The move to servitization (from a product service system point of view)

Product Service Systems (PSSs) emphasize the substitution of products with services. The term “Servitisation” was introduced by Sandra Vendermerwe in the 80s to represent the addition of services to increase a company’s competitive edge. Key to PSS, and Servitisation more generally, is the “informated product”. The informated product enables health monitoring of the product in use and can be key to a workable PSS. This paper reviews the evolution of servitisation and the associated business benefit. It also then reviews the concept of informated product reconfiguration techniques and remote services that enables PSS to be delivered.

Comparison of vesicle based antigen delivery systems for delivery of hepatitis B surface antigen

There is a clinical need for a more effective vaccine against hepatitis B, and in particular vaccines that may be suitable for therapeutic administration. This study assesses the potential of cationic surfactant vesicle based formulations using two agents; the cationic amine containing [N-(N′,N′-dimethylaminoethane)-carbamoyl] cholesterol (DC-Chol) or dimethyl dioctadecylammonium bromide (DDA) with hepatitis B surface antigen (HBsAg). Synthetic mycobacterial cord factor, trehalose 6,6′-dibehenate (TDB) has been used as an adjuvant and the addition of 1-monopalmitoyl glycerol (C16:0) (MP) and cholesterol (Chol) to DDA-TDB is assessed for its potential to facilitate formation of dehydration-rehydration vesicles (DRV) at room temperature, and the effect of this on immune responses. A DRV formulation is directly compared to an adsorbed formulation of the same composition and preparation protocol (MP:dioleoyl phosphoethanolamine (DOPE):Chol:DC-Chol) and the direct substitution of MP with phosphatidylcholine (PC) is also compared in DRV antigen-entrapped formulations. MP and Chol were shown to facilitate the use of DDA-TDB in DRV formulations prepared at room temperature, whilst there was marginal alteration of immunogenicity (a reduction in HBsAg-specific IL-2). The HBsAg adsorbed DRV formulation was not significantly different from the HBsAg entrapped DRV formulation. Overall, DDA formulations incorporating TDB showed markedly increased antigen specific splenocyte proliferation and elicited cytokine production concomitant with a strong T cell driven response, delineating formulations that may be useful for further evaluation of their clinical potential. © 2007 Elsevier B.V. All rights reserved.

Structure-activity relationships of the N-terminus of calcitonin gene-related peptide:key roles of alanine-5 and threonine-6 in receptor activation

Background and purpose - The N-terminus of calcitonin gene-related peptide (CGRP) is important for receptor activation, especially the disulphide-bonded ring (residues 1-7). However, the roles of individual amino acids within this region have not been examined and so the molecular determinants of agonism are unknown. This study has examined the role of residues 1, 3-6 and 8-9, excluding Cys-2 and Cys-7. Experimental approach - CGRP derivatives were substituted with either cysteine or alanine; further residues were introduced at position 6. Their affinity was measured by radioligand binding and their efficacy by measuring cAMP production in SK-N-MC cells and ß-arrestin 2 translocation in CHO-K1 cells at the CGRP receptor. Key results - Substitution of Ala-5 by cysteine reduced affinity 270-fold and reduced efficacy for production of cAMP in SK-N-MCs. Potency at ß-arrestin translocation was reduced by 9-fold. Substitution of Thr-6 by cysteine destroyed all measurable efficacy of both cAMP and ß-arrestin responses; substitution with either alanine or serine impaired potency. Substitutions at positions 1, 4, 8 and 9 resulted in approximately 10-fold reductions in potency at both responses. Similar observations were made at a second CGRP-activated receptor, the AMY1(a) receptor. Conclusions and implications - Ala-5 and Thr-6 are key determinants of agonist activity for CGRP. Ala-5 is also very important for receptor binding. Residues outside of the 1-7 ring also contribute to agonist activity.

