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Chemoresistance is one of the difficulties in the treatment of colorectal cancer (CRC), and the enhanced stemness of tumor cells is the underlying contributing factor. Leucine-rich repeat-containing G-protein-coupled receptor 5 (LGR5) is a classical marker of CRC stem cells and can be an important potential target for CRC chemotherapy. Quinoa, a protein-rich plant, offers potential as a source of high-quality active peptides. Novelly, the study obtained quinoa protein hydrolysate (QPH) from whole quinoa grains by simulated digestion. In vivoexperiments revealed that the tumor volume in the 5-FU+QPH group decreased from 145.90 ± 13.35 to 94.49 ± 13.05 mm3in the 5-FU group, suggesting that QPH enhances the chemosensitivity of CRC. Further, the most effective peptide QPH-FR from 631 peptides in QPH was screened by activity prediction, molecular docking, and experimental validation. Mechanistically, QPH-FR competitively suppressed the formation of the LGR5/RSPO1 complex by binding to LGR5, causing RNF43/ZNRF3 to ubiquitinate the FZD receptor, thereby suppressing the Wnt/β-catenin signaling pathway and exerting stemness inhibition. In summary, the study proposes that a novel peptide QPH-FR from quinoa elucidates the mechanism by which QPH-FR targets LGR5 to enhance chemosensitivity, providing theoretical support for the development of chemotherapeutic adjuvant drugs based on plant peptides.

Exploring the drawdown and dispersion behaviors of particles in stirred tanks can provide insights and valuable references for optimizing the design of equipment and improving the efficiency of the stirring process. In this article, the kinetic behaviors of drawdown and dispersion of floating particles in the stirred tank were simulated by the DEM-VOF (discrete element method–volume of fluid) model. The influences of impeller parameters (blade number n, rotation speed w, eccentric distance l, and off-bottom clearance h) on the granular characteristics (particle distribution, coupling force, total force, and translational/rotational kinetic energies), fluid dynamics (fluid velocity and turbulent kinetic energy), and gas–liquid free surface were investigated. The results show that the drawdown process of floating particles can be divided into the pull-down stage, dispersion stage, and cycle stage. With the increase in n, w, l, or h, the duration of the pull-down stage decreases, while the duration of the cycle stage increases. Due to the vortex effect and turbulent motion in the stirred tank, both the particle characteristics and flow dynamics change with the impeller parameters. Besides, large nor w, small l, and moderate hresult in the deeper gas–liquid free surface.

A lack of eco-friendly, highly active photocatalyst for peroxymonosulfate (PMS) activation and unclear environmental risks are significant challenges. Herein, we developed a double S-scheme Fe2O3/BiVO4(110)/BiVO4(010)/Fe2O3photocatalyst to activate PMS and investigated its impact on wheat seed germination. We observed an improvement in charge separation by depositing Fe2O3on the (010) and (110) surfaces of BiVO4. This enhancement is attributed to the formation of a dual S-scheme charge transfer mechanism at the interfaces of Fe2O3/BiVO4(110) and BiVO4(010)/Fe2O3. By introducing PMS into the system, photogenerated electrons effectively activate PMS, generating reactive oxygen species (ROS) such as hydroxyl radicals (·OH) and sulfate radicals (SO4·–). Among the tested systems, the 20% Fe2O3/BiVO4/Vis/PMS system exhibits the highest catalytic efficiency for norfloxacin (NOR) removal, reaching 95% in 40 min. This is twice the catalytic efficiency of the Fe2O3/BiVO4/PMS system, 1.8 times that of the Fe2O3/BiVO4system, and 5 times that of the BiVO4system. Seed germination experiments revealed that Fe2O3/BiVO4heterojunction was beneficial for wheat seed germination, while PMS had a significant negative effect. This study provides valuable insights into the development of efficient and sustainable photocatalytic systems for the removal of organic pollutants from wastewater.

The atomic precision of sub-nanometer-sized metal nanoclusters makes it possible to elucidate the kinetics of metal nanomaterials from the molecular level. Herein, the size reduction of an atomically precise [Au23(CHT)16]−(HCHT = cyclohexanethiol) cluster upon ligand exchange with HSAdm (1-adamantanethiol) has been reported. During the 16 h conversion of [Au23(CHT)16]−to Au16(SR)12, the neutral 6e Au21(SR)15, and its 1e-reduction state, i.e. the 5e, cationic radical, [Au21(SR)15]+, are active intermediates to account for the formation of thermodynamically stable Au16products. The combination of spectroscopic monitoring (with UV–vis and ESI-MS) and DFT calculations indicates the preferential size-reduction on the corner Au atoms on the core surface and the terminal Au atoms on longer AunSn+1staples. This study provides a reassessment on the electronic state of the Au21structure and highlights the single electron transfer processes in cluster systems and thus the importance of the EPR analysis on the mechanistic issues.

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To reveal the relationship between tool geometries and process parameters in Powder Bed Fusion (PBF), discrete element method is utilized for numerical simulation of PBF. The powder bed flatness and coefficient of variation are proposed to evaluate the quality of the powder bed. Results indicate that the powder bed voidage increases with the increase in the gap height, the decrease in the velocity and the increase in the blade fillet radius. When the blade inclination angle decreased from 45° to 30° and the average powder diameter is decreased from 50 to 30 μm, the porosity of the powder bed is decreased by 3.47% and 8.19%, respectively. The voidages in PBF with blade, roller and blade-roller are 55.78%, 49.08% and 47.57%. When the gap height is higher than 0.15 mm, the voidage in case of roller is obviously smaller than that in case of blade. The optimized combination of the parameters and tool can improve the powder bed flatness by 4.29% and reduce the voidage and coefficient of variation by 0.77% and 2.26%.

