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Abstract Background For decades, KRAS has always been a huge challenge to the field of drug discovery for its significance in cancer progression as well as its difficulties in being targeted as an “undruggable” protein. KRAS regulates downstream signaling pathways through protein–protein interactions, whereas many interaction partners of KRAS remain unknown. Results We developed a workflow to computationally predict and experimentally validate the potential KRAS-interacting proteins based on the interaction mode of KRAS and its known binding partners. We extracted 17 KRAS-interacting motifs from all experimentally determined KRAS-containing protein complexes as queries to identify proteins containing fragments structurally similar to the queries in the human protein structure database using our in-house protein–protein interaction prediction method, PPI-Miner. Finally, out of the 78 predicted potential interacting proteins of KRAS, 10 were selected for experimental validation, including BRAF, a previously reported interacting protein, which served as the positive control in our validation experiments. Additionally, a known peptide that binds to KRAS, KRpep-2d, was also used as a positive control. The predicted interacting motifs of these 10 proteins were synthesized to perform biolayer interferometry assays, with 4 out of 10 exhibiting binding affinities to KRAS, and the strongest, GRB10, was selected for further validation. Additionally, the interaction between GRB10 (RA-PH domain) and KRAS was confirmed via immunofluorescence and co-immunoprecipitation. Conclusions These results demonstrate the effectiveness of our workflow in predicting potential interacting proteins for KRAS and deepen the understanding of KRAS-driven tumor mechanisms and the development of therapeutic strategies.

Abstract Respiratory disease caused by coronavirus infection remains a global health crisis. Although several SARS-CoV-2-specific vaccines and direct-acting antivirals are available, their efficacy on emerging coronaviruses in the future, including SARS-CoV-2 variants, might be compromised. Host-targeting antivirals provide preventive and therapeutic strategies to overcome resistance and manage future outbreak of emerging coronaviruses. Cathepsin L (CTSL) and calpain-1 (CAPN1) are host cysteine proteases which play crucial roles in coronaviral entrance into cells and infection-related immune response. Here, two peptidomimetic α-ketoamide compounds, 14a and 14b, were identified as potent dual target inhibitors against CTSL and CAPN1. The X-ray crystal structures of human CTSL and CAPN1 in complex with 14a and 14b revealed the covalent binding of α-ketoamide groups of 14a and 14b to C25 of CTSL and C115 of CAPN1. Both showed potent and broad-spectrum anticoronaviral activities in vitro, and it is worth noting that they exhibited low nanomolar potency against SARS-CoV-2 and its variants of concern (VOCs) with EC50 values ranging from 0.80 to 161.7 nM in various cells. Preliminary mechanistic exploration indicated that they exhibited anticoronaviral activity through blocking viral entrance. Moreover, 14a and 14b exhibited good oral pharmacokinetic properties in mice, rats and dogs, and favorable safety in mice. In addition, both 14a and 14b treatments demonstrated potent antiviral potency against SARS-CoV-2 XBB 1.16 variant infection in a K18-hACE2 transgenic mouse model. And 14b also showed effective antiviral activity against HCoV-OC43 infection in a mouse model with a final survival rate of 60%. Further evaluation showed that 14a and 14b exhibited excellent anti-inflammatory effects in Raw 264.7 mouse macrophages and in mice with acute pneumonia. Taken together, these results suggested that 14a and 14b are promising drug candidates, providing novel insight into developing pan-coronavirus inhibitors with antiviral and anti-inflammatory properties.

In order to improve the surface quality of zirconia ceramic workpieces, the magnetic compound fluid polishing tool were utilized. This was done to lessen the material's surface roughness, minimize surface and subsurface damage. With a focus on the effects of magnet speed, processing gap, and abrasive particle size in the polishing fluid on surface roughness and material removal rate, a 3-factor, 3-level orthogonal test was created using Taguchi's method. The weights of each factor on the two evaluation indices were then analyzed using ANOVA. The best process parameter combination for surface roughness was 300 r/min for the magnet speed, 0.5 mm for the processing gap, and 1.25 μm for the abrasive particle size; the best process parameter combination for material removal rate was 400 r/min for the magnet speed, 0.5 mm for the processing gap, and 2 μm for the abrasive particle size. With these processing parameters, the surface roughness can reach up to 4.5 nm, and the material removal rate can reach up to 0.117 μm/min. The optimization effect is significant. The polishing prediction model was developed using a BP neural network that has been genetic algorithm optimized. The prediction error was 3.948 4%.

Abstract 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.

