Differential impact of amino acid substitutions on critical residues of the human glucagon-like peptide-1 receptor involved in peptide activity and small-molecule allosterys

The glucagon-like peptide-1 receptor (GLP-1R) is a class B G protein-coupled receptor that has a critical role in the regulation of glucose homeostasis, principally through the regulation of insulin secretion. The receptor systemis highly complex, able to be activated by both endogenous [GLP-1(1-36)NH2, GLP-1(1-37), GLP-1(7-36)NH2, GLP-1(7-37), oxyntomodulin], and exogenous (exendin-4) peptides in addition to small-molecule allosteric agonists (compound 2 [6,7-dichloro-2-methylsulfonyl-3-tertbutylaminoquinoxaline], BETP [4-(3-benzyloxy)phenyl)-2-ethylsulfinyl-6-(trifluoromethyl)pyrimidine]). Furthermore, the GLP-1R is subject to single-nucleotide polymorphic variance, resulting in amino acid changes in the receptor protein. In this study, we investigated two polymorphic variants previously reported to impact peptidemediated receptor activity (M149) and small-molecule allostery (C333). These residues were mutated to a series of alternate amino acids, and their functionality was monitored across physiologically significant signaling pathways, including cAMP, extracellular signal-regulated kinase 1 and 2 phosphorylation, and intracellular Ca2+ mobilization, in addition to peptide binding and cell-surface expression. We observed that residue 149 is highly sensitive to mutation, with almost all peptide responses significantly attenuated at mutated receptors. However, most reductions in activity were able to be restored by the small-molecule allosteric agonist compound 2. Conversely, mutation of residue 333 had little impact on peptide-mediated receptor activation, but this activity could not be modulated by compound 2 to the same extent as that observed at the wild-type receptor. These results provide insight into the importance of residues 149 and 333 in peptide function and highlight the complexities of allosteric modulation within this receptor system.

An Exploratory Analysis of John Dewey's Writings: Implications for School Leaders

The purpose of this study was to synthesize the operational definition of education through an exploratory analysis of John Dewey’s writings. Dewey’s definition of education changed from 1938 to 1896. Findings suggest that schools promote more social and emotional learning through instructional activities such as service-learning.

Five times daily: the dynamics of prayer worship among Muslim immigrants in St. John's, NL

This thesis explores the ritual of prayer among Muslim immigrants in the city of St. John's, NL. Immigration across national, cultural, religious, and ethnic borders is a moment in an individual's life marked by significant change. My premise is that in such contexts the relatively conservative nature of religious ritual can supply much-needed continuity, comfort, and consolation for individuals living through the immigrant experience. As well, ritual forms are often put under stress when transferred to a considerably different place and cultural context, where “facts on the ground” may be obstacles to traditional and familiar ritual forms. Changes to the understanding or practice of ritual are common in new cultural and geographic situations, and ritual itself often becomes not merely a means of social identification and cohesion, but a practical tool in processing change - in the context of immigration, in learning to live in a new community. St. John's is a lively and historic city and while Muslim immigrants may be a small group within it they nevertheless contribute to the city's energy and atmosphere. This thesis endeavours to better understand the life stories of ten of these newcomers to St. John's, focusing on their religious backgrounds and lives. In particular, this thesis seeks to better understand the place of prayer in the immigrant experience.

Characterisation of the TNF superfamily members CD40L and BAFF in the small-spotted catshark (Scyliorhinus canicula)

Copyright © 2015. Published by Elsevier Ltd.

Characterisation of the TNF superfamily members CD40L and BAFF in the small-spotted catshark (Scyliorhinus canicula)

Copyright © 2015. Published by Elsevier Ltd.

Using Doubly-Labeled Water to Measure Energy Expenditure in an Important Small Ectotherm Drosophila melanogaster

Open Access funded by Wellcome Trust for University College London (UCL) authors. Acknowledegements Funding for this work was provided by the Wellcome Trust (MDWP, LP). John Speakman was supported by the Strategic Priority Research Program of the Chinese Academy of Sciences (No. XDB13030000) a 1000 talents professorship. We are grateful to Peter Thomson and Paula Redman for technical assistance with isotope analysis

Common Bound: The Small Groups of Methodism

The system of small groups John Wesley established to promote a proper life of discipleship in early Methodist converts was, in many respects, the strength of the Methodist movement. Those who responded to Wesley’s initial invitation to “flee the wrath to come” were organized into large gatherings called “societies,” which were then subdivided into smaller bands, class meetings, select societies, and penitent bands. The smaller groups gave Wesley the opportunity, through a system of appointed leaders, to keep track of the spiritual progress of every member in his movement, which grew to tens of thousands by the time of his death in 1791. As Methodism shifted from renewal movement to institutional church in the nineteenth century, however, growth slowed, and participation in such groups declined rapidly. By the early twentieth century, classes and bands were virtually extinct in every sector of Methodism save the African-American tradition. In recent years, scholars in various sectors of the Wesleyan tradition, particularly David Lowes Watson and Kevin Watson, have called for a recovery of these small groups for purposes of renewal in the church. There is no consensus, however, concerning what exactly contributed to the vitality of these groups during Wesley’s ministry.

