A preliminary electron microscopic investigation into the interaction between Aβ1-42 peptide and a novel nanoliposome- coupled retro-inverso peptide inhibitor, developed as a potential treatment for Alzheimer's disease

Alzheimer's disease (AD) is a progressive neurodegenerative condition that results in severe cognitive and functional decline in sufferers and for which there are currently no effective treatments to halt or reverse disease progression. AD is the most common form of dementia and age is the major risk factor for this disease. With worldwide population structures changing as increasing number of individuals survive into old age, there is urgent need for novel disease modifying treatments for this condition, which has profound effects upon sufferers in addition to those around them. Some of us have previously developed a peptide inhibitor of Aβ1-42 aggregation (RI-OR2-TAT) that has been shown to reduce Aβ1-42 pathology in vivo in mouse models of AD. ~1690 copies of RI-OR2-TAT have been covalently attached to nanoliposome carrier particles forming Peptide Inhibitor NanoParticles (PINPs), and this study investigated the effect of PINPs upon Aβ1-42 aggregation at the molecular level. Our results show that PINPs are able to reduce Aβ1-42 aggregation and do so by binding early (oligomers) and late (fibrillar) stage aggregates. These results highlight the ability of PINPs to disrupt the formation of multiple Aβ1-42 aggregates capable of causing neurotoxicity and thus provide a strong case for PINPs to be carried forward into early stage clinical trials as a novel therapeutic option for the treatment of AD

Non-invasive respiratory monitoring using long-period fiber grating sensors

In non-invasive ventilation, continuous monitoring of respiratory volumes is essential. Here, we present a method for the measurement of respiratory volumes by a single fiber-grating sensor of bending and provide the proof-of-principle by applying a calibration-test measurement procedure on a set of 18 healthy volunteers. Results establish a linear correlation between a change in lung volume and the corresponding change in a local thorax curvature. They also show good sensor accuracy in measurements of tidal and minute respiratory volumes for different types of breathing. The proposed technique does not rely on the air flow through an oronasal mask or the observation of chest movement by a clinician, which distinguishes it from the current clinical practice

Strain shadow “megapores” in mid-crustal ultramylonites

Mylonitic shear zones are important fluid conduits in the Earth's crust. They host transient and permeable porosity that facilitates fluid transfer and controls fluid-rock interaction. Here we present microstructural observations from a mid-crustal ultramylonite with very large pores that occupy the strain shadows of albite porphyroclasts. Our non-invasive three-dimensional X-ray microtomographic data show that the largest of these strain shadow megapores have substantial volumes of as much as ∼1.7 × 105 µm3. Given that the sample shows no signs of retrogressive overprint or weathering, these pores must be synkinematic. Importantly, the close proximity of the pores to creep cavities in dynamically recrystallized quartz ribbon grains suggests a potential hydraulic link between fluid in the strain shadow megapores and fluid in the creeping rock matrix. The evolving megapores constitute very large syndeformational local fluid reservoirs in mylonites that likely fed into the granular fluid pump established by the dynamically evolving creep cavities. Our findings add to an emerging picture of the dynamic transport properties of ultramylonitic shear zones, where the formation and destruction of porosity are intrinsically linked to microscale deformation processes. They also suggest that despite many studies on porphyroclast systems, open questions remain, especially concerning the interaction of clasts with their matrix

Sensing characteristics of a novel two-section long-period grating

The behavior of a temperature self-compensating, fiber, long-period grating (LPG) device is studied. This device consists of a single 325-µm-period LPG recorded across two sections of a single-mode B-Ge-codoped fiber—one section bare and the other coated with a 1-µm thickness of Ag. This structure generates two attenuation bands associated with the eighth and ninth cladding modes, which are spectrally close together (~60 nm). The attenuation band associated with the Ag-coated section is unaffected by changes in the refractive index of the surrounding medium and can be used to compensate for the temperature of the bare-fiber section. The sensor has a resolution of ±1.0 × 10-3 for the refractive index and ±0.3 °C for the temperature. The effect of bending on the spectral characteristics of the two attenuation bands was found to be nonlinear, with the Ag-coated LPG having the greater sensitivity

