Roles of host proteases in the entry of SARS-CoV-2

The spike protein(S)of SARS-CoV-2 is responsible for viral attachment and entry,thus a major factor for host suscep-tibility,tissue tropism,virulence and pathogenicity.The S is divided with S1 and S2 region,and the S1 contains the receptor-binding domain(RBD),while the S2 contains the hydrophobic fusion domain for the entry into the host cell.Numerous host proteases have been implicated in the activation of SARS-CoV-2 S through various c leavage sites.In this article,we review host proteases including furin,trypsin,transmembrane protease serine 2(TMPRSS2)and cathepsins in the activation of SARS-CoV-2 S.Many betacoronaviruses including SARS-CoV-2 have polybasic residues at the S1/S2 site which is subjected to the cleavage by furin.The S1/S2 cleavage facilitates more assessable RBD to the receptor ACE2,and the binding triggers further conformational changes and exposure of the S2'site to proteases such as type Il transmembrane serine proteases(TTPRs)including TMPRSS2.In the presence of TMPRSS2 on the target cells,SARS-CoV-2 can utilize a direct entry route by fusion of the viral envelope to the cellular membrane.In the absence of TMPRSS2,SARS-CoV-2 enter target cells via endosomes where multiple cathepsins cleave the S for the successful entry.Additional host proteases involved in the cleavage of the S were discussed.This article also includes roles of 3C-like protease inhibitors which have inhibitory activity against cathepsin L in the entry of SARS-CoV-2,and discussed the dual roles of such inhibitors in virus replication.

Application of Thermodynamic Database to Corrosion of ZrO_(2) Containing Submerged Entry Nozzle in Steel Continuous Casting Process

The CALPHAD thermodynamic databases are very useful to analyze the complex chemical reactions happening in high temperature material process.The FactSage thermodynamic database can be used to calculate complex phase diagrams and equilibrium phases involving refractories in industrial process.In this study,the FactSage thermodynamic database relevant to ZrO_(2)-based refractories was reviewed and the application of the database to understanding the corrosion of continuous casting nozzle refractories in steelmaking was presented.

Numerical study on the cavity dynamics for vertical water entries of twin spheres

In this study, a three dimensional(3D) numerical model of six-degrees-of-freedom(6DOF) is applied to simulate the water entries of twin spheres side-by-side at different lateral distances and time intervals.The turbulence structure is described using the shear-stress transport k-ω(SST k-ω) model, and the volume of fluid(VOF) method is used to track the complex air-liquid interface. The motion of spheres during water entry is simulated using an independent overset grid. The numerical model is verified by comparing the cavity evolution results from simulations and experiments. Numerical results reveal that the time interval between the twin water entries evidently affects cavity expansion and contraction behaviors in the radial direction. However, this influence is significantly weakened by increasing the lateral distance between the two spheres. In synchronous water entries, pressure is reduced on the midline of two cavities during surface closure, which is directly related to the cavity volume. The evolution of vortexes inside the two cavities is analyzed using a velocity vector field, which is affected by the lateral distance and time interval of water entries.

Advances in discovery of novel investigational agents for functional cure of chronic hepatitis B:A comprehensive review of phases II and III therapeutic agents

Chronic hepatitis B virus(HBV)infection affects over 295 million people globally and an estimated 1.6 million people in the United States.It is associated with significant morbidity and mortality due to cirrhosis,liver failure,and liver cancer.Antiviral therapy with oral nucleos(t)ide analogues is associated with high rates of virologic suppression,which in turn has been associated with a decreased risk of liver complications.However,current antiviral regimens are limited by concerns with adverse effects,adherence,resistance,long-term treatment,and ongoing risk for liver events.Novel investigational agents are currently in development and are targeted at achieving functional cure with sustained hepatitis B surface antigen(HBsAg)loss and suppression of HBV DNA.Herein we review key evidence from phases II and III trials defining the efficacy and safety profiles for key investigational agents for functional cure of chronic hepatitis B,including core/capsid inhibitors,entry inhibitors,RNA interference(siRNA/ASO),HBsAg inhibitors,Toll-like receptor agonists,checkpoint inhibitors,and therapeutic vaccines.