The integration density of photonic integrated circuits (PICs) is significantly limited by the waveguide bend losses. Reducing waveguide losses by design of the geometry of waveguide bends is important for photonic integrated circuits. Currently, circular bend and Euler bend are the two most common bends used in bending waveguide designs. A modified n-adjustable bend is proposed for ultra-small radius (≤2 μm) by applying the widening width method to n-adjustable bends. Simulations and experiments indicate that the modified n-adjustable bends show excellent performances in bend loss when the radius is 0.5, 1.0, 1.5, and 2.0 μm. In the experiments, the reduction of measured bend loss was from 0.8197 dB/90° (Euler bend) to 0.0689 dB/90° (modified n-adjustable bend) when radius equals 1.0 μm, and from 0.1438 dB/90° (Euler bend) to 0.0167 dB/90° (modified n-adjustable bend) when radius equals 2.0 μm. The modified n-adjustable bends are potential candidates for waveguide components in ultra-compact photonic integrated circuits.

The simultaneous placement of different types of materials including polymers, ceramics, and metals, in their desired positions could be adopted to manufacture end-use devices/apparatuses with diverse functionalities and significantly reduce the fabrication cost and time. However, existing additive manufacturing (AM) approaches can only treat one material species at a time due to their intrinsic working mechanisms. Here we develop an AM manipulator for manufacturing a wide variety of material species, including polymers, ceramics, and metals, through a multifilament transport strategy assisted by laser power. The six-jaw manipulator contains three pairs of filament delivering/cutting systems for transporting diverse materials and a beam of tunable laser as the thermal source. The whole apparatus is integrated into a robotic manipulator to create a multifreedom manufacturing platform. With this innovation, products with multiple material species and desired complex geometries can be fabricated on demand. Furthermore, we synthesize a multimaterial (polymer/ceramic/metal) printed magnetoelectric pressure sensor that can convert applied mechanical forces to electricity and maintain efficiency even after undergoing 10000 cycles of pressure/recovery. With this multimaterial filament transport and laser manufacturing strategy, our AM manipulator exhibits promising application in the advanced manufacturing of embedded electronics, sensors, soft robotics, and customizable medical devices.

Target representations play an important role in performance improvement for Thermal Infrared tracking. To tackle this problem, we propose a Cross-Modal Distillation method to distill representations of the TIR modality from the RGB modality, which conducts on a large amount of unlabeled paired RGB-TIR data in a self-supervised way. Benefiting from the powerful model in the RGB modality, the cross-modal distillation can learn the TIR-specific representation for promoting TIR tracking. The proposed approach can be incorporated into different baseline trackers conveniently as a generic and independent component. In practice, three different approaches are explored to generate paired RGB-TIR patches with the same semantics for training in a self-supervised way. It is easy to extend to an even larger scale of unlabeled training data. Our tracker outperforms the baseline tracker by achieving an absolute gain of 2.3% Success Rate, 2.7% Precision, and 2.5% Norm Precision on published datasets, respectively.

Correlation filters with convolutional neural network (CNN) features have been successfully applied to visual tracking owing to their impressive combined capability for object representation. Unfortunately, further performance improvement is limited due to unwanted boundary effects of the circular structure. In this work, through an in‐depth study of the features’ characteristics, the authors propose a novel tracking strategy to achieve simultaneous filter matching and regularization with CNN features when tracking is on the fly. With a feature decomposed transform matrix, a spatial semantic regularization is generated to reduce the boundary effect effectively during filter optimization. Before each output, the regularized filter is then back performed to match with the extracted features of a search region to find the optimum candidate. Specifically, the most important advantage of the proposed spatial semantic map is to initialize only in the first frame as all the other tracking strategies. Besides, the authors design a novel updating strategy to tackle the cases where the object is occluded or disappeared in the scene. At this time, the maximum of the map is small, even negative. A substantial experiment has been carried out on the popular benchmark tracking datasets; the reliable results have demonstrated that the authors’ method is able to outperform most of the state‐of‐the‐art tracking works in both accuracy and robustness.

Physical exercise is generally beneficial to all aspects of human and animal health, slowing cognitive ageing and neurodegeneration1. The cognitive benefits of physical exercise are tied to an increased plasticity and reduced inflammation within the hippocampus2–4, yet little is known about the factors and mechanisms that mediate these effects. Here we show that ‘runner plasma’, collected from voluntarily running mice and infused into sedentary mice, reduces baseline neuroinflammatory gene expression and experimentally induced brain inflammation. Plasma proteomic analysis revealed a concerted increase in complement cascade inhibitors including clusterin (CLU). Intravenously injected CLU binds to brain endothelial cells and reduces neuroinflammatory gene expression in a mouse model of acute brain inflammation and a mouse model of Alzheimer’s disease. Patients with cognitive impairment who participated in structured exercise for 6 months had higher plasma levels of CLU. These findings demonstrate the existence of anti-inflammatory exercise factors that are transferrable, target the cerebrovasculature and benefit the brain, and are present in humans who engage in exercise.

