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Gear manufacturers need a dependable, comprehensive, and efficient inspection method to ensure manufacturing accuracy. Linear structured light provides a swift and effective solution to meet the rapid testing requirements of gear manufacturers. But its accuracy still needs to be improved. This method can obtain 33000 3D data points of a single gear tooth surface in less than 0.3 s. And based on this, evaluate the tooth profile error of the gear. The results indicate that the measurement deviation amounts to 1.47 μm in measuring gears of level 7 accuracy compared to the gear measurement center. The error mainly comes from the equipment error and the down-sampling process using the centroid method. In the measurement process, the larger the deviation between the contact position of the gear and the light and the focus position of the linear structured light, the greater the error. The larger the neighborhood search radius during the calculation process, the larger the error. [ABSTRACT FROM AUTHOR]

Thrombus is an extremely dangerous factor in the human body that can block the blood vessel. Once thrombosis happens in venous of lower limbs, local blood flow is impeded. This leads to venous thromboembolism (VTE) and even pulmonary embolism. In recent years, venous thromboembolism has frequently occurred in a variety of people, and there is no effective treatment for patients with different venous structures. For the patients with venous isomer with single valve structure, we establish a coupled computational model to simulate the process of thrombolysis with multi‐dose treatment schemes by considering the blood as non‐Newtonian fluid. Then, the corresponding in vitro experimental platform is built to verify the performance of the developed mathematical model. At last, the effects of different fluid models, valve structures and drug doses on thrombolysis are comprehensively studied through numerical and experimental observations. Comparing with the experimental results, the relative error of blood boosting index (BBI) obtained from non‐Newtonian fluid model is 11% smaller than Newtonian fluid. In addition, the BBI from venous isomer is 1300% times stronger than patient with normal venous valve while the valve displacement is 500% times smaller. As consequence, low eddy current and strong molecular diffusion near the thrombus in case of isomer promote thrombolysis rate up to 18%. Furthermore, the 80 μM dosage of thrombolytic drugs gets the maximum thrombus dissolution rate 18% while the scheme of 50 μM doses obtains a thrombolysis rate of 14% in case of venous isomer. Under the two administration schemes for isomer patients, the rates from experiments are around 19.1% and 14.9%, respectively. It suggests that the proposed computational model and the designed experiment platform can potentially help different patients with venous thromboembolism to carry out clinical medication prediction. [ABSTRACT FROM AUTHOR]

Background: Apostichopus japonicus is an economically important species in the global aquaculture industry. Russian A. japonicus, mainly harvested in the Vladivostok region, exhibits significant phenotypic differentiation, including in many economically important traits, compared with Chinese A. japonicus owing to differences in their habitat. However, both the genetic basis for the phenotypic divergence and the population genetic structure of Russian and Chinese A. japonicus are unknown. Result: In this study, 210 individuals from seven Russian and Chinese A. japonicus populations were sampled for whole-genome resequencing. The genetic structure analysis differentiated the Russian and Chinese A. japonicus into two groups. Population genetic analyses indicated that the Russian population showed a high degree of allelic linkage and had undergone stronger positive selection compared with the Chinese populations. Gene ontology terms enriched among candidate genes with group selection analysis were mainly involved in immunity, such as inflammatory response, antimicrobial peptides, humoral immunity, and apoptosis. Genome-wide association analysis yielded eight single-nucleotide polymorphism loci significantly associated with parapodium number, and these loci are located in regions with a high degree of genomic differentiation between the Chinese and Russia populations. These SNPs were associated with five genes. Gene expression validation revealed that three of these genes were significantly differentially expressed in individuals differing in parapodium number. AJAP08772 and AJAP08773 may directly affect parapodium production by promoting endothelial cell proliferation and metabolism, whereas AJAP07248 indirectly affects parapodium production by participating in immune responses. Conclusions: This study, we performed population genetic structure and GWAS analysis on Chinese and Russian A. japonicus, and found three candidate genes related to the number of parapodium. The results provide an in-depth understanding of the differences in the genetic structure of A. japonicus populations in China and Russia, and provide important information for subsequent genetic analysis and breeding of this species. [ABSTRACT FROM AUTHOR]

