Design, synthesis and biological evaluation of antidiabetic agents

Diabetes Mellitus is a metabolic disease characterised by hyperglycaemia, resulting from an inability to secrete insulin, a resistance to insulin or both. The number of individuals suffering from Type-2 diabetes (T2D) is currently 336 million and this number is expected to surpass 552 million by the year 2030. Consequently, there exists a need for novel antidiabetic agents for the treatment of T2D. The retinol transporter, RBP4, is a possible target for the treatment of T2D as elevated levels of this protein are found in T2D sufferers. Compounds that reduce the levels of RBP4 in vivo have been found to improve the diabetic condition. Disruption of the RBP4-TTR complex is a known method for decreasing the levels of RBP4. Therefore, reducing the levels of RBP4 provides a mechanism to treat/manage T2D and allows for the identification and synthesis of novel antidiabetic agents. Computational studies were used to identify compounds (1, 2 and 3) that bind within RBP4 and have the potential to prevent the formation of the RBP4-TTR complex. Biological assays (SPR, fluorometric binding assay) were performed on these compounds to verify their ability to bind within the protein cavity of RBP4 and inhibit the formation of the RBP4-TTR complex. A SAR study of compound 1 uncovered compound 4 which was more active than its parent compound in the SPR assay. A subsequent SAR study performed on the new lead compound 4 to identify the functional groups necessary for its biological activity. The derivatives required for this study were synthesised using a variety of chemical processes and were tested in an assay to assess their ability to stimulate muscle cells to take up glucose. This study uncovered a number of compounds with increased activity (64, 79 and 82). While the glucose uptake assay allowed for the identification of a number of active compound 4 derivatives, it also indicated that a secondary protein target was involved as the glucose uptake assay was RBP4 independent. A method for identifying this unknown target was therefore needed. The method chosen involved immobilising active compounds on an affinity column, which is composed of sepharose beads. A solution of cellular proteins is then passed through the column and the subsequent bound proteins are lysed and analysed by mass spectrometry. Immobilisation of compounds onto this column first required the attachment of a PEG linker to each molecule. Compounds 4 and 79 were successfully immobilised on the affinity column; at the time of writing, the results from their biological evulation remain outstanding. A SAR study was also performed on compounds 2 and 3. This uncovered compound 115, which proved to be highly active in the glucose uptake assay. A number of derivatives of compound 2 and 3 have been designed, synthesised and characterised and are currently awaiting biological evaluation. Animal studies were carried out on compounds 1, 4 and 2. Compounds 1 and 4 proved to be more effective than compound 2 at improving the insulin and glucose tolerance of diabetic mice, while also causing a reduced weight gain. Compound 4 was administered to animals after 17 weeks, once insulin resistance had been established. Compound 4 was found to restore both glucose and insulin sensitivity to normal levels. A number of additional animal studies were considered involving compound 4; however these required aqueous solutions of the compound. As compound 4 had proven to be insoluble in aqueous solutions, a method for preparing these solutions was needed. Cyclodextrins (CD) were chosen and the use of 20 eq of hydroxylpropyl-β-CD (HPBCD) gave a 0.02 M 5% DMSO/H2O solution of compound 4. The dissolution of compound 4 may have occurred due to the formation of an inclusion complex. A phase solubility diagram, SEM, DSC and NMR were used in the characterisation of the inclusion complex

Recommendations for Improving Firearms Vetting in Massachusetts

The United States is in a state of conflict over the ability to obtain firearms as well as their use in highly publicized mass shootings. On December 14, 2012, Adam Lanza obtained several firearms that were lawfully owned by his mother, but were improperly secured. Lanza killed his mother that morning and then drove a short distance to the Sandy Hook Elementary School in Newtown, Connecticut where he murdered twenty-six people, many of whom were small children. Lanza eventually turned a gun on himself before being confronted by responding officers. Though mass shootings are often headlines in this country, the vast majority of misused firearms by the mentally ill are tragically used in suicide. The lessons of these examples must be used to augment current firearms policy in an effort to reduce the availability of firearms to those suffering with afflictions that make them ill equipped to have access to them. Though the Commonwealth of Massachusetts asks pointed questions in these areas regarding the fitness of the potential license holder, it collects no data whatsoever regarding other full-time household members where a firearm may be kept, nor what measures the licensee takes to ensure its security. This Article illustrates a policy, grounded in facilitative principles, designed to reduce access to firearms by those mentally incapable of handling them or those with current substance addictions. Key components to the solution’s success should rely on increased vetting of the licensee’s environment and where lawfully owned firearms will be stored, in combination with assessing the risk factors of having been hospitalized for mental health, drug dependence, or alcohol dependence. This recommendation is merely an expansion of questions already used in the current Massachusetts firearms licensing application and would produce additional factors that a licensing official may consider when determining the suitability of an applicant. It is important to note that this would not be an outright prohibition for a licensee, which would likely be constitutionally impermissible. This Article concludes by reemphasizing the importance of giving licensing officials more information to consider in an effort to lower the risk of lawfully owned firearms ending up in the hands of the mentally ill or violent