Diabetes Mellitus: Disorder of Cellular Dysfunction Due to Lack of Entry into Cell of Glucose. The Most Efficient Fuel for Cellular Function*

Background: Diabetes Mellitus is established to be a chronic hyperglycemic disorder secondary to altered glucose metabolism. Alternatively, hyperglycemia may be one of several manifestations in subjects with type 1 and type 2 diabetes Mellitus. Most tissues require insulin for entry of glucose, exceptions being red blood cells, renal medulla and nervous system. Hyperglycemia in intravascular compartment and other extra cellular milieu may be attributed to impaired glucose entry into endothelial cells of the vessel wall and cells in other tissues due to absence of insulin in type 1 and both insulin resistance and decline in insulin secretion in type 2 Diabetes. Objective: Hypothesis is proposed that Diabetes mellitus is a disorder of cellular dysfunction due to lack of entry of glucose, the most efficient fuel. Literature review was conducted to establish the perspective. Results: Declines in both phases of insulin secretion are induced by lack of glucose entry into pancreatic beta cells. Hyperglycemia is perpetuated by increased hepatic glucose production caused by sustained hyperglucagonemia secondary to lack of glucose entry into the pancreatic alpha cells. Moreover, decline in insulin secretion by beta cells and rise in glucagon release by alpha cells are enhanced by fall in GLP1 and GIP caused by dysfunction of L cells and K cells secondary to lack of glucose entry in both types of diabetes. Increased prevalence of infections and thromboembolic events may be attributed to dysfunction of leukocytes and platelets due to impaired glucose entry. Finally, alterations in metabolemics including Adiponectin, TNF alpha, Plasminogen inhibitor factor 1, Homocysteine, CRP, Lipids etc. as well as dysfunction of several organs in both types of diabetes may also be attributed to the lack of glucose entry into specific cells. Hypothesis is validated by improvement in metabolemics and organ function on facilitation of glucose entry into cells by insulin administration and/or improvement in insulin sensitivity. Conclusion: Diabetes mellitus is a disorder manifesting dysfunction involving almost all organs and cells induced by lack of entry of glucose, the most efficient substrate for cellular function.

Study of the incidence of hyperuricemia in young males’population with rapid entry into the plateau of 4500m

Objective:To study the incidence and risk factors of hyperuricemia in young males who rapid entered into the plateau of 4500 m.Methods:The study contained 390 males aged 18-35 years(21.6±2.5 years),who rapidly entered the plateau with an altitude of 4500 m.According to their basic level of uric acid(UA),they were divided into two groups,high uric acid(HUA)group and normal uric acid(NUA)group.The characteristics and physiological index,such as the body weight and the height,of them were recorded.For the test of the biochemical indicators,the venous blood samples were collected at the altitude of 4500 m in the morning.The count of blood cells,blood urea nitrogen(BUN),serum creatinine(SCR),lactate dehydrogenase(LDH),total bilirubin(TBIL),direct bilirubin(DBIL)and indirect bilirubin(IDBIL)were compared between the two groups.Results:The incidence of hyperuricemia was 65.1%(254/390)at 4500 m.At the altitude of 4500 m,the mean hemoglobin concentration(MCHC)of red blood cells in the HUA group was significantly lower than that in the NUA group.Hemoglobin(HGB),mean red blood cell volume(MCV),TBIL,IDBIL,BUN,SCR and LDH in the HUA group were significantly higher than those in the NUA group,though without statistically significant differences in the other variables.Meanwhile,multivariate analysis showed at the altitude of 4500 m,the risk of HUA increased by 0.982,1.038 and 1.045 times when MCHC decreased by one unit and TBIL and SCR increased by one unit,respectively.Conclusion:The incidence of hyperuricemia was high of 65.1%rush entry into the plateau of young male.Decreased MCHC and elevated TBIL and SCR were independent risk factors for hyperuricemia when rapid enter into 4500 m.

Entry of hepatitis C virus into the cell: A therapeutic target

Several receptors have been identified as implicated on viral entry into the hepatocyte; and, this interaction between the virus and potential receptors could modulate infection, spontaneous viral clearance, persistence of the infection and the widespread of the virus as outbreak. Nevertheless, the playing role of each of them remains controversial. The NiemannPick type C1 like 1 gene (NPC1L1) receptor has been recently implicated on hepatitis C virus (HCV) entry into the cell and ezetimibe, an anti-cholesterol drug seems to block that, emerging the idea to control hepatitis C outbreak modulating lipid-related receptors. Hepatitis C infection seems to modulate lipid metabolism according to host genetic background. Indeed, it circulates like a lipoviroparticle. The main aim of this field of vision would be to discuss the role of hepatocyte receptors implicated on virus entry, especially NPC1L1 and the therapeutic options derived from the better knowledge about HCV-lipidsreceptors interaction.