ABSTRACTAs one of the common post-transcriptional modifications in tRNAs, dihydrouridine (D) has prominent effects on regulating the flexibility of tRNA as well as cancerous diseases. Facing with the expensive and time-consuming sequencing techniques to detect D modification, precise computational tools can largely promote the progress of molecular mechanisms and medical developments. We proposed a novel predictor, called iRNAD_XGBoost, to identify potential D sites using multiple RNA sequence representations. In this method, by considering the imbalance problem using hybrid sampling method SMOTEEEN, the XGBoost-selected top 30 features are applied to construct model. The optimized model showed high Snand Spvalues of 97.13% and 97.38% over jackknife test, respectively. For the independent experiment, these two metrics separately achieved 91.67% and 94.74%. Compared with iRNAD method, this model illustrated high generalizability and consistent prediction efficiencies for positive and negative samples, which yielded satisfactory MCCscores of 0.94 and 0.86, respectively. It is inferred that the chemical property and nucleotide density features (CPND), electron-ion interaction pseudopotential (EIIP and PseEIIP) as well as dinucleotide composition (DNC) are crucial to the recognition of D modification. The proposed predictor is a promising tool to help experimental biologists investigate molecular functions.

Background: RNA-binding proteins establish posttranscriptional gene regulation by coordinating maturation, editing, transport, stability, and translation of cellular RNAs. Immunoprecipitation experiments could identify the interaction between RNA and proteins, but they are limited due to the experimental environment and material. Therefore, it is essential to construct computational models to identify the function sites. Objective: Although some computational methods have been proposed to predict RNA binding sites, the accuracy could be further improved. Moreover, it is necessary to construct a dataset with more samples to design a reliable model. Here we present a computational model based on multi-information sources to identify RNA binding sites. Methods: We construct an accurate computational model named CSBPI_Site, based on extreme gradient boosting. The specifically designed 15-dimensional feature vector captures four types of information (chemical shift, chemical bond, chemical properties and position information). Results: The satisfied accuracy of 0.86 and AUC of 0.89 were obtained by leave-one-out crossvalidation. Meanwhile, the accuracies were slightly different (range from 0.83 to 0.85) among the three classifiers algorithm, which showed that the novel features are stable and fit to multiple classifiers. These results showed that the proposed method is effective and robust for the identification of noncoding RNA binding sites. Conclusion: Our method based on multi-information sources is effective to represent the binding sites information among ncRNAs. The satisfied prediction results of Diels-Alder riboz-yme based on CSBPI_Site indicates that our model is valuable to identify the function site.

Chromatin undergoes extensive reprogramming during immune cell differentiation. Here we report the repression of controlled histone H3 amino terminus proteolytic cleavage (H3ΔN) during monocyte-to-macrophage development. This abundant histone mark in human peripheral blood monocytes is catalyzed by neutrophil serine proteases (NSPs) cathepsin G, neutrophil elastase and proteinase 3. NSPs are repressed as monocytes mature into macrophages. Integrative epigenomic analysis reveals widespread H3ΔN distribution across the genome in a monocytic cell line and primary monocytes, which becomes largely undetectable in fully differentiated macrophages. H3ΔN is enriched at permissive chromatin and actively transcribed genes. Simultaneous NSP depletion in monocytic cells results in H3ΔN loss and further increase in chromatin accessibility, which likely primes the chromatin for gene expression reprogramming. Importantly, H3ΔN is reduced in monocytes from patients with systemic juvenile idiopathic arthritis, an autoinflammatory disease with prominent macrophage involvement. Overall, we uncover an epigenetic mechanism that primes the chromatin to facilitate macrophage development.

Lysine glutarylation is a newly reported post-translational modification (PTM) that plays significant roles in regulating metabolic and mitochondrial processes. Accurate identification of protein glutarylation is the primary task to better investigate molecular functions and various applications. Due to the common disadvantages of the time-consuming and expensive nature of traditional biological sequencing techniques as well as the explosive growth of protein data, building precise computational models to rapidly diagnose glutarylation is a popular and feasible solution. In this work, we proposed a novel AdaBoost-based predictor called iGlu_AdaBoost to distinguish glutarylation and non-glutarylation sequences. Here, the top 37 features were chosen from a total of 1768 combined features using Chi2 following incremental feature selection (IFS) to build the model, including 188D, the composition of k-spaced amino acid pairs (CKSAAP), and enhanced amino acid composition (EAAC). With the help of the hybrid-sampling method SMOTE-Tomek, the AdaBoost algorithm was performed with satisfactory recall, specificity, and AUC values of 87.48%, 72.49%, and 0.89 over 10-fold cross validation as well as 72.73%, 71.92%, and 0.63 over independent test, respectively. Further feature analysis inferred that positively charged amino acids RK play critical roles in glutarylation recognition. Our model presented the well generalization ability and consistency of the prediction results of positive and negative samples, which is comparable to four published tools. The proposed predictor is an efficient tool to find potential glutarylation sites and provides helpful suggestions for further research on glutarylation mechanisms and concerned disease treatments.

