Junior Recital

List of performers and performances

Identification of PKD1L1 Gene Variants in Children with the Biliary Atresia Splenic Malformation Syndrome

Biliary atresia (BA) is the most common cause of end‐stage liver disease in children and the primary indication for pediatric liver transplantation, yet underlying etiologies remain unknown. Approximately 10% of infants affected by BA exhibit various laterality defects (heterotaxy) including splenic abnormalities and complex cardiac malformations — a distinctive subgroup commonly referred to as the biliary atresia splenic malformation (BASM) syndrome. We hypothesized that genetic factors linking laterality features with the etiopathogenesis of BA in BASM patients could be identified through whole exome sequencing (WES) of an affected cohort. DNA specimens from 67 BASM subjects, including 58 patient‐parent trios, from the NIDDK‐supported Childhood Liver Disease Research Network (ChiLDReN) underwent WES. Candidate gene variants derived from a pre‐specified set of 2,016 genes associated with ciliary dysgenesis and/or dysfunction or cholestasis were prioritized according to pathogenicity, population frequency, and mode of inheritance. Five BASM subjects harbored rare and potentially deleterious bi‐allelic variants in polycystin 1‐like 1, PKD1L1, a gene associated with ciliary calcium signaling and embryonic laterality determination in fish, mice and humans. Heterozygous PKD1L1 variants were found in 3 additional subjects. Immunohistochemical analysis of liver from the one BASM subject available revealed decreased PKD1L1 expression in bile duct epithelium when compared to normal livers and livers affected by other non‐cholestatic diseases. Conclusion WES identified bi‐allelic and heterozygous PKD1L1 variants of interest in 8 BASM subjects from the ChiLDReN dataset. The dual roles for PKD1L1 in laterality determination and ciliary function suggest that PKD1L1 is a new, biologically plausible, cholangiocyte‐expressed candidate gene for the BASM syndrome

Influence of Beta-Blocker Continuation or Withdrawal on Outcomes in Patients Hospitalized With Heart Failure Findings From the OPTIMIZE-HF Program

ObjectivesThis study ascertains the relationship between continuation or withdrawal of beta-blocker therapy and clinical outcomes in patients hospitalized with systolic heart failure (HF).BackgroundWhether beta-blocker therapy should be continued or withdrawn during hospitalization for decompensated HF has not been well studied in a broad cohort of patients.MethodsThe OPTIMIZE-HF (Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure) program enrolled 5,791 patients admitted with HF in a registry with pre-specified 60- to 90-day follow-up at 91 academic and community hospitals throughout the U.S. Outcomes data were prospectively collected and analyzed according to whether beta-blocker therapy was continued, withdrawn, or not started.ResultsAmong 2,373 patients eligible for beta-blockers at discharge, there were 1,350 (56.9%) who were receiving beta-blockers before admission and continued on therapy, 632 (26.6%) newly started, 79 (3.3%) in which therapy was withdrawn, and 303 (12.8%) eligible but not treated. Continuation of beta-blockers was associated with a significantly lower risk and propensity adjusted post-discharge death (hazard ratio [HR]: 0.60; 95% confidence interval [CI]: 0.37 to 0.99, p = 0.044) and death/rehospitalization (odds ratio: 0.69; 95% CI: 0.52 to 0.92, p = 0.012) compared with no beta-blocker. In contrast, withdrawal of beta-blocker was associated with a substantially higher adjusted risk for mortality compared with those continued on beta-blockers (HR: 2.3; 95% CI: 1.2 to 4.6, p = 0.013), but with similar risk as HF patients eligible but not treated with beta-blockers.ConclusionsThe continuation of beta-blocker therapy in patients hospitalized with decompensated HF is associated with lower post-discharge mortality risk and improved treatment rates. In contrast, withdrawal of beta-blocker therapy is associated with worse risk and propensity-adjusted mortality. (Organized Program To Initiate Lifesaving Treatment In Hospitalized Patients With Heart Failure [OPTIMIZE-HF]; NCT00344513

The HST Key Project on the Extragalactic Distance Scale XVII. The Cepheid Distance to NGC 4725

The distance to NGC 4725 has been derived from Cepheid variables, as part of the Hubble Space Telescope Key Project on the Extragalactic Distance Scale. Thirteen F555W (V) and four F814W (I) epochs of cosmic-ray-split Wide Field and Planetary Camera 2 observations were obtained. Twenty Cepheids were discovered, with periods ranging from 12 to 49 days. Adopting a Large Magellanic Cloud distance modulus and extinction of 18.50+/-0.10 mag and E(V-I)=0.13 mag, respectively, a true reddening-corrected distance modulus (based on an analysis employing the ALLFRAME software package) of 30.50 +/- 0.16 (random) +/- 0.17 (systematic) mag was determined for NGC 4725. The corresponding of distance of 12.6 +/- 1.0 (random) +/- 1.0 (systematic) Mpc is in excellent agreement with that found with an independent analysis based upon the DoPHOT photometry package. With a foreground reddening of only E(V-I)=0.02, the inferred intrinsic reddening of this field in NGC 4725, E(V-I)=0.19, makes it one of the most highly-reddened, encountered by the HST Key Project, to date.Comment: To be published in The Astrophysical Journal, Vol. 512 (1999). 34 pages, LaTeX, 9 jpg figure

Gene-Wise Association of Variants in Four Lysosomal Storage Disorder Genes in Neuropathologically Confirmed Lewy Body Disease