Arctigenin, derived from Arctium lappa L., has multiple pharmacological activities, including immunoregulatory, anti-diabetic, anti-tumor, and neuroprotective effects. Nevertheless, the potential therapeutic target of arctigenin in modulating inflammation remains undefined. In the present study, we identified that arctigenin was a phosphodiesterase-4 (PDE4) selective inhibitor for the first time. Further investigations were performed to fully uncover the effects and mechanism of arctigenin on experimental murine psoriasis model. Crystal structure determination, PDEs enzyme assay, and isothermal titration calorimetry were included to illustrate the binding specialty, inhibitory effects, and selectivity of arctigenin on PDE4D. The anti-inflammatory effects were conducted in LPS-activated human peripheral blood mononuclear cells (PBMCs) and RAW264.7 cells. Imiquimod-induced murine psoriasis was performed to uncover the therapeutic effects and mechanism of arctigenin in vivo. Arctigenin could bind to the catalytic domain of PDE4D via formation of hydrogen bonds as well as π-π stacking interactions between the dibenzyl butyrolactone of arctigenin and several residues of PDE4D. Accordingly, arctigenin showed prominent anti-inflammation in human PBMCs and murine RAW264.7 cells. PDE4 inhibition by arctigenin resulted in elevation of intracellular cyclic adenosine monophosphate (cAMP) and phosphorylation of cAMP-response element binding protein (CREB), which were largely blocked through intervention of protein kinase A (PKA) activity by H89 treatment or reduction of protein expression by siRNA transfection. Moreover, we first identified that a topical application of arctigenin ameliorated experimental psoriatic manifestations in imiquimod-induced murine psoriasis model by decreasing adhesion and chemotaxis of several inflammatory cells. Further proteomics analysis revealed that arctigenin could rectify the immune dysfunction and hyperactivation of keratinocytes in the inflamed skin microenvironments, which might be largely related to the expression of Keratins. The research provided credible clew that inhibition of PDE4 by arctigenin might function as the potential therapeutic approach for the treatment of psoriasis. [ABSTRACT FROM AUTHOR]

Grinding force is the most important characteristic parameter in the study of grinding machining mechanism, and it has an important influence on the quality of the machined surface and the service life of the grinding wheel. Accurate prediction of grinding force is significant to process improvement, machine tool design, and condition diagnosis. This paper uses the ABAQUS software to simulate the end grinding process of Si3N4 ceramics. In the abrasive removal model, in order to express the complex grinding conditions of the fine-grained grinding wheel better, this paper adopts the truncated polyhedral abrasive grain model, and the abrasive grains are randomly rotated multiple times to verify the model, which reduces the simulation grinding force error caused by the randomness of irregular abrasive grain model and improves the prediction accuracy. This paper establishes an abrasive grain distribution model, the unit number of abrasive grains is calculated from the equivalent volume of abrasive grains, and the grinding force of a single abrasive grain extends to the end surface; in the process simulation model, considering the influence of the change of radial linear velocity on the grinding force, the final grinding force is obtained by partitioning and summing. The experimental comparison shows that the grinding force model has high prediction accuracy in the end grinding with the fine-grained grinding wheel. [ABSTRACT FROM AUTHOR]

Phosphodiesterase-4 (PDE4) and PDE5 responsible for the hydrolysis of intracellular cAMP and cGMP, respectively, are promising targets for therapeutic intervention in a wide variety of diseases. Here, we report the discovery of novel, drug-like PDE4 inhibitors by performing a high-throughput drug repurposing screening of 2560 approved drugs and drug candidates in clinical trial studies. It allowed us to identify eight potent PDE4 inhibitors with IC 50 values ranging from 0.41 to 2.46 μM. Crystal structures of PDE4 in complex with four compounds, namely ethaverine hydrochloride (EH), benzbromarone (BBR), CX-4945, and CVT-313, were further solved to elucidate molecular mechanisms of action of these new inhibitors, providing a solid foundation for optimizing the inhibitors to improve their potency as well as selectivity. Unexpectedly, selectivity profiling of other PDE subfamilies followed by crystal structure determination revealed that CVT-313 was also a potent PDE5 inhibitor with a binding mode similar to that of tadalafil, a marketed PDE5 inhibitor, but distinctively different from the binding mode of CVT-313 with PDE4. Structure-guided modification of CVT-313 led to the discovery of a new inhibitor, compound 2 , with significantly improved inhibitory activity as well as selectivity towards PDE5 over PDE4. Together, these results highlight the utility of the drug repurposing in combination with structure-based drug design in identifying novel inhibitors of PDE4 and PDE5, which provides a prime example for efficient discovery of drug-like hits towards a given target protein. [Display omitted] • 8 new drug-like PDE4 inhibitors were identified by drug repurposing screening. • The binding mode of the hits and PDE4 were validated by X-ray crystallography. • CVT-313 was revealed to be a potent inhibitor of PDE4 and PDE5. • Structure-guided optimization of CVT-313 resulted in compound 2. • Compound 2 showed increased potency and selectivity toward PDE5 over PDE4. [ABSTRACT FROM AUTHOR]

