A call for action to the biomaterial community to tackle antimicrobial resistance

The global surge of antimicrobial resistance (AMR) is a major concern for public health and proving to be a key challenge in modern disease treatment, requiring action plans at all levels. Microorganisms regularly and rapidly acquire resistance to antibiotic treatments and new drugs are continuously required. However, the inherent cost and risk to develop such molecules has resulted in a drying of the pipeline with very few compounds currently in development. Over the last two decades, efforts have been made to tackle the main sources of AMR. Nevertheless, these require the involvement of large governmental bodies, further increasing the complexity of the problem. As a group with a long innovation history, the biomaterials community is perfectly situated to push forward novel antimicrobial technologies to combat AMR. Although this involvement has been felt, it is necessary to ensure that the field offers a united front with special focus in areas that will facilitate the development and implementation of such systems. This paper reviews state of the art biomaterials strategies striving to limit AMR. Promising broad-spectrum antimicrobials and device modifications are showcased through two case studies for different applications, namely topical and implantables, demonstrating the potential for a highly efficacious physical and chemical approach. Finally, a critical review on barriers and limitations of these methods has been developed to provide a list of short and long-term focus areas in order to ensure the full potential of the biomaterials community is directed to helping tackle the AMR pandemic

The Hiyama Cross-Coupling Reaction: New Discoveries

In this account recent developments in the Hiyama cross-coupling reaction from 2010 up today are presented. The most important methodology involves formation of biaryl systems by using aryl bromides or iodides and aryl trialkoxy silanes: other variants are far less studied. The most useful procedures are collected paying special attention to the synthetic application of this methodology in synthetic organic chemistry.We thank the continuous financial support from our Ministerio de Ciencia e Innovación (MCINN; projects CTQ2007-62771/BQU, CTQ2010-20387, CONSOLIDER INGENIO 210-CDS2007-00006, CTQ2011-24151, CTQ2011-24165), the Ministerio de Economía y Competitividad (MINECO; projects CTQ2013-43446-P, CTQ2014-51912-REDC, CTQ2014-53695-P), FEDER, the Generalitat Valenciana (PROMETEO 2009/039, PROMETEOII/2014/017) and the University of Alicante

Synthetic polypeptides for biomedical and bioactive applications

© 2016 Dr. Steven Josef ShirbinSynthetic polypeptides are bioinspired mimics of natural polypeptides, readily prepared through controlled synthetic polymerization processes. Their use has offered chemists and biologists around the world the ability to precisely control the synthesis, scale-up, modification and engineering of polypeptides with properties similar to those seen in the natural world. The plethora of possible functionality gives synthetic polypeptides an array of properties shown to be highly useful in the biomedical and antimicrobial (bioactive) fields. Despite this, significant deficiencies surrounding the application of synthetic polypeptide materials in these fields remain. This thesis reports on the fabrication and testing of novel synthetic polypeptide and synthetic polypeptide-based materials to address deficiencies related to the application of synthetic polypeptides in nanoparticle drug delivery, cellular scaffolds for tissue engineering and antimicrobial materials for water treatment. For drug delivery, investigations into the use of synthetic polypeptide-based nanoparticles for cisplatin delivery have traditionally focused on micelle assemblies. Different synthetic polypeptide-based self-assemblies such as vesicles offers the prospect of introducing a new biocompatible and biodegradable architecture for cisplatin delivery. In this study, the preparation of novel cancer-targeting synthetic polypeptide-based vesicles for cisplatin drug delivery is described. The vesicles were prepared through a novel drug-induced self-assembly process. Folic acid was conjugated to the vesicle corona to form an active targeting drug delivery system. In vitro studies on these targeted vesicles showed significantly higher cellular binding/uptake and dose-dependent cytotoxicity toward cancerous cells (HeLa) compared to non-cancerous cells (NIH-3T3). Next, preliminary studies into the preparation of aptamer (advanced targeting ligands composed of single strand nucleotides) targeted synthetic poly(L-glutamic acid)-based drug delivery systems was investigated. Poly(L-glutamic acid) or PLG, has been utilized in a range of synthetic polypeptide-based drug delivery systems owing to its biocompatibility and favorable enzymatic biodegradability profiles. Whilst aptamers have been used as advanced targeting ligands in a wide range of polymeric nanoparticle drug delivery systems, they have yet to be investigated in delivery systems composed of PLG. Conjugation of a model single stranded DNA (ssDNA) aptamer to poly(ethylene glycol)-b-poly(L-glutamic acid) (PEG-b-PLG) block copolymers, common synthetic PLG-based nanoparticle precursors, was achieved through thiol-maleimide coupling chemistries and the conjugates successfully isolated through preparative gel electrophoresis. The DNA-polymer conjugation and isolation protocols established in this work offer potential use in future studies employing aptamer-targeting of PLG-based delivery systems. For tissue engineering, the biocompatible, biodegradable and cell adhesive properties of synthetic polypeptides makes them useful materials for the fabrication of 3D polymeric hydrogels with macroporous morphologies ideally suited for cell in-growth. Traditionally, synthetic polypeptides have been used as partial components of these gel networks, and often require side-chain modifications to allow for cross-linking to take place, thus hindering the effective study of these materials as cellular scaffolds. In this study, macroporous hydrogels composed entirely of synthetic polypeptides were prepared through direct cross-linking of a single poly(L-glutamic acid)-b-poly(L-lysine) (PLG-b-PLL) polypeptide component under cryogelation conditions. Tuning the relative ratios of the amino acid constituents could result in cryogels with very different pore structures, swelling, and mechanical properties, suitable for a range of soft tissue engineering applications. These cryogels were shown to be enzymatically biodegradable and demonstrated excellent biocompatibility, cell attachment and cell proliferation profiles with mammalian fibroblast (NIH-3T3) cells. The inherent antimicrobial (bioactive) properties of peptides are utilized in this study through the preparation of synthetic polypeptide-based cryogels with inherent antimicrobial (bioactive) properties, for potential water purification applications. Traditionally, the effective bioactive properties of antimicrobial cryogels come from the incorporation of known antimicrobial agents to the gel structure rather than from the polymer itself. The leaching of these toxic agents is commonly reported in these systems, leading to potential toxicity issues. Cryogels composed of a polycationic poly(L-lysine) and hydrophobic poly(D,L-valine) copolymer were prepared with the gels displaying high swelling, and inherent antimicrobial activity against E. coli after brief 1 h exposure, with no toxic leaching. Compared to a conventional ‘nanoporous’ hydrogel, the cryogel macropores and their integrity were found to be crucial for bactericidal activity where they allow for effective uptake of bacteria into the gels, and provide a confined environment and increased surface area for contact of the bacteria with the antimicrobial polymer walls. The materials prepared in this thesis and the study of their properties, demonstrate an advancement in the scientific understanding and applicability of synthetic polypeptides in the relevant biomedical and bioactive fields