The effects of different processing methods on the nutritional components of sea cucumber (Apostichopus japonicus) are of concern to consumers who select sea cucumber products. This study employed liquid chromatography tandem mass spectrometry to examine the metabolites in fresh, unsoaked salted, soaked salted, and instant sea cucumber body wall samples sourced from Dalian, China. Metabolites were evaluated utilizing partial least squares discriminant analysis (PLS-DA) and subsequently subjected to KEGG metabolic pathway analysis for further investigation. PLS-DA effectively discriminated the body wall metabolites of sea cucumbers obtained via various processing techniques. The differential metabolites identified predominantly encompassed amino acids, lipids, and carbohydrates. Subsequent KEGG metabolic pathway analysis demonstrated a significant association between lipid, carbohydrate, and amino acid metabolism and the specific processing methods employed. The assessment of nutritional differences corresponding to the various A. japonicus processing methods was conducted. The findings of this study can assist in the choice of sea cucumber products and the selection of suitable processing methods.

This paper explores the integration of eco-friendly materials in clothing design to maintain high-quality and aesthetically pleasing interior clothing design. Texture, as a fundamental element in images, reveals surface characteristics and aids in visual interpretation. The paper introduces an enhanced DCNN-based algorithm for extracting texture features from clothing materials. The algorithm addresses the limitation of moment invariants by combining them with boundary direction characteristics, enhancing its ability to capture shape and spatial distribution information across the entire image. Experimental results validate the algorithm’s effectiveness in image analysis and the extraction of apparel material texture features. Applying environmental design principles to the apparel design domain, this study offers a novel perspective on sustainable clothing design. Overall, the paper emphasizes the importance of using eco-friendly materials in clothing design for a better future.

The rational design of PROTACs is difficult due to their obscure structure-activity relationship. Here the authors present a deep neural network model - DeepPROTACs - for predicting the degradation capacity of a proposed PROTAC molecule.

ABSTRACT: 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.

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.

Introduction: 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. Objectives: 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. Methods: 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. Results: 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. Conclusion: The research provided credible clew that inhibition of PDE4 by arctigenin might function as the potential therapeutic approach for the treatment of psoriasis.

ABSTRACT: 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.

Apostichopus japonicas is an economically important species with high nutritional value. However, our knowledge of its genetic diversity and the genetic changes that occurred during its domestication or trait selection is quite limited. In this study, the whole genomes of 254 A. japonicas samples were resequenced. Analyses of the population genetic structure revealed that the genetic diversity of A. japonicas in the north of China is generally high, there was no difference in the population structure among the six cultured populations, and they were divided into two subpopulations together with AY-1 (new species). The results also showed that the genetic diversity of the AY-1 population was relatively low, the degree of linkage of alleles was high, and this population had been subjected to more positive selection. Based on Tajima’s D, FST analysis, and ROD analysis, the selected intervals and genes of the AY-1 population were identified, with some of the candidate intervals being related to an economically important trait and breeding target, namely, the number of parapodia. Gene Ontology analysis of the candidate genes revealed that the two subpopulations differed in their immune function, protein synthesis, decomposition, and transport, among others. Using GWAS, we identified 39 candidate genes for four economically important traits of A. japonicas, and we verified that those genes contained non-synonymous SNPs. Through this verification, BSL78_00022 and BSL78_00023 were found to be key genes for the number of parapodia in A. japonicas. Of these two genes, BSL78_00022 encodes a protein related to cell differentiation and proliferation, so it was assumed that three non-synonymous substitutions (Ser-Phe, Glu-Asp, and Ala-Val) in this gene are related to the changes in the number of parapodia. Meanwhile, the pleiotropic gene BSL78_04631, which is related to body weight and body wall weight, and promotes protein synthesis and cell growth, has a non-synonymous substitution (IlE-Val), which is assumed to be the reason for the difference in body weight and body wall weight of A. japonicas. These results provide a new perspective for explaining the genetic structure characteristics of A. japonicas and analyzing the selection and economically important traits in the breeding of new species.

In the context of global warming and continuous high temperatures in the northern part of China during summer, the mortality rate of our main breeding species, Strongylocentrotus intermedius, reached 80% in 2020. How sea urchins respond to high temperatures is of great concern to academia and industry. In this study, we examined the antioxidant enzyme activities of different color tube-footed sea urchins under heat stress and compared their transcriptome and microRNA (miRNA) profiles using RNA-Seq. The results showed that the antioxidant enzyme activities of sea urchins were altered by thermal stress, and the changes in peroxidase activities of red tube-footed sea urchins were particularly significant. Investigations revealed that 1,079 differentially expressed genes (DEGs), 11 DE miRNAs, and 104 “DE miRNA-DEG” pairs in total were detected in sea urchins under high temperature stress. Several mRNA and miRNAs were significantly changed (e.g. HSP70, DnaJ11, HYAL, CALR, miR-184-p5, miR-92a, miR-92c, and miR-124-p5), suggesting these genes and miRNAs exerted important functions in response to high temperature. At the transcriptional level, red tube-footed sea urchins were found to be more sensitive to high temperature and could respond to high temperature rapidly. DE miRNA-mRNA network showed that miR-92b-3p and PC-5p-7420 were the most corresponding miRNAs. Five mRNAs (DnaJ11, SAR1B, CALR, HYOU1, TUBA) may be potential markers of sea urchin response to high temperature. Possible interaction between miRNA-mRNA could be linked to protein folding in the endoplasmic reticulum, Phagosomes, and calcium transport. This study provides a theoretical basis for the molecular mechanism of sea urchin heat tolerance and information that will aid in the selection and breeding of sea urchins with high temperature tolerance.