Over the last century, sociological studies of group dynamics have revealed three common traits that are crucial to highly functioning groups: interdependence created by the existence of a common goal, interaction among group members that is “promotive” or cooperative in nature, and high levels of feedback associated with personal responsibility and individual accountability. All three of these were prevalent in the early Methodist groups. Interdependence existed around a shared goal, which for Wesley and the Methodists was holiness. That interdependence was cooperative in nature; individuals experienced the empowering grace of God as they each pursued the goal in the company of fellow pilgrims. Finally, the groups existed for purposes of feedback and accountability as individuals took responsibility both for themselves and others as they progressed together toward the goal of holy living. Wesley seemed to instinctively understand the essential nature of each of these characteristics in maintaining the vitality of the movement when he spoke of the importance of preserving the “doctrine, spirit and discipline” of early Methodism. Analysis of some of the present-day attempts to restore Wesley’s groups reveals frequent neglect to one or more of these three components. Perhaps most critical to recovering the vitality of the early Methodist groups will be reclaiming the goal of sanctification and coming to a consensus on what its pursuit means in the present day.

The effectiveness of corporate Web in small and médiumsized business: an analysis of Web Usability

Internet and the Web have changed the way that companies communicate with their publics, improving relations between them. Also providing substantial benefits for organizations. This has led to small and medium enterprises (SMEs) to develop corporate sites to establish relationships with their audiences. This paper, applying the methodology of content analysis, analyzes the main factors and tools that make the Websites usable and intuitive sites that promote better relations between SMEs and their audiences. Also, it has developed an index to measure the effectiveness of Webs from the perspective of usability. The results indicate that the Websites have, in general, appropriate levels of usability.

El multilateralismo como intervencionismo. Estados Unidos y la Sociedad de Naciones en América Latina (1930-1946)

Este artículo analiza una dinámica de intervenciones de Estados Unidos en América Latina que no ha atraído suficientemente la atención de los historiadores. En los años treinta y cuarenta, cuando Europa se hundía en una nueva confrontación bélica, ciertos sectores del gobierno y del mundo empresarial norteamericano intentaron articular una nueva relación con los países del continente basada en una propuesta de multilateralismo que se había configurado dentro de la Sociedad de Naciones (SN). Estos estadounidenses intentaron establecer una dinámica de relaciones triangulares con los gobiernos latinoamericanos y los organismos técnicos de la SN. Gracias a ello, como se mostrará en este artículo para el caso del funcionamiento del Comité Fiscal de la Sociedad de Naciones, los latinoamericanos fueron capaces de influir en el tipo de políticas que debían emanar de esta relación triangular. La importancia de esta historia no es menor. La relación triangular entre Estados Unidos, América Latina y la SN sirvió de base para la reconstrucción de la gobernanza global liderada por los Estados Unidos tras la guerra.

The Kepler-454 system: a small, not-rocky inner planet, a Jovian world, and a distant companion

Kepler-454 (KOI-273) is a relatively bright (V = 11.69 mag), Sun-like star that hosts a transiting planet candidate in a 10.6 day orbit. From spectroscopy, we estimate the stellar temperature to be 5687 ± 50 K, its metallicity to be [m/H] = 0.32 ± 0.08, and the projected rotational velocity to be v sin i <2.4 km s^-1. We combine these values with a study of the asteroseismic frequencies from short cadence Kepler data to estimate the stellar mass to be , the radius to be 1.066 ± 0.012 R_o, and the age to be Gyr. We estimate the radius of the 10.6 day planet as 2.37 ± 0.13 R_⊕. Using 63 radial velocity observations obtained with the HARPS-N spectrograph on the Telescopio Nazionale Galileo and 36 observations made with the HIRES spectrograph at the Keck Observatory, we measure the mass of this planet to be 6.8 ± 1.4 M_⊕. We also detect two additional non-transiting companions, a planet with a minimum mass of 4.46 ± 0.12 M_J in a nearly circular 524 day orbit and a massive companion with a period >10 years and mass >12.1 M_J. The 12 exoplanets with radii ⊕ and precise mass measurements appear to fall into two populations, with those ⊕ following an Earth-like composition curve and larger planets requiring a significant fraction of volatiles. With a density of 2.76 ± 0.73 g cm^-3, Kepler-454b lies near the mass transition between these two populations and requires the presence of volatiles and/or H/He gas.

Challenges in molecular testing in non-small-cell lung cancer patients with advanced disease

Lung cancer diagnostics have progressed greatly in the previous decade. Development of molecular testing to identify an increasing number of potentially clinically actionable genetic variants, using smaller samples obtained via minimally invasive techniques, is a huge challenge. Tumour heterogeneity and cancer evolution in response to therapy means that repeat biopsies or circulating biomarkers are likely to be increasingly useful to adapt treatment as resistance develops. We highlight some of the current challenges faced in clinical practice for molecular testing of EGFR, ALK, and new biomarkers such as PDL1. Implementation of next generation sequencing platforms for molecular diagnostics in non-small-cell lung cancer is increasingly common, allowing testing of multiple genetic variants from a single sample. The use of next generation sequencing to recruit for molecularly stratified clinical trials is discussed in the context of the UK Stratified Medicine Programme and The UK National Lung Matrix Trial.