A case-study investigating the physicochemical characteristics that dictate the function of a liposomal adjuvant

A range of particulate delivery systems have been considered as vaccine adjuvants. Of these systems, liposomes offer a range of advantages including versatility and flexibility in design format and their ability to incorporate a range of immunomodulators and antigens. Here we briefly outline research, from within our laboratories, which focused on the systematic evaluation of cationic liposomes as vaccines adjuvants. Our aim was to identify physicochemical characteristics that correlate with vaccine efficacy, with particular consideration of the interlink between depot-forming action and immune responses. A variety of parameters were investigated and over a range of studies we have confirmed that cationic liposomes, based on dimethyldioctadecylammonium bromide and trehalose 6,6'-dibehenate formed a depot at the injection site, which stimulates recruitment of antigen presenting cells to the injection site and promotes strong humoral and cell-mediated immune responses. Physicochemical factors which promote a strong vaccine depot include the combination of a high cationic charge and electrostatic binding of the antigen to the liposome system and the use of lipids with high transition temperatures, which form rigid bilayer vesicles. Reduction in vesicle size of cationic vesicles did not promote enhanced drainage from the injection site. However, reducing the cationic nature through substitution of the cationic lipid for a neutral lipid, or by masking of the charge using PEGylation, resulted in a reduced depot formation and reduced Th1-type immune responses, while Th2-type responses were less influenced. These studies confirm that the physicochemical characteristics of particulate-based adjuvants play a key role in the modulation of immune responses.

Sequence and chemistry requirements for a novel aptameric oligonucleotide inhibitor of EGF receptor tyrosine kinase activity

We have previously identified a phosphorothioate oligonucleotide (PS-ODN) that inhibited epidermal growth factor receptor tyrosine kinase (TK) activity both in cell fractions and in intact A431 cells. Since ODN-based TK inhibitors may have anti-cancer applications and may also help understand the non-antisense mediated effects of PS-ODNs, we have further studied the sequence and chemistry requirements of the parent PS-ODN (sequence: 5′-GGA GGG TCG CAT CGC-3′) as a sequence-dependent TK inhibitor. Sequence deletion and substitution studies revealed that the 5′-terminal GGA GGG hexamer sequence in the parent compound was essential for anti-TK activity in A431 cells. Site-specific substitution of any G with a T in this 5′-terminal motif within the parent compound caused a significant loss in anti-TK activity. The fully PS-modified hexameric motif alone exhibited equipotent activity as the parent 15-mer whereas phosphodiester (PO) or 2′-O-methyl-modified versions of this motif had significantly reduced anti-TK activity. Further, T substitutions within the two 5′-terminal G residues of the hexameric PS-ODN to produce a sequence, TTA GGG, representing the telomeric repeats in human chromosomes, also did not exhibit a significant anti-TK activity. Multiple repeats of the active hexameric motif in PS-ODNs resulted in more potent inhibitors of TK activity than the parent ODN. These results suggested that PS-ODNs, but not PO or 2′-O-methyl modified ODNs, containing the GGA GGG motif can exert potent anti-TK activity which may be desirable in some anti-tumor applications. Additionally, the presence of this previously unidentified motif in antisense PS-ODN constructs may contribute to their biological effects in vitro and in vivo and should be accounted for in the design of the PS-modified antisense ODNs. © 2002 Published by Elsevier Science Inc.

Novel dipeptidyl peptidase IV resistant analogues of glucagon-like peptide-1(7-36)amide have preserved biological activities in vitro conferring improved glucose-lowering action in vivo

Although the incretin hormone glucagon-like peptide-1 (GLP-1) is a potent stimulator of insulin release, its rapid degradation in vivo by the enzyme dipeptidyl peptidase IV (DPP IV) greatly limits its potential for treatment of type 2 diabetes. Here, we report two novel Ala8-substituted analogues of GLP-1, (Abu8)GLP-1 and (Val8)GLP-1 which were completely resistant to inactivation by DPP IV or human plasma. (Abu8)GLP-1 and (Val8)GLP-1 exhibited moderate affinities (IC50: 4.76 and 81.1 nM, respectively) for the human GLP-1 receptor compared with native GLP-1 (IC50: 0.37 nM). (Abu8)GLP-1 and (Val8)GLP-1 dose-dependently stimulated cAMP in insulin-secreting BRIN BD11 cells with reduced potency compared with native GLP-1 (1.5- and 3.5-fold, respectively). Consistent with other mechanisms of action, the analogues showed similar, or in the case of (Val8)GLP-1 slightly impaired insulin releasing activity in BRIN BD11 cells. Using adult obese (ob/ob) mice, (Abu8 )GLP-1 had similar glucose-lowering potency to native GLP-1 whereas the action of (Val8)GLP-1 was enhanced by 37%. The in vivo insulin-releasing activities were similar. These data indicate that substitution of Ala8 in GLP-1 with Abu or Val confers resistance to DPP IV inactivation and that (Val8)GLP-1 is a particularly potent N-terminally modified GLP-1 analogue of possible use in type 2 diabetes.