Macrocycles often exhibit good biological properties and potential druggability, which lead to versatile applications in the pharmaceutical industry. Herein, we report a highly efficient and practical methodology for the functionalization and macrocyclization of Trp and Trp-containing peptides via Pd(II)-catalyzed C–H alkenylation at the Trp C4 position. This method provides direct access to C4 maleimide-decorated Trp-containing peptidomimetics and maleimide-braced 17- to 30-membered peptide macrocycles. In particular, these unique macrocycles revealed low micro- to sub-micromolar EC50 values with promising anti-SARS-CoV-2 activities. Further explorations with computational methodologies and experimental validations indicated that these macrocycles exert antiviral effects through binding with the N protein of SARS-CoV-2. [ABSTRACT FROM AUTHOR]

Ion concentration polarization (ICP) is a promising mechanism for concentrating and/or separating charged molecules. This work simulates the extraction of Li+ ions in a diluted high Mg2+/Li+ ratio salt lake brines based on free flow ICP focusing (FF-ICPF). The model solution of diluted brine continuously flows through the system with Li+ slightly concentrated and Mg2+ significantly removed by ICP driven by external pressure and perpendicular electric field. In a typical case, our results showed that this system could focus Li+ concentration by ~1.28 times while decreasing the Mg2+/Li+ ratio by about 85% (from 40 to 5.85). Although Li+ and Mg2+ ions are not separated as an end product, which is preferably required by the lithium industry, this method is capable of decreasing the Mg2+/Li+ ratio significantly and has great potential as a preprocessing technology for lithium extraction from salt lake brines. [ABSTRACT FROM AUTHOR]

Human society is facing the threat of various viruses. Proteases are promising targets for the treatment of viral infections. In this study, we collected and profiled 170 protease sequences from 125 viruses that infect humans. Approximately 73 of them are viral 3-chymotrypsin-like proteases (3CLpro), and 11 are pepsin-like aspartic proteases (PAPs). Their sequences, structures, and substrate characteristics were carefully analyzed to identify their conserved nature for proposing a pan-3CLpro or pan-PAPs inhibitor design strategy. To achieve this, we used computational prediction and modeling methods to predict the binding complex structures for those 73 3CLpro with 4 protease inhibitors of SARS-CoV-2 and 11 protease inhibitors of HCV. Similarly, the complex structures for the 11 viral PAPs with 9 protease inhibitors of HIV were also obtained. The binding affinities between these compounds and proteins were also evaluated to assess their pan-protease inhibition via MM-GBSA. Based on the drugs targeting viral 3CLpro and PAPs, repositioning of the active compounds identified several potential uses for these drug molecules. As a result, Compounds 1–2, modified based on the structures of Ray1216 and Asunaprevir, indicate potential inhibition of DENV protease according to our computational simulation results. These studies offer ideas and insights for future research in the design of broad-spectrum antiviral drugs. [ABSTRACT FROM AUTHOR]

Sapphire single crystal has great potential applications in the semiconductor field. Due to its brittle characteristics. Crack failure on ultra-thin sapphire surface were prone to happen using tradition paraffin bonding clamping method during double-side processing, which severely restricted its processing efficiency. Thus, for overcoming the problem, the layer stacked clamping (LSC) method was proposed by using van der Waals forces and capillary forces that caused by dropping a liquid between workpiece and baseplate. A series of experiments were conducted for studying the characteristic of layer stacked clamping (LSC) method on polishing ultrathin sapphire wafer with double-side polishing machine. A self-made friction force test platform was built for learning the friction force between sapphire wafer and baseplate with different baseplate (stainless steel, cast iron, and aluminum alloy) and different baseplate surface roughness (Ra 3.6 nm, 68.2 nm, 210.1 nm, and 517.9 nm). Single-factor polishing experiments were carried out on baseplate with different flatness (PV value 5.3 μm, 9.8 μm, 19.9 μm, and 29.7 μm) and different thicknesses (0.082 mm, 0.104 mm, and 0.119 mm). The double-side polishing experiments were carried out to compare the polishing performance on the ultrathin sapphire polishing between LSC method and traditional paraffin bonding method. The results show that the friction forces of stainless steel and iron increase under the adsorption of droplets. Stainless steel performs higher friction force and is more suitable for making the baseplate. The inner fringe of limiter was cut off by the edge of the sapphire wafer, and a slope was thereby formed. According to polishing results, the LSC method has a higher efficiency on the clamping wafers than traditional paraffin bonding method. The surface roughness, flatness, and material removal rates are better than paraffin bonding. Finally, a smooth surface with a surface roughness (Sa) of 1.1 nm and flatness (PV) of 0.988 μm was obtained by the LSC method, significantly improving the clamping and processing efficiency of ultra-thin sapphire. [ABSTRACT FROM AUTHOR]

