Human γ-secretase is an intra-membrane protease that cleaves many different substrates. Aberrant cleavage of Notch is implicated in cancer, while abnormalities in cutting amyloid precursor protein ...lead to Alzheimer's disease. Our previous cryo-EM structure of γ-secretase revealed considerable disorder in its catalytic subunit presenilin. Here, we describe an image classification procedure that characterizes molecular plasticity at the secondary structure level, and apply this method to identify three distinct conformations in our previous sample. In one of these conformations, an additional transmembrane helix is visible that cannot be attributed to the known components of γ-secretase. In addition, we present a γ-secretase structure in complex with the dipeptidic inhibitor N-N-(3,5-difluorophenacetyl)-L-alanyl-S-phenylglycine t-butyl ester (DAPT). Our results reveal how conformational mobility in the second and sixth transmembrane helices of presenilin is greatly reduced upon binding of DAPT or the additional helix, and form the basis for a new model of how substrate enters the transmembrane domain.
Football is the most popular game in the world and has significant influence on various aspects including politics, economy and culture. The experience of the football developed nation has shown that ...the steady growth of youth football is crucial for elevating a nation's overall football proficiency. It is essential to develop techniques and create strategies that adapt to their individual physical features to resolve the football players’ problem of lacking exercise in various topics. In this manuscript, Computer aided technology depending on the Graph Sample and Aggregate Attention Network Optimized for Soccer Teaching and Training (CAT-GSAAN-STT) is proposed to improve the efficiency of Soccer teaching and training effectively. The proposed method contains four stages, like data collection, data preprocessing, prediction and optimization. Initially the input data are collected by Microsoft Kinect V2 smart camera. Then the collected data are preprocessed by using Improving graph collaborative filtering. After preprocessing the data is given for motion recognition layer here prediction is done using Graph Sample and Aggregate Attention Network (GSAAN) for improving the effectiveness of Soccer Teaching and Training. To enhance the accuracy of the system, the GSAAN are optimized by using Artificial Rabbits Optimization. The proposed CAT-GSAAN-STT method is executed in Python and the efficiency of the proposed technique is examined with different metrics, like accuracy, computation time, learning activity analysis, student performance ratio and teaching evaluation analysis. The simulation outcomes proves that the proposed technique attains provides28.33%, 31.60%, 25.63% higherRecognition accuracy and33.67%, 38.12% and 27.34%lesser evaluation time while compared with existing techniques like computer aided teaching system based upon artificial intelligence in football teaching with training (STT-IOT-CATS), Computer Aided Teaching System for Football Teaching and Training Based on Video Image (CAT-STT-VI) and method for enhancing the football coaching quality using artificial intelligence and meta verse-empowered in mobile internet environment (SI-STQ-AI-MIE) respectively.
Abrasive wear of the orifice cannot be avoided for a hopper which should be operated uninterruptedly for a long time in engineering applications. Consequently, the change of the orifice shape will ...lead to the variation of flow rate for the hopper. In this paper, the influence of orifice shape on the flow rate in ordinary flat-bottom hoppers is investigated both numerically and experimentally. The flow rate increases when the orifice is from sharp to smooth in both flat-bottom and conical-bottom hoppers. The data can be well fitted with a modified Beverloo's formula. The result is supported by the profile of kinetic pressure near the orifice. Moreover, the fluctuation of the instantaneous flow rate is reduced with smooth orifice. In addition, it is found that the diameter of the hopper D and the thickness of the bottom H do not influence the flow rate. This paper contributes to control the flow rate by optimizing the shape of orifice.
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•The first investigation of the influence of the orifice shape on the flow rates in a hopper•Both experimental and numerical studies are performed to explain this phenomenon.•The increasing of radius of the arc on the orifice reduces the empty annulus.
Bovine viral diarrhea virus (BVDV) is a critical animal pathogen that leads to cattle production losses associated with acute disease, immune dysregulation, reproductive failure, and respiratory ...disease. Due to the monotonous control technique and neglect of BVDV, increasing prevalence of BVDV has caused significant economic losses in the cattle industry worldwide. Therefore, novel anti-BVDV drugs are essential to prevent and control BVDV. Our previous studies have found that Forsythoside A (FTA) could inhibit the replication of BVDV via TRAF2-dependent CD28-4-1BB signaling in bovine peripheral blood mononuclear cells (PBMCs), but whether they can directly inhibit the BVDV remains unclear. Here, we further investigated the effects of FTA on BVDV and its underlying mechanisms of action. We found that FTA significantly inhibited the replication of BVDV in the MDBK cell directly. The results demonstrated that FTA could reduce the functional activation of Caspase-1 to inhibit the inflammatory response caused by BVDV infection and increase the expression of type I interferon (IFN-I) to clear the virus in vitro. The animal experiment was performed to evaluate the antiviral effect of FTA in vivo. Notably, after challenged with BVDV, mice with FTA + Erns-E2 protein displayed alleviated pathological damage and decreased the viral load in the spleen compared with mice inoculated with Erns-E2 protein. Furthermore, treatment with FTA enhanced body defense and delayed infection by the BVDV. Our results reveal that FTA suppresses BVDV replication both in vitro and in vivo and therefore shows promise as an anti-BVDV agent.
