Degradation, receptor binding, insulin secreting and antihyperglycaemic actions of palmitate-derivatised native and Ala(8)-substituted GLP-1 analogues

The hormone glucagonlike peptide-1(736)amide (GLP-1) is released in response to ingested nutrients and acts to promote glucosedependent insulin secretion ensuring efficient postprandial glucose homeostasis. Unfortunately, the beneficial actions of GLP-1 which give this hormone many of the desirable properties of an antidiabetic drug are short lived due to degradation by dipeptidylpeptidase IV (DPP IV) and rapid clearance by renal filtration. In this study we have attempted to extend GLP-1 action through the attachment of palmitoyl moieties to the epsilon-amino group in the side chain of the Lys(26) residue and to combine this modification with substitutions of the Ala(8) residue, namely Val or aminobutyric acid (Abu). In contrast to native GLP-1, which was rapidly degraded, [Lys(pal)(26)]GLP-1, [Abu(8),Lys(pal)(26)]GLP-1 and [Val(8),Lys(pal)(26)]GLP-1 all exhibited profound stability during 12 h incubations with DPP IV and human plasma. Receptor binding affinity and the ability to increase cyclic AMP in the clonal beta-cell line BRIN-BD11 were decreased by 86- to 167-fold and 15- to 62-fold, respectively compared with native GLP-1. However, insulin secretory potency tested using BRIN-BD11 cells was similar, or in the case of [Val(8),Lys(pal)(26)]GLP-1 enhanced. Furthermore, when administered in vivo together with glucose to diabetic (ob/ob) mice, [Lys(pal)(26)]GLP-1, [Abu(8),Lys(pal)(26)]GLP-1 and [Val8,Lys(pal)26]GLP-1 did not demonstrate acute glucoselowering or insulinotropic activity as observed with native GLP-1. These studies support the potential usefulness of fatty acid linked analogues of GLP-1 but indicate the importance of chain length for peptide kinetics and bioavailability.

Evidence that the major degradation product of glucose-dependent insulinotropic polypeptide, GIP(3-42), is a GIP receptor antagonist in vivo

The incretin hormone glucose-dependent insulinotropic polypeptide (GIP) is rapidly degraded in the circulation by dipeptidyl peptidase IV forming the N-terminally truncated peptide GIP(3-42). The present study examined the biological activity of this abundant circulating fragment peptide to establish its possible role in GIP action. Human GIP and GIP(3-42) were synthesised by Fmoc solid-phase peptide synthesis, purified by HPLC and characterised by electrospray ionisation-mass spectrometry. In GIP receptor-transfected Chinese hamster lung fibroblasts, GIP(3-42) dose dependently inhibited GIP-stimulated (10(-7) M) cAMP production (up to 75.4 +/-5.4%; P

Use of a batch rotating photocatalytic contactor for the degradation of organic pollutants in wastewater

Aqueous solutions of a chlorinated VOC, 3,4-dichlorobut-1-ene, as well as other pollutants, may be mineralised to carbon dioxide, water and hydrochloric acid using a sealed rotating photocatalytic reactor. The effect of pH, dissolved oxygen concentration, light intensity, pollutant concentration and rotation speed on the degradation rate have been investigated as well as competition kinetics with methanol. This reactor may be optimised to minimise competition effects in mixed solutions. (C) 2001 Elsevier Science B.V. All rights reserved.

Theoretical analysis on microwave heating of oil–water emulsions supported on ceramic, metallic or composite plates

A detailed theoretical analysis has been carried out to study efficient heating due to microwaves for one-dimensional (1D) oil–water emulsion samples placed on various ceramic, metallic (reflective) and ceramic–metallic composite supports. Two typical emulsion systems are considered such as oil-in-water (o/w) and water-in-oil (w/o). A preliminary study has been carried out via average power vs emulsion thickness diagram to estimate microwave power absorption within emulsion samples for various cases. The maxima in average power, also termed as ‘resonances’, are observed for specific emulsion thicknesses and the two consecutive resonances of significant magnitudes are termed as R1 and R2 modes. For both o/w and w/o emulsions, it is observed that microwave power absorption is enhanced in presence of metallic and composite supports during both R1 and R2 modes. The efficient heating strategies characterized by ‘large heating rates’ with ‘minimal thermal runaway’ i.e. uniform temperature distributions within the sample have been assessed for each type of emulsion. Based on the detailed spatial distributions of power and temperature for various cases, SiC-metallic composite support may be recommended as an optimal heating strategy for o/w samples with higher oil fractions (0.45) whereas metallic and Alumina-metallic composite supports may be favored for samples with smaller oil fractions (=0.3) during R1 mode. For w/o samples, SiC-metallic composite support may be suitable heating strategy for all ranges of water fractions during R1 mode. During R2 mode, metallic and Alumina-metallic composite supports are favored for both o/w and w/o emulsion samples. Current study recommends the efficient way to use microwaves in a single mode waveguide and the heating strategy can be suitably extended for heating of any other emulsions for which dielectric properties are easily measurable or available in the literature.

Optimization of an open-ended microwave oven for microelectronics packaging

A physically open, but electrically shielded, microwave open oven can be produced by virtue of the evanescent fields in a waveguide below cutoff. The below cutoff heating chamber is fed by a transverse magnetic resonance established in a dielectric-filled section of the waveguide exploiting continuity of normal electric flux. In order to optimize the fields and the performance of the oven, a thin layer of a dielectric material with higher permittivity is inserted at the interface. Analysis and synthesis of an optimized open oven predicts field enhancement in the heating chamber up to 9.4 dB. Results from experimental testing on two fabricated prototypes are in agreement with the simulated predictions, and demonstrate an up to tenfold improvement in the heating performance. The open-ended oven allows for simultaneous precision alignment, testing, and efficient curing of microelectronic devices, significantly increasing productivity gains.