Objective Variants in GBA are associated with Lewy Body (LB) pathology. We investigated whether variants in other lysosomal storage disorder (LSD) genes also contribute to disease pathogenesis. Methods We performed a genetic analysis of four LSD genes including GBA, HEXA, SMPD1, and MCOLN1 in 231 brain autopsies. Brain autopsies included neuropathologically defined LBD without Alzheimer Disease (AD) changes (n = 59), AD without significant LB pathology (n = 71), Alzheimer disease and lewy body variant (ADLBV) (n = 68), and control brains without LB or AD neuropathology (n = 33). Sequencing of HEXA, SMPD1, MCOLN1 and GBA followed by ‘gene wise’ genetic association analysis was performed. To determine the functional effect, a biochemical analysis of GBA in a subset of brains was also performed. GCase activity was measured in a subset of brain samples (n = 64) that included LBD brains, with or without GBA mutations, and control brains. A lipidomic analysis was also performed in brain autopsies (n = 67) which included LBD (n = 34), ADLBV (n = 3), AD (n = 4), PD (n = 9) and control brains (n = 17), comparing GBA mutation carriers to non-carriers. Results In a ‘gene-wise’ analysis, variants in GBA, SMPD1 and MCOLN1 were significantly associated with LB pathology (p range: 0.03–4.14 x10-5). Overall, the mean levels of GCase activity were significantly lower in GBA mutation carriers compared to non-carriers (p<0.001). A significant increase and accumulation of several species for the lipid classes, ceramides and sphingolipids, was observed in LBD brains carrying GBA mutations compared to controls (p range: p<0.05-p<0.01). Interpretation Our study indicates that variants in GBA, SMPD1 and MCOLN1 are associated with LB pathology. Biochemical data comparing GBA mutation carrier to non-carriers support these findings, which have important implications for biomarker development and therapeutic strategies

Governance and Susceptibility in Conflict Resolution: Possibilities Beyond Control

Governmentality analysis offers a nuanced critique of informal Western conflict resolution by arguing that recently emerged alternatives to adversarial court processes both govern subjects and help to constitute rather than challenge formal regulation. However, this analysis neglects possibilities for transforming governance from within conflict resolution that are suggested by Foucault's contention that there are no relations of power without resistances. To explore this lacuna, I theorise and explore the affective and interpersonal nature of governance in mediation through autoethnographic reflection upon mediation practice, and Levina's insights about the relatedness of selves. The paper argues that two qualitatively different mediator capacities - technical ability and susceptibility - operate in concert to effect liberal governance. Occasionally though, difficulties and failures in mediation practice bring these capacities into tension and reveal the limits of governance. By considering these limits in mediation with Aboriginal Australian people, I argue that the susceptibility of mediator selves contains prospects for mitigating and transforming the very operations of power occurring through conflict resolution. This suggests options for expanded critical thinking about power relations operating through informal processes, and for cultivating a susceptible sensibility to mitigate liberal governance and more ethically respond to difference through conflict resolution

Assessing the carcinogenic potential of low-dose exposures to chemical mixtures in the environment: the challenge ahead.

Lifestyle factors are responsible for a considerable portion of cancer incidence worldwide, but credible estimates from the World Health Organization and the International Agency for Research on Cancer (IARC) suggest that the fraction of cancers attributable to toxic environmental exposures is between 7% and 19%. To explore the hypothesis that low-dose exposures to mixtures of chemicals in the environment may be combining to contribute to environmental carcinogenesis, we reviewed 11 hallmark phenotypes of cancer, multiple priority target sites for disruption in each area and prototypical chemical disruptors for all targets, this included dose-response characterizations, evidence of low-dose effects and cross-hallmark effects for all targets and chemicals. In total, 85 examples of chemicals were reviewed for actions on key pathways/mechanisms related to carcinogenesis. Only 15% (13/85) were found to have evidence of a dose-response threshold, whereas 59% (50/85) exerted low-dose effects. No dose-response information was found for the remaining 26% (22/85). Our analysis suggests that the cumulative effects of individual (non-carcinogenic) chemicals acting on different pathways, and a variety of related systems, organs, tissues and cells could plausibly conspire to produce carcinogenic synergies. Additional basic research on carcinogenesis and research focused on low-dose effects of chemical mixtures needs to be rigorously pursued before the merits of this hypothesis can be further advanced. However, the structure of the World Health Organization International Programme on Chemical Safety 'Mode of Action' framework should be revisited as it has inherent weaknesses that are not fully aligned with our current understanding of cancer biology

Digital methods for ethnography: analytical concepts for ethnographers exploring social media environments

The aim of this article is to introduce some analytical concepts suitable for ethnographers dealing with social media environments. As a result of the growth of social media, the Internet structure has become a very complex, fluid, and fragmented space. Within this space, it is not always possible to consider the 'classical' online community as the privileged field site for the ethnographer, in which s/he immerses him/herself. Differently, taking inspiration from some methodological principles of the Digital Methods paradigm, I suggest that the main task for the ethnographer moving across social media environments should not be exclusively that of identifying an online community to delve into but of mapping the practices through which Internet users and digital devices structure social formations around a focal object (e.g., a brand). In order to support the ethnographer in the mapping of social formations within social media environments, I propose five analytical concepts: community, public, crowd, self-presentation as a tool, and user as a device