Pharmacoperone Identification for Therapeutic Rescue of Misfolded Mutant Proteins

G protein-coupled receptors (GPCRs), which includes the gonadotropin-releasing hormone (GnRH) receptor (GnRHR), comprises the largest family of validated drug targets – more than half of all approved drugs derive their benefits by selective targeting of GPCRs. Most drugs in this class are either agonists or antagonists of GPCRs and high throughput screens have typically been designed and performed with a view toward identification of such compounds as lead drug candidates. This manuscript presents the case that valuable drugs which effect the trafficking of GPCRs may have been overlooked because pharmacoperones have been selected from existing screens that identify agonists and antagonists. A “gain of activity assay” is proposed; this assay relies on the expression of a mutant of the GnRHR that is known to be rescuable by pharmacoperone drugs, and which is restored to activity in their presence. Accordingly, “hits” are identified by the appearance of activity. The gene for the mutant is under control of tetracycline and may be prevented from being expressed. This is a valuable feature since it allows false positives to be identified. Such drugs will show apparent activity whether or not the mutant is expressed. This assay will enable identification of these drugs from chemical libraries and does not rely on their activity as agonists or antagonists

The Canis Major Dwarf Galaxy

Recent observational evidence suggests that the Sagittarius dwarf galaxy represents the only major ongoing accretion event in the Galactic halo, accounting for the majority of stellar debris identified there. This paper summarizes the recent discovery of another potential Milky Way accretion event, the Canis Major dwarf galaxy. This dwarf satellite galaxy is found to lie just below the Galactic plane and appears to be on an equatorial orbit. Unlike Sagittarius, which is contributing to the Galactic halo, the location and eventual demise of Canis Major suggests that it represents a building block of the thick disk.Comment: Refereed contribution to "Structure & Dynamics in the Local Universe, a workshop to honour Brent Tully's 60th birthday", Nov 2003. 4 pages + 2 figures (quality reduced due to size restrictions). To appear in PAS

An Exploratory Study of Suboxone (Buprenorphine/ Naloxone) Film Splitting: Cutting Methods, Content Uniformity, and Stability

Suboxone films are U.S. Food and Drug Administration approved to treat opioid dependence. While the package insert states that films should not be cut, physicians often prescribe film fractions for treatment and tapering. There is no data to support this practice, and this study was initiated to evaluate cutting methods, content uniformity, and stability of split films. Suboxone 8-mg buprenorphine/2-mg naloxone films were split using four methods: 1) ruler/razor cut, 2) scissor cut, 3) fold/rip, and 4) fold/scissor cut. United States Pharmacopeia Chapter \u3c905\u3e was used to evaluate the weight variation and content uniformity of split films. The stability of split films stored in polybags was evaluated over 7 days. A stability-indicating high-performance liquid chromatography method was used for content uniformity and stability evaluation. The weight variation results were acceptable for the half films from all four cutting methods, but this was not true for the quarter films. The method of ruler/razor cut was determined most favorable and used for the content uniformity test. Based on the high-performance liquid chromatography results, the half films from the ruler/razor cut method met the passing criteria of United States Pharmacopeia Chapter \u3c905\u3e with acceptance values of 9.8 to 10.4 for buprenorphine and 8.4 to 11.5 for naloxone (≤15 is considered passing). The stability results indicated that both actives retained \u3e97.7% of initial strength. Four cutting methods were found to be acceptable for splitting Suboxone films into half but not quarter fractions. The half films from the ruler/razor cut method also passed United States Pharmacopeia Chapter \u3c905\u3e content uniformity test. Both actives remained stable for 7 days when the half films were stored in polybags at room temperature

Business and in-work benefits: perspectives and priorities

In the UK alone, millions of individuals receive in-work benefits (IWBs), and these form a substantial part of total government spending. Previous research has given attention to the costs and delivery of IWBs, but relatively little is known about business perspectives on IWBs and how policymakers perceive business’ relationship with IWBs, which form the subject of this thesis. The thesis also seeks to understand how this important policy area affects business priorities and what this means for their collectively expressed views. These issues are investigated through a review of literature from the social sciences, and original research analysing material from Hansard, business responses to relevant government consultations, and the Confederation of British Industry archives. Each covers a different combination of actors, document types, and periods, enabling a study of the developing understandings of the relationship between business and in-work benefits. IWBs are government subsidies to people who are in current work, or their dependents; where being in current employment is a qualifying criterion for the benefit or an element of it. They tend to be viewed primarily as social welfare benefits that are aimed at workers, but they also operate as important corporate welfare benefits. This fact tends to be absent from mainstream debate and is often downplayed or ignored by business. A deeper and more detailed exploration of this area reveals some recognition of the corporate welfare dimensions of in-work benefits. Benefits and disbenefits to both individuals and business are recognised by Parliamentarians and by business. Some business organisations put significant effort into influencing IWB policy, with success in the area of administrative costs. This research expands the literature in the field, and provides lessons for policymakers in ensuring businesses are aware of the benefits they receive from IWBs

