SARS-CoV-2 Spike protein activates TMEM16F-mediated platelet pro-coagulant activity

Background: Thrombosis of the lung micro-vasculature is a characteristic of COVID-19 disease, which is observed in large excess compared to other forms of acute respiratory distress syndrome and thus suggests a trigger for thrombosis endogenous to the lung. Our recent work has shown that the SARS-CoV-2 Spike protein activates the cellular TMEM16F chloride channel and scramblase. Through a screening on >3,000 FDA/EMA approved drugs, we identified Niclosamide and Clofazimine as the most effective molecules at inhibiting this activity. As TMEM16F plays an important role in the stimulation of the pro-coagulant activity of platelets, and considering that platelet abnormalities are common in COVID-19 patients, we investigated whether Spike directly affects platelet activation and pro-thrombotic function and tested the effect of Niclosamide and Clofazimine on these processes. Methods: We produced SARS-CoV-2 Spike or VSV-G protein-pseudotyped virions, or generated cells expressing Spike on their plasma membrane, and tested their effects on platelet adhesion (fluorescence), aggregation (absorbance), exposure of phosphatidylserine (flow cytometry for annexin V binding), calcium flux (flow cytometry for fluo-4 AM), and clot formation and retraction. These experiments were also conducted in the presence of the TMEM16F activity inhibitors Niclosamide and Clofazimine. Results: Here we show that exposure to SARS-CoV-2 Spike promotes platelet activation, adhesion and spreading, both when present on the envelope of virions or upon expression on the plasma membrane of cells. Spike was effective both as a sole agonist or by enhancing the effect of known platelet activators, such as collagen and collagen-related peptide. In particular, Spike exerted a noticeable effect on the procoagulant phenotype of platelets, by enhancing calcium flux, phosphatidylserine externalisation, and thrombin generation. Eventually, this resulted in a striking increase in thrombin-induced clot formation and retraction. Both Niclosamide and Clofazimine almost abolished this Spike-induced pro-coagulant response. Conclusions: Together, these findings provide a pathogenic mechanism to explain thrombosis associated to COVID-19 lung disease, by which Spike present in SARS-CoV-2 virions or exposed on the surface of infected cells, leads to local platelet stimulation and subsequent activation of the coagulation cascade. As platelet TMEM16F is central in this process, these findings reinforce the rationale of repurposing drugs targeting this protein, such as Niclosamide, for COVID-19 therapy.

Nonlinear Varying-Network Magnetic Circuit Analysis of Consequent-Pole Permanent-Magnet Motor for Electric Vehicles

To conserve rare earth resources, consequent-pole permanent-magnet (CPPM) machine has been studied, which employs iron-pole to replace half PM poles. Meanwhile, to increase flux-weakening ability, hybrid excitation CPPM machine with three-dimensional (3-D) flux flow has been proposed. Considering finite element method (FEM) is time-consuming, for the analysis of the CPPM machine, this paper presents a nonlinear varying-network magnetic circuit (NVNMC), which can analytically calculate the corresponding electromagnetic performances. The key is to separate the model of CPPM machine into different elements reasonably; thus, the reluctances and magnetomotive force (MMF) sources in each element can be deduced. While taking into account magnetic saturation in the iron region, the proposed NVNMC method can accurately predict the 3-D magnetic field distribution, hence determining the corresponding back-electromotive force and electromagnetic power. Apart from providing fast calculation, this analytical method can provide physical insight on how to optimize the design parameters of this CPPM machine. Finally, the accuracy of the proposed model is verified by comparing the analytical results with the results obtained by using FEM. As a result, with so many desired attributes, this method can be employed for machine initial optimization to achieve higher power density.

Vortex phase diagram in 1111-type CaFe0.89Co0.11AsF single crystal

Studying the vortex properties in high-Tc superconductors is crucial for understanding the high temperature superconducting mechanism. However, until now, only few vortex studies have been performed in 1111-type iron-based superconductors due to their smaller-sized single crystals. In this study, we have synthesized the millimeter-sized CaFe0.89Co0.11AsF single crystals by self-flux method. Three dimensional vortex nature was confirmed in the thermally activated flux flow region. Second magnetization peak was observed on the isothermal magnetization curves. Meanwhile, the dominated role of the normal point pinning was also confirmed. Finally, the various phase boundaries of the vortex were determined based on the analysis of the resistivity and magnetization data, and a complete vortex phase diagram of CaFe0.89Co0.11AsF single crystals was established.

Use of Horizontal Drift-Flux Models For Simulating Wellbore Flow in SAGD Operations

The paper examines new horizontal drift-flux correlations for their ability to accurately model phase flow rates and pressure drops in horizontal and undulating wells that are part of a Steam-Assisted Gravity Drainage (SAGD) field operation. Pressure profiles within each well correlate to the overall performance of the pair. SAGD is a low-pressure process that is sensitive to reservoir heterogeneity and other factors, hence accurate simulation of in situ wellbore pressures is critical for both mitigating uneven steam chamber evolution and optimizing wellbore design and operation. Recently published horizontal drift-flux correlations have been implemented in a commercial thermal reservoir simulator with a multi-segment well model. Valid for horizontally drilled wells with undulations, they complement previously reported drift-flux models developed for vertical and inclined wells down to approximately 5 degrees from horizontal. The formulation of these correlations has a high degree of nonlinearity. These models are tested in simulations of SAGD field operations. First, an overview of drift-flux models is discussed. This differentiates those based on vertical flow with gravity segregation to those that model horizontal flow with stratified and slug flow regimes. Second, the most recent and significant drift-flux correlation by Bailey et al. (2018, and hereafter referred to as Bailey-Tang-Stone) was robustly designed to be used in the well model of a reservoir simulator, can handle all inclination angles and was optimized to experimental data from the largest available databases to date. This and earlier drift-flux models are reviewed as to their strengths and weaknesses. Third, governing equations and implementation details are given of the Bailey-Tang-Stone model. Fourth, six case studies are presented that illustrate homogeneous and drift-flux flow model differences for various well scenarios.

Role of Cattaneo–Christov heat flux in an MHD Micropolar dusty nanofluid flow with zero mass flux condition

This investigation aims to look at the thermal conductivity of dusty Micropolar nanoliquid with MHD and Cattaneo–Christov heat flux flow over an elongated sheet. The novelty of the envisioned mathematical model is augmented with the added impacts of the heat source/sink, chemical reaction with slip, convective heat, and zero mass flux boundary conditions. The salient feature of the existing problem is to discuss the whole scenario with liquid and dust phases. The graphical depiction is attained for arising pertinent parameters by using bvp4c a built-in MATLAB function. It is noticed that the thermal profile and velocity field increases for greater values of liquid particle interaction parameter in the case of the dust phase. An escalation in the thermal profile of both liquid and dust phases is noticed for the magnetic parameter. The rate of mass transfer amplifies for large estimates of the Schmidt number. The thickness of the boundary layer and the fluid velocity are decreased as the velocity slip parameter is augmented. In both dust and liquid phases, the thermal boundary layer thickness is lessened for growing estimates of thermal relaxation time. The attained results are verified when compared with a published result.