RNA-seq reveals post-transcriptional regulation of Drosophila insulin-like peptide dilp8 and the neuropeptide-like precursor Nplp2 by the exoribonuclease Pacman/XRN1

Ribonucleases are critically important in many cellular and developmental processes and defects in their expression are associated with human disease. Pacman/XRN1 is a highly conserved cytoplasmic exoribonuclease which degrades RNAs in a 5' - 3' direction. In Drosophila, null mutations in pacman result in small imaginal discs, a delay in onset of pupariation and lethality during the early pupal stage. In this paper, we have used RNA-seq in a genome-wide search for mRNAs misregulated in pacman null wing imaginal discs. Only 4.2% of genes are misregulated ±>2-fold in pacman null mutants compared to controls, in line with previous work showing that Pacman has specificity for particular mRNAs. Further analysis of the most upregulated mRNAs showed that Pacman post-transcriptionally regulates the expression of the secreted insulin-like peptide Dilp8. Dilp8 is related to human IGF-1, and has been shown to co-ordinate tissue growth with developmental timing in Drosophila. The increased expression of Dilp8 is consistent with the developmental delay seen in pacman null mutants. Our analysis, together with our previous results, show that the normal role of this exoribonuclease in imaginal discs is to suppress the expression of transcripts that are crucial in apoptosis and growth control during normal development

Testing Random Effects in the Linear Mixed Model Using Approximate Bayes Factors

Deciding which predictor effects may vary across subjects is a difficult issue. Standard model selection criteria and test procedures are often inappropriate for comparing models with different numbers of random effects due to constraints on the parameter space of the variance components. Testing on the boundary of the parameter space changes the asymptotic distribution of some classical test statistics and causes problems in approximating Bayes factors. We propose a simple approach for testing random effects in the linear mixed model using Bayes factors. We scale each random effect to the residual variance and introduce a parameter that controls the relative contribution of each random effect free of the scale of the data. We integrate out the random effects and the variance components using closed form solutions. The resulting integrals needed to calculate the Bayes factor are low-dimensional integrals lacking variance components and can be efficiently approximated with Laplace’s method. We propose a default prior distribution on the parameter controlling the contribution of each random effect and conduct simulations to show that our method has good properties for model selection problems. Finally, we illustrate our methods on data from a clinical trial of patients with bipolar disorder and on data from an environmental study of water disinfection by-products and male reproductive outcomes

Clinically relevant variants identified in thoracic aortic aneurysm patients by research exome sequencing

Thoracic aortic aneurysm (TAA) is a genetically heterogeneous disease involving subclinical and progressive dilation of the thoracic aorta, which can lead to life-threatening complications such as dissection or rupture. Genetic testing is important for risk stratification and identification of at risk family members, and clinically available genetic testing panels have been expanding rapidly. However, when past testing results are normal, there is little evidence to guide decision-making about the indications and timing to pursue additional clinical genetic testing. Results from research based genetic testing can help inform this process. Here we present 10 TAA patients who have a family history of disease and who enrolled in research-based exome testing. Nine of these ten patients had previous clinical genetic testing that did not identify the cause of disease. We sought to determine the number of rare variants in 23 known TAA associated genes identified by research-based exome testing. In total, we found 10 rare variants in six patients. Likely pathogenic variants included a TGFB2 variant in one patient and a SMAD3 variant in another. These variants have been reported previously in individuals with similar phenotypes. Variants of uncertain significance of particular interest included novel variants in MYLK and MFAP5, which were identified in a third patient. In total, clinically reportable rare variants were found in 6/10 (60%) patients, with at least 2/10 (20%) patients having likely pathogenic variants identified. These data indicate that consideration of re-testing is important in TAA patients with previous negative or inconclusive results

Oxidation of tertiary amine-derivatized surfaces to control protein adhesion

Selective oxidation of omega-tertiary amine self-assembled thiol monolayers to tertiary amine N-oxides is shown to transform the adhesion of model proteins lysozyme and fibrinogen upon them. Efficient preparation of both secondary and tertiary linker amides as judged by X-ray photoelectron spectroscopy (XPS) and water droplet contact angle was achieved with an improved amide bond formation on gold quartz crystal microbalance (QCM) sensors using 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl hexafluorophosphate methanaminium uronium (HATU). Oxidation with hydrogen peroxide was similarly assessed, and adhesion of lysozyme and fibrinogen from phosphate buffered saline was then assayed by QCM and imaged by AFM. Tertiary amine-functionalized sensors adsorbed multilayers of aggregated lysozyme, whereas tertiary amine N-oxides and triethylene glycol-terminated monolayers are consistent with small protein aggregates. The surface containing a dimethylamine N-oxide headgroup and ethyl secondary amide linker showed the largest difference in adsorption of both proteins. Oxidation of tertiary amine decorated surfaces therefore holds the potential for selective deposition of proteins and cells through masking and other patterning techniques

Use of decongestants may disrupt cell signaling pathways that control Tbx gene expression, leading to hypoplastic left heart syndrome