Operating Small Sat Swarms as a Single Entity: Introducing SODA

NASA’s decadal survey determined that simultaneous measurements from a 3D volume of space are advantageous for a variety of studies in space physics and Earth science. Therefore, swarm concepts with multiple spacecraft in close proximity are a growing topic of interest in the small satellite community. Among the capabilities needed for swarm missions is a means to maintain operator-specified geometry, alignment, or separation. Swarm stationkeeping poses a planning challenge due to the limited scalability of ground resources. To address scalable control of orbital dynamics, we introduce SODA – Swarm Orbital Dynamics Advisor – a tool that accepts high-level configuration commands and provides the orbital maneuvers needed to achieve the desired type of swarm relative motion. Rather than conventional path planning, SODA’s innovation is the use of artificial potential functions to define boundaries and keepout regions. The software architecture includes high fidelity propagation, accommodates manual or automated inputs, displays motion animations, and returns maneuver commands and analytical results. Currently, two swarm types are enabled: in-train distribution and an ellipsoid volume container. Additional swarm types, simulation applications, and orbital destinations are in planning stages

A mathematical model for LH release in response to continuous and pulsatile exposure of gonadotrophs to GnRH

In a previous study, a model was developed to investigate the release of luteinizing hormone (LH) from pituitary cells in response to a short pulse of gonadotropin-releasing hormone (GnRH). The model included: binding of GnRH to its receptor (R), dimerization and internalization of the hormone receptor complex, interaction with a G protein, production of inositol 1,4,5-trisphosphate (IP(3)), release of calcium from the endoplasmic reticulum (ER), entrance of calcium into the cytosol via voltage gated membrane channels, pumping of calcium out of the cytosol via membrane and ER pumps, and release of LH. The extended model, presented in this paper, also includes the following physiologically important phenomena: desensitization of calcium channels; internalization of the dimerized receptors and recycling of some of the internalized receptors; an increase in G(q )concentration near the plasma membrane in response to receptor dimerization; and basal rates of synthesis and degradation of the receptors. With suitable choices of the parameters, good agreement with a variety of experimental data of the LH release pattern in response to pulses of various durations, repetition rates, and concentrations of GnRH were obtained. The mathematical model allows us to assess the effects of internalization and desensitization on the shapes and time courses of LH response curves

Molecular recognition of adenosine derivatives

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemistry, 1994.Includes bibliographical references (p. 127-131).by Michael Morgan Conn.Ph.D

Affirming Michigan\u27s Action: The Michigan Journal of Race & Law\u27s Response to Dr. Carcieri\u27s Grutter v. Bollinger and Civil Disobedience

One of two articles in this issue on Grutter v. Bollinger; this is a response to Martin D. Carcieri\u27s article Grutter v. Bollinger and Civil Disobedience

2U Chassis Accepts PCIe or PXIe Cards

PCIe and PXIe are both open-standards for expansion and I/O cards, both enabling the end user of the system to configure the desired I/O to suit their needs. The problem is that the two cards are not space-compatible, requiring systems manufacturers to create two separate product to address both markets. This article discloses a modular design that can accept either a PCIe or PXI/PCIe card carrier, thus allowing the main chassis and compute solution to be common for both versions. This example is a compact, 2U tall, industrial compute platform

Propulsion Trade Studies for Spacecraft Swarm Mission Design

Spacecraft swarms constitute a challenge from an orbital mechanics standpoint. Traditional mission design involves the application of methodical processes where predefined maneuvers for an individual spacecraft are planned in advance. This approach does not scale to spacecraft swarms consisting of many satellites orbiting in close proximity; non-deterministic maneuvers cannot be preplanned due to the large number of units and the uncertainties associated with their differential deployment and orbital motion. For autonomous small sat swarms in LEO, we investigate two approaches for controlling the relative motion of a swarm. The first method involves modified miniature phasing maneuvers, where maneuvers are prescribed that cancel the differential delta V of each CubeSat's deployment vector. The second method relies on artificial potential functions (APFs) to contain the spacecraft within a volumetric boundary and avoid collisions. Performance results and required delta V budgets are summarized, indicating that each method has advantages and drawbacks for particular applications. The mini phasing maneuvers are more predictable and sustainable. The APF approach provides a more responsive and distributed performance, but at considerable propellant cost. After considering current state of the art CubeSat propulsion systems, we conclude that the first approach is feasible, but the modified APF method of requires too much control authority to be enabled by current propulsion systems