Major histocompatibility complex (MHC)-presented peptides (pMHC) give insight into T cell immune responses, a critical step toward developing a new generation of targeted immunotherapies. Recent instrumentation advances have propelled mass spectrometry to being arguably the most robust technology for discovering and quantifying naturally presented pMHC from cells and tissues. However, sample preparation has remained a major limitation due to time-consuming and labor-intensive workflows. We developed a high-throughput and automated platform with enhanced speed, sensitivity, and reproducibility relative to prior studies. This pipeline is capable of processing up to 96 samples in 6 h or less yielding high-quality pMHC mixtures ready for mass spectrometry. Here, we describe our efforts to optimize purification and mass spectrometer parameters, ultimately allowing us to identify as many as almost 5000 pMHC I and 7400 pMHC II from as little as 2.5 × 107Raji cells each. We believe that this platform will facilitate and accelerate immunopeptidome profiling and benefit clinical research for immunotherapies.

The vascular interface of the brain, known as the blood–brain barrier (BBB), is understood to maintain brain function in part via its low transcellular permeability1–3. Yet, recent studies have demonstrated that brain ageing is sensitive to circulatory proteins4,5. Thus, it is unclear whether permeability to individually injected exogenous tracers—as is standard in BBB studies—fully represents blood-to-brain transport. Here we label hundreds of proteins constituting the mouse blood plasma proteome, and upon their systemic administration, study the BBB with its physiological ligand. We find that plasma proteins readily permeate the healthy brain parenchyma, with transport maintained by BBB-specific transcriptional programmes. Unlike IgG antibody, plasma protein uptake diminishes in the aged brain, driven by an age-related shift in transport from ligand-specific receptor-mediated to non-specific caveolar transcytosis. This age-related shift occurs alongside a specific loss of pericyte coverage. Pharmacological inhibition of the age-upregulated phosphatase ALPL, a predicted negative regulator of transport, enhances brain uptake of therapeutically relevant transferrin, transferrin receptor antibody and plasma. These findings reveal the extent of physiological protein transcytosis to the healthy brain, a mechanism of widespread BBB dysfunction with age and a strategy for enhanced drug delivery.

Background: Gram-negative bacteria interact with their environment by secreting a wide range of particular substrates (such as proteins) across two lipid bilayers from the cytoplasm to the extracellular space. Determining the types of secreted proteins is beneficial for further research on secreted proteins and secretion systems. Objective: As an essential alternative for experimental methods, an accurate machine learningbased multi-type Gram-negative bacterial secreted protein prediction method was proposed in this study. Methods: The main contribution is combining auto-cross-correlation analysis and feature ranking technology to build an effective support vector machine-based multi-type Gram-negative bacterial secreted protein predictor. The specifically designed auto-cross-correlation descriptor can capture evolutionary correlation information between amino acid pairs along protein sequence from position specific scoring matrices. Feature ranking technique was used to analyze and select the most informative features for building prediction model. Results: Several kinds of prediction accuracies obtained by independent dataset test are reported on two benchmark datasets. Compared with the state-of-the-art prediction methods, the proposed method improves overall accuracies by 2.91% and 2.25%, respectively. Conclusion: Our study will provide an important guide to utilize protein evolutionary information for further research on bacterial secreted proteins.

Background: Amino acid physicochemical properties encoded in protein primary structure play a crucial role in protein folding. However, it is not yet clear which of the properties are the most suitable for protein fold classification. Objective: To avoid exhaustively searching the total properties space, an amino acid properties selection method was proposed in this study to rapidly obtain a suitable properties combination for protein fold classification. Methods: The proposed amino acid properties selection method was based on sequential floating forward selection strategy. Beginning with an empty set, variable number of features were added iteratively until achieving the iteration termination condition. Results: The experimental results indicate that the proposed method improved prediction accuracies by 0.26-5% on a widely used benchmark dataset with appropriately selected amino acid properties. Conclusion: The proposed properties selection method can be extended to other biomolecule property related classification problems in bioinformatics.

Intermittent hyperbaric oxygen exposure (IE-HBO) can protect the body against oxygen toxicity, but the underlying mechanisms are not very clear. Peroxiredoxin 6 (Prdx6) is a special endogenous antioxidative protein. We explored if the protective effects of IE-HBO are related to Prdx6. Mice were exposed to 280 kPa O2for 60 min, followed by 30-min exposure to 20% O2/N2mixture with equal pressure, repeated for six cycles. The Prdx6 protein level and non-selenium glutathione peroxidase (NSGPx) activity in the brain and lungs were then measured and the injury degree of lung and the oxidation level of brain and lung were evaluated. On this basis, the relationship between Prdx6 and IE-HBO’s protection was explored. Generally, both IE-HBO and continuous exposure to HBO (CE-HBO) could increase the protein and mRNA levels of Prdx6, and such increases were more significant 24 h after cessation of exposure; moreover, the Prdx6 level of IE-HBO was higher than that of CE-HBO in both brain and lung, also more significantly 24 h after cessation of exposure. In addition, IE-HBO exposure could more effectively potentiate the activity of NSGPx and increase GSH content in brain and lung tissues. At the same time, it could reduce oxidation products in these tissues. IE-HBO could also provide protection for the lungs against injuries resulting from prolonged HBO exposure. These data showed that IE-HBO can potentiate the production and the activity of Prdx6 and consequently mitigate oxidative damages in brain and lungs. The influences of IE-HBO on Prdx6 may form an important basis for its protection against oxygen toxicity.

