Factors That Contribute to hIAPP Amyloidosis in Type 2 Diabetes Mellitus

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 understand how hIAPP misfolds and aggregates and, importantly, help identify potential therapeutic targets for inhibiting amyloidosis so alternate and more effective treatments for T2DM can be developed

Recent advances in understanding mammalian prion structure

Prions are lethal pathogens, which cause fatal neurodegenerative diseases in mammals. They are unique infectious agents and are composed of self-propagating multi-chain assemblies of misfolded host-encoded prion protein (PrP). Understanding prion structure is fundamental to understanding prion disease pathogenesis however to date, the high-resolution structure of authentic ex vivo infectious prions remains unknown. Advances in determining prion structure have been severely impeded by the difficulty in recovering relatively homogeneous prion particles from infected brain and definitively associating infectivity with the PrP assembly state. Recently, however, images of highly infectious ex vivo PrP rods that produce prion-strain specific disease phenotypes in mice have been obtained using cryo-electron microscopy and atomic force microscopy. These images have provided the most detailed description of ex vivo mammalian prions reported to date and have established that prions isolated from multiple strains have a common hierarchical structure. Misfolded PrP is assembled into 20 nm wide rods containing two fibers, each with double helical repeating substructure, separated by a characteristic central gap 8-10 nm in width. Irregularly structured material with adhesive properties distinct to that of the fibers is present within the central gap of the rod. Prions are clearly distinguishable from non-infectious recombinant PrP fibrils generated in vitro and from all other propagating protein structures so far described in other neurodegenerative diseases. The basic architecture of mammalian prions appears to be exceptional and fundamental to their lethal pathogenicity

Evaluating pasture species for less fertile soils in a subtropical aseasonal low rainfall zone

Grasses, legumes, saltbushes and herbs were evaluated at 6 sites in southern inland Queensland to identify potential pasture and forage plants for use on marginal cropping soils. The region experiences summer heat waves and severe winter frosts. Emphasis was on perennial plants, and native species were included. Seedlings were transplanted into the unfertilized fields in either summer or autumn to suit the growing season of plants, and watered to ensure estab-lishment. Summer-growing grasses were the most successful group, while cool season-growing perennials mostly failed. Summer legumes were disappointing, with Stylosanthes scabra and Indigofera schimperi performing best. Some lines such as I. schimperi and the Eragrostis hybrid cv. Cochise were assessed as potential weeds owing to low animal acceptance. Native Rhynchosia minima grew well at some sites and deserves more study. Cenchrus ciliaris was always easy to establish and produced the highest yields. Persistence of some Digitaria and Bothriochloa species, Eragrostis curvula and Fingerhuthia africana at specific sites was encouraging, but potential weediness needs careful assessment. Standard species were identified to represent the main forage types, such as Austrostipa scabra for cool season-growing grasses, for incorporation into future trials with new genetic materials. The early field testing protocol used should be considered for use elsewhere, if unreliable rainfall poses a high risk of establishment failure from scarce seed

Evaluating pasture species for less fertile soils in a subtropical aseasonal low rainfall zone

Grasses, legumes, saltbushes and herbs were evaluated at 6 sites in southern inland Queensland to identify potential pasture and forage plants for use on marginal cropping soils. The region experiences summer heat waves and severe winter frosts. Emphasis was on perennial plants, and native species were included. Seedlings were transplanted into the unfertilized fields in either summer or autumn to suit the growing season of plants, and watered to ensure estab-lishment. Summer-growing grasses were the most successful group, while cool season-growing perennials mostly failed. Summer legumes were disappointing, with Stylosanthes scabra and Indigofera schimperi performing best. Some lines such as I. schimperi and the Eragrostis hybrid cv. Cochise were assessed as potential weeds owing to low animal acceptance. Native Rhynchosia minima grew well at some sites and deserves more study. Cenchrus ciliaris was always easy to establish and produced the highest yields. Persistence of some Digitaria and Bothriochloa species, Eragrostis curvula and Fingerhuthia africana at specific sites was encouraging, but potential weediness needs careful assessment. Standard species were identified to represent the main forage types, such as Austrostipa scabra for cool season-growing grasses, for incorporation into future trials with new genetic materials. The early field testing protocol used should be considered for use elsewhere, if unreliable rainfall poses a high risk of establishment failure from scarce seed

Linking hIAPP misfolding and aggregation with type 2 diabetes mellitus: a structural perspective

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 is one of these protein misfolding disorders and involves human islet amyloid polypeptide 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 Type 2 Diabetes Mellitus. 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 UK alone and is predicted to increase as our population ages

Factors that contribute to hIAPP amyloidosis in type 2 diabetes mellitus

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 understand how hIAPP misfolds and aggregates and, importantly, help identify potential therapeutic targets for inhibiting amyloidosis so alternate and more effective treatments for T2DM can be developed