Nucleic acid extraction (NAE) is an essential step in the whole process of nucleic acid detection (NAT). Traditional manual extraction methods are time-consuming and laborious, unfavorable to the point-of-care testing of nucleic acids. Ultrasound has been emphasized due to its noncontact and easy-to-manipulate characteristics, and integration with microfluidic chip can realize rapid NAE through acoustic streaming effect. The uniformity of magnetic bead mixing in this process is a critical factor affecting the extraction effect. In this study, we developed an ultrasound-assisted NAE technique based on the magnetic bead method and optimized the chip structure to achieve rapid NAE. We use ultrasonic-assisted coupled with magnetic bead method for ultra-fast NAE. The mixing process of magnetic beads driven by acoustic streaming is simulated by a dispersive two-phase flow model, and the ultrasonic incidence angle (θ in), cone structure aspect ratio (D c / H c) and sheet structure thickness (H p) are optimized to enhance the mixing performance. Furthermore, the effectiveness of NAE is validated by utilizing quantitative real-time PCR (qPCR) detection. The findings reveal that a θ in value of 10° yields superior mixing performance compared to other incidence angles, resulting in a maximum increase of 84 % in mixing intensity. When D c / H c = 0.5 and H p = 0.5 mm, the maximum mixing index in the localized region of the chamber after 1 s of ultrasound action can reach 83.6 % and 92.5 %, respectively. Compared to the original chamber, the CT values extracted after 5 s of ultrasound action shifted forward by up to 1.9 ct and 4.1 ct, respectively. The dispersed two-phase flow model can effectively simulate the mixing process of magnetic beads, which plays an important role in assisting the structural design of chip extraction chambers. The single-step mixing of ultrasound-assisted NAE takes only 15s to achieve an extraction performance comparable to manual extraction. The extraction process can be completed within 7 min after integrating this technology with microfluidic chips and automated equipment, providing a solution for automated and efficient NAE. Ultrasound-assisted nucleic acid extraction based on acoustic streaming mixing enables fully automated extraction of nucleic acid in less than 7 min [Display omitted] • Non-contact extraction with ultrasound. • Dispersed two-phase flow for simulated bead mixing. • Microstructure enhances acoustic streaming and promotes magnetic bead mixing. • Ultrasound-assisted nucleic acid extraction can be done in only about 7 min. [ABSTRACT FROM AUTHOR]

Psoriasis is a kind of chronic inflammatory skin disorder, while the long-term use of conventional therapies for this disease are limited by severe adverse effects. Novel small molecules associated with new therapeutic mechanisms are greatly needed. It is known that phosphodiesterase 4 (PDE4) plays a central role in regulating inflammatory responses through hydrolyzing intracellular cyclic adenosine monophosphate (cAMP), making PDE4 to be an important target for the treatment of inflammatory diseases (e.g. psoriasis). In our previous work, we identified a series of novel PDE4 inhibitors with a tetrahydroisoquinoline scaffold through structure-based drug design, among which compound 1 showed moderate inhibition activity against PDE4. In this study, a series of novel tetrahydroisoquinoline derivatives were developed based on the crystal structure of PDE4D in complex with compound 1. Anti-inflammatory effects of these compounds were evaluated, and compound 36, with high safety, permeability and selectivity, exhibited significant inhibitory potency against the enzymatic activity of PDE4D and the TNF-α release from the LPS-stimulated RAW 264.7 and hPBMCs. Moreover, an in vivo study demonstrated that a topical administration of 36 achieved more significant efficacy than calcipotriol to improve the features of psoriasis-like skin inflammation. Overall, our study provides a basis for further development of tetrahydroisoquinoline-based PDE4 inhibitors against psoriasis. Image 1 • 51 tetrahydroisoquinolines derivatives as novel PDE4 inhibitors were designed, synthesized and evaluated. • The optimum compound 36 exhibited high safety, potency, permeability and selectivity in vitro. • The crystal structure of PDE4D in complex with compound 36 was solved. • Compound 36 exhibited superior therapeutic efficacy than calcipotriol against the IMQ-induced murine psoriasis-like skin inflammation. [ABSTRACT FROM AUTHOR]

