Novel free fatty acid receptor 1 (GPR40) agonists based on 1,3,4-thiadiazole-2-carboxamide scaffold

Free fatty acid receptor 1 (FFA1), previously known as GPR40 is a G protein-coupled receptor and a new target for treatment of type 2 diabetes. Two series of FFA1 agonists utilizing a 1,3,4-thiadiazole-2-caboxamide scaffold were synthetized. Both series offered significant improvement of the potency compared to the previously described 1,3,4-thiadiazole-based FFA1 agonists and high selectivity for FFA1. Molecular docking predicts new aromatic interactions with the receptor that improve agonist potency. The most potent compounds from both series were profiled for in vitro ADME properties (plasma and metabolic stability, LogD, plasma protein binding, hERG binding and CYP inhibition). One series suffered very rapid degradation in plasma and in presence of mouse liver microsomes. However, the other series delivered a lead compound that displayed a reasonable ADME profile together with the improved FFA1 potency.

Footbridge system identification using wireless inertial measurement units for force and response measurements

With the main focus on safety, design of structures for vibration serviceability is often overlooked or mismanaged, resulting in some high profile structures failing publicly to perform adequately under human dynamic loading due to walking, running or jumping. A standard tool to inform better design, prove fitness for purpose before entering service and design retrofits is modal testing, a procedure that typically involves acceleration measurements using an array of wired sensors and force generation using a mechanical shaker. A critical but often overlooked aspect is using input (force) to output (response) relationships to enable estimation of modal mass, which is a key parameter directly controlling vibration levels in service.

This paper describes the use of wireless inertial measurement units (IMUs), designed for biomechanics motion capture applications, for the modal testing of a 109 m footbridge. IMUs were first used for an output-only vibration survey to identify mode frequencies, shapes and damping ratios, then for simultaneous measurement of body accelerations of a human subject jumping to excite specific vibrations modes and build up bridge deck accelerations at the jumping location. Using the mode shapes and the vertical acceleration data from a suitable body landmark scaled by body mass, thus providing jumping force data, it was possible to create frequency response functions and estimate modal masses.

The modal mass estimates for this bridge were checked against estimates obtained using an instrumented hammer and known mass distributions, showing consistency among the experimental estimates. Finally, the method was used in an applied research application on a short span footbridge where the benefits of logistical and operational simplicity afforded by the highly portable and easy to use IMUs proved extremely useful for an efficient evaluation of vibration serviceability, including estimation of modal masses.

Free fatty acid receptor 1 (GPR40) agonists containing spirocyclic periphery inspired by LY2881835

The free fatty acid receptor 1 (FFA1), a G protein-coupled receptor (GPCR) naturally activated by long-chain fatty acids is a novel target for the treatment of metabolic diseases. The basic amine spirocyclic periphery of Eli Lilly's drug candidate LY2881835 for treatment of type 2 diabetes mellitus (which reached phase I clinical trials) inspired a series of novel FFA1 agonists. These were designed to incorporate the 3-[4-(benzyloxy)phenyl]propanoic acid pharmacophore core decorated with a range of spirocyclic motifs. The latter were prepared via the Prins cyclization and subsequent modification of the 4-hydroxytetrahydropyran moiety in the Prins product. Here, we synthesize 19 compounds and test for FFA1 activity. Within this pilot set, a nanomolar potency (EC50=55nM) was reached. Four lead compounds (EC50 range 55-410nM) were characterized for aqueous solubility, metabolic stability, plasma protein binding and Caco-2 permeability. While some instability in the presence of mouse liver microsomes was noted, mouse pharmacokinetic profile of the compound having the best overall ADME properties was evaluated to reveal acceptable bioavailability (F=10.3%) and plasma levels achieved on oral administration.

This battle was not over: Parade’s End as a transitional text in the development of ‘disenchanted’ First World War literature.

This chapter argues that the novels of Ford's Parade's End tetralogy occupy a significant place in the development of "disenchanted" fiction about the First World War. The values of Ernest Raymond's patriotic Tell England are contrasted with those of C. E Montague's Disenchantment, providing a brief synopsis of the early 1920s response to the conflict. Parade's End is seen as introducing several key themes in to the post-First World War discursive field, including national identity, psychology, memory, and time. The presentation of these aligned with the formal aspects of the novel, allows it to push the boundaries of the readerly horizon of expectations. Frayn argues that Ford's readership, though moderately-sized, was influential from a literary point of view, and thus facilitated the reception of later, more vitriolic, criticisms of war.

Lucien Wolf and David Mowshowitch papers, [ca. 1869-1959]

Correspondence, reports, minutes, manuscripts, and clippings relating to the activities of Wolf, Mowshowitch, and the Joint Foreign Committee, as well as to the political situation of Jews in various countries and to the Paris Peace Conference. Papers of Lucien Wolf include his diary, lectures on English-German relations and English-Russian relations; bibliography of Wolf's works on Jewish themes; clippings of Wolf's articles; congratulations on his seventieth birthday; article on his last interview with Chamberlain; and correspondence with parents, 1869-1882, A. Abrahams, 1914-1925, Chief Rabbi Dr. J.H. Hertz, 1892-1923, Clara Melchior, 1913-1929, Jacob Schiff, 1910, Maxim Vinawer, 1917, Mark Wischnitzer, 1926-1928, Lord Robert Cecil, 1916-1919, Lord Rothschild, 1906, Cyrus Adler, Count J. Bernstorff, Szymon Ashkenazy, Solomon Dingol, Louis Marshall, Claude G. Montefiore, Sir Edward Sassoon, Jacob Schiff, Lord William Selborne, Nakhum Sokolow, Oscar Straus, Chaim Weizmann, the American Jewish Congress, 1916-1923, Hilfsverein der Deutschen Juden, 1913, and Jewish Historical Society of England.