Strongylocentrotus intermedius is an economically valuable sea urchin species in China. However, its growth and survival are severely constrained by ocean warming and the hypoxia that often accompanies high water temperatures. MicroRNAs (miRNAs) are important regulators of gene expression in response to environmental change. In this study, high-throughput RNA sequencing was used to investigate changes in miRNA expression in S. intermedius under heat (25°C), hypoxia (2 mg/L O2), and combined heat and hypoxia stresses. Twelve small RNAs libraries were constructed and 17, 14, and 23 differentially expressed miRNAs (DEMs) were identified in the heat, hypoxia, and combined stress groups (P

Ultra-thin sapphire wafer processing is receiving increasing attention in the LED substrate industry. In the cascade clamping method, the motion state of the wafer determines the uniformity of material removal, while the motion state of the wafer is related to its friction coefficient in the biplane processing system, but there is little relevant literature discussing the relationship between the motion state of wafer and friction coefficient. In this study, an analytical model of the motion state of sapphire wafers in the layer-stacked clamping process based on the frictional moment is established, the effect of each friction coefficient on its motion is discussed, the base plate of different materials and different roughness are experimentally studied, the layer-stacked clamping fixture is prepared in this way, and finally the failure form of the limiting tab is analyzed experimentally. The theoretical analysis shows that the sapphire wafer is mainly driven by the polishing plate, while the base plate is mainly driven by the holder, and the rotation speed of the two is not the same; the material of the base plate of the layer-stacked clamping fixture is stainless steel, the material of the limiter is glass fiber plate, and the main form of failure of the limiter is to be cut by the edge of the sapphire wafer and damage the material structure.

In the grinding process, the friction energy generated by grains and the workpiece in the grinding zone will affect the service life of the grinding wheel. Ultrasonic-vibration-assisted grinding (UVAG) can reduce the friction force and reduce the generation of friction energy during grinding. In this work, the wear mechanism of grinding wheels in UVAG is discussed in detail from the perspective of the grain grinding trajectory and tribology. The results show that UVAG has a smaller friction force than conventional grinding (CG). Furthermore, when the initial included angles of grains are 90° and 150°, the friction energy of a single grinding surface in UVAG is reduced by 24% and 37% compared with that of CG, respectively. In UVAG, the grains are prone to microfractures, and the self-sharpening ability of the grinding wheel is enhanced, which can obtain a lower grinding force and better grinding surface quality.

COVID-19, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is still an emergent pandemic for humans. The virus infection is achieved by penetrating its spike protein to host cells via binding with ACE2. Moreover, recent studies show that SARS-CoV-2 may have multiple receptors that need to be further revealed. SARS-CoV-2 shares similar sequences of the spike protein with the Middle East Respiratory Syndrome Coronavirus (MERS-CoV), which can invade host cells by binding to either DPP4 or sialic acids. Sialic acids can be linked to the terminal of glycoproteins and gangliosides are used as one of the receptors of many types of viruses. Therefore, it is very interesting to determine whether sialic acid is a potential receptor of SARS-CoV-2. To address this question, we took N-Acetylneuraminic acid (Neu5Ac), a type of predominant sialic acid found in human cells, as the molecular probe to computationally search the surface of the spike protein to locate the potential binding sites of Neu5Ac. SPR analysis and mass spectrum analysis confirmed the interaction between Neu5Ac and spike protein. This study shows that sialic acids can moderately interact with the spike protein of SARS-CoV-2 by binding between the two RBDs of the spike protein, indicating it could be a potential secondary or auxiliary receptor of SARS-CoV-2.