Intermittent hyperbaric oxygen exposure (IE-HBO) can protect the body against oxygen toxicity, but the underlying mechanisms are not very clear. Peroxiredoxin 6 (Prdx6) is a special endogenous antioxidative protein. We explored if the protective effects of IE-HBO are related to Prdx6. Mice were exposed to 280 kPa O2for 60 min, followed by 30-min exposure to 20% O2/N2mixture with equal pressure, repeated for six cycles. The Prdx6 protein level and non-selenium glutathione peroxidase (NSGPx) activity in the brain and lungs were then measured and the injury degree of lung and the oxidation level of brain and lung were evaluated. On this basis, the relationship between Prdx6 and IE-HBO’s protection was explored. Generally, both IE-HBO and continuous exposure to HBO (CE-HBO) could increase the protein and mRNA levels of Prdx6, and such increases were more significant 24 h after cessation of exposure; moreover, the Prdx6 level of IE-HBO was higher than that of CE-HBO in both brain and lung, also more significantly 24 h after cessation of exposure. In addition, IE-HBO exposure could more effectively potentiate the activity of NSGPx and increase GSH content in brain and lung tissues. At the same time, it could reduce oxidation products in these tissues. IE-HBO could also provide protection for the lungs against injuries resulting from prolonged HBO exposure. These data showed that IE-HBO can potentiate the production and the activity of Prdx6 and consequently mitigate oxidative damages in brain and lungs. The influences of IE-HBO on Prdx6 may form an important basis for its protection against oxygen toxicity.

Endoscopic sphincterotomy is the established treatment for common bile duct stones. Balloon dilation offers an alternative. Prolonged dilation (300 s) with a 10 mm diameter balloon decreases the occurrence of pancreatitis after endoscopic retrograde cholangiopancreatography (ERCP). We aimed to determine the optimal duration of dilation for combined endoscopic sphincterotomy and balloon dilation for the removal of common bile duct stones.

ABSTRACTGrowth in the pharmaceutical industry has led to an increasing demand for rapid characterization of therapeutic monoclonal antibodies. The current methods for antibody sequence confirmation (e.g., N-terminal Edman sequencing and traditional peptide mapping methods) are not sufficient; thus, we developed a fast method for sequencing recombinant monoclonal antibodies using a novel digestion-on-emitter technology. Using this method, a monoclonal antibody can be denatured, reduced, digested, and sequenced in less than an hour. High throughput and satisfactory protein sequence coverage were achieved by using a non-specific protease from Aspergillus saitoi, protease XIII, to digest the denatured and reduced monoclonal antibody on an electrospray emitter, while electrospray high voltage was applied to the digestion mixture through the emitter. Tandem mass spectrometry data was acquired over the course of enzyme digestion, generating similar information compared to standard peptide mapping experiments in much less time. We demonstrated that this fast protein sequencing method provided sufficient sequence information for bovine serum albumin and two commercially available monoclonal antibodies, mouse IgG1 MOPC21 and humanized IgG1 NISTmAb. For two monoclonal antibodies, we obtained sequence coverage of 90.5–95.1% for the heavy chains and 98.6–99.1% for the light chains. We found that on-emitter digestion by protease XIII generated peptides of various lengths during the digestion process, which was critical for achieving sufficient sequence coverage. Moreover, we discovered that the enzyme-to-substrate ratio was an important parameter that affects protein sequence coverage. Due to its highly automatable and efficient design, our method offers a major advantage over N-terminal Edman sequencing and traditional peptide mapping methods in the identification of protein sequence, and is capable of meeting an ever-increasing demand for monoclonal antibody sequence confirmation in the biopharmaceutical industry.

Protein structural class prediction is beneficial to protein structure and function analysis. Exploring good feature representation is a key step for this prediction task. Prior works have demonstrated the effectiveness of the secondary structure based feature extraction methods especially for lowsimilarity protein sequences. However, the prediction accuracies still remain limited. To explore the potential of secondary structure information, a novel feature extraction method based on a generalized chaos game representation of predicted secondary structure is proposed. Each protein sequence is converted into a 20-dimensional distance-related statistical feature vector to characterize the distribution of secondary structure elements and segments. The feature vectors are then fed into a support vector machine classifier to predict the protein structural class. Our experiments on three widely used lowsimilarity benchmark datasets (25PDB, 1189 and 640) show that the proposed method achieves superior performance to the state-of-the-art methods. It is anticipated that our method could be extended to other graphical representations of protein sequence and be helpful in future protein research.

Green tea accounts for approximately 20% of the world’s total tea yield. (−)-Epigallocatechin gallate (EGCG) is an active catechin in green tea, which suppresses tumor growth and enhances drug sensitivity in various cancers, but the molecular mechanism is still unclear. Chemotherapy drugs, such as 5-fluorouracil (5-FU), are a common strategy for clinical treatment of cancer patients; however, the lower response rate caused by prolonged use becomes the main reason for tumor recurrence. Therefore, discovering a safe and effective chemo-sensitizer is an urgent task required to be solved. Here, we report that EGCG reinforces the sensitivity of colon cancer cells to 5-FU, and the IC50values of 5-FU is decreased from 40 ± 4.2 μM to 5 ± 0.36 μM in one human colon carcinoma cell line-HCT-116, and from 150 ± 6.4 μM to 11 ± 0.96 μM in the other human colon carcinoma cell line-DLD1 when these cells are cotreated with 50 μM EGCG. Consistently, compared to 5-FU or EGCG treatment alone, the combination of both significantly promotes cancer cell apoptosis and DNA damage. Further mechanism research reveals that treatment of colorectal cancer (CRC) with 50 μM EGCG inhibits GRP78 expression, activates the NF-κB (2.55 ± 0.05-fold for HCT-116 and 2.27 ± 0.08-fold for DLD1) pathway, and enhances miR-155-5p (2.12 ± 0.02-fold for HCT-116 and 2.01 ± 0.01-fold for DLD1) level. The elevated miR-155-5p strongly suppresses target gene MDR1 expression, which blocks the efflux of 5-FU. The accumulation of 5-FU resulted in caspase-3 and PARP activation, Bcl-2 reduction, and Bad increase, which ultimately lead to cancer cell apoptosis. Overall, our data show that EGCG may be act as a novel chemo-sensitizer, and the GRP78/NF-κB/miR-155-5p/MDR1 pathway plays a vital role in EGCG enhancing the sensitivity of colorectal cancer to 5-FU.