Abstract
The voltage-gated potassium channel AKT1 is responsible for primary K
+
uptake in
Arabidopsis
roots. AKT1 is functionally activated through phosphorylation and negatively regulated by a ...potassium channel α-subunit AtKC1. However, the molecular basis for the modulation mechanism remains unclear. Here we report the structures of AKT1, phosphorylated-AKT1, a constitutively-active variant, and AKT1-AtKC1 complex. AKT1 is assembled in 2-fold symmetry at the cytoplasmic domain. Such organization appears to sterically hinder the reorientation of C-linkers during ion permeation. Phosphorylated-AKT1 adopts an alternate 4-fold symmetric conformation at cytoplasmic domain, which indicates conformational changes associated with symmetry switch during channel activation. To corroborate this finding, we perform structure-guided mutagenesis to disrupt the dimeric interface and identify a constitutively-active variant Asp379Ala mediates K
+
permeation independently of phosphorylation. This variant predominantly adopts a 4-fold symmetric conformation. Furthermore, the AKT1-AtKC1 complex assembles in 2-fold symmetry. Together, our work reveals structural insight into the regulatory mechanism for AKT1.
To solve the problem of particle clogging in slit funnels and to obtain a stable discharge flow rate, we proposed a new funnel structure, namely the slit baffle funnel. We conducted a systematic ...investigation using the discrete element method (DEM) to study the effects of funnel half-angle θ, outlet width W, and baffle height H on flow rate and flow pattern. We found that the proposed structure could effectively avoid particle clogging and guarantee a continuous and stable flow rate with small outlet width. Under the condition of H >3 d, a bigger flow rate was obtained at a smaller funnel half-angle. This new funnel structure could be applied to solve clogging problems associated with granular matter in the slit geometry in mining, agriculture, food, and pharmaceuticals.
Bovine viral diarrhea virus (BVDV) is a harmful pathogen that easily causes large-scale infections and huge economic losses to the cattle industry. Berbamine hydrochloride (BBH) is a natural product ...extracted from berberis and has a wide range of pharmacological effects. However, the antiviral effect of BBH against BVDV needs to be further elucidated. This study aimed to evaluate the antiviral activities of BBH against BVDV infection. We mainly used RT-qPCR, Western blotting, immunofluorescence, and TEM assays to assess the inhibitory activity of BBH against BVDV. The results showed that BBH had an inhibitory effect on BVDV and higher inhibitory activity in the viral attachment and release in MDBK cells. This study found that BVDV could induce and use autophagy to replicate itself. Further results showed that BBH inhibited BVDV infection by inhibiting autophagy integrity in BVDV-infected cells, which was proven by the detection of autophagy-related proteins. Our data show that in BBH-treated BVDV-infected cells, the expression of p62 and LC3 increased over time. After the addition of an autophagy inhibitor, chloroquine (CQ), and an autophagy promoter, rapamycin (Rapa), we found that promoting autophagy was beneficial to the replication of BVDV, while inhibiting autophagy could reduce the number of infections by BVDV, which was evidenced by the expression of the BVDV E2 protein. Furthermore, BBH blocked the normal binding of LC3 and LAMP1 in BVDV-infected cells. In conclusion, BBH inhibited BVDV infection by inhibiting BVDV-induced autophagy in cells, and its inhibitory effect was obvious in the viral attachment and release stages. Therefore, our study provides a new idea for exploring novel anti-BVDV drugs.
Under the background of global nitrogen deposition, temperate forest ecosystems are suffering increasing threats, and species diversity is gradually decreasing. In this study, nitrogen addition ...experiments were conducted on Korean pine (Pinus koraiensis) plantations in Northeast China to explore the effect of long‐term nitrogen addition on herb species diversity to test the following hypothesis: long‐term nitrogen addition further reduced plant species diversity by affecting plant growth, which may be due to soil acidification caused by excessive nitrogen addition. Experimental nitrogen addition was conducted from 2014 to 2021, and the nitrogen treatment levels were as follows: N0 (control treatment, 0/(kg N ha−1 year−1)), N20 (low nitrogen treatment, 20/(kg N ha−1 year−1)), N40 (medium nitrogen treatment, 40/(kg N ha−1 year−1)) and N80 (high nitrogen treatment, 80/(kg N ha−1 year−1)). A herb community survey was conducted in the region from 2015 to 2021. The results showed that long‐term nitrogen addition decreased soil pH, changed the species and composition of herbaceous plants, and decreased the species diversity of understory herbaceous plants. With the increase in nitrogen application years, middle‐ and high‐nitrogen treatments significantly reduced the diversity of early‐spring flowering herbs and early‐spring foliating herbs, and their diversity decreased with the decrease in soil pH, indicating that soil acidification caused by long‐term nitrogen addition may lead to the decrease of plant diversity. However, for early‐spring growing herbs, adequate nitrogen addition may promote their growth. Our results show that plants have evolved different life‐history strategies based on their adaptation mechanisms to the environment, and different life‐history strategies have different responses to long‐term nitrogen addition. However, for most plants, long‐term nitrogen application will have a negative impact on the growth and diversity of herbs in temperate forests.