Phosphodiesterase-4 (PDE4) functions as a critical intracellular enzyme in immune cells and keratinocytes through the hydrolysis of cAMP. Inhibition of PDE4 has been considered as an effective therapeutic strategy in multiple inflammatory diseases. This study was intended to assess the anti-inflammatory effects of the PDE4 inhibitor, DC591017, both in vitro and in vivo. Murine RAW264.7 cells, BMDMs, BMDCs, and human NHEKs were incubated with DC591017 and then inflammatory mediators, intracellular cAMP and cAMP-mediated signaling pathways were analyzed. Carrageenan-induced acute inflammation in murine air pouches and rat paws, as well as imiquimod (IMQ)-induced psoriasis-like skin lesions were conducted to explore the therapeutic effects and underlying mechanisms of DC591017. We demonstrated herein that DC591017 suppressed the inflammatory responses of macrophages and DCs through promoting cAMP-dependent PKA-CREB signaling. Addition of forskolin functioned synergistically with DC591017, which could be blocked following H89 intervention or knockdown of PKA expression by siRNA transfection. In vivo , DC591017 treatment alleviated the leukocytes infiltration and secretion of inflammatory cytokines in murine air pouches and significantly attenuated carrageenan-induced paw swelling in rats. Moreover, we also illustrated that topical application of DC591017 ointment ameliorated IMQ-caused experimental psoriatic skin lesions, as evidenced by decreasing epidermal thickening and inflammatory infiltrations to inflamed skins. Consistently, DC591017 decreased expression of PDE4 isoforms and subsequently regulated PKA-CREB and NF-κB signaling. In brief, our study brought out a patent PDE4 inhibitor with robust anti-inflammation and provided the credible evidence in the treatment of patients with psoriasis. [ABSTRACT FROM AUTHOR]

• The new Zn-MOF was prepared. • The prepared MOF is suitable for loading and unloading of I 2. • The loading and delivery of I 2 were performed using the organic solutions. A new metal-organic framework, [Zn 2 (NDC)(BDT)] n.4DMF (TMU-18) (NDC = 1,6 naphtalenedicarboxylate, BDT = 1,4-benzeneditetrazole) was synthesized and characterized using elemental analysis, FT-IR and X-ray crystallography. The thermal stability of compound TMU-18 was studied by thermal gravimetric (TG). TMU-18 was used for loading the I 2 by suspending it in a solution of I 2 in cyclohexane. The delivery of I 2 from TMU-18 performed in ethanol at room temperature. The loading and unloading of I 2 were investigated by UV/vis spectroscopy. [ABSTRACT FROM AUTHOR]

Betulinic acid (BA) is a natural pentacyclic triterpenoid that has a wide range of biological and pharmacological effects. Here, computational methods such as pharmacophore screening and reverse docking were used to predict the potential target for BA. Retinoic acid receptor-related orphan receptor gamma (RORγ) was confirmed as its target by several molecular assays as well as crystal complex structure determination. RORγ has been the focus of metabolic regulation, but its potential role in cancer treatment has only recently come to the fore. In this study, rationale optimization of BA was performed and several new derivatives were generated. Among them, the compound 22 showed stronger binding affinity with RORγ (K D = 180 nM), good anti-proliferative activity against cancer cell lines, and potent anti-tumor efficacy with a TGI value of 71.6% (at a dose of 15 mg/kg) in the HPAF-II pancreatic cancer xenograft model. Further RNA-seq analysis and cellular validation experiments supported that RORγ antagonism was closely related to the antitumor activity of BA and 22 , resulting in suppression of the RAS/MAPK and AKT/mTORC1 pathway and inducing caspase-dependent apoptosis in pancreatic cancer cells. RORγ was highly expressed in cancer cells and tissues and positively correlated with the poor prognosis of cancer patients. These results suggest that BA derivatives are potential RORγ antagonists worthy of further exploration. RORγ has been identified as a natural anti-tumor product targeting betulinic acid. A series of new, more potent betulinic acid derivatives were designed, synthesized, and evaluated. 22 proved to be the best lead. [Display omitted] • RORγ was identified as a target of betulinic acid combining the strategy of reverse docking and X-ray crystallography. • Utilizing structure and QSAR-based approach, a series of BA derivatives as RORγ antagonists were synthesized and evaluated. • The compound 22 exhibited good anti-proliferation activity and the pharmacological mechanism of anti-tumor was studied. • Compound 22 had potent anti-tumor efficacy in the HPAF-II pancreatic cancer xenograft model. [ABSTRACT FROM AUTHOR]

