. Results will be disseminated by data sharing via academically established means, presentation at local and national scientific meetings and publication as a peer-reviewed manuscript. PROSPERO REGISTRATION NUMBER: The protocol has been submitted to International Prospective Register of Systematic Reviews and is awaiting registration

Is measurement error altered by participation in a physical activity intervention?

WINKLER, E., L. WATERS, E. EAKIN, B. FJELDSOE, N. OWEN, and M. REEVES. Is Measurement Error Altered by Participation in a Physical Activity Intervention? Med. Sci. Sports Exerc., Vol. 45, No. 5, pp. 1004-1011, 2013. Purpose: There is no "gold standard" measure for moderate to vigorous physical activity (MVPA); some error is inherent to self-report and device-based measures. Few studies have examined agreement between self-report and device-based measures in the intervention trial context or whether the difference between measures is influenced by intervention participation. Methods: MVPA was measured at baseline and after 6 months by Active Australia Survey (AAS) and by the GT1M accelerometer (>= 1952 counts per minute) in the intervention (n = 135) and usual care control (n = 141) participants of a randomized trial targeting weight loss by MVPA increases and energy intake reductions in adults with type 2 diabetes. Agreement (for each group at each assessment) was examined using the Bland-Altman approach and regression-based modeling. Because the differences between MVPA measures varied with average values ([AAS + GT1M]/2), they were examined as a percentage of average physical activity. t-tests were used to assess unadjusted group differences and changes over time. ANCOVA models tested intervention effects on measurement error at follow-up, adjusted for baseline. Results: Agreement worsened, and variability in the difference measures became greater, as the average amount of MVPA increased. Measurement error differed significantly between groups at follow-up (P = 0.010) but not at baseline (P = 0.157) and changed significantly within the intervention group (P = 0.001) but not the control group (P = 0.164). There was a statistically significant effect of the intervention on measurement error (P = 0.026). Conclusions: Measurement error of self-report relative to the accelerometer appeared to be affected by intervention. Because measurement error cannot be definitively attributed to self-report or accelerometer, it would be prudent to measure both in future studies

Can grit be taught? Lessons from a nationwide field experiment with middle-school students

We study whether a particular socio-emotional skill - grit (the ability to sustain effort and interest towards long-term goals) - can be cultivated through a large-scale program, and how this affects student learning. Using a randomized control trial, we evaluate the first nationwide implementation of a low-cost intervention designed to foster grit and self-regulation among sixth and seventh-grade students in primary schools in North Macedonia (about 33,000 students across 350 schools). The results of this interventions are mixed. Exposed students report improvements in self-regulation, in particular the perseverance-of-effort facet of grit, relative to students in a control condition. Impacts on students are larger when both students and teachers are exposed to the curriculum than when only students are treated. For disadvantaged students, we also find positive impacts on grade point averages, with gains of up to 28 percent of a standard deviation one-year post-treatment. However, while this intervention made students more perseverant and industrious, it reduced the consistency-of-interest facet of grit. This means that exposed students are less able to maintain consistent interests for long periods

Dental microwear texture analysis correlations in guinea pigs (Cavia porcellus) and sheep (Ovis aries) suggest that dental microwear texture signal consistency is species-specific

Dental microwear texture (DMT) analysis is used to differentiate abrasive dental wear patterns in many species fed different diets. Because DMT parameters all describe the same surface, they are expected to correlate with each other distinctively. Here, we explore the data range of, and correlations between, DMT parameters to increase the understanding of how this group of proxies records wear within and across species. The analysis was based on subsets of previously published DMT analyses in guinea pigs, sheep, and rabbits fed either a natural whole plant diet (lucerne, grass, bamboo) or pelleted diets with or without added quartz abrasives (guinea pigs and rabbits: up to 45 days, sheep: 17 months). The normalized DMT parameter range (P4: 0.69 0.25; M2: 0.83 0.16) and correlation coefficients (P4: 0.50 0.31; M2: 0.63 0.31) increased along the tooth row in guinea pigs, suggesting that strong correlations may be partially explained by data range. A comparison between sheep and guinea pigs revealed a higher DMT data range in sheep (0.93 0.16; guinea pigs: 0.47 0.29), but this did not translate into more substantial correlation coefficients (sheep: 0.35 0.28; guinea pigs: 0.55 0.32). Adding rabbits to an interspecies comparison of low abrasive dental wear (pelleted lucerne diet), the softer enamel of the hypselodont species showed a smaller data range for DMT parameters (guinea pigs 0.49 0.32, rabbit 0.19 0.18, sheep 0.78 0.22) but again slightly higher correlations coefficients compared to the hypsodont teeth (guinea pigs 0.55 0.31, rabbits 0.56 0.30, sheep 0.42 0.27). The findings suggest that the softer enamel of fast-replaced ever-growing hypselodont cheek teeth shows a greater inherent wear trace consistency, whereas the harder enamel of permanent and non-replaced enamel of hypsodont ruminant teeth records less coherent wear patterns. Because consistent diets were used across taxa, this effect cannot be ascribed to the random overwriting of individual wear traces on the more durable hypsodont teeth. This matches literature reports on reduced DMT pattern consistency on harder materials; possibly, individual wear events become more random in nature on harder material. Given the species-specific differences in enamel characteristics, the findings suggest a certain species-specificity of DMT patterns