The influence of end of day silicone hydrogel daily disposable contact lens fit on ocular comfort, physiology and lens wettability

Purpose: To quantify the end-of-day silicone-hydrogel daily disposable contact lens fit and its influence of on ocular comfort, physiology and lens wettability. Methods: Thirty-nine subjects (22.1. ±. 3.5 years) were randomised to wear each of 3 silicone-hydrogel daily-disposable contact lenses (narafilcon A, delefilcon A and filcon II 3), bilaterally, for one week. Lens fit was assessed objectively using a digital video slit-lamp at 8, 12 and 16. h after lens insertion. Hyperaemia, non-invasive tear break-up time, tear meniscus height and comfort were also evaluated at these timepoints, while corneal and conjunctival staining were assessed on lens removal. Results: Lens fit assessments were not different between brands (P > 0.05), with the exception of the movement at blink where narafilcon A was more mobile. Overall, lag reduced but push-up speed increased from 8 to 12. h (P <. 0.05), but remained stable from 12 to 16. h (P > 0.05). Movement-on-blink was unaffected by wear-time (F = 0.403, P = 0.670). A more mobile lens fit with one brand did not indicate that person would have a more mobile fit with another brand (r = -0.06 to 0.63). Lens fit was not correlated with comfort, ocular physiology or lens wettability (P > 0.01). Conclusions: Among the lenses tested, objective lens fit changed between 8. h and 12. h of lens wear. The weak correlation in individual lens fit between brands indicates that fit is dependent on more than ocular shape. Consequently, substitution of a different lens brand with similar parameters will not necessarily provide comparable lens fit.

Price transmission in the EU wholesale petroleum markets

This article employs nonlinear smooth transition models to analyze the relationship between upstream and midstream prices of petroleum products. We test for the presence of nonlinearities in price linkages using both weekly series constructed using official EU procedures and also daily industry series applied for the first time. Our results show that the estimated shape of the transition function and equilibrium reversion path depend on the frequency of the price dataset. Our analysis of the crude oil to wholesale price transmission provides evidence of nonlinearities when prices are observed with daily frequency. The nature of the nonlinearities provides evidence in support of the existence of menu costs or, more generally, frictions in the markets rather than supply adjustment costs. This result differs from that found for the U.S. petroleum markets. © 2012 American Statistical Association.

Synthesis and thermoelectric properties of Yb-doped Ca0.9-x Yb x La0.1MnO3 ceramics

The microstructure and thermoelectric properties of Yb-doped Ca0.9-x Yb x La0.1 MnO3 (0 ≤ x ≤ 0.05) ceramics prepared by using the Pechini method derived powders have been investigated. X-ray diffraction analysis has shown that all samples exhibit single phase with orthorhombic perovskite structure. All ceramic samples possess high relative densities, ranging from 97.04% to 98.65%. The Seebeck coefficient is negative, indicating n-type conduction in all samples. The substitution of Yb for Ca leads to a marked decrease in the electrical resistivity, along with a moderate decrease in the absolute value of the Seebeck coefficient. The highest power factor is obtained for the sample with x = 0.05. The electrical conduction in these compounds is due to electrons hopping between Mn3+ and Mn4+, which is enhanced by increasing Yb content.

Impact of electric vehicles on GB electricity demand and associated benefits for system control

This paper investigates the impact that electric vehicle uptake will have on the national electricity demand of Great Britain. Data from the National Travel Survey, and the Coventry and Birmingham Low Emissions Demonstration (CABLED) are used to model an electrical demand profile in a future scenario of significant electric vehicle market penetration. These two methods allow comparison of how conventional cars are currently used, and the resulting electrical demand with simple substitution of energy source, with data showing how electric vehicles are actually being used at present. The report finds that electric vehicles are unlikely to significantly impact electricity demand in GB. The paper also aims to determine whether electric vehicles have the potential to provide ancillary services to the grid operator, and if so, the capacity for such services that would be available. Demand side management, frequency response and Short term Operating Reserve (STOR) are the services considered. The report finds that electric cars are unlikely to provide enough moveable demand peak shedding to be worthwhile. However, it is found that controlling vehicle charging would provide sufficient power control to viably act as frequency response for dispatch by the transmission system operator. This paper concludes that electric vehicles have technical potential to aid management of the transmission network without adding a significant demand burden. © 2013 IEEE.