In the work by Zha et al.,1 the order of authorship should have appeared as follows:

Strongyloides stercoralisis an important soil-transmitted helminth occurring world-wide and affecting 30–100 million people. Because many cases are asymptomatic and sensitive diagnostic methods are lacking, S. stercoralisinfection is frequently underdiagnosed. The increasing incidence of autoimmune and wasting diseases and increased use of immunosuppressive agents, as well as the increased use of immunosuppressants and cytotoxic drugs, have increased S. stercoralisinfection and their mortality. This review provides information about S. stercoralisepidemiology, life cycle, aetiology, pathology, comorbidities, immunology, vaccines, diagnosis, treatment, prevention, control and makes some recommendations for future prevention and control of this important parasite.

Additive manufacturing (AM) technology enables the creation of a wide variety of assemblies and complex shapes from three-dimensional model data in a bottom-up, layer-by-layer manner. Therefore, AM has revolutionized the modern manufacturing industry, attracting increasing interest from both academic and industrial fields. The Rapid Manufacturing Center (RMC) of the School of Materials Science and Engineering at the Huazhong University of Science and Technology (HUST), one of the earliest and most powerful AM research teams in China, has been engaged in AM research since 1991. Aiming to address the “stuck neck” problems of specific high-strength products for AM, the RMC has conducted full-chain research in the aspects of special materials, processes, equipment, and applications for AM. Moreover, it has formed a multi-disciplinary research team over the past three decades. Relevant research achievements in the AM field include winning five national awards, more than ten first prizes, and more than ten second prizes at the provincial and ministerial levels. The RMC was complimented as “the world's most influential organization in the laser AM field in 2018” by Virtual and Physical Prototyping (an international authoritative magazine of AM). Moreover, their industrialization achievements were evaluated as “having affected countries such as Singapore, South Korea, and the United States” by an international authoritative Wohlers Report on AM. In this study, we first summarize the representative research achievements of the RMC in the AM field. These include the preparation and processing technology of high-performance polymeric, metallic, and ceramic materials for AM; advanced processing technology and software/equipment for AM; and typical AM-fabricated products and their applications. Further, we discuss the latest research achievements in cutting-edge 4D printing in terms of feedstock selection, printing processes, induction strategies, and potential applications. Finally, we provide insights into the future directions of AM technology development: (ⅰ) Evolving from three-dimensional printing to multi-dimensional printing, (ⅱ) transitioning from plane slicing to curved surface slicing to woven slicing, (ⅲ) enhancing efficient formation from dot-line-sheet-volume printing, (ⅳ) shifting from single material to multi-materials AM, (ⅴ) advancing from the multiscale direction of macroscopic–mesoscopic–microscopic structures, (ⅵ) integrating material preparation with forming integration, (ⅶ) expanding from small batch to large batch.

The combination of the dipping effect and hydromechanical (H-M) coupling effect can easily lead to water inrush disasters in water-rich roadways with different dip angles in coal mines. Therefore, H-M coupling tests of bedded sandstones under identical osmotic pressure and various confining pressures were conducted. Then, the evolution curves of stress-strain, permeability and damage, macro- and mesoscopic failure characteristics were obtained. Subsequently, the mechanical behaviour was characterized, and finally the failure mechanism was revealed. The results showed that: (1) The failure of the sandstone with the bedding angle of 45° or 60° was the structure-dominant type, while that with the bedding angle of 0°, 30° or 90° was the force-dominant type. (2) When the bedding angle was in the range of (0°, 30°) or (45°, 90°), the confining pressure played a dominant role in influencing the peak strength. However, within β∈(30°, 45°), the bedding effect played a dominant role in the peak strength. (3) With the increase in bedding angle, the cohesion increased first, then decreased and finally increased, while the internal friction angle was the opposite. (4) When the bedding angle was 0° or 30°, the “water wedging” effect and the “bedding buckling” effect would lead to the forking or converging shear failure. When the bedding angle was 45° or 60°, the sliding friction effect would lead to the shear slipping failure. When the bedding angle was 90°, the combination of the “bedding buckling” effect and shear effect would lead to the mixed tension-shear failure. The above conclusions obtained are helpful for the prevention of water inrush disasters in water-rich roadways with different dips in coal mines.