Liposome delivery systems for the treatment of Alzheimer’s disease

Alzheimer’s disease (AD) will affect around 115 million people worldwide by the year 2050. It is associated with the accumulation of misfolded and aggregated proteins (β-amyloid and tau) in the senile plaques and neurofibrillary tangles found in the brain. Currently available drugs for AD only temporarily alleviate symptoms and do not slow the inevitable progression of this disease. New drugs are required that act on key pathologies in order to arrest or reverse cognitive decline. However, there has been a spectacular failure rate in clinical trials of conventional small molecule drugs or biological agents. Targeted nanoliposomes represent a viable and promising drug delivery system for AD that have not yet reached clinical trials. They are biocompatible, highly flexible, and have the potential to carry many different types of therapeutic molecules across the blood–brain barrier (BBB) and into brain cells. They can be tailored to extend blood circulation time and can be directed against individual or multiple pathological targets. Modifications so far have included the use of brain-penetrating peptides, together with Aβ-targeting ligands, such as phosphatidic acid, curcumin, and a retro-inverted peptide that inhibits Aβ aggregation. Combining several modifications together into multifunctional liposomes is currently a research area of great interest. This review focuses on recent liposomal approaches to AD therapy, including mechanisms involved in facilitating their passage across the BBB, and the evaluation of new therapeutic agents for blocking Aβ and/or tau aggregation

Visual Search Behavior in Individuals With Retinitis Pigmentosa During Level Walking and Obstacle Crossing

Purpose: Investigate the visual search strategy of individuals with retinitis pigmentosa (RP) when negotiating a floor-based obstacle compared with level walking, and compared with those with normal vision. Methods: Wearing a mobile eye tracker, individuals with RP and normal vision walked along a level walkway or walked along the walkway negotiating a floor-based obstacle. In the level walking condition, tape was placed on the floor to act as an object attracting visual attention. Analysis compared where individuals looked within the environment. Results: In the obstacle compared with level walking condition: (1) the RP group reduced the length of time and the number of times they looked Ahead, and increased the time and how often they looked at features on the ground (Object and Down, P < 0.05); and (2) the visual normal group reduced the time (by 19%) they looked Ahead (P = 0.076), and increased the time and how often they looked at the Object (P < 0.05). Compared with the normal vision group, in both level walking and obstacle conditions, the RP group reduced the time looking Ahead and looked for longer and more often Down (P < 0.05). Conclusions: The RP group demonstrated a more active visual search pattern, looking at more areas on the ground in both level walking and obstacle crossing compared with visual normals. This gaze strategy was invariant across conditions. This is most likely due to the constricted visual field and inability to rely on inferior peripheral vision to acquire information from the floor within the environment when walking

Development of proteolytically stable N-methylated peptide inhibitors of aggregation of the amylin peptide implicated in type 2 diabetes

Islet amyloid polypeptide, also known as amylin, is the main component of the amyloid deposits present in approximately 90% of people with type 2 diabetes mellitus (T2DM). In this disease, amylin aggregates into multimeric β-pleated sheet structures which cause damage to pancreatic islet β-cells. Inhibitors of early-stage amylin aggregation could therefore provide a disease-modifying treatment for T2DM. In this study, overlapping peptides were designed to target the ‘binding’ region (RLANFLVHSS, residues 11-20) of human amylin, and their effects on amyloid fibril formation were determined by Thioflavin-T assay. The first generation peptides showed less than 50% inhibition of aggregation, but a second generation peptide (H2N-RGANFLVHGR-CONH2) showed strong inhibitory effects on amylin aggregation, and this was confirmed by negative stain electron microscopy. Cytotoxicity studies revealed that this peptide protected human pancreatic 1.4E7 (ECACC 10070102) insulin-secreting cells from the toxic effects of human amylin. Unlike the retro-inverso version of this peptide, which stimulated aggregation, two N-methylated peptides (H2N-RGAmNFmLVmHGR-CONH2 and H2N-RGANmFLmVHmR-CONH2) gave very clear dose-dependent inhibition of fibril formation. These two peptides were also stable against a range of different proteolytic enzymes, and in human plasma. These N-methylated peptides could provide a novel treatment for slowing progression of T2DM