The grinding force is the most sensitive physical measure of reaction loads in the grinding process. To enhance surface quality and assure high efficiency and stability of the grinding process, it is essential to accomplish adaptive control of the grinding force. This paper suggests a grinding force adaptive control system based on spindle motor power feedback, considering the process–machine interaction. The spindle motor power is utilized as a proxy for the grinding force because of the mapping relationship between the two variables. The machine tool’s feed rate is automatically modified to achieve adaptive control of the grinding force, after assessing the discrepancy between the collected spindle motor power and the preset power. Finally, a cemented carbide tool grinding experiment was performed on a 2MZK7150 CNC tool grinder. During the experiment, the grinding force was precisely controlled between 80 and 100 N, ensuring machining quality and increasing machining efficiency. The experimental results show that the adaptive control system can meet the high-efficiency and high-quality machining requirements of cemented carbide rotary blades.

Elliptical elements are essential optical surfaces for modifying optical systems. For polishing the whole elliptical surface using doughnut-shaped MCF polishing tool with variable tilt angle, an experimental investigation was conducted in this work. Firstly, a flat workpiece was polished to determine the polishing feasibility. It was found that the middle portion of the polishing tool had optimal ability to remove materials, and the surface roughness Sa at the material removal peak was changed from 134 nm to 17.5 nm within 50 min of polishing. A smoother surface could be obtained using MCF2 slurry and MCF3 slurry, but the use of MCF1 slurry resulted in a rough surface. Then, the effects of working gap h, revolution speed of MCF polishing tool and polishing time on the polishing results were tested to study the polishing characteristics. Sa 9.6 nm and glossiness 278 Gu were obtained, and form error improved from 2.3 μm to 1.3 μm. Finally, the MCF polishing tool was dried to observe the microstructure of the MCF polishing tool after polishing. Abrasive particles were distributed evenly after polishing. It was seen that the abrasive particles were grabbed by the ferric clusters, and the α-celluloses were interleaved between the clusters.

Image semantic segmentation has great development in many fields, and the lack of fully supervised segmentation labels has always been a major problem in the development of image semantic segmentation. In this paper, we propose a WAILS method to solve this problem. First, the image is coarsely segmented through a weakly supervised network at the image level. Second, to further obtain the shape of the target in the image, the watershed algorithm is used to refine the result of the coarse segmentation. Third, this refined image is used as a label for the first round of training of a fully supervised image semantic segmentation network. At last, the results are refined through the watershed as the label of the second round of fully supervised training and then it iterates. This method achieves the pixel-level semantic segmentation only through image-level labels and watershed pre-segmentation. Our method achieved good performance on the PASCAL 2012 dataset and the COCO dataset, while its segmentation accuracy surpasses all current weakly supervised semantic segmentation models in the category of bird, airplane, sheep, and so on.

Summary: Hsp90 is a target for anti-cancer drug development. Both the conformational events tuned by ATP/ADP and co-chaperones and the chaperoning cycle timing are required for Hsp90's fully functional display. Interfering with either one of the conformational events or the cycle timing will down-regulate Hsp90's function. In this manuscript, non-covalent allosteric modulators (SOMCL-16-171 and SOMCL-16-175) targeting Hsp90α’s middle domain (Hsp90M) were developed for the first time. Multiple techniques were then applied to characterize the interactions between two active compounds and Hsp90α. Two loops and one α-helix (F349-N360, K443-E451, and D372-G387) in Hsp90M were identified responsible for the recognition of SOMCL-16-171 and SOMCL-16-175. Meanwhile, the binding of SOMCL-16-171 and SOMCL-16-175 to Hsp90M was demonstrated to allosterically modulate the structure and function of Hsp90α’s N-terminal domain. Finally, cellular assays were conducted to evaluate the cellular activity of SOMCL-16-175, and the results indicate that SOMCL-16-175 destabilizes Hsp90's client proteins and reduces cell viability. : Molecular Biology; Molecular Structure; Cancer Subject Areas: Molecular Biology, Molecular Structure, Cancer

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.

A novel milling force model for cutting aviation aluminum alloy 7075 using carbide end mill is established in this article. A two-dimensional end-milling model is set up to investigate the influence of tool geometric parameters on milling force with the single-factor analysis. The relationship between milling forces and tool geometric parameters is obtained by nonlinear regression fitting method. Based on the existing empirical model of milling force, quadratic polynomial factor is taken into consideration to explore the influence of tool geometric parameters on milling force. Thus, a novel milling force model is built up which includes tool geometric parameters and milling parameters. The coefficients of the novel model are identified by the direct method and the loop method. The precisions of the coefficients obtained by the two methods are compared between prediction values and experiment values. After comparison, the model whose coefficients are obtained by loop method has higher prediction ability. End-milling experiments were carried out to verify the prediction accuracy of the novel milling force model. The result shows that the novel model of milling force has high accuracy in prediction. The method of building the milling force model proposed in this article can be applied to other types of milling cutter.

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.

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.