Alzheimer's Therapeutics Targeting Amyloid Beta 1-42 Oligomers II: Sigma-2/PGRMC1 Receptors Mediate Abeta 42 Oligomer Binding and Synaptotoxicity

Amyloid beta (Abeta) 1–42 oligomers accumulate in brains of patients with Mild Cognitive Impairment (MCI) and disrupt synaptic plasticity processes that underlie memory formation. Synaptic binding of Abeta oligomers to several putative receptor proteins is reported to inhibit long-term potentiation, affect membrane trafficking and induce reversible spine loss in neurons, leading to impaired cognitive performance and ultimately to anterograde amnesia in the early stages of Alzheimer's disease (AD). We have identified a receptor not previously associated with AD that mediates the binding of Abeta oligomers to neurons, and describe novel therapeutic antagonists of this receptor capable of blocking Abeta toxic effects on synapses in vitro and cognitive deficits in vivo. Knockdown of sigma-2/PGRMC1 (progesterone receptor membrane component 1) protein expression in vitro using siRNA results in a highly correlated reduction in binding of exogenous Abeta oligomers to neurons of more than 90%. Expression of sigma-2/PGRMC1 is upregulated in vitro by treatment with Abeta oligomers, and is dysregulated in Alzheimer's disease patients' brain compared to age-matched, normal individuals. Specific, high affinity small molecule receptor antagonists and antibodies raised against specific regions on this receptor can displace synthetic Abeta oligomer binding to synaptic puncta in vitro and displace endogenous human AD patient oligomers from brain tissue sections in a dose-dependent manner. These receptor antagonists prevent and reverse the effects of Abeta oligomers on membrane trafficking and synapse loss in vitro and cognitive deficits in AD mouse models. These findings suggest sigma-2/PGRMC1 receptors mediate saturable oligomer binding to synaptic puncta on neurons and that brain penetrant, small molecules can displace endogenous and synthetic oligomers and improve cognitive deficits in AD models. We propose that sigma-2/PGRMC1 is a key mediator of the pathological effects of Abeta oligomers in AD and is a tractable target for small molecule disease-modifying therapeutics

Experimental study on tribological property of mechanical seals with changeable pore diameter

To study tribological property of mechanical seals when distributing micropores along the radial face with changeable parameter, friction experiments of mechanical seals under a certain condition were carried out while the pore diameter changed. The results show that: the introduction of micropores on the surface can reduce the friction efficiently, but its antifriction effect is closely related to the distribution of micropores. The friction coefficient is the smallest when pore diameters increasing by degrees along the seal radial face from the inside out, while complexly distributed of pore diameter has a poor effect on antifriction of mechanical seals. The results can offer some help for optimal design of mechanical seals with micropores

Research on PID Controller of Excavator Electro-Hydraulic System Based on Improved Differential Evolution

An electrical hydraulic control system (electro-hydraulic system) is thought to be a key component in excavator operation systems. Control methods with fixed parameters may not yield optimal system performances because a hydraulic system has various nonlinear uncertainties due to the leakage and compressibility of the fluid medium. Hence, a novel PID controller based on improved differential evolution (IDE) is introduced to excavator electro-hydraulic systems for interconnected hydraulic systems. The proposed algorithm not only adjusts the PID parameters of the different working conditions but also adjusts the scaling factor and crossover probability. Then, the proposed PID controller based on IDE and the excavator bucket control system are modeled and simulated on the MATLAB simulation platform. The simulation results demonstrate that the proposed controller has better performance in settling time, rise time, and convergence speed compared to the PID controller based on standard differential evolution and the Ziegler–Nichols (ZN) PID controller with a novel object function. Eventually, the IDE-PID controller is assessed on a 23-ton excavator, and good transient behavior and trajectory accuracy are obtained in comparison to the SDE-PID controller

Performance Analysis of the Self-Pumping Hydrodynamic Mechanical Seal with a Conical Convergent Diffuser Groove