Background and Objective: Protein structural class prediction is a first and key step in protein structure prediction and has become an active research area in biochemistry and bioinformatics. An important aspect for this prediction task is exploring good feature representation. Prior works have demonstrated the effectiveness of the PSI-BLAST profile based feature extraction methods especially for low-similarity protein sequences. However, the prediction accuracies still remain limited. This highlights the need for keeping on exploring the potential of evolutionary information. Method: In this study, three novel sequence evolutionary modes of pseudo amino acid composition (PseAAC) are proposed and optimized by a two-stage feature selection process based on recursive feature elimination strategy. The selected top-ranking features are then fed into a linear kernel support vector machine classifier to predict the protein structure class. To evaluate the performance of the proposed method, jackknife tests are performed on three widely used low-similarity benchmark datasets (25PDB, 1189 and 640). Results: With comprehensive comparison with the current state-of-the-art methods, the proposed method achieves superior performance. The overall accuracies on 25PDB, 1189 and 640 datasets are 96.2%, 97.9% and 99.5%, which are 1.9%, 1.5% and 2.3% higher than previous best-performing method. Conclusion: The satisfactory prediction accuracies achieved by the proposed method are attributed to the specially designed sequence evolutionary modes of PseAAC and the effective feature selection strategy, which cover more discriminative sequence order information. It is anticipated that our method would be helpful in other prediction problems in protein research.

Plasmodiumparasites contain several unique membrane compartments in which prenylated proteins may play important roles in pathogenesis. Protein prenylation has also been proposed as an antimalarial drug target because farnesyltransferase inhibitors cause potent growth inhibition of blood-stage Plasmodium. However, the specific prenylated proteins that mediate antimalarial activity have yet to be identified. Given the potential for new parasite biology and elucidating drug mechanism-of-action, we performed a large-scale identification of the prenylated proteome in blood-stage P. falciparumparasites using an alkyne-labeled prenyl analog to specifically enrich parasite prenylated proteins. Twenty high-confidence candidates were identified, including several examples of pathogen-specific prenylation activity. One unique parasite prenylated protein was FYVE-containing coiled-coil protein (FCP), which is only conserved in Plasmodiumand related Apicomplexan parasites and localizes to the parasite food vacuole. Targeting of FCP to this parasite-specific compartment was dependent on prenylation of its CaaX motif, as mutation of the prenylation site caused cytosolic mislocalization. We also showed that PfRab5b, which lacks C-terminal cysteines that are the only known site of Rab GTPase modification, is prenylated. Finally, we show that the THQ class of farnesyltransferase inhibitors abolishes FCP prenylation and causes its mislocalization, providing the first demonstration of a specific prenylated protein disrupted by antimalarial farnesyl transferase inhibitors. Altogether, these findings identify prenylated proteins that reveal unique parasite biology and are useful for evaluating prenyltransferase inhibitors for antimalarial drug development.

Cancer somatic mutations can generate neoantigens that distinguish malignant from normal cells. However, the personalized identification and validation of neoantigens remains a major challenge. Here we discover neoantigens in human mantle-cell lymphomas by using an integrated genomic and proteomic strategy that interrogates tumour antigen peptides presented by major histocompatibility complex (MHC) class I and class II molecules. We applied this approach to systematically characterize MHC ligands from 17 patients. Remarkably, all discovered neoantigenic peptides were exclusively derived from the lymphoma immunoglobulin heavy- or light-chain variable regions. Although we identified MHC presentation of private polymorphic germline alleles, no mutated peptides were recovered from non-immunoglobulin somatically mutated genes. Somatic mutations within the immunoglobulin variable region were almost exclusively presented by MHC class II. We isolated circulating CD4+T cells specific for immunoglobulin-derived neoantigens and found these cells could mediate killing of autologous lymphoma cells. These results demonstrate that an integrative approach combining MHC isolation, peptide identification, and exome sequencing is an effective platform to uncover tumour neoantigens. Application of this strategy to human lymphoma implicates immunoglobulin neoantigens as targets for lymphoma immunotherapy.

AbstractElectrochemical oxidation of C.I. Acid Red 73 (AR 73) in aqueous solution is performed in an undivided cell using Ti/SnO2-Sb-CNT as anode. Cyclic voltammetric experiments suggest that electrochemical oxidation of AR 73 is totally irreversible and direct electron transfer does not occur on anode surface. The influence of operating parameters on the degradation efficiency is investigated systematically, including current density (25–100 mA cm−2), initial dye concentration (0.5–1.5 g L−1), initial pH (3–11), and different kinds of supporting electrolyte. The electrochemical degradation of AR 73 follows pseudo-first-order kinetics. The removal efficiency of AR 73 degradation increases from 78.3 to 95.7% with increased current density from 25 to 100 mA cm−2. The initial AR 73 concentration has a negative effect on degradation rates at higher value, and pH has no obvious effect on the dye removal rate. The comparative experiments using Na2SO4, NaCl, and Na3PO4as supporting electrolyte indicate that NaCl has the most significant effect on AR 73 degradation, but shows poor mineralization ability with only 51.5% removal rate of total organic carbon. The electrogenerated oxidant using Na2SO4supporting electrolyte also contributes the dye degradation and mineralization compared with Na3PO4. Samples during the electrochemical oxidation process are characterized with UV–vis spectra and high performance liquid chromatography. The results show that the AR 73 and intermediates formed during the degradation are both completely removed after 3 h electrochemical oxidation. The electrochemical technique is expected to be an interesting alternative for the treatment of azo dye in wastewater.

