Single molecule analysis reveals reversible and irreversible steps during spliceosome activation

The spliceosome is a complex machine composed of small nuclear ribonucleoproteins (snRNPs) and accessory proteins that excises introns from pre-mRNAs. After assembly the spliceosome is activated for catalysis by rearrangement of subunits to form an active site. How this rearrangement is coordinated is not well-understood. During activation, U4 must be released to allow U6 conformational change, while Prp19 complex (NTC) recruitment is essential for stabilizing the active site. We used multi-wavelength colocalization single molecule spectroscopy to directly observe the key events in Saccharomyces cerevisiae spliceosome activation. Following binding of the U4/U6.U5 tri-snRNP, the spliceosome either reverses assembly by discarding tri-snRNP or proceeds to activation by irreversible U4 loss. The major pathway for NTC recruitment occurs after U4 release. ATP stimulates both the competing U4 release and tri-snRNP discard processes. The data reveal the activation mechanism and show that overall splicing efficiency may be maintained through repeated rounds of disassembly and tri-snRNP reassociation

Informing mHealth and Web-Based Eating Disorder Interventions: Combining Lived Experience Perspectives With Design Thinking Approaches

Background: App-based interventions designed to prevent and treat eating disorders have considerable potential to overcome known barriers to treatment seeking. Existing apps have shown efficacy in terms of symptom reduction; however, uptake and retention issues are common. To ensure that apps meet the needs and preferences of those for whom they were designed, it is critical to understand the lived experience of potential users and involve them in the process of design, development, and delivery. However, few app-based interventions are pretested on and co-designed with end users before randomized controlled trials. Objective: To address the issue, this study used a highly novel design thinking approach to provide the context and a lived experience perspective of the end user, thus allowing for a deeper level of understanding. Methods: In total, 7 young women (mean age 25.83, SD 5.34, range 21-33 years) who self-identified as having a history of body image issues or eating disorders were recruited. Participants were interviewed about their lived experience of body image and eating disorders and reported their needs and preferences for app-based eating disorder interventions. Traditional (thematic analysis) and novel (empathy mapping; visually depicting and empathizing with the user’s personal experience) analyses were performed, providing a lived experience perspective of eating disorders and identifying the needs and preferences of this population in relation to app-based interventions for eating disorders. Key challenges and opportunities for app-based eating disorder interventions were also identified. Results: Findings highlighted the importance of understanding and identifying problematic eating disorder symptoms for the user, helpful practices for recovery that identify personal values and goals, the role of social support in facilitating hope, and aspects of usability to promote continued engagement and recovery. Conclusions: Practical guidance and recommendations are described for those developing app-based eating disorder interventions. These findings have the potential to inform practices to enhance participant uptake and retention in the context of app-based interventions for this population

Mutations in HYAL2, Encoding Hyaluronidase 2, Cause a Syndrome of Orofacial Clefting and Cor Triatriatum Sinister in Humans and Mice.

Orofacial clefting is amongst the most common of birth defects, with both genetic and environmental components. Although numerous studies have been undertaken to investigate the complexities of the genetic etiology of this heterogeneous condition, this factor remains incompletely understood. Here, we describe mutations in the HYAL2 gene as a cause of syndromic orofacial clefting. HYAL2, encoding hyaluronidase 2, degrades extracellular hyaluronan, a critical component of the developing heart and palatal shelf matrix. Transfection assays demonstrated that the gene mutations destabilize the molecule, dramatically reducing HYAL2 protein levels. Consistent with the clinical presentation in affected individuals, investigations of Hyal2-/- mice revealed craniofacial abnormalities, including submucosal cleft palate. In addition, cor triatriatum sinister and hearing loss, identified in a proportion of Hyal2-/- mice, were also found as incompletely penetrant features in affected humans. Taken together our findings identify a new genetic cause of orofacial clefting in humans and mice, and define the first molecular cause of human cor triatriatum sinister, illustrating the fundamental importance of HYAL2 and hyaluronan turnover for normal human and mouse development

The global meningitis genome partnership.

Genomic surveillance of bacterial meningitis pathogens is essential for effective disease control globally, enabling identification of emerging and expanding strains and consequent public health interventions. While there has been a rise in the use of whole genome sequencing, this has been driven predominately by a subset of countries with adequate capacity and resources. Global capacity to participate in surveillance needs to be expanded, particularly in low and middle-income countries with high disease burdens. In light of this, the WHO-led collaboration, Defeating Meningitis by 2030 Global Roadmap, has called for the establishment of a Global Meningitis Genome Partnership that links resources for: N. meningitidis (Nm), S. pneumoniae (Sp), H. influenzae (Hi) and S. agalactiae (Sa) to improve worldwide co-ordination of strain identification and tracking. Existing platforms containing relevant genomes include: PubMLST: Nm (31,622), Sp (15,132), Hi (1935), Sa (9026); The Wellcome Sanger Institute: Nm (13,711), Sp (> 24,000), Sa (6200), Hi (1738); and BMGAP: Nm (8785), Hi (2030). A steering group is being established to coordinate the initiative and encourage high-quality data curation. Next steps include: developing guidelines on open-access sharing of genomic data; defining a core set of metadata; and facilitating development of user-friendly interfaces that represent publicly available data