Cortisol as a biological marker of depression and memory difficulties in the early stages of Huntington's disease

Huntington’s disease (HD) is a genetic neurodegenerative condition which manifests a motor disorder, psychiatric disturbance, and a decline in cognitive functioning. Cortisol dysregulation in HD has been reported in a limited number of human and mouse model studies, but no published research has focussed on investigating the relationship between cortisol levels and the clinical signs of HD. Cortisol is a stress hormone produced by the hypothalamic-pituitary-adrenal (HPA) axis, and it is involved in a broad range of physical, behavioural, and cognitive functions. The concentration of circulating cortisol is a marker of HPA axis integrity and the ability of the HPA axis negative feedback loop to regulate itself. HPA axis dysfunction is associated with psychiatric and cognitive signs in a number of medical conditions, neuropsychiatric disorders, and neurodegenerative diseases. There is strong evidence of relationships between high cortisol, particularly around the time of morning awakening, and depression as well as between high cortisol and poor memory ability. In HD, however, these relationships have not been studied despite the fact that depression and memory decline are prominent early psychiatric and cognitive signs of this disease. A link between a neurobiological marker of HD progression and the first clinical signs of depression and memory decline may provide an objective indication of early pathophysiological changes in HD. Such a relationship may also make it possible to clinically assess the therapeutic benefit of an early intervention. The aim of the current research project was to extend on previous HD research by examining the relationship between cortisol levels and cognitive and psychiatric signs and symptoms in the early stages of HD. This thesis comprises two studies that have been written up as manuscripts and submitted for publication. Individually, the papers aim to examine the relationship between cortisol levels and signs of depression (Study 1) and memory performance (Study 2) in pre-diagnosed participants (pre-HD) and patients who had received a diagnosis of HD in the past 5 years (early-HD). Salivary cortisol was collected at four time points over a 24-hour period in 57 participants (17 early-HD, 20 pre-HD, 20 gene-normal healthy controls). To place this research project in the context of previous HPA axis studies of HD, cortisol levels within the subject sample of this project were first analysed at four time points across a 24-hour period, without taking into account clinical signs. The results indicated a trend for higher cortisol levels in pre-HD at all four time points. Study 1 of the thesis reports depression symptoms as measured by the Inventory of Depressive Symptomatology – Self-Report (IDS–SR), and Study 2 reports verbal learning and memory ability as measured using the California Verbal Learning Test – Second Edition (CVLT–II). Results from Study 1 indicated that the morning cortisol concentration in early-HD was dependent on the severity of depression, such that higher levels of depression were associated with higher morning cortisol than in non-depressed early-HD. This pattern was not observed in control and pre-HD. Study 2 reports an association between poorer memory encoding and retrieval, and higher evening cortisol in participants with more severe HD motor signs. This association was also not evident in control and pre-HD. Overall, these results indicate that cortisol dysregulation appears to begin well in advance of an HD diagnosis, perhaps resulting in chronic hypercortisolism through the pre-HD phase. Once HD is diagnosed, cortisol may be differentially influenced depending on the presence or absence of depression. Cortisol also appears to be related to memory decline in HD, but only once motor signs have become pronounced. Neuropathological changes related to HPA axis function, which worsen with disease progression, could account for these findings. Cortisol, and therefore HPA axis function, could thus be considered as a candidate biomarker of HD progression which is meaningfully associated with early neuropsychiatric and cognitive signs of HD

Speech acoustic markers of early stage and prodromal Huntington's disease: A marker of disease onset?

