There are over 40 identified human disorders that involve certain proteins folding incorrectly, a... more There are over 40 identified human disorders that involve certain proteins folding incorrectly, accumulating in the body causing damage to cells and organs and causing disease. Type 2 Diabetes Mellitus (T2DM) is one of these protein misfolding disorders (PMDs) and involves human islet amyloid polypeptide (hIAPP) misfolding and accumulating in parts of the body, primarily in the pancreas, causing damage to islet cells and affecting glucose regulation. In this review, we have summarised our current understanding of what causes hIAPP to misfold, what conformations are found in different parts of the body with a particular focus on what is known about the structure of hIAPP and how this links to T2DM. Understanding the molecular basis behind these misfolding events is essential for understanding the role of hIAPP to develop better therapeutics since type 2 diabetes currently affects over 4.9 million people in the United Kingdom alone and is predicted to increase as our population ages.
Here we describe a proof-of-concept case study focusing on the design and development of a novel ... more Here we describe a proof-of-concept case study focusing on the design and development of a novel computer interface that uses facial muscles to control interactivity within a virtual environment. We have developed a system comprised of skin-mounted electrodes that detect underlying muscle activity through electromyography. The signals from the electrodes are filtered and smoothed, then used as input data to an application that displays a virtual environment with a 3D animated avatar. The user’s expressions control the facial movements of the avatar, thus conveying user emotions through real-time animation of a representative face in a virtual scenario. To achieve this, we collaborated with our Public and Patient Involvement focus group to discuss concepts and design appropriate interactions, while simultaneously developing a prototype system. Programmers and 3D artists worked together to create a system whereby individual user facial muscles are connected to 3D animated models of th...
Cases of Type 2 Diabetes Mellitus (T2DM) are increasing at an alarming rate due to the rise in ob... more Cases of Type 2 Diabetes Mellitus (T2DM) are increasing at an alarming rate due to the rise in obesity, sedentary lifestyles, glucose-rich diets and other factors. Numerous studies have increasingly illustrated the pivotal role that human islet amyloid polypeptide (hIAPP) plays in the pathology of T2DM through damage and subsequent loss of pancreatic β-cell mass. HIAPP can misfold and form amyloid fibrils which are preceded by pre-fibrillar oligomers and monomers, all of which have been linked, to a certain extent, to β-cell cytotoxicity through a range of proposed mechanisms. This review provides an up-to-date summary of recent progress in the field, highlighting factors that contribute to hIAPP misfolding and aggregation such as hIAPP protein concentration, cell stress, molecular chaperones, the immune system response and cross-seeding with other amyloidogenic proteins. Understanding the structure of hIAPP and how these factors affect amyloid formation will help us better understa...
The yeast mitochondrial ATPase has been genetically modified to include a His(6) Ni-affinity tag ... more The yeast mitochondrial ATPase has been genetically modified to include a His(6) Ni-affinity tag on the amino end of the mature beta-subunit. The modified beta-subunit is imported into the mitochondrion, properly processed to the mature form, and assembled into a mature and fully active ATP synthase. The F(1)-ATPase has been purified from submitochondrial particles after release from the membrane with chloroform, followed by Ni-chelate-affinity and gel filtration chromatography. The final enzyme is a homogeneous preparation with full activity and no apparent degradation products. This enzyme preparation has been used to obtain crystals that diffract to better than 2.8 A resolution.
Bacteria of the genera Bacillus and Clostridium form highly resistant spores, which in the case o... more Bacteria of the genera Bacillus and Clostridium form highly resistant spores, which in the case of some pathogens act as the infectious agents. An exosporium forms the outermost layer of some spores; it plays roles in protection, adhesion, dissemination, host targeting in pathogens, and germination control. The exosporium of the Bacillus cereus group, including the anthrax pathogen, contains a 2D-crystalline basal layer, overlaid by a hairy nap. BclA and related proteins form the hairy nap, and require ExsFA (BxpB) for their localisation on the basal layer. Until now, the identity of the main structural protein components of the basal layer were unknown. We demonstrate here that ExsY forms one of the essential components. Through heterologous expression in E. coli, we also demonstrate that ExsY can self-assemble into ordered 2D arrays that mimic the structure of the exosporium basal layer. Self-assembly is likely to play an important role in the construction of the exosporium. The E...
