A novel therapeutic strategy for pancreatic neoplasia using a novel RNAi platform targeting PDX-1

Bi-functional shRNA (bi-shRNA), a novel RNA interference (RNAi) effector platform targeting PDX-1 utilizing a systemic DOTAP-Cholesterol delivery vehicle, was studied in three mouse models of progressive pancreatic neoplasia. Species-specific bi-functional PDX-1 shRNA (bi-shRNAPDX-1) lipoplexes inhibited insulin expression and secretion while also substantially inhibiting proliferation of mouse and human cell lines via disruption of cell cycle proteins in vitro. Three cycles of either bi-shRNA<sup>mousePDX-1</sup> or shRNA<sup>mousePDX-1</sup> lipoplexes administered intravenously prevented death from hyperinsulinemia and hypoglycemia in a lethal insulinoma mouse model. Three cycles of shRNA<sup>mousePDX-1</sup> lipoplexes reversed hyperinsulinemia and hypoglycemia in an immune-competent mouse model of pancreatic neoplasia. Moreover, three cycles of the bi-shRNA<sup>humanPDX-1</sup> lipoplexes resulted in near complete ablation of tumor volume and considerably improved survival in a human PANC-1 implanted SCID-mouse model. Human pancreatic neoplasia specimens also stained strongly for PDX-1 expression. Together, these data support the clinical development of a novel therapeutic strategy using systemic bi-shRNA<sup>PDX-1</sup> lipoplexes against pancreatic neoplasia

MS

thesisThis study was conducted to examine four catheter-transducer systems and their variations that were found clinical. The dynamic response characteristics (f[n] and zeta) were determined for each system in both a laboratory and clinical setting. These dynamic responses characteristics provided information about each system in regard to its ability to faithfully reproduce a pressure waveform. From this study it was found that the simpler catheter transducer system has more adequate dynamic response characteristics and thus was more capable of faithfully reproducing the pressure waveforms. The membrane dome was found to be equal in function with the non-membrane dome provided that the manufacturer’s recommended method of attachment, i.e., water instillation on the transducer diaphragm and pressure distension of the dome membrane, was adhered to. It was determined that extension tubing was detrimental to the system’s dynamic response characteristics and, moreover, impedes faithful waveform reproduction. With regard to the pulmonary artery catheter transducer system, it was found that the use of extension rubbing results in an undesirable elongation of the system. In all clinical trials of the pulmonary artery catheter-transducer system, the dynamic response characteristics were over-damped. Finally, it was ascertained that response testing may be easily performed in the clinical setting and provides valuable information with regard to the adequacy of each system. This testing allows for determination of the accuracy of the reproduced waveform to the original patient waveform

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

Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche.

Age at menarche is a marker of timing of puberty in females. It varies widely between individuals, is a heritable trait and is associated with risks for obesity, type 2 diabetes, cardiovascular disease, breast cancer and all-cause mortality. Studies of rare human disorders of puberty and animal models point to a complex hypothalamic-pituitary-hormonal regulation, but the mechanisms that determine pubertal timing and underlie its links to disease risk remain unclear. Here, using genome-wide and custom-genotyping arrays in up to 182,416 women of European descent from 57 studies, we found robust evidence (P < 5 × 10(-8)) for 123 signals at 106 genomic loci associated with age at menarche. Many loci were associated with other pubertal traits in both sexes, and there was substantial overlap with genes implicated in body mass index and various diseases, including rare disorders of puberty. Menarche signals were enriched in imprinted regions, with three loci (DLK1-WDR25, MKRN3-MAGEL2 and KCNK9) demonstrating parent-of-origin-specific associations concordant with known parental expression patterns. Pathway analyses implicated nuclear hormone receptors, particularly retinoic acid and γ-aminobutyric acid-B2 receptor signalling, among novel mechanisms that regulate pubertal timing in humans. Our findings suggest a genetic architecture involving at least hundreds of common variants in the coordinated timing of the pubertal transition