To accurately evaluate the effects of vegetation restoration strategies on soil carbon (C) and nitrogen (N) in erosion zones, we conducted a meta-analysis of 88 papers to analyze the dynamics of soil organic carbon (SOC) and soil total nitrogen (STN) contents under forestland and grassland restoration. The results indicated that i) vegetation restoration could reduce runoff and soil loss and increase SOC content, and forestland had a non-significant increase in STN content. ii) Vegetation restoration had the strongest soil C and N sequestration effects in the 0–20 cm soil layer and medium-textured soil. iii) Grassland restoration was more conducive to increasing the STN content and could increase the SOC and STN contents in the short term. iv) Forestland was more sustainable way to improve SOC contents compared with grassland, because its positive effects were not limited by mean annual precipitation (MAP), mean annual temperature (MAT), slope position. v) Grassland or forestland restoration could increase simultaneously both SOC and STN contents, when MAP < 800 mm, MAT < 15 °C, and at the foot position. Our findings indicate that when SOC sequestration is one of the main goals of vegetation restoration strategies, forestland restoration may be a better choice. ● The runoff and sediment reduction benefits differed little between vegetation types. ● Forestland restoration could not increase the STN content. ● Vegetation had higher SOC or STN sequestration potential in medium-textured soil. ● Grassland could increase the SOC and STN contents in a short time. [ABSTRACT FROM AUTHOR]

The 3C-like protease (3CLpro) is essential for the replication and transcription of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), making it a promising target for the treatment of corona virus disease 2019 (COVID-19). In this study, a series of 2,3,5-substituted [1,2,4]-thiadiazole analogs were discovered to be able to inhibit 3CLpro as non-peptidomimetic covalent binders at submicromolar levels, with IC 50 values ranging from 0.118 to 0.582 μM. Interestingly, these compounds were also shown to inhibit PLpro with the same level of IC 50 values, but had negligible effect on proteases such as chymotrypsin, cathepsin B, and cathepsin L. Subsequently, the antiviral abilities of these compounds were evaluated in cell-based assays, and compound 6g showed potent antiviral activity with an EC 50 value of 7.249 μM. It was proposed that these compounds covalently bind to the catalytic cysteine 145 via a ring-opening metathesis reaction mechanism. To understand this covalent-binding reaction, we chose compound 6a , one of the identified hit compounds, as a representative to investigate the reaction mechanism in detail by combing several computational predictions and experimental validation. The process of ring-opening metathesis was theoretically studied using quantum chemistry calculations according to the transition state theory. Our study revealed that the 2,3,5-substituted [1,2,4]-thiadiazole group could covalently modify the catalytic cysteine in the binding pocket of 3CLpro as a potential warhead. Moreover, 6a was a known GPCR modulator, and our study is also a successful computational method-based drug-repurposing study. 2,3,5-substituted [1,2,4]-thiadiazoles as potent inhibitors targeting 3C-Like protease were proposed to covalently bind with the catalytic cysteine via a ring-opening metathesis reaction mechanism. [Display omitted] • Discovery of a new type of non-peptidomimetic covalent inhibitor against 3CLpro of SARS-CoV-2 with inhibition as strong as sub-micromolar level. • A molecular mechanism of the ring-opening metathesis was explored by combining types of computational and experimental technologies. • A multi-technologies integrated research paradigm for lead identification, validation and molecular mechanism study was explored. [ABSTRACT FROM AUTHOR]

Strongylocentrotus intermedius is one of the most economically valuable sea urchin species in China and has experienced mass mortality owing to outbreaks of bacterial diseases such as black mouth disease. This has caused serious economic losses to the sea urchin farming industry. To investigate the immune response mechanism of S. intermedius with different tube feet colors in response to Vibrio harveyi infection, we examined the different tube feet-colored S. intermedius under V. harveyi challenge and compared their transcriptome and microRNA (miRNA) profiles using RNA-Seq. We obtained 1813 differentially expressed genes (DEGs), 28 DE miRNAs, and 303 DE miRNA–DEG pairs in different tube feet-colored S. intermedius under V. harveyi challenge. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis showed that the most significant DEGs were associated with the Notch signaling and phagosome pathways. The target genes of immune-related miRNAs (miR-71, miR-184, miR-193) and genes (CALM1 , SPSB4 , DMBT , CSRP1) in S. intermedius were predicted and validated. This study provides insight into the molecular mechanisms that regulate genes involved in the immune response of S. intermedius infected with V. harveyi. • The valuable database of miRNA was constructed for S. intermedius under V. harveyi infection. • A large number of miRANs and their targets, such as CALM1 , CAL1A2 , SPSB4 were response to V. harveyi infection. • The interaction of multiple mRNA-miRNAs in the immune-related process in S. intermedius. [ABSTRACT FROM AUTHOR]