Financial Inclusion of The Small and Marginal Farmers by the Banking Sector in Kerala

Financial inclusion for inclusive growth is central to the developmental philosophy of most of the nations over the past decade. It has been a priority for policy makers and regulators in financial sector development for improving access and usage of financial services to achieve comprehensive financial inclusion. The initiatives taken towards financial inclusion can promote a more effective and efficient process to achieve significant improvements in financial inclusion are to establish and achieve shared and sustainable development and growth. Realising this, an increasing number of countries are committing to promote financial inclusion, encouraged by the growing body of country level experiences (World Bank, 2012). Financial inclusion basically means, broad based growth through participation as well as sharing the benefits from the growth process along with the under privileged and marginal segments of the economy. Evidence suggests that it has substantial benefits for equitable and sustainable growth. Inclusive growth ensures that while economy grows rapidly, all segments of society are involved in this growth process, ensuring equal opportunities, devoid of any regional or sectoral disparitiesIt is widely acknowledged that the objective ofinclusive growth is accomplished through the process of financial inclusion. Financial inclusion envisages bringing everyone, irrespective of financial status, into the banking fold for the individual progress and development and thereby achieving comprehensive growth with equity

Midwest Technology Assistance Center for Small Public Water Systems Final Report

U.S. Environmental Protection Agency

Futuretalk: one small step towards a Chronolinguistics

In the area of linguistics and language teaching, science fiction is useful in very many ways. An obvious way is that it sets up many complex and rich worlds and outlines the sorts of adjustments that language must make in those contexts. It thus draws a strong link between language and context; it shows how the construction of reality is largely a matter of language; and it speculates on where we are linguistically heading. It is a useful mirror on language development. Extrapolating the dialects of the future has been the province of science fiction in the last century. Though few SF writers are professional linguists, their method in general tends to take a holistic view of form, meaning and social context. Characters in science fiction are not individuals but are 'everyman' tokens, and the language they use symbolises the culture they inhabit. Linguistic extrapolation in science fiction thus treats language both as the technology of communication and as an index of social change. In this paper, I argue that predicting the language of the future, though extremely difficult, is possible. I call this new discipline chronolinguistics, and I set out the draft principles and parameters of a chronolinguistics, based on the future languages speculated by John Brunner, Russell Hoban, William Gibson, Greg Bear, Neal Stephenson and Iain M.Banks.

Conflitos ambientais e progresso técnico na indústria mineira e metalúrgica em Portugal (1858-1938)

This chapter explores the relationship between environmental conflicts and technical progress, trying to understand, in the case of large mines of the Iberian Pyrite Belt, in Alentejo, how emerging environmental problems conditioned the performance or led to the search for alternative technical solutions, taking as chronological limit for this observation the beginning of World War II. In the absence of the archives of the companies, the research was based on existing administrative documents in the state archives (mining engineers reports, the licensing of mining activities), on reports and documents published in specialized mining press, in particular, the Bulletin of the Ministry of Public Works, Trade and Industry, the Journal of Public Works, Trade and Industry (both in Portuguese), and finally in the local press. Despite that limitation, the information available shows that in global competition markets, the success of the British enterprise in Santo Domingo had the active search for new technical solutions for the creation and adaptation of existing knowledge to local problems in order to maximize the mineral resources available. The early development of the hydrometallurgical processes for the treatment of poor ores, named ‘natural cementation’, can be explained as the way these companies tried to solve problems of competitiveness, boosting economies of scale. Thus, they transferred the environmental costs previously limited to agriculture to more fragile social groups, the poor fishermen of Guadiana River and of Vila Real de Santo António. Therefore, the hydrometallurgy of pyrites was developed locally, pioneered in Santo Domingo that allowed the survival and expansion of the British company from the late 1870s, that is, at a time when most small mines shut since they were not able to compete globally. Through different consented and regulated processes (judicial), through conflict or parliamentary mediation, the State imposed exceptionally additional costs to companies, either for compensation, the imposing the application of remediation measures to reduce the environmental damage in some cases, thus contributing to derail some projects. These cases suggest that the interaction between local conflicts, corporate behavior and technological progress proves to be complex. This article aims to contribute to the debate on economic and social history between the environment and technological progress, arguing that the fixed costs and economic imponderable social risks were factors that encouraged the companies to search for new solutions and to introduce innovations since that would allow the expansion of their activity. In this process the companies sometimes faced environmental dilemmas and unforeseen costs with consequences on the economy of firms. The nature of the knowledge needed to address the environmental problems they created, however, is of a very different nature from that knowledge needed to face the environmental burdens that were inherent to the development of its activity.