Infected PK1/2 cells generate PrPSc by recruitment of PrPC which occurs at a rate faster than the... more Infected PK1/2 cells generate PrPSc by recruitment of PrPC which occurs at a rate faster than the cells innate clearance systems and dilutional effect of cell division, thus the cells remain chronically infected. However when ADDLs are added they bind to PrPC at the cell surface preventing conversion to PrPSc. This reduction in the conversion rate allows the PrPSc to be cleared over time, resulting in reduction in PrPSc levels and cell curing.
Mammalian prions cause lethal neurodegenerative diseases such as Creutzfeldt–Jakob disease (CJD) ... more Mammalian prions cause lethal neurodegenerative diseases such as Creutzfeldt–Jakob disease (CJD) and consist of multi-chain assemblies of misfolded cellular prion protein (PrP<sup>C</sup>). Ligands that bind to PrP<sup>C</sup> can inhibit prion propagation and neurotoxicity. Extensive prior work established that certain soluble assemblies of the Alzheimer's disease (AD)-associated amyloid β-protein (Aβ) can tightly bind to PrP<sup>C</sup>, and that this interaction may be relevant to their toxicity in AD. Here, we investigated whether such soluble Aβ assemblies might, conversely, have an inhibitory effect on prion propagation. Using cellular models of prion infection and propagation and distinct Aβ preparations, we found that the form of Aβ assemblies which most avidly bound to PrP <i>in vitro</i> also inhibited prion infection and propagation. By contrast, forms of Aβ which exhibit little or no binding to PrP were unable to attenu...
There are over 40 identified human disorders that involve certain proteins folding incorrectly, a... more There are over 40 identified human disorders that involve certain proteins folding incorrectly, accumulating in the body causing damage to cells and organs and causing disease. Type 2 Diabetes Mellitus (T2DM) is one of these protein misfolding disorders (PMDs) and involves human islet amyloid polypeptide (hIAPP) misfolding and accumulating in parts of the body, primarily in the pancreas, causing damage to islet cells and affecting glucose regulation. In this review, we have summarised our current understanding of what causes hIAPP to misfold, what conformations are found in different parts of the body with a particular focus on what is known about the structure of hIAPP and how this links to T2DM. Understanding the molecular basis behind these misfolding events is essential for understanding the role of hIAPP to develop better therapeutics since type 2 diabetes currently affects over 4.9 million people in the United Kingdom alone and is predicted to increase as our population ages.
Here we describe a proof-of-concept case study focusing on the design and development of a novel ... more Here we describe a proof-of-concept case study focusing on the design and development of a novel computer interface that uses facial muscles to control interactivity within a virtual environment. We have developed a system comprised of skin-mounted electrodes that detect underlying muscle activity through electromyography. The signals from the electrodes are filtered and smoothed, then used as input data to an application that displays a virtual environment with a 3D animated avatar. The user’s expressions control the facial movements of the avatar, thus conveying user emotions through real-time animation of a representative face in a virtual scenario. To achieve this, we collaborated with our Public and Patient Involvement focus group to discuss concepts and design appropriate interactions, while simultaneously developing a prototype system. Programmers and 3D artists worked together to create a system whereby individual user facial muscles are connected to 3D animated models of th...