This study aimed to explore the effects of trans -anethole (TA) on lipopolysaccharide (LPS)-induced acute jejunal inflammation model of broilers. A total of 160 one-day-old broilers (male; Arbor Acres) were randomly allocated into four treatment groups with 8 replicates of 5 birds each. On d 20, the dose of 5 mg/kg body weight LPS solution and the equal amount of sterile saline were intraperitoneally injected into LPS-challenged and unchallenged broilers, respectively. Compared with the control group, LPS decreased (P < 0.05) the villus height (VH) and the ratio of villus height to crypt depth (VCR) but increased (P < 0.05) the crypt depth (CD), meanwhile, enhanced (P < 0.01) the levels of interleukin-6 (IL-6), interleukin-1beta (IL-1β) and tumor necrosis factor-alpha (TNF-α) but decreased (P < 0.01) the level of interleukin-10 (IL-10). The group supplemented with 600 mg/kg of TA had lower (P < 0.01) CD and higher (P < 0.01) VCR than the LPS group. TA increased (P < 0.01) the level of IL-10 and decreased (P < 0.01) the level of IL-1β. The mRNA expression levels of IL-6 , nuclear factor kappa B ( NF-κB ), TNF-α were up-regulated (P < 0.05) and the levels of IL-10 and inhibitor of NF-κB alpha ( IκBα ) were down-regulated (P < 0.05) by LPS as compared with the control group. TA down-regulated (P < 0.05) the increased mRNA expression levels of genes caused by LPS, as well as up-regulated (P < 0.05) the levels of IL-10 and IκBα. Furthermore, LPS down-regulated (P < 0.05) and up-regulated (P < 0.05) the protein expression levels of IκBα and NF-κB p65, respectively. TA up-regulated (P < 0.05) the level of IκBα and down-regulated (P < 0.05) the level of NF-κB p65. The conclusion of this study is that TA could exert protective effect on the LPS-induced acute jejunal inflammation of broilers via repressing the activation of NF-κB and the 600 mg/kg is the optimal dose against LPS-induced acute jejunal inflammation of broilers. [ABSTRACT FROM AUTHOR]

The aim of this study was to investigate the protective effect of trans -anethole (TA) on lipopolysaccharide-induced acute liver inflammation model of chickens by determining the levels of inflammatory mediators in serum and liver, relative mRNA expression and protein expression of inflammation-related genes in NF-κB signaling pathway. A total of 160 one-day-old male chickens (Arbor Acres) were assigned into 4 treatments with 8 replicates of 5 birds each. On d 20, the control group was intraperitoneally injected with sterile saline and the other groups were injected with lipopolysaccharide (LPS ; 5 mg/kg body weight). There were no significant differences in average daily gain (ADG), average daily feed intake (ADFI) and feed conversion ratio (FCR) among groups. However, compared with the control group, the LPS group significantly increased (P < 0.01) the serum levels of interleukin-6 (IL-6), interleukin-1beta (IL-1β), tumor necrosis factor-alpha (TNF-α), alanine aminotransferase (ALT) and aspartate aminotransferase (AST), and decreased (P < 0.01) the interleukin-10 (IL-10) level. TA attenuated (P < 0.01) these increases in IL-1β, TNF-α, ALT, and AST levels and improved (P < 0.01) the IL-10 level. In liver, the groups fed with TA had lower (P < 0.01) concentrations of IL-6 and TNF-α as well as higher (P < 0.05) concentration of IL-10. Furthermore, TA downregulated (P < 0.05) the mRNA expression levels of nuclear factor kappa B p65 ( NF-κB p65 ) and TNF-α , also upregulated (P < 0.05) IL-10 and inhibitor of NF-κB alpha ( IκBα ) upon LPS challenge. In protein level, supplementation of 600 mg/kg of TA downregulated (P < 0.05) and upregulated (P < 0.05) the protein expression of NF-κB p65 and IκBα, respectively. The present findings suggest that TA could alleviate the acute liver inflammation induced by LPS via blocking the activation of NF-κB and the 600 mg/kg of TA plays more fruitful role in protecting broilers against LPS stimulus. [ABSTRACT FROM AUTHOR]

The machining precision plays an important role in the operation reliability and service life of screw rotors. However, the actual machined rotor profile of screw rotors is different from its theoretical profile due to the errors of the machine tool. This paper proposes a novel method of error tracing and compensation to reduce the machined errors of rotor profile on the basis of the limited sample trials, and the method is based on a matrix of error compensation. The errors of rotor profile are obtained based on limited sample trials machining of screw rotors,and fitted into piecewise smooth data. A matrix of error compensation is established to compute the errors of rotor profile to generate a compensated rotor profile. The compensated rotor profile is then used to regenerate forming tool and a new rotor product is processed on the same machine tool. And the errors of new rotor profile are smaller and can be reduced within (−0.01 mm, 0.01 mm) after compensations. Finally, the actual machining examples illustrate that the method of error compensation can not only satisfy the machining requirement of high-precision rotors, but also has the characteristics of good stability and applicability. [ABSTRACT FROM AUTHOR]