Tratamentos de fibras de carnaúba [copernicia prunífera (miller) h. e. moore] para o desenvolvimento de compósito biodegradável com matriz de polihidroxibutirato

The use of raw materials from renewable sources for production of materials has been the subject of several studies and researches, because of its potential to substitute petrochemical-based materials. The addition of natural fibers to polymers represents an alternative in the partial or total replacement of glass fibers in composites. In this work, carnauba leaf fibers were used in the production of biodegradable composites with polyhydroxybutyrate (PHB) matrix. To improve the interfacial properties fiber / matrix were studied four chemical treatments to the fibers..The effect of the different chemical treatments on the morphological, physical, chemical and mechanical properties of the fibers and composites were investigated by scanning electron microscopy (SEM), infrared spectroscopy, X-ray diffraction, tensile and flexural tests, dynamic mechanical analysis (DMA), thermogravimetry (TGA) and diferential scanning calorimetry (DSC). The results of tensile tests indicated an increase in tensile strength of the composites after the chemical treatment of the fibers, with best results for the hydrogen peroxide treated fibers, even though the tensile strength of fibers was slightly reduced. This suggests a better interaction fiber/matrix which was also observed by SEM fractographs. The glass transition temperature (Tg) was reduced for all composites compared to the pure polymer which can be attributed to the absorption of solvents, moisture and other low molecular weight molecules by the fibers

As experiências femininas na AIB, 1932-1938: revendo o passado : gênero e representações

Pós-graduação em Ciências Sociais - FFC

A contemporaneidade da produção do Circo Chiarini no Brasil de 1869-1872

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

A “REVOLTA” DE JEÚ E A ESTELA DE DÃ: Um Estudo Em 2 Reis 10,28-36

A pesquisa tem por objetivo trabalhar o evento da Revolta de Jeú, em conjunto com a Estela de Dã, tendo como ponto de partida para tal, a exegese da perícope de 2 Reis 10-28,36. A história Deuteronomista apresenta o ato da Revolta de Jeú como sendo um feito demasiadamente importante, na restauração do culto a Javé em Israel, a partir de um contexto onde o culto a outras divindades, em Israel Norte, estava em pleno curso. No entanto, a partir da análise conjunta da Estela de Dã, que tem como provável autor o rei Hazael de Damasco, somos desafiados a ler esta história pelas entrelinhas não contempladas pelo texto, que apontam para uma participação ativa de Hazael, nos desfechos referentes a Revolta de Jeú, como sendo o responsável direto que proporcionou a subida de Jeú ao trono em Israel, clarificando desta forma este importante período na história Bíblica. Para tal análise, observar-se-á três distintos tópicos, ligados diretamente ao tema proposto: (1) A Revolta de Jeú e a Redação Deuteronomista, a partir do estudo exegético da perícope de 2 Reis 10,28-36, onde estão descritas informações pontuais sobre período em que Jeú reinou em Israel; (2) Jeú e a Estela de Dã, a partir da apresentação e análise do conteúdo da Estela de Dã, tratando diretamente dos desdobramentos da guerra em Ramote de Gileade, de onde se dá o ponto de partida à Revolta de Jeú; e por fim (3) O Império da Síria, onde a partir da continuidade da análise do conteúdo da Estela de Dã, demonstraremos a significância deste reino, além de apontamentos diretamente ligados ao reinado de Hazael, personagem mui relevante no evento da Revolta de Jeú.

Catharine Waugh McCullouch papers in the Mary Earhart Dillon collection, 1869-1945

Collection primarily documents McCulloch's research on women's legal status, and her work with the Illinois Equal Suffrage Association, the National American Woman Suffrage Association, and the League of Women Voters. There is also documentation of women in the legal profession, of McCulloch's friendships with the other women suffragists and lawyers, and some biographical material. The papers contain little information about her family or social life.

Account book : manuscript, 1793-1869

Account of cash paid out to various people.

La geografia di Dante secondo Edoardo Moore;

Translation of: The geography of Dante.

Early American families : the Williams, Moore, McKitrick, Fonda, Van Allen, Lanning, King, Justice, Cunningham, Longacre, Swanson and Cox families, with numerous related families embracing the ancestors of perhaps 100,000 or more, covering over 330 years, from 1580 to 1916 /

The plates, printed on both sides, consist of family portraits.

Speech of the Hon. Daniel Webster at the National Republican convention, in Worcester, Oct. 12, 1832.

Sabin 102282.

A history of the Daniel Boone National Forest, 1770-1970 /

Includes appendices.