The Habitable Exoplanet Observatory (HabEx) Mission Concept Study Final Report

The Habitable Exoplanet Observatory, or HabEx, has been designed to be the Great Observatory of the 2030s. For the first time in human history, technologies have matured sufficiently to enable an affordable space-based telescope mission capable of discovering and characterizing Earthlike planets orbiting nearby bright sunlike stars in order to search for signs of habitability and biosignatures. Such a mission can also be equipped with instrumentation that will enable broad and exciting general astrophysics and planetary science not possible from current or planned facilities. HabEx is a space telescope with unique imaging and multi-object spectroscopic capabilities at wavelengths ranging from ultraviolet (UV) to near-IR. These capabilities allow for a broad suite of compelling science that cuts across the entire NASA astrophysics portfolio. HabEx has three primary science goals: (1) Seek out nearby worlds and explore their habitability; (2) Map out nearby planetary systems and understand the diversity of the worlds they contain; (3) Enable new explorations of astrophysical systems from our own solar system to external galaxies by extending our reach in the UV through near-IR. This Great Observatory science will be selected through a competed GO program, and will account for about 50% of the HabEx primary mission. The preferred HabEx architecture is a 4m, monolithic, off-axis telescope that is diffraction-limited at 0.4 microns and is in an L2 orbit. HabEx employs two starlight suppression systems: a coronagraph and a starshade, each with their own dedicated instrument

The Habitable Exoplanet Observatory (HabEx) Mission Concept Study Final Report

The Habitable Exoplanet Observatory, or HabEx, has been designed to be the Great Observatory of the 2030s. For the first time in human history, technologies have matured sufficiently to enable an affordable space-based telescope mission capable of discovering and characterizing Earthlike planets orbiting nearby bright sunlike stars in order to search for signs of habitability and biosignatures. Such a mission can also be equipped with instrumentation that will enable broad and exciting general astrophysics and planetary science not possible from current or planned facilities. HabEx is a space telescope with unique imaging and multi-object spectroscopic capabilities at wavelengths ranging from ultraviolet (UV) to near-IR. These capabilities allow for a broad suite of compelling science that cuts across the entire NASA astrophysics portfolio. HabEx has three primary science goals: (1) Seek out nearby worlds and explore their habitability; (2) Map out nearby planetary systems and understand the diversity of the worlds they contain; (3) Enable new explorations of astrophysical systems from our own solar system to external galaxies by extending our reach in the UV through near-IR. This Great Observatory science will be selected through a competed GO program, and will account for about 50% of the HabEx primary mission. The preferred HabEx architecture is a 4m, monolithic, off-axis telescope that is diffraction-limited at 0.4 microns and is in an L2 orbit. HabEx employs two starlight suppression systems: a coronagraph and a starshade, each with their own dedicated instrument.Comment: Full report: 498 pages. Executive Summary: 14 pages. More information about HabEx can be found here: https://www.jpl.nasa.gov/habex

Testing for funnel plot asymmetry of standardized mean differences

Publication bias and other forms of outcome reporting bias are critical threats to the validity of findings from research syntheses. A variety of methods have been proposed for detecting selective outcome reporting in a collection of effect size estimates, including several methods based on assessment of asymmetry of funnel plots, such as Egger's regression test, the rank correlation test, and the Trim-and-Fill test. Previous research has demonstated that Egger's regression test is mis-calibrated when applied to log-odds ratio effect size estimates, due to artifactual correlation between the effect size estimate and its standard error. This study examines similar problems that occur in meta-analyses of the standardized mean difference, a ubiquitous effect size measure in educational and psychological research. In a simulation study of standardized mean difference effect sizes, we assess the Type I error rates of conventional tests of funnel plot asymmetry, as well as the likelihood ratio test from a three-parameter selection model. Results demonstrate that the conventional tests have inflated Type I error due to correlation between the effect size estimate and its standard error, while tests based on either a simple modification to the conventional standard error formula or a variance-stabilizing transformation both maintain close-to-nominal Type I error

Evaluating Meta-Analytic Methods to Detect Selective Reporting in the Presence of Dependent Effect Sizes

Selective reporting of results based on their statistical significance threatens the validity of meta-analytic findings. A variety of techniques for detecting selective reporting, publication bias, or small-study effects are available and are routinely used in research syntheses. Most such techniques are univariate, in that they assume that each study contributes a single, independent effect size estimate to the meta-analysis. In practice, however, studies often contribute multiple, statistically dependent effect size estimates, such as for multiple measures of a common outcome construct. Many methods are available for meta-analyzing dependent effect sizes, but methods for investigating selective reporting while also handling effect size dependencies require further investigation. Using Monte Carlo simulations, we evaluate three available univariate tests for small-study effects or selective reporting, including the Trim & Fill test, Egger's regression test, and a likelihood ratio test from a three-parameter selection model (3PSM), when dependence is ignored or handled using ad hoc techniques. We also examine two variants of Egger’s regression test that incorporate robust variance estimation (RVE) or multi-level meta-analysis (MLMA) to handle dependence. Simulation results demonstrate that ignoring dependence inflates Type I error rates for all univariate tests. Variants of Egger's regression maintain Type I error rates when dependent effect sizes are sampled or handled using RVE or MLMA. The 3PSM likelihood ratio test does not fully control Type I error rates. With the exception of the 3PSM, all methods have limited power to detect selection bias except under strong selection for statistically significant effects