Interaction of process and machine in grinding of hard and brittle materials such as cemented carbide may cause dynamic instability of the machining process resulting in machining errors and a decrease in productivity. Commonly, the process and machine tools were dealt with separately, which does not take into consideration the mutual interaction between the two subsystems and thus cannot represent the real cutting operations. This paper proposes a method of modeling and simulation to understand well the process-machine interaction in grinding process of cemented carbide indexable inserts. First, a virtual grinding wheel model is built by considering the random nature of abrasive grains and a kinematic-geometrical simulation is adopted to describe the grinding process. Then, a wheel-spindle model is simulated by means of the finite element method to represent the machine structure. The characteristic equation of the closed-loop dynamic grinding system is derived to provide a mathematic description of the process-machine interaction. Furthermore, a coupling simulation of grinding wheel-spindle deformations and grinding process force by combining both the process and machine model is developed to investigate the interaction between process and machine. This paper provides an integrated grinding model combining the machine and process models, which can be used to predict process-machine interactions in grinding process. [ABSTRACT FROM AUTHOR]

[Display omitted] • The generation of OH in the presence of iron oxides and AA was quantified. • The formed OH showed the largest concentration at pH 7.0. • Coexistence of MnO 2 reduced the OH amount in iron oxide/AA systems. • OH was not detected in AA/β-MnO 2 system due to the H 2 O 2 limitation. The interaction between iron oxides and ascorbic acid (AA) normally leads to the degradation of organic pollutants by inducing the generation of hydroxyl radical (OH). However, the influence of different iron oxides on such processes is poorly understood. Moreover, a more complex but very common scenario in real environment is the coexistence of iron oxides with other reactive minerals (e.g., MnO 2), while the underlying mechanism of the interplay of different reactive minerals is still unclear, and knowledge of how the participation of MnO 2 impacts OH generation and pollutant transformation in iron oxides/AA system is an unsolved problem. This study quantified the yields of OH in three iron oxide/AA systems and the transformation of bisphenol A (BPA). We found that AA greatly promoted electron-transfer and OH production on iron oxides, and the OH concentrations were 0.42 mM, 0.24 mM, and 0.08 mM in FeOOH, Fe 2 O 3 , and Fe 3 O 4 systems, respectively. In addition, coexistence of β-MnO 2 inhibited BPA transformation by decreasing OH concentration to 0.19 mM in FeOOH/AA system. This is because β-MnO 2 strongly competed for AA species against FeOOH. In β-MnO 2 system the generated H 2 O 2 was very limited in spite of the greater reaction rate, and consequently almost no OH was detected. Interestingly, AA enhanced O 2 − production while interacting with MnO 2. Accordingly, the reaction mechanism for the interaction between β-MnO 2 and AA involving reactive oxygen species (ROS) generation was achieved at the molecular level. This study elucidates the effect of environmental factors on the ROS formation by Fe/Mn oxides, and provides a theoretical basis for understanding realistic environmental processes. [ABSTRACT FROM AUTHOR]

• A modified contact detection judgment in MPM for coining process is proposed. • The improved method overcomes small time step and abnormal termination of simulation. • The proposed method avoids virtual contact distance and obtains fine patterns. • The novel method reduces amount of data storage and computations. • Predicted insufficient filling agrees well with experimental result. [Display omitted] Extremely small time step caused by large deformation in coining process significantly increases computational time in dynamic explicit finite element method (FEM). Furthermore, negative volumes of distortion elements in the rim of coin lead to abnormal termination of simulation. In order to overcome these problems, dynamic explicit material point method (MPM) is employed for coining process. However, most of the point-to-point contact algorithms in MPM cause fake contacting detection. In addition, abundant tiny patterns on die surfaces put forward high requirement for the contact algorithm to calculate the normal vectors. A point-to-segment based contact algorithm is proposed to obtain accurate normal vectors at real physical contact point and embedded into the framework of modified update stress last (MUSL) for simulating coining. Amount of data storage and computations are reduced since the background domain only contains the deformable workpiece and one velocity field is required. The improved MPM is applied to predict insufficient filling during minting, and its performance is validated by experimental results. [ABSTRACT FROM AUTHOR]