Published Version© 2012 Elsevier Ltd. All rights reserved.The research outputs in this collection have been funded in whole or in part by the National Health and Medical Research Council (NHMRC).Speech disturbances (e.g., altered prosody) have been described in symptomatic Huntington's Disease (HD) individuals, however, the extent to which speech changes in gene positive pre-manifest (PreHD) individuals is largely unknown. The speech of individuals carrying the mutant HTT gene is a behavioural/motor/cognitive marker demonstrating some potential as an objective indicator of early HD onset and disease progression. Speech samples were acquired from 30 individuals carrying the mutant HTT gene (13 PreHD, 17 early stage HD) and 15 matched controls. Participants read a passage, produced a monologue and said the days of the week. Data were analysed acoustically for measures of timing, frequency and intensity. There was a clear effect of group across most acoustic measures, so that speech performance differed in-line with disease progression. Comparisons across groups revealed significant differences between the control and the early stage HD group on measures of timing (e.g., speech rate). Participants carrying the mutant HTT gene presented with slower rates of speech, took longer to say words and produced greater silences between and within words compared to healthy controls. Importantly, speech rate showed a significant correlation to burden of disease scores. The speech of early stage HD differed significantly from controls. The speech of PreHD, although not reaching significance, tended to lie between the performance of controls and early stage HD. This suggests that changes in speech production appear to be developing prior to diagnosis.10.1016/j.neuropsychologia.2012.09.01

The Interplay between Internal Values and External Values in the Brand Building Process

The purpose of this thesis is to investigate the interplay between internal and external values, mainly by exploring the relationship between core values and brand values in a case study.This paper is based on a qualitative approach using various semi-structured interviews.The theoretical perspective aim to develop existing brand building process literature and provide enhanced understanding of the creation and origin of internal as well as external values.Empirical data was collected from Axis Communication across five aspects; top management, brand management, employee level, and an external branding agency. Last aspect concerns secondary data material regarding the Axis customers‘ perspective.The study show an array of interpretations regarding the definition of core values and brand values both among academics and practitioners. Yet, based on the case study, it can be argued that a mismatch between internal and external values of a brand may be beneficial for its on-going growth and development

Can we detect altered disease state in early stage Huntington’s Disease using acoustic markers of speech?

Altered prosody has been described in symptomatic Huntington’s Disease (HD) individuals, however, the extent to which acoustic analysis of speech is sensitive to gene positive pre-manifest (PreHD) individuals is unknown. Speech samples were acquired from 30 individuals carrying the mutant HTT gene (13 PreHD, 17 early stage HD) and 15 matched controls. Participants read a passage, produced a monologue, counted from 1-20 and said the days of the week. Data were analysed acoustically for measures of timing, frequency and intensity. Tasks were compared to determine their relative sensitivity to disease state. Tasks with greater cognitive demand appeared more suitable for detecting Huntington’s disease compared to tasks with high levels of automaticity

Lower cognitive control network connectivity in stroke participants with depressive features

Around one-third of people develop depression following ischaemic stroke, yet the underlying mechanisms are poorly understood. Post-stroke depression has been linked to frontal infarcts, mainly lesions in the left dorsolateral prefrontal cortex (DLPFC). But depression is a network disorder that cannot be fully characterised through lesion-symptom mapping. Researchers of depression in non-stroke populations have successfully tapped into the cognitive control network (CCN) using the bilateral DLPFC as a seed, and found that CCN resting-state connectivity is reduced in even mildly depressed subjects, compared to healthy controls. Hence, we aimed to investigate the association between post-stroke depressive features and the CCN resting-state connectivity in a stroke population. We analysed DLPFC resting-state connectivity in 64 stroke participants, 20 of whom showed depressive features assessed with the Patient Health Questionnaire (PHQ-9) at 3 months after stroke. We directly compared groups showing symptoms of depression with those who did not, and performed a regression with PHQ-9 scores in all participants, controlling for age, gender, lesion volume and stroke severity. Post-stroke depression was associated with lower connectivity between the left DLPFC and the right supramarginal gyrus (SMG) in both group and regression analyses. Neither the seed nor the results overlapped with stroke lesions. These findings confirm an important role of the left DLPFC in post-stroke depression, but now show that large-scale network disruptions following stroke associated with depressive features occur without lesions in the DLPFC

Copper-free palladium-catalyzed Sonogashira and Hiyama cross-couplings using aryl imidazol-1-ylsulfonates

Aryl imidazylates are effective electrophilic partners in copper-free palladium-catalyzed Hiyama and Sonogashira cross-coupling reactions. The Sonogashira cross-coupling of estron-3-yl imidazylate afforded the corresponding phenylacetylene derivative in excellent yield