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Mark J. Howard

Bio: Mark J. Howard is an academic researcher from University of Leeds. The author has contributed to research in topics: Metabolome & Pyridine. The author has an hindex of 6, co-authored 16 publications receiving 128 citations. Previous affiliations of Mark J. Howard include University of Western Australia & University of Kent.

Papers
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Journal ArticleDOI
TL;DR: The aim of this review is to highlight and summarize recent literature that have contributed insight into the implications of altered membrane composition on amyloid precursor protein (APP) proteolysis, production of Aβ, its internalization in to cells via permeabilization and receptor mediated uptake.

45 citations

Journal ArticleDOI
TL;DR: It is demonstrated that hIAPP promotes Aβ oligomerization and formation of small oligomer and large aggregate heterocomplexes, and rIAPP exhibited reductions in Aβ induced neuronal cell death that was independent of its ability to interact with Aβ and form heterocom complex; suggesting mediation by other pathways.
Abstract: Human pancreatic islet amyloid polypeptide (hIAPP) and beta amyloid (Aβ) can accumulate in Type 2 diabetes (T2D) and Alzheimer’s disease (AD) brains and evidence suggests that interaction between the two amyloidogenic proteins can lead to the formation of heterocomplex aggregates However, the structure and consequences of the formation of these complexes remains to be determined The main objective of this study was to characterise the different types and morphology of Aβ-hIAPP heterocomplexes and determine if formation of such complexes exacerbate neurotoxicity We demonstrate that hIAPP promotes Aβ oligomerization and formation of small oligomer and large aggregate heterocomplexes Co-oligomerized Aβ42-hIAPP mixtures displayed distinct amorphous structures and a 3-fold increase in neuronal cell death as compared to Aβ and hIAPP alone However, in contrast to hIAPP, non-amyloidogenic rat amylin (rIAPP) reduced oligomer Aβ-mediated neuronal cell death rIAPP exhibited reductions in Aβ induced neuronal cell death that was independent of its ability to interact with Aβ and form heterocomplexes; suggesting mediation by other pathways Our findings reveal distinct effects of IAPP peptides in modulating Aβ aggregation and toxicity and provide new insight into the potential pathogenic effects of Aβ-IAPP hetero-oligomerization and development of IAPP based therapies for AD and T2D

43 citations

Journal ArticleDOI
01 Feb 2018
TL;DR: This study has revealed what is likely to be a very large new family of orbitides, uniquely buried alongside albumin and processed by asparaginyl endopeptidase (AEP).
Abstract: Orbitides are cyclic ribosomally-synthesized and post-translationally modified peptides (RiPPs) from plants; they consist of standard amino acids arranged in an unbroken chain of peptide bonds. These cyclic peptides are stable and range in size and topologies making them potential scaffolds for peptide drugs; some display valuable biological activities. Recently two orbitides whose sequences were buried in those of seed storage albumin precursors were said to represent the first observable step in the evolution of larger and hydrophilic bicyclic peptides. Here, guided by transcriptome data, we investigated peptide extracts of 40 species specifically for the more hydrophobic orbitides and confirmed 44 peptides by tandem mass spectrometry, as well as obtaining solution structures for four of them by NMR. Acquiring transcriptomes from the phylogenetically important Corymboideae family confirmed the precursor genes for the peptides (called PawS1-Like or PawL1) are confined to the Asteroideae, a subfamily of the huge plant family Asteraceae. To be confined to the Asteroideae indicates these peptides arose during the Eocene epoch around 45 Mya. Unlike other orbitides, all PawL-derived Peptides contain an Asp residue, needed for processing by asparaginyl endopeptidase. This study has revealed what is likely to be a very large new family of orbitides, uniquely buried alongside albumin and processed by asparaginyl endopeptidase.

31 citations

Journal ArticleDOI
TL;DR: Using a 1H nuclear magnetic resonance approach to metabolomics, the nature of the mouse gut metabolome is explored as well as providing the first insight into the metabolome of an infected cell line, which will spearhead understanding of the Cryptosporidium-host metabolic exchange and provide novel targets for tackling this deadly parasite.
Abstract: Cryptosporidium is an important gut microbe whose contributions towards infant and immunocompromise patient mortality rates are steadily increasing. Over the last decade, we have seen the development of various tools and methods for studying Cryptosporidium infection and its interactions with their hosts. One area that is sorely overlooked is the effect infection has on host metabolic processes. Using a 1H nuclear magnetic resonance approach to metabolomics, we have explored the nature of the mouse gut metabolome as well as providing the first insight into the metabolome of an infected cell line. Statistical analysis and predictive modelling demonstrated new understandings of the effects of a Cryptosporidium infection, while verifying the presence of known metabolic changes. Of note is the potential contribution of host derived taurine to the diarrhoeal aspects of the disease previously attributed to a solely parasite-based alteration of the gut environment, in addition to other metabolites involved with host cell catabolism. This approach will spearhead our understanding of the Cryptosporidium-host metabolic exchange and provide novel targets for tackling this deadly parasite.