Long‐term nitrogen addition reduced early spring herb species. Long‐term nitrogen addition significantly reduced the diversity of early‐spring flowering herbs and early‐spring foliating herbs. Soil acidification might be the main mechanism of species diversity reduction.
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•Multi-functional SiO2 nanospheres are synthesized to prepare TFN membrane.•Interfacial interactions between polymer matrix and nanospheres are manipulated.•Different ...polymer–nanosphere interfacial morphologies are proposed.•The relationship between membrane microstructure and SRNF performance is explored.•Tunable organic solvent flux and enhanced solute rejection are achieved.
Herein, a series of thin film nanocomposite (TFN) membranes are prepared by incorporating functionalized silica nanospheres into polyethyleneimine (PEI) matrix for solvent resistant nanofiltration (SRNF). Three functional groups are grafted onto the nanospheres in form of polymer layer via distillation–precipitation polymerization for manipulating the free volume cavities of PEI matrix by interfacial interactions along PEI-nanosphere domains. The effects of nanospheres on the microstructures, physicochemical and permeation properties of TFN membranes are investigated systematically. The tested data suggest that the nanospheres are uniformly dispersed in PEI matrix without obvious defects, offering the excellent thermal stability and appropriate solvent resistance to the membranes. The microstructures of TFN membranes are elaborately regulated by varying the fractional free volume (FFV) and surface hydrophilic/hydrophobic nature, jointly yielding the tunable permeation properties. In particular, the permeate flux of ethanol is elevated from 21.2 to 30.8Lm−1h−1 with the increase of FFV from 0.452% to 0.473% by incorporating various hydrophilic nanospheres. Meanwhile, the addition of hydrophobic nanospheres provided much higher fluxes for n-heptane from 0.1 to 21.7Lm−1h−1, due to the enhanced solution capability. Moreover, the presence of nanospheres donates high rejection ability and promising operation stability to the TFN membranes.
Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease with the primary clinical symptoms of joint swelling and pain. Early detection of erosion and synovial inflammation at an active ...stage resulting from RA can prevent damage to the joints and activity restriction. However, there are still many patients who do not respond to these treatments; the development of newer, safer drugs is urgently needed. Compared to Western medicine, Guizhi-Shaoyao-Zhimu decoction has equal or higher efficacy and safety for RA patients. With the widespread use of musculoskeletal ultrasound (MSUS), this technology holds great value for the degree of joint damage in RA patients, guiding the clinical selection of treatments, and assessing of prognosis. Therefore, we designed a double-blinded randomized controlled clinical trial to measure the safety and efficacy of Guizhi-Shaoyao-Zhimu decoction in treating early-stage RA using MSUS.
This study is a randomized, double-blinded, parallel group, placebo-controlled trial. A total of 152 adult participants with early RA will be enrolled, with balanced treatment allocation (1:1). The experimental intervention will be Guizhi-Shaoyao-Zhimu decoction plus the conventional medicine methotrexate and the control intervention will be placebo plus the conventional drug methotrexate for 3 months. In addition, both groups will receive folic acid during treatment to prevent side effects from methotrexate. The primary outcomes are the erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), hepatic and renal function, visual analog scale, disease activity score in 28 joints, measurement scale for TCM symptoms, and 7-joint ultrasound score.
We designed this double-blinded randomized controlled clinical trial to evaluate the efficacy and safety of Guizhi-Shaoyao-Zhimu decoction in RA patients using MSUS. The results of this trial may provide insights into how to improve the clinical symptoms of RA patients and delay further joint destruction. We hope that this trial may provide preliminary evidence of the efficacy of Guizhi-Shaoyao-Zhimu decoction in treating RA patients and that these results aid researchers, practitioners, and patients alike.
The main aim of the study is to clarify the efficacy and safety of Guizhi-Shaoyao-Zhimu decoction in patients with early RA.
Chinese Clinical Trials Register ChiCTR2000036141 . Registered on 21 August 2020 (retroactively registered).
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