Exploring the Impact of Glyoxal Glycation on ß-Amyloid Peptide (Aß) Aggregation in Alzheimer's Disease.

Alzheimer's disease (AD) is characterized by the presence of extracellular senile plaques formed by ß-amyloid (Aß) peptides in the patient's brain. Previous studies have shown that the plaques in the AD brains are colocalized with the advanced glycation end products, which is mainly formed from a series of nonenzymatic reactions of proteins with reducing sugars or reactive dicarbonyls. Glycation was also demonstrated to increase the neurotoxicity of the Aß peptides. To clarify the impact of glycation on Aß aggregation, we synthesized two glycated Aß42 peptides by replacing Lys16 and Lys28 with Nε-carboxymethyllysine respectively to mimic the occurrence of protein glycation. Afterward, we monitored the aggregation kinetics and conformational change for two glycated peptides. We also used fluorescence correlation spectroscopy to probe the early stage of peptide oligomerization and tested their abilities in copper binding and reactive oxygen species production. Our data show that glycation significantly slows down the aggregation process and induces more cytotoxicity especially at position 28. We speculated that the higher toxicity might result from a relatively stable oligomeric form of peptide and not from ROS production. The data shown here emphasized that glycated proteins would be an important therapeutic target in AD treatments.

Inhibiting Human Calcitonin Fibril Formation with Its Most Relevant Aggregation-Resistant Analog.

The most common obstacles to the development of therapeutic polypeptides are peptide stability and aggregation. Human calcitonin (hCT) is a 32-residue hormone polypeptide secreted from the C-cells of the thyroid gland and is responsible for calcium and phosphate regulation in the blood. hCT reduces calcium levels by inhibiting the activity of osteoclasts, which are bone cells that are mainly responsible for breaking down the bone tissue or decreasing the resorption of calcium from the kidneys. Thus, calcitonin injection has been used to treat osteoporosis and Paget's disease of bone. hCT is an aggregation-prone peptide with a high tendency to form amyloid fibrils. As a result, salmon calcitonin (sCT), which is different from hCT at 16-residue positions and has a lower propensity to aggregate, has been chosen as a clinical substitute for hCT. However, significant side effects, including immune reactions, have been shown with the use of sCT injection. In this study, we found that two residues, Tyr-12 and Asn-17, play key roles in inducing the fibrillization of hCT. Double mutation of hCT at these two crucial sites could greatly enhance its resistance to aggregation and provide a peptide-based inhibitor to prevent amyloid formation by hCT. Double-mutated hCT retains its ability to interact with its receptor in vivo. These findings suggest that this variant of hCT would serve as a valuable therapeutic alternative to sCT.

Performance of two different constitutive models and microstructural evolution of GH4169 superalloy.

The hot compression tests of GH4169 superalloy were performed in the deformation temperature range of 970 to 1150 ℃ and at the strain rate range of 0.001 to 10 s⁻¹. The flow stress is dependent on temperature and strain rate. The flow stresses were respectively predicted by Arrhenius-type and artificial neural network (ANN) models, and the predicted flow stresses were compared with the experimental data. A processing map can be obtained using the dynamic material models (DMM). A three-dimensional (3D) FEM model was established to simulate the hot compression process of GH4169 superalloy. Investigation of the microstructure of the deformed specimen was carried out using theoretical analysis, experimental research and FEM simulation. And the FEM model of compression tests were verified by experimental data.

Granular core phenomenon induced by convection in a vertically vibrated cylindrical container.

A mixture of 13X molecular sieve (13XMS) particles and glass particles with identical diameters is placed in a cylindrical container. Under vertical vibration, heavier glass particles tend to cluster and are wrapped inside the convection of 13XMS particles, resulting in the granular core phenomenon. The vibration frequency f strongly influences particle convection and particle cluster modes. By contrast, the effect of the dimensionless acceleration amplitude Γ can be neglected. For different f ranges, the granular core is classified as center-type and ring-type cores. For the center-type core, heavy particles are distributed as an approximate zeroth-order Bessel function of the first kind in the radial direction and an exponential function in the height direction. For the ring-type core, the concentration of heavy particles follows the power-series function in the radial direction. A granular transport model is then established based on heavy-particle movements under steady state to analyze the effect of vibration parameters and granular convection on density segregation.

Convecting particle diffusion in a binary particle system under vertical vibration.

We studied the separation behaviour of binary granular particles in a vertically vibrated container. The final separation of the binary particle system exhibited the Brazil-Nut (BN) effect, though it was not complete. Particle convection occurred, and four different typical convection modes were observed when the frequency f changed from 20 Hz to 80 Hz at constant dimensionless acceleration Γ = 4πAf(2)/g. However, when Γ changed from 2 to 4 at constant f, the system's convection mode stayed almost the same. In our experiments, one type of particle generally moved much faster than the other, so the former was termed the 'convecting' particle, and the latter was termed the 'non-convecting' particle. To study the separation results qualitatively, we divided the system into vertical layers and calculated the mass distribution of the binary particles along the z axis. The results showed that when f increased at constant Γ or Γ decreased at constant f, the convecting particles, usually the smaller and lighter ones, distributed less to the top side and more to the bottom side of the container. Finally, to explain the experimental results, we derived a mass conservation equation for the convecting particles considering simultaneous convection and diffusion. The equation described the experimental results well. We also analysed the effects of f, Γ, diameter ratio, density ratio, etc., on the final separation results.