Open-ended microwave oven for flip-chip assembly

A novel open-ended waveguide cavity resonator for the microwave curing of bumps, underfills and encapsulants is described. The open oven has the potential to provide fast alignment of devices during flip-chip assembly, direct chip attach, surface mount assembly or wafer-scale level packaging. The prototype microwave oven was designed to operate at X-band for ease of testing, although a higher frequency version is planned. The device described in the paper takes the form of a waveguide cavity resonator. It is approximately square in cross-section and is filled with a low-loss dielectric with a relative permittivity of 6. It is excited by end-fed probes in order to couple power preferentially into the TM3,3,k mode with the object of forming nine 'hot-spots' in the open end. Low power tests using heat sensitive film demonstrate clearly that selective heating in multiple locations in the open end of the oven is achievable.

Design of asymmetrical RF and microwave bandpass filters by computer optimization

This paper presents an optimization-based approach to the design of asymmetrical filter structures having the maximum number of return- or insertion-loss ripples in the passband such as those based upon Chebyshev function prototypes. The proposed approach. has the following advantages over the general purpose optimization techniques adopted previously such as: less frequency sampling is required, optimization is carried out with respect to the Chebyshev (or minimax) criterion, the problem of local minima does not arise, and optimization is usually only required for the passband. When implemented around an accurate circuit simulation, the method can be used to include all the effects of discontinuities, junctions, fringing, etc. to reduce the amount of tuning required in the final filter. The design of asymmetrical ridged-waveguide bandpass filters is considered as an example. Measurements on a fabricated filter confirm the accuracy of the design procedure.

Improved preparations of ionic liquids using microwave irradiation

Controlled, multimode microwave irradiation has been employed in a generic solvent-free process to prepare a wide range of ionic liquids based on nitrogen-containing heterocycles. The developed method offers a flexible, small to large-scale approach to prepare ionic liquids, in either sealed or open vessels, in a faster and greener process than any previously described.

MODULATED BACKSCATTER MICROWAVE SECURITY SENSOR

A system capable of deployment as a microwave security sensor which can automatically reject background clutter is presented. The principle of operation is based on analog homodyne detection using 1. Q single side-band down conversion of an AM backscattered modulating signal envelope. A demonstrator is presented which operates with a carrier frequency of 2 GHz and 500 KHz backscattered signal. When deployed in a multipath rich open plan office environment the S/N ratio obtained at the detection output was better than 20 dB at 20 in range with 20 dBm EIRP in a 2 MHz detection bandwidth despite the presence of time varying and static clutter. (C) 2009 Wiley Periodicals, Inc. Microwave Opt Technol Lett 51: 2492-2495, 2009; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/mop.24636

Characterisation of microwave phase conjugate signal generation using nonlinearly loaded wire frequency selective surface (FSS)

Both experimental and theoretical information regarding the scattering and phase conjugate mixing properties of a 2D double-periodic array of wires loaded with nonlinear/linear lumped elements have been provided. An experimental means for assessing the phase conjugate energy production capability for the array is given. These investigations enable identification of the fundamental operational characteristics and underlying mechanisms associated with the production of phase conjugate energy by this type of artificial electromagnetic media. Means for enhancing the phase conjugate energy production capability of the structure by using additional linear lumped loads is examined theoretically and limits on the production of phase conjugate energy established. Theoretical far-field prediction of the behaviour of the structure indicates that retro-directive reflector action as well as negative refraction should be possible.

Electro-thermal theory of intermodulation distortion in lossy microwave components

An analytic formulation of dynamic electro-thermally induced nonlinearity is developed for a general resistive element, yielding a self-heating circuit model based on a fractional derivative. The model explains the 10 dB/decade slope of the intermodulation products observed in two-tone testing. Two-tone testing at 400 MHz of attenuators, microwave chip terminations, and coaxial terminations is reported with tone spacing ranging from 1 to 100 Hz.

Delivery of rSLPI in a liposomal carrier for inhalation provides protection against cathepsin L degradation

Secretory leukocyte protease inhibitor (SLPI) is an endogenous serine protease inhibitor that protects the lungs from excessive tissue damage caused by leukocyte proteases released during inflammation. Recombinant SLPI (rSLPI) has shown potential as a treatment for inflammatory lung conditions. To date, its clinical application has been limited by rapid enzymatic cleavage by cathepsins and rapid clearance from the lungs after inhalation. In this study, rSLPI was encapsulated in 1,2-Dioleoyl-sn-Glycero-3-[Phospho-L-Serine] : Cholesterol (DOPS : Chol) liposomes for inhalation. Incubation of rSLPI with cathepsin L leads to complete loss of activity while encapsulation of rSLPI in DOPS : Chol liposomes retained 92.6 of its activity after challenge with cathepsin L. rSLPI-loaded liposomes were aerosolized efficiently using a standard nebulizer with a minimal loss of activity and stability. This formulation was biocompatible and encapsulation did not appear to diminish access to intracellular sites of action in in vitro cell culture studies. Liposome encapsulation of rSLPI therefore improves stability and potentially reduces the level and frequency of dosing required for therapeutic effect after inhalation.