Some kinetic and thermodynamic aspects of molecular beam epitaxy

The main aim of the work presented in this thesis is to investigate the role of kinetics and thermodynamics in some of the processes encountered during Molecular Beam Epitaxial growth of III-V semiconductors. Comparisons are made with conventional Liquid Phase and Vapour Phase Epitaxial growth which are governed mainly by thermodynamic and kinetic influences respectively. A symmetry-induced kinetic barrier to the incorporation of group II dopants has been identified by application of gas-phase Molecular Orbital (MO) methods to reactions on solid surfaces. As a precursor to this, MO methods have also been used to explain the nature of the surface dimer structure on the (100) surfaces of semiconductors. A thermodynamic model has been developed to describe the native defect concentrations in GaAs and AlGaAs in an ambient As-overpressure. The applicability of this model to MBE growth is discussed. Conditions leading to the diffusion of Be in GaAs and AlGaAs during growth have been examined. This has led to an understanding of the practical growth limits within which Be-doping can be utilised. Thermodynamic and kinetic factors influencing the behaviour of the Be have been discussed. The above-mentioned effect has been used to provide a controllable source of Be for diffusion studies in AlAs/GaAs superlattices. In particular, the role of the superlattice electronic structure in determining the diffusivity has been illuminated

Alien Invasion: America's Battle with Non-Native Animals and Plants

1 p. Review produced for HC 441: Science Colloquium: Willamette River Environmental Health, Robert D. Clark Honors College, University of Oregon, Spring term, 2004

Indigenous free prior informed consent: a case for self determination in World Heritage nomination processes

Free prior informed consent is a critical concept in enacting the rights of Indige- nous People according to the United Nations Declaration on the Rights of Indig- enous Peoples. This paper outlines a case for the inclusion of free prior informed consent in World Heritage nomination processes and examines issues that are problematic when enacting free prior informed consent. Case research was used to analyse current issues in the potential nomination of certain areas of Cape York Peninsula, Australia. The authors’ reflexive engagement within this case offers insights into the praxis of developing a World Heritage nomina- tion consent process. The outcomes of this research were: preconditions need to be addressed to avoid self-exclusion by indigenous representative organisations; the nature of consent needs to account for issues of representation and Indige- nous ways of decision making; the power of veto needs to have formal recogni- tion in the nomination process; and prioritising self-determination within free prior informed consent ensures the intent of the United Nations Declaration on the Rights of Indigenous Peoples. The paper contributes to the human rights agenda of Indigenous People and conservation management processes by help- ing address the issues that will be raised during a World Heritage nomination process

Contributors to the March Issue/Notes

Notes by Nicholas T. Tsiolis, Robert B. Devine, John A. Berry, John L. Towne, John H. Logan, Jr., August P. Petrillo, Richard A. Molique, and J. Frederick Meister

Contributors to the March Issue/Notes

Notes by Nicholas T. Tsiolis, Robert B. Devine, John A. Berry, John L. Towne, John H. Logan, Jr., August P. Petrillo, Richard A. Molique, and J. Frederick Meister

Rocaglates induce gain-of-function alterations to eIF4A and eIF4F

Rocaglates are a diverse family of biologically active molecules that have gained tremendous interest in recent years due to their promising activities in pre-clinical cancer studies. As a result, this family of compounds has been significantly expanded through the development of efficient synthetic schemes. However, it is unknown whether all of the members of the rocaglate family act through similar mechanisms of action. Here, we present a comprehensive study comparing the biological activities of >200 rocaglates to better understand how the presence of different chemical entities influences their biological activities. Through this, we find that most rocaglates preferentially repress the translation of mRNAs containing purine-rich 5' leaders, but certain rocaglates lack this bias in translation repression. We also uncover an aspect of rocaglate mechanism of action in which the pool of translationally active eIF4F is diminished due to the sequestration of the complex onto RNA.P50 GM067041 - NIGMS NIH HHS; R24 GM111625 - NIGMS NIH HHS; R35 GM118173 - NIGMS NIH HHSPublished versio

Techniques for Solution- Assisted Optical Contacting

A document discusses a solution-assisted contacting technique for optical contacting. An optic of surface flatness Lambda/20 was successfully contacted with one of moderate surface quality, or Lambda/4. Optics used were both ultra-low expansion (ULE) glass (Lambda/4 and Lambda/20) and fused silica (Lambda/20). A stainless steel template of the intended interferometer layout was designed and constructed with three contact points per optic. The contact points were all on a common side of the template. The entire contacting jig was tilted at about 30 . Thus, when the isopropanol was applied, each optic slid due to gravity, resting on the contact points. All of the contacting was performed in a relatively dusty laboratory. A number of successful contacts were achieved where up to two or three visible pieces of dust could be seen. These were clearly visible due to refraction patterns between the optic and bench. On a number of optics, the final step of dropping isopropyl between the surfaces was repeated until a successful contact was achieved. The new procedures realized in this work represent a simplification for optical contacting in the laboratory. They will both save time and money spent during the contacting process, and research and development phases. The techniques outlined are suitable for laboratory experiments, research, and initial development stages

Active chiral plasmonics: flexoelectric control of nanoscale chirality

The ability to electrically control the optical properties of metamaterials is an essential capability required for technological innovation. The creation of dynamic electrically tuneable metamaterials in the visible and near IR region are important for a range of imaging and fibre optic technologies. However current approaches require complex nanofabrication processes which are incompatible for low cost device production. Here, we report a novel simple approach for electrical control of optical properties which utilises a flexoelectric dielectric element to electromechanically manipulate the form factor of a chiral nanostructure. By altering the dimensions of the chiral nanostructure, we allow the polarisation properties of light to be electrically controlled. The flexoelectric element is part of a composite metafilm that is templated on to a nanostructured polymer substrate. Since the flexoelectric element does not require in situ high temperature annealing it can be readily combined with polymer‐based substrates produced by high throughput methods. This is not the case for piezoelectric elements, routinely used in microelectromechanical (MEM) devices which require high temperature processing. Consequently, combining amorphous flexoelectric dielectric and low‐cost polymer‐based materials provides a route to the high throughput production of electrically responsive disposable metadevices