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The benzofuran core inhibitors HCV-796, BMS-929075, MK-8876, compound 2, and compound 9B exhibit good pan-genotypic activity against various genotypes of NS5B polymerase. To elucidate their mechanism of action, multiple molecular simulation methods were used to investigate the complex systems of these inhibitors binding to GT1a, 1b, 2a, and 2b NS5B polymerases. The calculation results indicated that these five inhibitors can not only interact with the residues in the palm II subdomain of NS5B polymerase, but also with the residues in the palm I subdomain or the palm I/III overlap region. Interestingly, the binding of inhibitors with longer substituents at the C5 position (BMS-929075, MK-8876, compound 2, and compound 9B) to the GT1a and 2b NS5B polymerases exhibits different binding patterns compared to the binding to the GT1b and 2a NS5B polymerases. The interactions between the para-fluorophenyl groups at the C2 positions of the inhibitors and the residues at the binding pockets, together with the interactions between the substituents at the C5 positions and the residues at the reverse β-fold (residues 441–456), play a key role in recognition and the induction of the binding. The relevant studies could provide valuable information for further research and development of novel anti-HCV benzofuran core pan-genotypic inhibitors. [ABSTRACT FROM AUTHOR]

In order to explore the formation mechanism of the emulsion gel induced by high pressure processing (HPP) and its encapsulation and protection of functional ingredients, a curcumin-loaded whey protein isolate (WPI)/κ-carrageenan (κ-CG) composite emulsion gel induced by HPP was prepared. The effect of pressure (400, 500 and 600 MPa), holding time (10, 20 and 30 min) and concentration of κ-CG (0.8%, 1.0% and 1.2%, w/v) on the swelling rate, gel strength, the stability of curcumin in the emulsion gel, water distribution and its mobility, as well as the contents of interface protein were characterized. The results showed that the addition of κ-CG significantly reduced the protein concentration required for the formation of emulsion gel induced by HPP and greatly reduced the swelling rate of the emulsion gel. The gel strength and storage stability of the composite emulsion gels increased with the increase in pressure (400–600 MPa) and holding time (10–30 min). When the pressure increased to 500 MPa, the stability of curcumin in the emulsion gel significantly improved. When the ratio of WPI to κ-CG was 12:1 (the κ-CG concentration was 1.0%), both the photochemical and thermal stability of curcumin were higher than those of the other two ratios. The HPP significantly increased the mobility of monolayer water in the system, while the mobility of multilayer water and immobilized water was significantly reduced. Increasing the holding time and the concentration of κ-CG both can result in an increase in the interfacial protein content in the oil/water system, and the HPP treatment had a significant effect on the composition of the interfacial protein of the emulsion gel. [ABSTRACT FROM AUTHOR]

The stimulator of interferon genes (STING) plays a significant role in immune defense and protection against tumor proliferation. Many cyclic dinucleotide (CDN) analogues have been reported to regulate its activity, but the dynamic process involved when the ligands activate STING remains unclear. In this work, all-atom molecular dynamics simulations were performed to explore the binding mode between human STING (hSTING) and four cyclic adenosine–inosine monophosphate analogs (cAIMPs), as well as 2′,3′-cGMP-AMP (2′,3′-cGAMP). The results indicate that these cAIMPs adopt a U-shaped configuration within the binding pocket, forming extensive non-covalent interaction networks with hSTING. These interactions play a significant role in augmenting the binding, particularly in interactions with Tyr167, Arg238, Thr263, and Thr267. Additionally, the presence of hydrophobic interactions between the ligand and the receptor further contributes to the overall stability of the binding. In this work, the conformational changes in hSTING upon binding these cAIMPs were also studied and a significant tendency for hSTING to shift from open to closed state was observed after binding some of the cAIMP ligands. [ABSTRACT FROM AUTHOR]