Hypoplastic left heart syndrome (HLHS) collectively refers to a range of congenital heart defects, all involving some degree of left ventricular hypoplasia, or underdevelopment of the left ventricle. Additionally, HLHS often involves coarctation of the aorta, and can also include hypoplasia of the ascending aorta, as well as mitral and/or aortic valve stenosis or atresia. HLHS is extremely rare, as it has been reported to occur in only 1 in 5000 live births each year. The cause of HLHS is currently unknown, however much research is being done to discover how and why these defects occur. HLHS is known to be familially inherited in some instances and is also associated with many well-characterized genetic disorders, including Holt-Oram syndrome, Turner’s syndrome, Noonan syndrome, Smith-Lemli-Opitz syndrome, as well as trisomies 13, 18, and 21. Additionally, an autosomal recessive pattern of inheritance has been found amongst some siblings, however, no specific genes have been implicated. Incidence of HLHS also varies significantly in certain geographical regions and some studies have found a seasonal correlation in HLHS, indicating a possible environmental cause

Factors affecting follower responses to movement calls in cooperatively breeding dwarf mongooses

In social species, individuals maximize the benefits of group living by remaining cohesive and coordinating their actions. Communication is key to collective action, including ensuring that group members move together; individuals often produce signals when attempting to lead a group to a new area. However, the function of these signals, and how responses to them are affected by intrinsic characteristics of the caller and extrinsic factors, has rarely been experimentally tested. We conducted a series of field-based playback experiments with habituated wild dwarf mongooses, Helogale parvula, a cooperatively breeding and territorial species, to investigate follower responses to movement calls. In our first experiment, we found that focal individuals were more likely to respond to playback of ‘movement calls’ than control ‘close calls’, indicating movement calls function as recruitment signals. In a second experiment, we found that focal individuals responded similarly to the movement calls of dominant and subordinate groupmates, suggesting that dominance status (an intrinsic factor) does not influence receiver responses. In a final experiment, we found that individuals responded to the simulated presence of a rival group, but that this outgroup conflict (an extrinsic factor) did not affect responses to movement calls compared to a control situation. This may be because attention is instead focused on the potential presence of an imminent threat. By using playbacks to isolate the acoustic signal from physical movement cues, our results provide experimental evidence of how movement calls help leaders to attract followers and thus adds to our understanding of recruitment signals more generally

A robust method for comparing two treatments in a confirmatory clinical trial via multivariate time-to-event methods that jointly incorporate information from longitudinal and time-to-event data

We consider regulatory clinical trials that required a pre-specified method for the comparison of two treatments for chronic diseases (e.g. Chronic Obstructive Pulmonary Disease) in which patients suffer deterioration in a longitudinal process until death occurs. We define a composite endpoint structure that encompasses both the longitudinal data for deterioration and the time-to-event data for death, and use multivariate time-to-event methods to assess treatment differences on both data structures simultaneously, without a need for parametric assumptions or modeling. Our method is straightforward to implement, and simulations show the method has robust power in situations in which incomplete data could lead to lower than expected power for either the longitudinal or survival data. We illustrate the method on data from a study of chronic lung disease

Assessing variance components in multilevel linear models using approximate Bayes factors: A case study of ethnic disparities in birthweight

Racial/ethnic disparities in birthweight are a large source of differential morbidity and mortality worldwide and have remained largely unexplained in epidemiologic models. We assess the impact of maternal ancestry and census tract residence on infant birth weights in New York City and the modifying effects of race and nativity by incorporating random effects in a multilevel linear model. Evaluating the significance of these predictors involves the test of whether the variances of the random effects are equal to zero. This is problematic because the null hypothesis lies on the boundary of the parameter space. We generalize an approach for assessing random effects in the two-level linear model to a broader class of multilevel linear models by scaling the random effects to the residual variance and introducing parameters that control the relative contribution of the random effects. After integrating over the random effects and variance components, the resulting integrals needed to calculate the Bayes factor can be efficiently approximated with Laplace’s method

GIS Day across the Association of Research Libraries: Outreach, Education, and Collaboration

GIS Day is an annual, international celebration of geographic information systems (GIS) and geospatial technologies that provides organizations with an opportunity to help others learn about the real-world applications and positive societal impacts of geography and GIS, highlight services, and celebrate accomplishments. Many academic libraries participate in GIS Day programs, using this well-known event to engage with their campus and local communities. In this article, we build on earlier research conducted by Weimer, Olivares, and Bedenbaugh to reassess the landscape of Association of Research Libraries (ARL) member involvement in GIS Day programs and, in particular, how these events demonstrate the educational and collaborative aspects of geospatial information services in libraries. For our web content analysis, we specifically focus on gathering information about GIS Day programs in 2019 and 2020, allowing for an examination of how libraries participating in GIS Day responded to the operational challenges posed by the COVID-19 pandemic, as well as new opportunities that may have emerged during this period. Finally, we offer our own 2020 GIS Day program as a brief example highlighting how it led to our first cross-institutional collaboration and fostered new opportunities for promoting and partnering on digital scholarship projects at our institutions.Publisher allows immediate open acces