The Development of BSN272 From Prevention of Diet-Induced Hyperlipidemia in Mice to a Potential Therapy For Prader-Willi Syndrome in Humans

While type 2 diabetes mellitus (T2DM) is distinguished as a disorder of blood glucose homeostasis, the vast majority of patients afflicted with this disease in the US present with the entire complement of the metabolic syndrome: abdominal obesity, hypertriglyceridemia, low HDL levels, elevated blood pressure, and elevated fasting plasma glucose. Current guidelines aim to treat each of these disorders, but do so individually even though they are manifestations of common pathologies. In other words, a patient will be prescribed different medications for diabetes, blood pressure, CVD prevention, etc., while the only single treatment aimed at the myriad of disorders together is changes to dietary and exercise habits. Diet and exercise, when executed properly, has been shown consistently to be the most effective treatment for T2DM. The rate of type 2 diabetes in the US is close to 10%, but the rate of type 2 diabetes is even higher in patients with Prader-Willi Syndrome (a genetic disease that causes excessive weight gain from overeating, resulting in approximately double the risk of diabetes). BSN272 is a combination of 2 molecules (D-tagatose and trans-polydatin) that have shown benefits in treating individual manifestations of the metabolic syndrome presentation as monotherapy and have proved synergistic when taken together to treat the entire complement of the disorders. Previous research in our lab with D-tagatose included safety studies in animal models and humans for use as a dietary ingredient which culminated with the generally recognized as safe (GRAS) designation by the FDA and EU for use in foods. Based on these exposures to determine safety, an IND was granted to evaluate the safety and efficacy of D-tagatose in treating hyperglycemia in T2DM. Phase 2 and 3 global clinical trials were completed showing D-tagatose to be highly safe and moderately effective. The decision was made to search for a molecular complement to D-tagatose that could more completely treat T2DM. Dihydromyricetin and trans-polydatin were identified through literature searches as potentially synergistic with D-tagatose. Both molecules were tested in combination with D-tagatose for their ability to prevent diet-induced elevations in cholesterol markers in ApoE-/- mice. Dihydromyricetin appeared to be additively effective with D-tagatose for lipids, but transpolydatin showed synergy in prevention of cholesterol elevations as results were greater for the combination than were the additive benefits of either as monotherapy. Trans-polydatin also showed this property in a hyperlipidemic hamster model and a LDLr-/- mouse model. Following safety and efficacy results in three animal models for BSN272, an exploratory Phase 1 PK microdose study was submitted to the FDA in an IND filing to investigate whether the presence of D-tagatose has any effects on the kinetics of trans-polydatin when administered in concert compared to trans-polydatin alone. The indication sought for the IND is Prader-Willi Syndrome (PWS) due to the added potential of D-tagatose to impart satiety and reduce weight gain. PWS is a genetic disorder in which patients develop insatiable hunger that leads to obesity and often diabetes while in childhood. There is currently only symptomatic treatment of the disease and none of the medications in treatment guidelines for adult type 2 diabetes are approved for pediatric use

TWO PROLIFIC COMPOSERS FOR SOLO TUBA: THE COMPLETE WORKS OF ELIZABETH RAUM AND JAMES GRANT

This project began with a search for a single composer that, in the last twenty years, had written challenging, artistically fulfilling music for solo tuba. The objectives were to present their complete repertoire for solo tuba, show the solo tuba range and length of each work, and provide a reference for other tuba players wishing to perform their compositions. Guide to the Tuba Repertoire: The New Tuba Source Book, published in 2006, is a reference book containing, at the time of publication, all known repertoire for the tuba. The first six chapters discuss the tuba and its use in solo literature. Upon examining these chapters I found that no single composer had published enough works to present three full recitals of music that met all my parameters: challenging, artistically fulfilling, and written in the last twenty years. David Uber had written twentyseven pieces, but the majority had either been composed before 1990 or were designed for younger students. André Ameller and Alec Wilder each had twelve works that were very challenging, but fell outside the twenty-year parameter. I had to either alter my standards or look elsewhere for source material. I enjoyed performing the Three Furies for Solo Tuba by James Grant and the Pershing Concerto by Elizabeth Raum before in recitals. I wondered if Grant and Raum had composed more than only those works, so I searched the Internet and found their personal websites. Raum listed eleven works for tuba solo on her website and Grant’s homepage listed nine compositions for tuba. All works of both composers were written between 1991 and 2008. I had met my search parameters

Polyamide/Polyimide Aerogels

An aerogel and method of making the aerogel is disclosed. The aerogel is a polyimide/polyamide hybrid with a cross-linking agent that induces gelation

Prospectus, December 3, 2003

https://spark.parkland.edu/prospectus_2003/1031/thumbnail.jp

Effects of Three Low-Doses of D-Tagatose on Glycemic Control Over Six Months in Subjects with Mild Type 2 Diabetes Mellitus Under Control with Diet and Exercise

