Comparative effects of GLP-1 and GIP on cAMP production, insulin secretion, and in vivo antidiabetic actions following substitution of Ala8/Ala2 with 2-aminobutyric acid

The two major incretin hormones, glucagon-like peptide-1 (GLP-1), and glucose-dependent insulinotropic polypeptide (GIP), are currently being considered as prospective drug candidates for treatment of type 2 diabetes. Interest in these gut hormones was initially spurred by their potent insulinotropic activities, but a number of other antihyperglycaemic actions are now established. One of the foremost barriers in progressing GLP-1 and GIP to the clinic concerns their rapid degradation and inactivation by the ubiquitous enzyme, dipeptidyl peptidase IV (DPP IV). Here, we compare the DPP IV resistance and biological properties of Abu(8)/ Abu(2) (2-aminobutyric acid) substituted analogues of GLP-1 and GIP engineered to impart DPP IV resistance. Whereas (Abu(8))GLP-1 was completely stable to human plasma (half-life > 12h), GLP-1, GIP, and (Abu(2))GIP were rapidly degraded (half-lives: 6.2, 6.0, and 7.1 h, respectively). Native GIP, GLP-1, and particularly (Abu(8))GLP-1 elicited significant adenylate cyclase and insulinotropic activity, while (Abu(2))GIP was less effective. Similarly, in obese diabetic (ob/ob) mice, GIP, GLP-1, and (Abu(8))GLP-1 displayed substantial glucose-lowering and insulin -releasing activities, whereas (Abu(2))GIP was only weakly active. These studies illustrate divergent effects of penultimate amino acid Ala(8)/Ala(2) substitution with Abu on the biological properties of GLP-1 and GIP, suggesting that (Abu(8))GLP-1 represents a potential candidate for future therapeutic development. (C) 2004 Elsevier Inc. All rights reserved.

Celtic languages in European Higher Education: CRAMLAP - Celtic, Regional and Minority Languages Abroad Project

The Celtic, Regional and Minority Languages Abroad
Project (CRAMLAP) is funded by the European Commission
to research the provision and pedagogy of regional
and minority languages outside their national borders in
Europe. The teaching of Celtic languages across Europe
was the focus in year one (2003-2004). This article summarizes
the qualitative data received in response to
questionnaires sent to institutions across Europe offering
Celtic Studies. Responses indicated that Celtic Studies
are quite widely available across Europe. The languages
are taught in comparative linguistics, linguistics and English
departments, with few dedicated Celtic departments
or sections outside the Celtic countries. Irish is supported
abroad by Irish government grant aid which will
become more widely available in the immediate future.
Many of the teachers have considerable experience, but
limited pedagogic training. The lack of suitable teaching
resources is the most commonly expressed concern.

Efficient FPGA Hardware Development: A Multi-Language Approach

This paper presents a multi-language framework to FPGA hardware development which aims to satisfy the dual requirement of high-level hardware design and efficient hardware implementation. The central idea of this framework is the integration of different hardware languages in a way that harnesses the best features of each language. This is illustrated in this paper by the integration of two hardware languages in the form of HIDE: a structured hardware language which provides more abstract and elegant hardware descriptions and compositions than are possible in traditional hardware description languages such as VHDL or Verilog, and Handel-C: an ANSI C-like hardware language which allows software and hardware engineers alike to target FPGAs from high-level algorithmic descriptions. On the one hand, HIDE has proven to be very successful in the description and generation of highly optimised parameterisable FPGA circuits from geometric descriptions. On the other hand, Handel-C has also proven to be very successful in the rapid design and prototyping of FPGA circuits from algorithmic application descriptions. The proposed integrated framework hence harnesses HIDE for the generation of highly optimised circuits for regular parts of algorithms, while Handel-C is used as a top-level design language from which HIDE functionality is dynamically invoked. The overall message of this paper posits that there need not be an exclusive choice between different hardware design flows. Rather, an integrated framework where different design flows can seamlessly interoperate should be adopted. Although the idea might seem simple prima facie, it could have serious implications on the design of future generations of hardware languages.

Zipf and Type-Token rules for the English, Spanish, Irish and Latin languages

The Zipf curves of log of frequency against log of rank for a large English corpus of 500 million word tokens, 689,000 word types and for a large Spanish corpus of 16 million word tokens, 139,000 word types are shown to have the usual slope close to –1 for rank less than 5,000, but then for a higher rank they turn to give a slope close to –2. This is apparently mainly due to foreign words and place names. Other Zipf curves for highlyinflected Indo-European languages, Irish and ancient Latin, are also given. Because of the larger number of word types per lemma, they remain flatter than the English curve maintaining a slope of –1 until turning points of about ranks 30,000 for Irish and 10,000 for Latin. A formula which calculates the number of tokens given the number of types is derived in terms of the rank at the turning point, 5,000 for both English and Spanish, 30,000 for Irish and 10,000 for Latin.