EXPLORING THE VARIOUS APPROACHES OF A RESEARCH INSTITUTE'S ENTRY INTO THE MARKET

To meet the demands posed by the socialist market economy, to foster the close integration of science & technology with the national economy and thus to promote the development of the forces of production are targets pursued by the current drive of restructuring China’s existing S&T system.For this,the CAS Shenyang Branch has conducted rewarding exploration by diversifying various approaches when moving into the market.As a result,it is not only boosting its own development,but also increasing the strength of the local economy.

Rock burst mechanism analysis in an advanced segment of gob-side entry under different dip angles of the seam and prevention technology

In order to investigate the frequent occurrences of rock burst in gob-side entry during the mining process of the mining zone No. 7, the mechanical model of main roof of fully-mechanized caving mining before breaking was established by the Winkler foundation beam theory, and the stress evolution law of surrounding rock with different dip angles of the seam during the mining process was analyzed by using FLAC3 D. The results show that: with the dip angle changing from 45° to 0°, the solid-coal side of gobside entry begins to form an L-shaped stress concentration zone at a dip angle of 30°, and the stress concentration degree goes to higher and higher levels. However, the stress concentration degree of the coalpillar side goes to lower and lower levels; the influence range and peak stress of the abutment at the lateral strata of adjacent gob increase with dip angle decreasing and reach a maximum value at a dip angle of 0°, but the tailgate is not affected; the abutment pressure superposition of two adjacent gobs leads to stress concentration further enhancing in both sides of gob-side entry. With the influence of strong mining disturbance, rock burst is easily induced by dynamic and static combined load in the advanced segment of gob-side entry. To achieve stability control similar to that in the roadway, the key control strategy is to reinforce surrounding rock and unload both sides. Accordingly, the large-diameter drilling and high-pressure water injection combined unloading and reinforced support cooperative control technology was proposed and applied in field test. The results of Electromagnetic Emission(EME) and field observation showed that unloading and surrounding rock control effect was obvious.

How hepatitis C virus invades hepatocytes: The mystery of viral entry

Hepatitis C virus(HCV)infection is a global health problem,with an estimated 170 million people being chronically infected.HCV cell entry is a complex multi-step process,involving several cellular factors that trigger virus uptake into the hepatocytes.The high-density lipoprotein receptor scavenger receptor class B type I,tetraspanin CD81,tight junction protein claudin-1,and occludin are the main receptors that mediate the initial step of HCV infection.In addition,the virus uses cell receptor tyrosine kinases as entry regulators,such as epidermal growth factor receptor and ephrin receptor A2.This review summarizes the current understanding about how cell surface molecules are involved in HCV attachment,internalization,and membrane fusion,and how host cell kinases regulate virus entry.The advances of the potential antiviral agents targeting this process are introduced.

The Form of Literary Translation——“Foregrounding Translation” and the Translator's Poetic Entry

From the epistemological perspective translating sense is to pursue truth,while translating flavor is to pursue beauty.Rational knowledge is aimed at"fidelity";perceptive knowledge the"beauty".Literary language approaches fidelity because of beauty while non-literary language approaches beauty because of its fidelity.

Thermochemical ablation of spherical cone during re-entry

Presents the use of the similar transform and potential theory for calculation of the bypass flow factor and pressure gradient and the analysis of the influence of bypass flow factor and pressure gradient on heat transfer is analyzed, and the distribution of nose cone ablation obtained by combining the controlling equations of boundary layer, the compatible relation of interface and the heat conduction of interior.

Study on the Effect of Two-Dimensional Helicopter V-buoy’s Way of Water Entry on Water Impact

To analyze the effect of the way of water entry on water impact, the FLUENT software was adopted to simulate a two-dimensional (2D) helicopter V-buoy’s free fall and forced fall at a constant velocity.Combining with the UDF program and the dynamic mesh model, the standard k-ε turbulence model was used and the VOF technique was adopted to capture free surface.The physical parameters such as velocity and force were calculated and compared with those results of boundary element method with good agreement obtained.It was found that the force of 2D V-buoy at a constant velocity was much greater than that in free fall motion.Meanwhile, the maximum pressure coefficients C p max in both cases were almost equal and the dimensionless water-entry depths y' corresponding to C p max were also similar.

