32 research outputs found
Hyaluronan (HA) glycopolymers and self-assembling HA-binding peptides: a synthetic toolbox for probing HA-peptide/protein interactions and creating supramolecular HA biomaterials
No full textPhDHyaluronan (HA) is a highly abundant anionic polysaccharide found throughout mammalian connective tissues. Unlike other glycosaminoglycans, HA is non-sulfated and its alternating chemical structure is invariable. Despite its simplicity, HA is involved in the extracellular matrix organization and many other aspects of cell behaviour. Using HA as a model polymer, we took inspiration to design and synthesize glycopolymers based on HA and self-assembling HA-binding peptides. Glycopolymers provide an alternative to conventional polysaccharides by offering the possibility to display sugars across the polymer at defined densities, while providing a robust polymer backbone rather than the glycosidic bonds, potentially forming more stable biomaterials with similar biological activity. The synthesis of alternating, homo and statistical HA neoglycopolymers was achieved via reversible addition fragmentation chain transfer (RAFT) polymerisation. The monosaccharides are grafted onto the polymers backbone by post-polymerisation click reactions to achieve the desired glycopolymers. These glycopolymers share some properties of native HA, such as water solubility and negative charge. Binding studies showed the ability of these glycopolymers to interact with HA-binding peptides and proteins, whilst not presenting any cytotoxicity behaviour. This approach provides control over the type and variation of saccharides, not be possible using natural HA, suggesting their potential use in mechanistic studies to understand HA binding processes. Peptides, on the other hand, have received increasing interest as potential biomaterials due to their inherent biocompatibility and biodegradability. Peptides can be engineered to drive their self-assembly into defined nanostructures, such as micelles and fibers. By designing HA-binding peptides with self-assembling properties, their combination with natural HA resulted in the formation of supramolecular hydrogels or membranes. Whilst the synthesis of large molecules like proteins is still a challenge, peptide synthesis is relatively simple and their self-assembly can result in nanomaterials with structures and functions resembling proteins. The synthetic molecules described in this thesis can be used as probes to better understand the role and binding of HA as well as reveal new applications.European Union (FP7), Maria Curie Career Integration Grant, SupraHApolymers (PCIG-GA2013-6318717
Inter-agency Cooperation and New Approaches to Employability
No full textThis article examines the role of inter-agency cooperation, which is one form of ‘partnership’, in new approaches to employability in the UK. The article articulates a ‘model for effective partnership working’ on employability. This model is applied first in a general review of employability policy and then to discuss case study research on the recent ‘Pathways to Work’ and ‘Working Neighbourhoods’ pilots. It is argued that successful partnerships need a clear strategic focus based on a necessity for inter-agency cooperation and institutional arrangements that allow for shared ownership, trust and mutualism, and flexibility in resource-sharing. While some of these factors are apparent in UK employability services, an over-reliance on contractualism and centralized organizational structures may undermine partnership-based approaches. Many of the success factors associated with effective partnership working appeared to be in place, even though the role of the Public Employment Service was fundamentally different in each case (as a key actor in implementing the first pilot, but largely withdrawing from the implementation role in the second). The article concludes by outlining the relevance of this model and the case study findings to discussions of the future development of employability policies and related partnership working
Subcontracting in public employment services: the design and delivery of ‘outcome based’ and ‘black box’ contracts: analytical paper
No full textUnintended consequences: local housing allowance meets the right to buy
No full textRecent rapid expansion of the Private Rented Sector (PRS) is recognised but the extensive involvement of ex local authority stock in this new PRS is not. This paper uses existing literature to outline the commodification processes through which Right to Buy (RTB) housing enters the PRS. Other published research is used to estimate a likely range of council to PRS tenure change over 30 years of RTB in the UK. Then using detailed data matching, we present one local authority example at individual dwelling level across the whole stock to establish the true scale of this transfer from council housing to private rental. Finally, to stimulate debate about the revenue cost of this switch of rental tenures we speculate on the additional annual cost of Housing Benefit support to this ex RTB stock given that the PRS is invariably more expensive than council renting for equivalent dwellings. This may well be over £1bn per year. We conclude that UK government’s plans to expand the RTB scheme will simply increase revenue costs year on year for no discernable social or housing supply benefit
Proline-Rich Peptides with Improved Antimicrobial Activity against E. coli, K. Pneumoniae, and A. Baumannii.