20 citations

Journal ArticleDOI
TL;DR: Examination of the interactions between individual components, experimentally and computationally, provided a rationale for the product distribution during each phase of a cascade, resulting in the construction of a biomimetic network in which the presence or absence of different components provides multiple unique pathways to distinct self‐sorted configurations.
Abstract: A current objective in supramolecular chemistry is to mimic the transitions between complex self‐sorted systems that represent a hallmark of regulatory function in nature. In this work, a self‐sorting network, comprising linear hydrogen motifs, was created. Selecting six hydrogen‐bonding motifs capable of both high‐fidelity and promiscuous molecular recognition gave rise to a complex self‐sorting system, which included motifs capable of both narcissistic and social self‐sorting. Examination of the interactions between individual components, experimentally and computationally, provided a rationale for the product distribution during each phase of a cascade. This reasoning holds through up to five sequential additions of six building blocks, resulting in the construction of a biomimetic network in which the presence or absence of different components provides multiple unique pathways to distinct self‐sorted configurations.

18 citations


Cited by
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Journal ArticleDOI
TL;DR: This review will focus on the applications of various cutting-edge bioactive hydrogels systems in bone regeneration, as well as their advantages and limitations, and classify recently developed polymeric materials for hydrogel synthesis.

325 citations

Journal ArticleDOI
TL;DR: A review of the current knowledge of the structures and pathology associated with hIAPP self-assembly and point out the opportunities for therapy that a detailed biochemical, biophysical, and cellular understanding of its aggregation may unveil.
Abstract: The possible link between hIAPP accumulation and β-cell death in diabetic patients has inspired numerous studies focusing on amyloid structures and aggregation pathways of this hormone. Recent studies have reported on the importance of early oligomeric intermediates, the many roles of their interactions with lipid membrane, pH, insulin, and zinc on the mechanism of aggregation of hIAPP. The challenges posed by the transient nature of amyloid oligomers, their structural heterogeneity, and the complex nature of their interaction with lipid membranes have resulted in the development of a wide range of biophysical and chemical approaches to characterize the aggregation process. While the cellular processes and factors activating hIAPP-mediated cytotoxicity are still not clear, it has recently been suggested that its impaired turnover and cellular processing by proteasome and autophagy may contribute significantly toward toxic hIAPP accumulation and, eventually, β-cell death. Therefore, studies focusing on the restoration of hIAPP proteostasis may represent a promising arena for the design of effective therapies. In this review we discuss the current knowledge of the structures and pathology associated with hIAPP self-assembly and point out the opportunities for therapy that a detailed biochemical, biophysical, and cellular understanding of its aggregation may unveil.

101 citations

Journal ArticleDOI
TL;DR: This review article focuses on the biophysical processes underlying the cross-seeding for some of the most commonly studied amyloid proteins, including hIAPP, human islet amyloids polypeptide (hIAPP), and alpha-synuclein.

95 citations

Journal ArticleDOI
TL;DR: It is proposed that AD could be tackled not only using combination therapies including Aβ and tau, but also considering insulin and cholesterol metabolism, vascular function, synaptic plasticity, epigenetics, neurovascular junction and blood–brain barrier targets that have been studied recently.
Abstract: Alzheimer's disease (AD), the most frequent cause of dementia, is escalating as a global epidemic, and so far, there is neither cure nor treatment to alter its progression. The most important feature of the disease is neuronal death and loss of cognitive functions, caused probably from several pathological processes in the brain. The main neuropathological features of AD are widely described as amyloid beta (Aβ) plaques and neurofibrillary tangles of the aggregated protein tau, which contribute to the disease. Nevertheless, AD brains suffer from a variety of alterations in function, such as energy metabolism, inflammation and synaptic activity. The latest decades have seen an explosion of genes and molecules that can be employed as targets aiming to improve brain physiology, which can result in preventive strategies for AD. Moreover, therapeutics using these targets can help AD brains to sustain function during the development of AD pathology. Here, we review broadly recent information for potential targets that can modify AD through diverse pharmacological and nonpharmacological approaches including gene therapy. We propose that AD could be tackled not only using combination therapies including Aβ and tau, but also considering insulin and cholesterol metabolism, vascular function, synaptic plasticity, epigenetics, neurovascular junction and blood-brain barrier targets that have been studied recently. We also make a case for the role of gut microbiota in AD. Our hope is to promote the continuing research of diverse targets affecting AD and promote diverse targeting as a near-future strategy.

90 citations