Lysine-specific demethylase 1 (LSD1/KDM1A) has emerged as a promising therapeutic target for treating various cancers (such as breast cancer, liver cancer, etc.) and other diseases (blood diseases, cardiovascular diseases, etc.), owing to its observed overexpression, thereby presenting significant opportunities in drug development. Since its discovery in 2004, extensive research has been conducted on LSD1 inhibitors, with notable contributions from computational approaches. This review systematically summarizes LSD1 inhibitors investigated through computer-aided drug design (CADD) technologies since 2010, showcasing a diverse range of chemical scaffolds, including phenelzine derivatives, tranylcypromine (abbreviated as TCP or 2-PCPA) derivatives, nitrogen-containing heterocyclic (pyridine, pyrimidine, azole, thieno[3,2-b]pyrrole, indole, quinoline and benzoxazole) derivatives, natural products (including sanguinarine, phenolic compounds and resveratrol derivatives, flavonoids and other natural products) and others (including thiourea compounds, Fenoldopam and Raloxifene, (4-cyanophenyl)glycine derivatives, propargylamine and benzohydrazide derivatives and inhibitors discovered through AI techniques). Computational techniques, such as virtual screening, molecular docking and 3D-QSAR models, have played a pivotal role in elucidating the interactions between these inhibitors and LSD1. Moreover, the integration of cutting-edge technologies such as artificial intelligence holds promise in facilitating the discovery of novel LSD1 inhibitors. The comprehensive insights presented in this review aim to provide valuable information for advancing further research on LSD1 inhibitors. [ABSTRACT FROM AUTHOR]

The droplet size, zeta potential, interface protein adsorption rate, physical stability and microrheological properties of high-pressure-homogenization (HPH)-modified, dual-protein-based whey–soy (whey protein isolate—soy protein isolate) emulsions containing different oil phase concentrations (5%, 10% and 15%; w/w) were compared in this paper. The in vitro digestion characteristics and storage stability of the dual-protein emulsions before and after HPH treatment were also explored. The results show that with an increase in the oil phase concentration, the droplet size and interface protein adsorption rate of the untreated dual-protein emulsions increased, while the absolute value of the zeta potential decreased. When the oil phase concentration was 10% (w/w), HPH treatment could significantly reduce the droplet size of the dual-protein emulsion, increase the interface protein adsorption rate, and improve the elasticity of the emulsion. Compared with other oil phase concentrations, the physical stability of the dual-protein emulsion containing a 10% (w/w) oil phase concentration was the best, so the in vitro digestion characteristics and storage stability of the emulsions were studied. Compared with the control group, the droplet size of the HPH-modified dual-protein emulsion was significantly reduced after gastrointestinal digestion, and the in vitro digestibility and release of free amino groups both significantly increased. The storage stability results show that the HPH-modified dual-protein emulsion showed good stability under different storage methods, and the storage stability of the steam-sterilized dual-protein emulsion stored at room temperature was the best. These results provide a theoretical basis for the development of new nutritional and healthy dual-protein liquid products. [ABSTRACT FROM AUTHOR]

Simple Summary: Dietary methionine deficiency can limit the body growth and cashmere production of cashmere goats, leading to excessive nitrogen (N) excretion. This study demonstrated that rumen-protected methionine supplementation improved the growth performance of cashmere goats and reduced their manure N excretions and plasma urea N levels during the seasonal growth of cashmere fibres. The formulation of diets supplemented with rumen-protected methionine can enhance the utilisation of N and maximise the production capacity of cashmere goats. This study determined the effects of rumen-protected methionine (RPM) supplementation on the growth performance, nutrient digestibility, nitrogen (N) utilisation and plasma amino acid profiles of Liaoning cashmere goats during cashmere fibre growth. Twenty-four yearling male cashmere goats (body weight: 35.41 ± 1.13 kg) were randomly assigned to four dietary treatments: a corn–soybean meal basal diet deficient in methionine (negative control, NC) and a basal diet supplemented with 1, 2 and 3 g/kg of RPM. The RPM supplementation quadratically increased the average daily gain (ADG) and decreased the feed to gain ratio (p = 0.001) without affecting the final body weight and dry matter intake. In particular, compared to NC, 2 g/kg RPM supplementation increased the ADG by 35 g/d (p < 0.001) and resulted in the lowest feed to gain ratio (p < 0.001). RPM increased the apparent total tract digestibility of N and decreased the faecal N levels, both in a linear fashion (p = 0.005). Urinary N levels did not have an effect, but the N retention levels increased linearly with PRM (p = 0.032). Moreover, the RPM decreased the plasma urea N levels (p < 0.001) and increased the plasma Met levels quadratically (p < 0.001). In conclusion, RPM supplementation in the diet of cashmere goats can enhance the utilisation of N and improve ADG during the cashmere fibre growing period, and 2 g/kg of RPM in the diet is suggested. [ABSTRACT FROM AUTHOR]