No full textProline-rich antimicrobial peptides (PrAMPs) are promising agents to combat multi-drug resistant pathogens due to a high antimicrobial activity, yet low cytotoxicity. A library of derivatives of the PrAMP Bac5(1-17) was synthesized and screened to identify which residues are relevant for its activity. In this way, we discovered that two central motifs -PIRXP- cannot be modified, while residues at N- and C- termini tolerated some variations. We found five Bac5(1-17) derivatives bearing 1-5 substitutions, with an increased number of arginine and/or tryptophan residues, exhibiting improved antimicrobial activity and broader spectrum of activity while retaining low cytotoxicity toward eukaryotic cells. Transcription/translation and bacterial membrane permeabilization assays showed that these new derivatives still retained the ability to strongly inhibit bacterial protein synthesis, but also acquired permeabilizing activity to different degrees. These new Bac5(1-17) derivatives therefore show a dual mode of action which could hinder the selection of bacterial resistance against these molecules
Symmetry breaking and tunneling dynamics of a dipolar Bose-Einstein condensate in a double-well potential
No full textWe investigate the properties of a three-dimensional (3D) dipolar Bose–Einstein condensate (BEC) in a double-well potential (DWP). Symmetry breaking and tunneling dynamics phenomena are demonstrated for 164Dy atoms in the 3D DWP using an effective two-mode model. The results show that the symmetry properties of the dynamics are affected markedly by the long-range nature and anisotropy of the dipolar interaction and the isotropic contact interaction.The accepted manuscript in pdf format is listed with the files at the bottom of this page. The presentation of the authors' names and (or) special characters in the title of the manuscript may differ slightly between what is listed on this page and what is listed in the pdf file of the accepted manuscript; that in the pdf file of the accepted manuscript is what was submitted by the author
The effect of lipidation and glycosylation on short cationic antimicrobial peptides
No full textThe global health threat surrounding bacterial resistance has resulted in antibiotic researchers shifting their focus away from ‘traditional’ antibiotics and concentrating on other antimicrobial agents, including antimicrobial peptides. These low molecular weight "mini-proteins" exhibit broad-spectrum activity against bacteria, including multi-drug resistant strains, viruses, fungi and protozoa and constitute a major element of the innate-immune system of many multicellular organisms. Some naturally occurring antimicrobial peptides are lipidated and/or glycosylated and almost all antimicrobial peptides in clinical use are either lipopeptides (Daptomycin and Polymyxin E and B) or glycopeptides (Vancomycin). Lipidation, glycosylation and PEGylation are an option for improving stability and activity in serum and for reducing the rapid clearing via the kidneys and liver. Two broad-spectrum antimicrobial peptides NH2-RIRIRWIIR-CONH2 (A1) and NH2-KRRVRWIIW-CONH2 (B1) were conjugated via a linker, producing A2 and B2, to individual fatty acids of C8, C10, C12 and C14 and in addition, A2 was conjugated to either glucose, N-acetyl glucosamine, galactose, mannose, lactose or polyethylene glycol (PEG). Antimicrobial activity against two Gram-positive strains (methicillin resistant Staphylococcus aureus (MRSA) and vancomycin resistant Enterococcus faecalis (VRE)) and three Gram-negative strains (Salmonella typhimurium, E. coli and Pseudomonas aeruginosa) were determined. Activity patterns for the lipidated versions are very complex, dependent on sequence, bacteria and fatty acid. Two reciprocal effects were measured; compared to the parental peptides, some combinations led to a 16-fold improvement whereas other combinations let to a 32-fold reduction in antimicrobial activity. Glycosylation decreased antimicrobial activity by 2 to 16-fold in comparison to A1, respectively on the sugar-peptide combination. PEGylation rendered the peptide inactive. Antimicrobial activity in the presence of 25% human serum of A1 and B1 was reduced 32-fold and 8-fold, respectively. The longer chain fatty acids almost completely restored this activity; however, these fatty acids increased hemolytic activity. B1 modified with C8 increased the therapeutic index by 2-fold for four bacterial strains. Our results suggest that finding the right lipid-peptide combination can lead to improved activity in the presence of serum and potentially more effective drug candidates for animal studies. Glycosylation with the optimal sugar and numbers of sugars at the right peptide position could be an alternative route or could be used in addition to lipidation to counteract solubility and toxicity issues