Requirements such as high opening force, low leakage rate, and design without matching auxiliary flushing systems are expected of the modern fluid machinery shaft seals used in the process industry. A self-pumping hydrodynamic mechanical seal with a conical convergent diffuser groove is proposed and its sealing performance is studied by numerical simulation in this paper. Further, its sealing performance is compared to that of a flat-bottomed equal cross-sectional diffuser groove and the results have shown that the proposed seal has more superior sealing performance. The influence of structural and operating parameters on the sealing performance of the proposed seal is discussed and its working mechanism is explained. The results have shown that when the structural parameters of the spiral groove and the operating parameters are the same, the proposed design has a similar leakage rate and a higher opening force. The conical convergent diffuser groove has better wrapping properties, whereas the fluid energy is utilized more efficiently, improving the sealing interface opening force. The taper degree variation causes a slight change to the pressure at the root of the spiral groove, causing slight fluctuations in the seal leakage rate. The research results broaden the design of non-contact mechanical seals and provide a theoretical basis for the engineering application of the proposed self-pumping hydrodynamic mechanical seal with a conical convergent diffuser groove

Investigations of Adhesion under Different Slider-Lube/Disk Contact States at the Head–Disk Interface

Adhesion is the key factor influencing the failure of the hard disk drive operating under ultra-low flying height. In order to mitigate the negative effects of adhesion at the head–disk interface (HDI) and promote further development of the thermal flying height control (TFC) technology, an adhesive contact model based on the Lifshitz theory accounting for the thermal protrusion (TP) geometry of TFC slider, the layered structures of the head and disk, and the operation states of the slider was proposed to investigate the static contact characteristics at the HDI. The simulation results demonstrated the undesirable unstable regions during the transitions between different operation states and the necessity of applying TFC technology. The reduction in the head–media spacing (HMS) was found to be achieved by properly increasing the TP height, decreasing the thickness of the lubricant layer or the thickness of the diamond–like carbon (DLC) layer during the flying state or the TP–lube contact state. At the TP–DLC contact regime, the attractive interaction was stronger than other states, and the strong repulsive interaction made the HMS difficult to be further reduced through the increase in the TP height or the decrease in the lubricant thickness

Experimental investigation on frictional property of mechanical seals with varying dimple diameter along the radial face

To study frictional property of mechanical seals when distributing dimples with varying parameters along the radial face, friction experiments, including seal faces with varying dimple diameter in various types, invariable dimple diameter, and without dimples, were carried out on end-face tester under different loads and rotation speeds. The results show that the introduction of dimples on seal face does reduce friction coefficient efficiently, but its anti-friction effect is closely related to the arrangement manner of dimple diameter and the operation condition. The type with increasing dimple diameters along the radial face from the inner to the outer diameter should be more suitable for the design of seal faces for its smaller friction coefficient when comparing with the type with optimum invariable dimple diameter. On the other hand, the operation condition, including loads and rotation speeds, must be taken into account to determine how to increase the dimple diameter along the radial face from the inner to the outer diameter. The results could be a good start for further theoretical study to search for the optimum varying dimple parameters of mechanical seals

A Leakage Model of Contact Mechanical Seals Based on the Fractal Theory of Porous Medium

A theoretical model for calculating the leakage rate of contact mechanical seals based on the fractal theory of the porous media, which can consider the real seal contact interface and objectively reflect the flow of the interfacial fluid from a microscopic perspective, is established. In order to obtain the microstructural parameters of the porous media included in the leakage model, such as the fractal dimension and the maximum pore diameter, the real seal contact interface obtained from experiments is reconstructed, a contact model between the dynamic and static rings is proposed, and then the calculation methods for the interface characteristic parameters are provided. Numerical simulation results show that as the contact pressure increases from 0.05 to 0.5 MPa, the interface porosity and the maximum pore diameter decreases gradually. Furthermore, the fractal dimension of the pore area increases and the leakage rate of the interface decreases from 0.48 to 0.33 mL/h. The proposed method provides a novel way of calculating the leakage rate of contact mechanical seals

Optimal strategy for a periodic review inventory system with discounted variable cost and finite ordering capacity

We study a periodic review inventory system with finite ordering capacity, and assume the variable ordering cost would be discounted when the ordering quantity is the full capacity. Applying the concept of strong CK-concavity, we show that the optimal pricing and ordering strategy could be partially characterized by an (S, S′, p) strategy in four regions depending on the starting inventory level per period. Numerical experiments verify the proposed strategy