Bodily crises in skilled performance: Considering the need for artistic habits

Empirical evidence demonstrates that performing artists are confronted by a variety of ‘bodily crises’ (e.g., injury, attrition of habits induced by ageing) over the course of their careers (Wainwright, Williams, & Turner, 2005). Such crises may present a serious threat to the embodied subject. Unfortunately, many prominent theories of skill acquisition (e.g., Fitts & Posner, 1967) appear to evacuate the body from performance by suggesting that any form of conscious processing (i.e., paying conscious attention to one's action during motor skill execution) will disrupt habitual behaviour. As a result, few researchers have considered how performers might tackle bodily anomalies. In the current paper, we seek to address this issue by discussing a variety of the ‘crises’ that confront the performing body. We start by discussing a number of disciplinary practices that may contribute to these crises. Next, we argue that habitual movements must be open to ‘acts of creativity’ in order to maintain a productive relationship between the performing body and the environment. Then we consider what this ‘creative action’ might involve and discuss a number of approaches (e.g., mindfulness, somaesthetic awareness) that could maintain and improve one's movement proficiency. Here, our argument draws on Dewey's (1922) pragmatist philosophy and his belief that ‘intelligent habit’ was required to help people to improve their movement functioning. Finally, we consider the implications of our argument for current conceptualisations of ‘habitual’ movement and recommend that researchers explore the adaptive and flexible capacity of the performing body

Abnormal Cortical Development after Premature Birth Shown by Altered Allometric Scaling of Brain Growth

BACKGROUND: We postulated that during ontogenesis cortical surface area and cerebral volume are related by a scaling law whose exponent gives a quantitative measure of cortical development. We used this approach to investigate the hypothesis that premature termination of the intrauterine environment by preterm birth reduces cortical development in a dose-dependent manner, providing a neural substrate for functional impairment. METHODS AND FINDINGS: We analyzed 274 magnetic resonance images that recorded brain growth from 23 to 48 wk of gestation in 113 extremely preterm infants born at 22 to 29 wk of gestation, 63 of whom underwent neurodevelopmental assessment at a median age of 2 y. Cortical surface area was related to cerebral volume by a scaling law with an exponent of 1.29 (95% confidence interval, 1.25–1.33), which was proportional to later neurodevelopmental impairment. Increasing prematurity and male gender were associated with a lower scaling exponent (p < 0.0001) independent of intrauterine or postnatal somatic growth. CONCLUSIONS: Human brain growth obeys an allometric scaling relation that is disrupted by preterm birth in a dose-dependent, sexually dimorphic fashion that directly parallels the incidence of neurodevelopmental impairments in preterm infants. This result focuses attention on brain growth and cortical development during the weeks following preterm delivery as a neural substrate for neurodevelopmental impairment after premature delivery

An Optical Fiber Viscometer Based on Long-Period Fiber Grating Technology and Capillary Tube Mechanism

This work addresses the development and assessment of a fiber optical viscometer using a simple and low-cost long-period fiber grating (LPFG) level sensor and a capillary tube mechanism. Previous studies of optical viscosity sensors were conducted by using different optical sensing methods. The proposed optical viscometer consists of an LPFG sensor, a temperature-controlled chamber, and a cone-shaped reservoir where gravitational force could cause fluid to flow through the capillary tube. We focused on the use of LPFGs as level sensors and the wavelength shifts were not used to quantify the viscosity values of asphalt binders. When the LPFG sensor was immersed in the constant volume (100 mL) AC-20 asphalt binder, a wavelength shift was observed and acquired using LabVIEW software and GPIB controller. The time spent between empty and 100 mL was calculated to determine the discharge time. We simultaneously measured the LPFG-induced discharge time and the transmission spectra both in hot air and AC-20 asphalt binder at five different temperatures, 60, 80, 100, 135, and 170 Celsius. An electromechanical rotational viscometer was also used to measure the viscosities, 0.15–213.80 Pa·s, of the same asphalt binder at the above five temperatures. A non-linear regression analysis was performed to convert LPFG-induced discharge time into viscosities. Comparative analysis shows that the LPFG-induced discharge time agreed well with the viscosities obtained from the rotational viscometer