Plants and Animals as Concept Generators for the Development of Biomimetic Cable Entry Systems

Many animals and plants have high potential to serve as concept generators for developing biomimetic materials and structures. We present some ideas based on structural and functional properties of plants and animals that led to the development of two types ofbiomimetic cable entry systems. Those systems have been realized on the level of functional demonstrators.

A Numerical Study on the Asymmetric Water Entry of A Wedge Section

The effect of the asymmetric water entry over a submerged part of a ship on the hydrodynamic impact is investigated numerically. A wedge body is considered and the problem is assumed to be two-dimensional. The results of symmetric and asymmetric impacts are compared. The effect is found significant in the numerical simulation. The maximum hydrodynamic pressure at a heel angle of 10 degrees becomes about 95% more than that of the symmetric entry. The result of the present work proves the importance of asymmetrical hydrodynamic impact loading for structural design of a ship. Besides, the numerical procedure is not limited to a wedge type cross section and it is possible to apply it for any real geometry of ships and high-speed craft.

A Mechanism-based 3D-QSAR and DFT Approach for the Prediction of H5N1 Entry Inhibitory Potency of 3-O-β-chacotriosyl Ursolic Acid Derivatives

In this work, 25 3-O-β-chacotriosyl ursolic acid derivatives were employed to achieve the highly reliable and predictive 3 D-QSAR models by Co MFA and Co MSIA methods, respectively. The predictive capabilities of two constructed CoMFA and CoMSIA models were verified by the leave-one-out cross-validation method. The results showed that the cross-validated coefficient（q2） and non-cross-validated coefficient（R2） were 0.559, 0.981 in the CoMFA model and 0.696, 0.978 in the CoM SIA model, respectively, which suggests that these two models are robust and have good exterior predictive capabilities. Furthermore, based on the contour maps information of two models, ten novel inhibitors with higher inhibitory potency were designed, and the quantum chemical calculation of density functional theory（DFT） was performed to investigate the mechanism why the designed molecules have stronger inhibitory activity than the lead compound. The calculations show that the C-50 position of lead compound is a key active site for the enhancement of inhibitory activity, and it should be introduced into the large electron withdrawing group, which would result in generating potent and selective H5 N1 entry inhibitors. We expect that the results in this paper could provide important information to develop new potent H5 N1 entry inhibitors.

Influence of abnormal stress under a residual bearing coal pillar on the stability of a mine entry

Mine entries close to residual bearing coal pillars(RBCPs) will suffer large deformation that may cause rock burst. To better understand the deformation mechanism and develop safe and practical guidelines for entry design, most studies focus on the absolute size of the stress field in and around the pillar. In this paper, we present a new approach to analyze the abnormal stress field close to a RBCP that uses the stress concentration coefficient(SCC), stress gradient(SG), and coefficient of lateral pressure(CLP) to describe the stress state induced by the RBCP. Based on elastic theory and a mathematical model for the abutment stress in the RBCP, an analytical solution for the abnormal stress in the strata below the RBCP was derived and the characteristics of the abnormal stress for a case study of a coal mine in China were analyzed. The results show that the abnormal stress field around the pillar is characterized by four distinct zones: a zone of high SCC, high SG, and CLP less than 1, a zone of high SCC, low SG, and CLP less than 1, a zone of low SCC, SG close to 0, and CLP greater than 1, and a zone of SCC close to 1, SC close to 0, and CLP close to 1. Based on this zoning pattern, a numerical model was established to study the combined effects of the abnormal stress on the stability of the entry. The most stable zone was determined based on a model of the Xinrui coal mine and verified by field measurements at the mine. Our conclusions can be used as guidelines for designing safe entry layouts in similar geological and mining settings.

Synthesis of aromatic-linked polyamine macrocyclic derivatives as HIV-1 entry inhibitors

A series of novel aromatic-linked polyamine macrocyclic derivatives have been synthesized. Their structures were confirmed by MS and ^1H NMR. These compounds exhibited potent anti-HIV-1 activities.