It has been proven that high-pressure homogenization (HPH) could improve the functional properties of proteins by modifying their structure. This study researched the effect of HPH on the structural and functional properties of whey-soy dual-protein (Soy Protein Isolation-Whey Protein Isolation, SPI-WPI). Different protein solution samples were treated with HPH at 30, 60, 90, 120 and 150 MPa, and the structure changed under different pressures was analyzed by measuring particle size, zeta potential, Fourier infrared spectrum (FTIR), fluorescence spectrum and scanning electron microscope (SEM). The results showed that HPH significantly reduced the particle size of SPI-WPI, changed the secondary and tertiary structures and improved the hydrophobic interaction between molecules. In addition, HPH significantly improved the solubility and emulsification of all proteins, and the improvement effect on SPI-WPI was significantly better than SPI and WPI. It was found that SPI-WPI treated with 60 MPa had the best physicochemical properties. Secondly, we researched the effect of HPH by 60 MPa on the emulsion properties of SPI-WPI. In this study, the SPI-WPI had the lowest surface tension compared to a single protein after HPH treatment. The emulsion droplet size was obviously decreased, and the elastic properties and physical stability of SPI-WPI emulsion were significantly enhanced. In conclusion, this study will provide a theoretical basis for the application of HPH in modifying the structure of dual-protein to improve its development and utilization in liquid specialty food. [ABSTRACT FROM AUTHOR]

Route guidance strategies are an important part of advanced traveler information systems, which are a subsystem of intelligent transportation systems (ITSs). In previous research, many scholars have proposed a variety of route guidance strategies to guide vehicles in order to relieve traffic congestion, but few scholars have considered a strategy to control transportation infrastructure. In this paper, to cope with tidal traffic, we propose a dynamic lane reversal strategy (DLRS) based on the density of congestion clusters over the total road region. When the density reaches 0.37, the reversible lane converts to the opposite direction. When the density falls off to below 0.22, the reversible lane returns back to the conventional direction. The simulation results show that the DLRS has better adaptability for coping with the fluctuation in tidal traffic. [ABSTRACT FROM AUTHOR]

The emergence of new variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has generated recurring worldwide infection outbreaks. These highly mutated variants reduce the effectiveness of current coronavirus disease 2019 (COVID-19) vaccines, which are designed to target only the spike (S) protein of the original virus. Except for the S of SARS-CoV-2, the immunoprotective potential of other structural proteins (nucleocapsid, N; envelope, E; membrane, M) as vaccine target antigens is still unclear and worthy of investigation. In this study, synthetic DNA vaccines encoding four SARS-CoV-2 structural proteins (pS, pN, pE, and pM) were developed, and mice were immunized with three doses via intramuscular injection and electroporation. Notably, co-immunization with two DNA vaccines that expressed the S and N proteins induced higher neutralizing antibodies and was more effective in reducing the SARS-CoV-2 viral load than the S protein alone in mice. In addition, pS co-immunization with either pN or pE + pM induced a higher S protein-specific cellular immunity after three immunizations and caused milder histopathological changes than pS alone post-challenge. The role of the conserved structural proteins of SARS-CoV-2, including the N/E/M proteins, should be investigated further for their applications in vaccine design, such as mRNA vaccines. [ABSTRACT FROM AUTHOR]

Lysine-specific demethylase 1 (LSD1) is a histone-modifying enzyme, which is a significant target for anticancer drug research. In this work, 40 reported tetrahydroquinoline-derivative inhibitors targeting LSD1 were studied to establish the three-dimensional quantitative structure–activity relationship (3D-QSAR). The established models CoMFA (Comparative Molecular Field Analysis (q2 = 0.778, R pred 2 = 0.709)) and CoMSIA (Comparative Molecular Similarity Index Analysis (q2 = 0.764, R pred 2 = 0.713)) yielded good statistical and predictive properties. Based on the corresponding contour maps, seven novel tetrahydroquinoline derivatives were designed. For more information, three of the compounds (D1, D4, and Z17) and the template molecule 18x were explored with molecular dynamics simulations, binding free energy calculations by MM/PBSA method as well as the ADME (absorption, distribution, metabolism, and excretion) prediction. The results suggested that D1, D4, and Z17 performed better than template molecule 18x due to the introduction of the amino and hydrophobic groups, especially for the D1 and D4, which will provide guidance for the design of LSD1 inhibitors. [ABSTRACT FROM AUTHOR]