Asymmetric price transmission in EU petroleum markets

This research investigates the determinants of asymmetric price transmission (APT) in European petroleum markets. APT is the faster response of retail prices to cost increases than to cost decreases; resulting in a welfare transfer from consumers to fuel retailers. I investigate APT at 3 different levels: the EU, the UK and at the Birmingham level. First, I examine the incidence of asymmetries in the retail markets of six major EU countries; significant asymmetries are found in all countries except from the UK. The market share data suggest that asymmetries are more important in more concentrated markets; this finding supports the collusion theory. I extend the investigation to 12 EU countries and note that APT is greater in diesel markets. The cross-country analysis suggests that vertical and horizontal concentration at least partly explains the degree of asymmetry. I provide evidence justifying scrutiny over retail markets’ pricing and structure. Second daily data unveil the presence of APT in the UK fuel markets. I use break tests to identify segments with different pricing regimes. Two main types of periods are identified: periods of rising oil price exhibit significant asymmetries whilst periods of recession do not. Our results suggest that oligopolistic coordination between retailers generate excess rents during periods of rising oil price whilst the coordination fails due to price wars when oil prices are going downwards. Finally I investigate the pricing behaviour of petroleum retailers in the Birmingham (UK) area for 2008. Whilst the market structure data reveals that the horizontal concentration is higher than the national UK average, I find no evidence of APT. In contrast, I find that retail prices are sticky upwards and downwards and that firms with market power (majors and supermarkets) adjust their prices slower than other firms.

Controversy over generic substitution

Substitution of branded medicine with a generic equivalent is already common. Robin Ferner, Warren Lenney, and John Marriott argue that concerns about UK plans to let pharmacists make the decision are unwarranted.

The correlation of structure and electronic properties near the surface of transition metal oxides

The strong couplings between different degrees of freedom are believed to be responsible for novel and complex phenomena discovered in transition metal oxides (TMOs). The physical complexity is directly responsible for their tunability. Creating surfaces/interfaces add an additional ' man-made' twist, approaching the quantum phenomena of correlated materials. ^ The dissertation focused on the structural and electronic properties in proximity of surface of three prototype TMO compounds by using three complementary techniques: scanning tunneling microscopy, angle-resolved photoelectron spectroscopy and low energy electron diffraction, particularly emphasized the effects of broken symmetry and imperfections like defects on the coupling between charge and lattice degrees of freedom. ^ Ca1.5Sr0.5RuO4 is a layered ruthenate with square lattice and at the boundary of magnetic/orbital instability in Ca2-xSrxRuO4. That the substitution of Sr 2+ with Ca2+ causing RuO6 rotation narrows the dxy band width and changes the Fermi surface topology. Particularly, the γ(dxy) Fermi surface sheet exhibited hole-like in Ca1.5Sr0.5RuO4 in contrast to electron-like in Sr2RuO4, showing a strong charge-lattice coupling. ^ Na0.75CoO2 is a layered cobaltite with triangular lattice exhibiting extraordinary thermoelectric properties. The well-ordered CoO2-terminated surface with random Na distribution was observed. However, lattice constants of the surface are smaller than that in bulk. The surface density of states (DOS) showed strong temperature dependence. Especially, an unusual shift of the minimum DOS occurs below 230 K, clearly indicating a local charging effect on the surface. ^ Cd2Re2O7 is the first known pyrochlore oxide superconductor (Tc ∼ 1K). It exhibited an unusual second-order phase transition occurring at TS1 = 200 K and a controversial first-order transition at TS2 = 120 K. While bulk properties display large anomalies at TS1 but rather subtle and sample-dependent changes at TS2, the surface DOS near the EF show no change at T s1 but a substantial increase below TS2---a complete reversal as the signature for the transitions. We argued that crystal imperfections, mainly defects, which were considerably enhanced at the surface, resulted in the transition at TS2. ^