Cases of Type 2 Diabetes Mellitus (T2DM) are increasing at an alarming rate due to the rise in ob... more Cases of Type 2 Diabetes Mellitus (T2DM) are increasing at an alarming rate due to the rise in obesity, sedentary lifestyles, glucose-rich diets and other factors. Numerous studies have increasingly illustrated the pivotal role that human islet amyloid polypeptide (hIAPP) plays in the pathology of T2DM through damage and subsequent loss of pancreatic β-cell mass. HIAPP can misfold and form amyloid fibrils which are preceded by pre-fibrillar oligomers and monomers, all of which have been linked, to a certain extent, to β-cell cytotoxicity through a range of proposed mechanisms. This review provides an up-to-date summary of recent progress in the field, highlighting factors that contribute to hIAPP misfolding and aggregation such as hIAPP protein concentration, cell stress, molecular chaperones, the immune system response and cross-seeding with other amyloidogenic proteins. Understanding the structure of hIAPP and how these factors affect amyloid formation will help us better understa...
The yeast mitochondrial ATPase has been genetically modified to include a His(6) Ni-affinity tag ... more The yeast mitochondrial ATPase has been genetically modified to include a His(6) Ni-affinity tag on the amino end of the mature beta-subunit. The modified beta-subunit is imported into the mitochondrion, properly processed to the mature form, and assembled into a mature and fully active ATP synthase. The F(1)-ATPase has been purified from submitochondrial particles after release from the membrane with chloroform, followed by Ni-chelate-affinity and gel filtration chromatography. The final enzyme is a homogeneous preparation with full activity and no apparent degradation products. This enzyme preparation has been used to obtain crystals that diffract to better than 2.8 A resolution.
Bacteria of the genera Bacillus and Clostridium form highly resistant spores, which in the case o... more Bacteria of the genera Bacillus and Clostridium form highly resistant spores, which in the case of some pathogens act as the infectious agents. An exosporium forms the outermost layer of some spores; it plays roles in protection, adhesion, dissemination, host targeting in pathogens, and germination control. The exosporium of the Bacillus cereus group, including the anthrax pathogen, contains a 2D-crystalline basal layer, overlaid by a hairy nap. BclA and related proteins form the hairy nap, and require ExsFA (BxpB) for their localisation on the basal layer. Until now, the identity of the main structural protein components of the basal layer were unknown. We demonstrate here that ExsY forms one of the essential components. Through heterologous expression in E. coli, we also demonstrate that ExsY can self-assemble into ordered 2D arrays that mimic the structure of the exosporium basal layer. Self-assembly is likely to play an important role in the construction of the exosporium. The E...
Infected PK1/2 cells generate PrPSc by recruitment of PrPC which occurs at a rate faster than the... more Infected PK1/2 cells generate PrPSc by recruitment of PrPC which occurs at a rate faster than the cells innate clearance systems and dilutional effect of cell division, thus the cells remain chronically infected. However when ADDLs are added they bind to PrPC at the cell surface preventing conversion to PrPSc. This reduction in the conversion rate allows the PrPSc to be cleared over time, resulting in reduction in PrPSc levels and cell curing.
Mammalian prions cause lethal neurodegenerative diseases such as Creutzfeldt–Jakob disease (CJD) ... more Mammalian prions cause lethal neurodegenerative diseases such as Creutzfeldt–Jakob disease (CJD) and consist of multi-chain assemblies of misfolded cellular prion protein (PrP<sup>C</sup>). Ligands that bind to PrP<sup>C</sup> can inhibit prion propagation and neurotoxicity. Extensive prior work established that certain soluble assemblies of the Alzheimer's disease (AD)-associated amyloid β-protein (Aβ) can tightly bind to PrP<sup>C</sup>, and that this interaction may be relevant to their toxicity in AD. Here, we investigated whether such soluble Aβ assemblies might, conversely, have an inhibitory effect on prion propagation. Using cellular models of prion infection and propagation and distinct Aβ preparations, we found that the form of Aβ assemblies which most avidly bound to PrP <i>in vitro</i> also inhibited prion infection and propagation. By contrast, forms of Aβ which exhibit little or no binding to PrP were unable to attenu...
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