Chronic hepatitis B is a critical cause of many serious liver diseases such as hepatocellular carcinoma (HCC). The main challenges in hepatitis B treatment include the rebound of hepatitis B virus (HBV)-related antigen levels after drug withdrawal and the immunosuppression caused by the virus. Herein, we demonstrate that the HBV-related antigen can be effectively inhibited and antiviral immunity can be successfully reactivated through codelivery of the small interfering RNA (siRNA) targeting HBV X protein (HBx) and the plasmid encoding interleukin 12 (pIL-12) to hepatocytes and immune cells. After being treated by the siRNA/pIL-12 codelivery system, HBx mRNA and hepatitis B surface antigen (HBsAg) are dramatically reduced in HepG2.215 cells. More importantly, the downregulated CD47 and programmed death ligand 1 (PD-L1) and the upregulated interferon-β promoter stimulator-1 (IPS-1), retinoic acid-inducible gene-1 (RIG-1), CD80, and human leukocyte antigen-1 (HLA-1) in treated HepG2.215 cells indicate that the immunosuppression is reversed by the codelivery system. Furthermore, the codelivery system results in inhibition of extracellular regulated protein kinases (ERK) and phosphoinositide-3-kinase (PI3K)/protein kinase B (Akt) pathways, as well as downregulation of B-cell lymphoma-2 (Bcl-2) and upregulation of p53, implying its potential in preventing the progression of HBV-induced HCC. In addition, J774A.1 macrophages treated by the codelivery system were successfully differentiated into the M1 phenotype and expressed enhanced cytokines with anti-hepatitis B effects such as interleukin 6 (IL-6) and tumor necrosis factor-α (TNF-α). Therefore, we believe that codelivery of siRNA and pIL-12 can effectively inhibit hepatitis B virus, reverse virus-induced immunosuppression, reactivate antiviral immunity, and hinder the progression of HBV-induced hepatocellular carcinoma. This investigation provides a promising approach for the synergistic treatment of HBV infection. [ABSTRACT FROM AUTHOR]

The main purpose of this article is using the elementary methods, the properties of Dirichlet L-functions to study the computational problem of a certain mean square value involving Dirichlet L-functions at positive integer points, and give some exact calculating formulae. As some applications, we obtain some interesting identities and inequalities involving character sums and trigonometric sums. [ABSTRACT FROM AUTHOR]

In this paper, we utilize the mathematical induction, the properties of symmetric polynomial sequences and Chebyshev polynomials to study the calculating problems of a certain reciprocal sums of Chebyshev polynomials, and give two interesting identities for them. These formulae not only reveal the close relationship between the trigonometric function and the Riemann ζ -function, but also generalized some existing results. At the same time, an error in an existing reference is corrected. [ABSTRACT FROM AUTHOR]

Orbital angular momentum (OAM) mode-division multiplexing (MDM) has recently been under intense investigations as a new way to increase the capacity of fiber communication. In this paper, a two-layer Erbium-doped fiber amplifier (EDFA) for an OAM multiplexing system is proposed. The amplifier is based on the circular photonic crystal fiber (C-PCF), which can maintain a stable transmission for 14 OAM modes by a large index difference between the fiber core and the cladding. Further, the two-layer doped region can balance the amplification performance of different modes. The relationship between the performance and the parameters of the amplifier is analyzed numerically to optimize the amplifier design. The optimized amplifier can amplify 18 modes (14 OAM modes) simultaneously over the C-band with a differential mode gain (DMG) lower than 0.1 dB while keeping the modal gain over 23 dB and noise figure below 4 dB. Finally, the fabrication tolerance and feasibility are discussed. The result shows a relatively large fabrication tolerance in the OAM EDFA parameters. [ABSTRACT FROM AUTHOR]

Metal injection molding (MIM) is a quick manufacturing method that produces elaborate and complex items accurately and repeatably. The success of MIM is highly impacted by green part characteristics. This work characterized the green part of steel produced using MIM from feedstock with a powder/binder ratio of 93:7. Several parameters were used, such as dual gates position, injection temperature of ~150 °C, and injection pressure of ~180 MPa. Analysis using Moldflow revealed that the aformentioned parameters were expected to produce a green part with decent value of confidence to fill. However, particular regions exhibited high pressure drop and low-quality prediction, which may lead to the formation of defects. Scanning electron microscopy, as well as three-dimensional examination using X-ray computed tomography, revealed that only small amounts of pores were formed, and critical defects such as crack, surface wrinkle, and binder separation were absent. Hardness analysis revealed that the green part exhibited decent homogeneity. Therefore, the observed results could be useful to establish guidelines for MIM of steel in order to obtain a high quality green part.