Return to work with chronic pain: employers' and employees' views
No full textThis conference papers given to the Society of Occupational Medicine's Annual Scientific Meeting discusses tensions and some possible ameliorating activities from our 2013 paper of the same name., published in their journal: Wainwright, E., Wainwright, D., Keogh, E. and Eccleston, C. Return to work with chronic pain: employers’ and employees’ views. Occupational Medicine 2013: doi:0.1093/occmed/kqt109. The conference homepage is here;http://www.som-asm.org.uk/Programme_SOM_ASM.aspAbstractBackgroundThe sickness certification and return to work (RTW) of people with chronic pain are important health and economic issues for employees, employers, taxpayers and the UK government. The ‘fit note’ and a national educational programme promoting RTW were introduced in 2010 to curb rising rates of sickness absence. AimsTo investigate employers’ and employees’ experiences of managing RTW when someone has taken sick leave for chronic pain, and to explore the perceived efficacy of the fit note.MethodsA qualitative study, comprising semi-structured interviews with employers who had managed sick leave cases and employees who had experienced sick leave for chronic pain. Interviews were recorded, transcribed and the data analysed using constructivist grounded theory principles.ResultsFive themes were elicited. Firstly, frequent enquiry after health status was seen as intrusive by some employees but part of good practice by employers and acknowledging this difference was useful. Secondly, being able to trust employees due to their performance track record was helpful for employers when dealing with complex chronic pain conditions. Thirdly, feeling valued increased employees’ motivation to return to work. Fourthly, guidelines about maintaining contact with absent employees were useful if used flexibly. Finally, both parties valued the fit note for its positive language, interrogative format and biomedical authority. ConclusionsThe fit note was perceived to be helpful if used in combination with other strategies for managing sick leave and RTW for people with chronic pain. These strategies may be applicable to other fluctuating, long-term conditions with medically unexplained elements. <br/
Investigation of the regeneration process of the softeners at DWP-Botlek: Determination if other sources can be used as a regenerant
No full textSanitary EngineeringWater ManagementCivil Engineering and Geoscience
Peptide inhibitors of bacterial protein synthesis with broad spectrum and SbmA-independent bactericidal activity against clinical pathogens.
No full textProline-rich antimicrobial peptides (PrAMPs) are promising lead compounds for developing new antimicrobials, however their narrow spectrum of action is limiting. PrAMPs kill bacteria binding to their ribosomes and inhibiting protein synthesis. In this study, 133 derivatives of the PrAMP Bac7(1-16) were synthesized to identify the crucial residues for ribosome inactivation and antimicrobial activity. Then, five new Bac7(1-16) derivatives were conceived and characterized by antibacterial and membrane permeabilization assays, by X-ray crystallography and molecular dynamics simulations. Some derivatives displayed broad spectrum activity, encompassing Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumanii, Pseudomonas aeruginosa and Staphylococcus aureus. Two peptides out of five, acquired a weak membrane-perturbing activity, while maintaining the ability to inhibit protein synthesis. These derivatives became independent of the SbmA transporter, commonly used by native PrAMPs, suggesting that they obtained a novel route to enter bacterial cells. PrAMP-derived compounds could become new-generation antimicrobials to combat the antibiotic-resistant pathogens