The primary objective of this study was to evaluate the safety and the effect of D-tagatose on the glycemic control of subjects with type 2 diabetes as determined by HbA1c levels at the end of 6 months of therapy using the subject\u27s own baseline HbA1c level as a comparator. The determination of the minimal dose required to cause a statistically significant reduction in HbA1c was of particular interest. Eight weeks after screening, the qualifying subjects were randomized to receive one of three doses of D-tagatose: 2.5 g TID, 5.0 g TID or 7.5 g TID. Blood levels of HbA1c, fasting blood glucose concentrations, plasma lipids, changes in body weight, changes in body mass index, and change in insulin levels were checked at each study visit and at the end of the study. Treatment success, as measured by the reduction of HbA1c, was greatest for the 7.5 g D-tagatose dose group, although the difference between the treatments was not statistically significant. For fasting glucose, only the 7.5 g dosage group exhibited reductions from baseline at the 3- and 6-month time points. Mean body weights reduced in a dose-response fashion, with the 5.0 g and the 7.5 g D-tagatose doses providing the greatest reductions. D-tagatose at dosages of 2.5 g, 5.0 g, and 7.5 g TID for six months were well tolerated by this subject population. D-tagatose at 5.0 g TID was the minimal dose required to reduce HbA1c. D-tagatose at 7.5 g TID provided the greatest effect in most measured efficacy parameters

Synthesis and Properties of Cross-Linked Polyamide Aerogels

We report our ongoing research on polyamide aerogels made by step growth polymerization using a combination of terephthaloyl chloride, isophthaloyl chloride and m-phenylenediamine. Crosslinking of the amine capped polymer chains with 1,3,5-benzenetricarbonyl trichloride causes gelation in as little as two to five minutes. Removing the reaction solvent is accomplished through solvent exchange, followed by drying using supercritical CO2 extraction to give colorless aerogels with densities ranging from 0.07 to 0.33 grams per cubic centimeter and surface areas as high as 440 square meters per gram. Statistical experimental design methodology has been utilized to investigate dependence of properties of these aerogels, such as density, compressive modulus, and surface area, on changes in fabrication parameters including formulated number of amide oligomer repeat units (n-value), acid chloride (meta, para or combination), and solids concentration of solution used for gelation. For example, the density of these materials was found to be dependent on the acid chloride type and the solids concentration, but n was not a significant variable. However, surface area was significantly influenced by all three parameters. The polyamide aerogels represent a potential cost savings over previously reported polyimide aerogels, since monomers are all inexpensive and commercially available. Surface area and density were both highest when 100 terephthaloyl chloride was used but a combination of 5 solid concentration, 100 terephthaloyl chloride and n of 20 gave the best combination of properties

Melanesian back-arc basin and arc development: Constraints from the eastern Coral Sea

The eastern Coral Sea is a poorly explored area at the north-eastern corner of the Australian Tectonic Plate, where interaction between the Pacific and Australian plate boundaries, and accretion of the world's largest submarine plateau – the Ontong Java Plateau – has resulted in a complex assemblage of back-arc basins, island arcs, continental plateaus and volcanic products. This study combines new and existing magnetic anomaly profiles, seafloor fabric from swath bathymetry data, Ar–Ar dating of E-MORB basalts, palaeontological dating of carbonate sediments, and plate modelling from the eastern Coral Sea. Our results constrain commencement of the opening of the Santa Cruz Basin and South Rennell Trough to c. 48 Ma and termination at 25–28 Ma. Simultaneous opening of the Melanesian Basin/Solomon Sea further north suggests that a single > 2000 km long back-arc basin, with at least one triple junction existed landward of the Melanesian subduction zone from Eocene–Oligocene times. The cessation of spreading corresponds with a reorganisation of the plate boundaries in the area and the proposed initial soft collision of the Ontong Java Plateau. The correlation between back-arc basin cessation and a widespread plate reorganisation event suggests that back-arc basins may be used as markers for both local and global plate boundary changes.We thank the Captain and crew of R/V Southern Surveyor and Australia's Marine National Facility (MNF) for the success of voyage SS2012_V06. Mineral separation was done by John Simes and Belinda Smith Lyttle. We thank Hugh Davies for his attempts to locate old Solomon Sea dredge samples and Geoscience Australia and New Caledonia agencies for voyage support. We acknowledge funding from the Australian Research Council through grants DP0987713 and FT130101564 (MS), FL0992245 (SEW), IH130200012 (SZ) and DP130101946 (KJM). Support from the New Zealand Government through core funding to GNS Science (NM) is also acknowledged. We thank Robert Holm and an anonymous reviewer for their comments, which improved the quality of the manuscript

The Physical Activity 4 Everyone Cluster Randomized Trial : 2-Year Outcomes of a School Physical Activity Intervention Among Adolescents

Acknowledgments The Physical Activity 4 Everyone intervention trial was funded by the New South Wales Ministry of Health through the New South Wales Health Promotion Demonstration Research Grants Scheme and conducted by Hunter New England Population Health (a unit of the Hunter New England Local Health District), in collaboration with the University of Newcastle and University of Wollongong. Infrastructure support was provided by Hunter Medical Research Institute. The research team acknowledges the importance of making research data publically available. Access to the accelerometer data from this study may be made available to external collaborators following the development of data transfer agreements. Further results arising from the study can be found at www.goodforkids.nsw.gov.au/high-schools/. No financial disclosures were reported by the authors of this paper.Peer reviewedPublisher PD