Content, Services, and Space: The Future of the Library as Lines Blur

Traditional roles of libraries, publishers, service providers, and even patrons are continually changing. Libraries increasingly take on functions previously managed by publishers—in some cases, by actually becoming traditional publishers, through the absorption of university press operations and the creation of IR-based journals, and in some cases by making direct investments in dissemination, by underwriting Open Access APCs. Librarians are expanding into learning, instructional design, software development, and more, providing services around the world to a much wider range of patrons. Meanwhile, patron-driven initiatives are continue to alter the way libraries acquire content, giving rise to questions about how collections are built and how publisher business models are morphing. Content types are blurring. Textbooks, reference works, journals, books, audio, video, learning tools, lectures, primary sources, and more are all fair game for course materials, often delivered via Learning Management Systems—bringing publishers and services into the space, as well. Four industry veterans discuss this rapidly changing landscape, identifying key trends and key questions: What happens when libraries become publishers or service providers? How do we measure the success and value of patrons as selectors? What role does discovery play in the modern library? How can subscription content best be leveraged in the classroom? How can pricing be more visible to all? How can assessment help instructors and libraries make better informed decisions? If these overlapping trends continue, they bring with them interesting possibilities for the shifting nature of the library and for a new understanding of what it means to publish. Will the library of the future be the disruptor or the disrupted

Let's hear what we can see

I began with the investigation of sound, especially in relation to the writings of John Cage, and decided to explore the creative relationships of aural and visual perceptions possible through the use of electronic sound and light. It was my intention, through this combination of aural and visual media, to create an environment - one in which the participant would be more aware of what he saw because of what he heard. The physical structure consists of a floating 4'x4'x20½" wood base, and sixteen colored plexiglass cubes on the top, that are internally lighted. The light in each plexiglass cube is wired to respond to high, medium and low frequencies received from the sound source. The tape I am using is a thirty minute continuous loop cartridge. Through experimentation, various electronic sounds and combinations of sounds were selected. I wanted the main emphasis to be on the sound, and as such, to be the controlling factor in the chromatic dispersion of the light

Evolutionary response to global change: Climate and land use interact to shape color polymorphism in a woodland salamander

Evolutionary change has been demonstrated to occur rapidly in human‐modified systems, yet understanding how multiple components of global change interact to affect adaptive evolution remains a critical knowledge gap. Climate change is predicted to impose directional selection on traits to reduce thermal stress, but the strength of directional selection may be mediated by changes in the thermal environment driven by land use. We examined how regional climatic conditions and land use interact to affect genetically based color polymorphism in the eastern red‐backed salamander (Plethodon cinereus). P. cinereus is a woodland salamander with two primary discrete color morphs (striped, unstriped) that have been associated with macroclimatic conditions. Striped individuals are most common in colder regions, but morph frequencies can be variable within climate zones. We used path analysis to analyze morph frequencies among 238,591 individual salamanders across 1,170 sites in North America. Frequency of striped individuals was positively related to forest cover in populations occurring in warmer regions (\u3e7°C annually), a relationship that was weak to nonexistent in populations located in colder regions (≤7°C annually). Our results suggest that directional selection imposed by climate warming at a regional scale may be amplified by forest loss and suppressed by forest persistence, with a mediating effect of land use that varies geographically. Our work highlights how the complex interaction of selection pressures imposed by different components of global change may lead to divergent evolutionary trajectories among populations

Genome-wide association study of Tourette Syndrome

Tourette Syndrome (TS) is a developmental disorder that has one of the highest familial recurrence rates among neuropsychiatric diseases with complex inheritance. However, the identification of definitive TS susceptibility genes remains elusive. Here, we report the first genome-wide association study (GWAS) of TS in 1285 cases and 4964 ancestry-matched controls of European ancestry, including two European-derived population isolates, Ashkenazi Jews from North America and Israel, and French Canadians from Quebec, Canada. In a primary meta-analysis of GWAS data from these European ancestry samples, no markers achieved a genome-wide threshold of significance (p<5 × 10−8); the top signal was found in rs7868992 on chromosome 9q32 within COL27A1 (p=1.85 × 10−6). A secondary analysis including an additional 211 cases and 285 controls from two closely-related Latin-American population isolates from the Central Valley of Costa Rica and Antioquia, Colombia also identified rs7868992 as the top signal (p=3.6 × 10−7 for the combined sample of 1496 cases and 5249 controls following imputation with 1000 Genomes data). This study lays the groundwork for the eventual identification of common TS susceptibility variants in larger cohorts and helps to provide a more complete understanding of the full genetic architecture of this disorder