Design and synthesis of S-ribosylhomocysteine analogues

Bacteria are known to release a large variety of small molecules known as autoinducers (AI) which effect quorum sensing (QS) initiation. The interruption of QS effects bacterial communication, growth and virulence. ^ Three novel classes of S-ribosylhomocysteine (SRH) analogues as potential inhibitors of S-ribosylhomocysteinase (LuxS enzyme) and AI-2 modulators of QS were developed. The synthesis of 2-deoxy-2-bromo-SRH analogues was attempted by coupling of the corresponding 2-bromo-2-deoxypentafuranosyl precursors with the homocysteinate anion. The displacement of the bromide from C2 rather than the expected substitution of the mesylate from C5 was observed. The synthesis of 4-C-alkyl/aryl-S-ribosylhomocysteine analogues involved the following steps: (i) conversion of the D-ribose to the ribitol-4-ulose; (ii) diastereoselective addition of various alkyl or aryl or vinyl Grignard reagents to 4-ketone intermediate; (iii) oxidation of the primary hydroxyl group at C1 followed by the intramolecular ring closure to the corresponding 4-C-alkyl/aryl-substituted ribono-1,4-lactones; (iv) displacement of the activated 5-hydroxyl group with the protected homocysteinate. Treatment of the 4-C-alkyl/aryl-substituted SRH analogues with lithium triethylborohydride effected reduction of the ribonolactone to the ribose (hemiacetal) and subsequent global deprotection with trifluoroacetic acid provided 4-C-alkyl/aryl-SRHs. ^ The 4-[thia]-SRH were prepared from the 1-deoxy-4-thioribose through the coupling of the &agr;-fluoro thioethers (thioribosyl fluorides) with homocysteinate anion. The 4-[thia]-SRH analogues showed concentration dependent effect on the growth on las (50% inhibitory effect at 200 µg/mL). The most active was 1-deoxy-4-[thia]-SRH analogue with sufur atom in the ring oxidized to sulfoxide decreasing las gene activity to approximately 35% without affecting rhl gene. Neither of the tested compounds had effect on bioluminescence nor on total growth of V. harveyi, but had however slight inhibition of the QS.^

High pressure and low temperature study of ammonia borane and lithium amidoborane

Hydrogen has been considered as a potentially efficient and environmentally friendly alternative energy solution. However, one of the most important scientific and technical challenges that the "hydrogen economy" faces is the development of safe and economically viable on-board hydrogen storage for fuel cell applications, especially to the transportation sector. Ammonia borane (BH3NH 3), a solid state hydrogen storage material, possesses exceptionally high hydrogen content (19.6 wt%).However, a fairly high temperature is required to release all the hydrogen atoms, along with the emission of toxic borazine. Recently research interests are focusing on the improvement of H2 discharge from ammonia borane (AB) including lowering the dehydrogenation temperature and enhancing hydrogen release rate using different techniques. Till now the detailed information about the bonding characteristics of AB is not sufficient to understand details about its phases and structures. ^ Elemental substitution of ammonia borane produces metal amidoboranes. Introduction of metal atoms to the ammonia borane structure may alter the bonding characteristics. Lithium amidoborane is synthesized by ball milling of ammonia borane and lithium hydride. High pressure study of molecular crystal provides unique insight into the intermolecular bonding forces and phase stability. During this dissertation, Raman spectroscopic study of lithium amidoborane has been carried out at high pressure in a diamond anvil cell. It has been identified that there is no dihydrogen bond in the lithium amidoborane structure, whereas dihydrogen bond is the characteristic bond of the parent compound ammonia borane. It has also been identified that the B-H bond becomes weaker, whereas B-N and N-H bonds become stronger than those in the parent compound ammonia borane. At high pressure up to 15 GPa, Raman spectroscopic study indicates two phase transformations of lithium amidoborane, whereas synchrotron X-ray diffraction data indicates only one phase transformation of this material. ^ Pressure and temperature has a significant effect on the structural stability of ammonia borane. This dissertation explored the phase transformation behavior of ammonia borane at high pressure and low temperature using in situ Raman spectroscopy. The P-T phase boundary between the tetragonal (I4mm) and orthorhombic (Pmn21) phases of ammonia borane has been determined. The transition has a positive Clapeyron slope which indicates the transition is of exothermic in nature. Influence of nanoconfinemment on the I4mm to Pmn2 1 phase transition of ammonia borane was also investigated. Mesoporus silica scaffolds SBA-15 with pore size of ~8 nm and MCM-41 with pore size of 2.1-2.7 nm, were used to nanoconfine ammonia borane. During cooling down, the I4mm to Pmn21 phase transition was not observed in MCM-41 nanoconfined ammonia borane, whereas the SBA-15 nanocondfined ammonia borane shows the phase transition at ~195 K. Four new phases of ammonia borane were also identified at high pressure up to 15 GPa and low temperature down to 90 K.^