Design Goals for Playful Technology to Support Physical Activity Among Wheelchair Users

Playful technology has the potential to support physical activity (PA) among wheelchair users, but little is known about design considerations for this audience, who experience significant access barriers. In this paper, we leverage the Integrated Behavioural Model (IBM) to understand wheelchair users’ perspectives on PA, technology, and play. First, we present findings from an interview study with eight physically active wheelchair users. Second, we build on the interviews in a survey that received 44 responses from a broader group of wheelchair users. Results show that the anticipation of positive experiences was the strongest predictor of engagement with PA, and that accessibility concerns act as barriers both in terms of PA participation and technology use. We present four design goals - emphasizing enjoyment, involving others, building knowledge and enabling flexibility - to make our findings actionable for researchers and designers wishing to create accessible playful technology to support PA

A Toolkit for Pediatric CT Dose Reduction in Community Hospitals

"Eighty percent of success is just showing up."—Woody Allen Pediatric CT radiation dose optimization is a challenging process for pediatric-focused facilities and community hospitals alike. Ongoing experience and trial-and-error approaches to dose reduction in the large academic hospital setting may position these centers to help community hospitals that strive for CT quality improvement. We describe our hands-on approach in a pilot project to create a partnership between an academic medical center and a community hospital to develop a toolkit for implementing CT dose reduction. Our aims were to (1) assess the acceptability of an interactive educational program and electronic toolkit booklet, (2) conduct a limited test of the efficacy of the toolkit in promoting knowledge and readiness to change, and (3) assess the acceptability and practicality of a collaborative approach to implementing dose reduction protocols in community hospitals. In partnering with the community hospital, we found that they had size-specific radiation doses two to three times higher than those at our center. Survey results after a site visit with interactive educational presentations revealed an increase in knowledge, stronger opinions about the health risks of radiation from CT scans, and willingness and perceived ability to reduce pediatric CT doses

Observing protoplanetary discs with the Square Kilometre Array -- I. Characterising pebble substructure caused by forming planets

High angular resolution observations of discs at mm wavelengths (on scales of a few au) are now commonplace, but there is a current lack of a comparable angular resolution for observations at cm wavelengths. This presents a significant barrier to improving our understanding of planet formation, in particular how dust grains grow from mm to cm sizes. In this paper, we examine the ability of the Square Kilometre Array (SKA) to observe dust substructure in a young, planet-forming disc at cm wavelengths. We use dusty hydrodynamics and continuum radiative transfer to predict the distribution and emission of 1 cm dust grains (or pebbles) within the disc, and simulate continuum observations with the current SKA1-MID design baseline at frequencies of 12.5 GHz (Band 5b, ~2.4 cm) on 5-10 au scales. The SKA will provide high-fidelity observations of the cm dust emission substructure in discs for integration times totalling 100's of hours. Radial structure can be obtained at a sufficient resolution and S/N from shorter (10's of hours) integration times by azimuthal averaging in the image plane. By modelling the intensity distribution directly in the visibility plane, it is possible to recover a similar level of (axisymmetric) structural detail from observations with integration times 1-2 orders of magnitude lower than required for high-fidelity imaging. Our results demonstrate that SKA1-MID will provide crucial constraints on the distribution and morphology of the raw material for building planets, the pebbles in protoplanetary discs.Comment: 12 pages, 8 figures, accepted for publication in MNRA

Structural features distinguishing infectious ex vivo mammalian prions from non-infectious fibrillar assemblies generated in vitro

Seeded polymerisation of proteins forming amyloid fibres and their spread in tissues has been implicated in the pathogenesis of multiple neurodegenerative diseases: so called "prion-like" mechanisms. While ex vivo mammalian prions, composed of multichain assemblies of misfolded host-encoded prion protein (PrP), act as lethal infectious agents, PrP amyloid fibrils produced in vitro generally do not. The high-resolution structure of authentic infectious prions and the structural basis of prion strain diversity remain unknown. Here we use cryo-electron microscopy and atomic force microscopy to examine the structure of highly infectious PrP rods isolated from mouse brain in comparison to non-infectious recombinant PrP fibrils generated in vitro. Non-infectious recombinant PrP fibrils are 10 nm wide single fibres, with a double helical repeating substructure displaying small variations in adhesive force interactions across their width. In contrast, infectious PrP rods are 20 nm wide and contain two fibres, each with a double helical repeating substructure, separated by a central gap of 8-10 nm in width. This gap contains an irregularly structured material whose adhesive force properties are strikingly different to that of the fibres, suggestive of a distinct composition. The structure of the infectious PrP rods, which cause lethal neurodegeneration, readily differentiates them from all other protein assemblies so far characterised in other neurodegenerative diseases