Electrochemical oxidation of C.I. Acid Red 73 (AR 73) in aqueous solution is performed in an undivided cell using Ti/SnO2-Sb-CNT as anode. Cyclic voltammetric experiments suggest that electrochemical oxidation of AR 73 is totally irreversible and direct electron transfer does not occur on anode surface. The influence of operating parameters on the degradation efficiency is investigated systematically, including current density (25–100 mA cm−2), initial dye concentration (0.5–1.5g L−1), initial pH (3–11), and different kinds of supporting electrolyte. The electrochemical degradation of AR 73 follows pseudo-first-order kinetics. The removal efficiency of AR 73 degradation increases from 78.3 to 95.7% with increased current density from 25 to 100 mA cm−2. The initial AR 73 concentration has a negative effect on degradation rates at higher value, and pH has no obvious effect on the dye removal rate. The comparative experiments using Na2SO4, NaCl, and Na3PO4as supporting electrolyte indicate that NaCl has the most significant effect on AR 73 degradation, but shows poor mineralization ability with only 51.5% removal rate of total organic carbon. The electrogenerated oxidant S2O82-using Na2SO4supporting electrolyte also contributes the dye degradation and mineralization compared with Na3PO4. Samples during the electrochemical oxidation process are characterized with UV–vis spectra and high performance liquid chromatography. The results show that the AR 73 and intermediates formed during the degradation are both completely removed after 3 h electrochemical oxidation. The electrochemical technique is expected to be an interesting alternative for the treatment of azo dye in wastewater.

Methodology for sequence analysis of ∼150 kDa monoclonal antibodies (mAb), including location of post-translational modifications and disulfide bonds, is described. Limited digestion of fully denatured (reduced and alkylated) antibody was accomplished in seconds by flowing a sample in 8 murea at a controlled flow rate through a micro column reactor containing immobilized aspergillopepsin I. The resulting product mixture containing 3–9 kDa peptides was then fractionated by capillary column liquid chromatography and analyzed on-line by both electron-transfer dissociation and collisionally activated dissociation mass spectrometry (MS). This approach enabled identification of peptides that cover the complete sequence of a murine mAb. With customized tandem MS and ProSightPC Biomarker search, we verified 95% amino acid residues of this mAb and identified numerous post-translational modifications (oxidized methionine, pyroglutamylation, deamidation of Asn, and several forms of N-linked glycosylation). For disulfide bond location, native mAb is subjected to the same procedure but with longer digestion times controlled by sample flow rate through the micro column reactor. Release of disulfide containing peptides from accessible regions of the folded antibody occurs with short digestion times. Release of those in the interior of the molecule requires longer digestion times. The identity of two peptides connected by a disulfide bond is determined using a combination of electron-transfer dissociation and ion–ion proton transfer chemistry to read the two N-terminal and two C-terminal sequences of the connected peptides.

Multifunctional components with various information such as material, structure, process, and performance have become viable and accessible to the industry due to the rapid growth of additive manufacturing (AM) technology from contour modeling to functional modeling. However, multi-information additive manufacturing requirements far outpaced the processing capabilities of current data processing systems to model and interpret multi-information digital models. This paper proposes a field-driven processing paradigm with the ability to describe and parse complex, multi-information distributions. The robustness and flexibility of field-driven design are fully exploited by uniformly converting data including common AM models such as meshes, function formulas, and point clouds into control field representations and setting reasonable control-property mapping rules. The complexity of multi-information modeling is significantly reduced via a combined strategy of control fields and mapping relationships. A complete multi-information model only consists of initial data related to desired properties and corresponding mapping rules. Compared with the voxel method, the amount of data is reduced by more than 80%. The multi-information model is discretely parsed in different dimensions according to manufacturing requirements to efficiently and accurately generate property data for industrial manufacturing. Two representative multi-information demonstrators incorporating material-structure dual gradients and structure-process integration are designed and printed while 3 AM techniques are employed to validate the utility of this paradigm. The paradigm is anticipated to open up an efficient route for the realization of material-structure-process-property integrated AM.

Wheat (Triticum aestivum, BBAADD) is an allohexaploid species that originated from two polyploidization events. The progenitors of the A and D subgenomes have been identified as Triticum urartuand Aegilops tauschii, respectively. Current research suggests that Aegilops speltoidesis the closest but not the direct ancestor of the B subgenome. However, whether A. speltoideshas contributed genomically to the wheat B subgenome and which chromosome regions are conserved between A. speltoidesand the B subgenome remain unclear. Here, we assembled a high-quality reference genome for A. speltoides, resequenced 53 accessions from seven species (Aegilops bicornis, Aegilops longissima, Aegilops searsii, Aegilops sharonensis, A. speltoides, Aegilops mutica[syn. Amblyopyrum muticum], and Triticum dicoccoides) and revealed their genomic contributions to the wheat B subgenome. Our results showed that centromeric regions were particularly conserved between Aegilopsand Triticum and revealed 0.17 Gb of conserved blocks between A. speltoidesand the B subgenome. We classified five groups of conserved and non-conserved genes between Aegilopsand Triticum, revealing their biological characteristics, differentiation in gene expression patterns, and collinear relationships between A. speltoidesand the wheat B subgenome. We also identified gene families that expanded in A. speltoidesduring its evolution and 789 genes specific to A. speltoides. These genes can serve as genetic resources for improvement of adaptability to biotic and abiotic stress. The newly constructed reference genome and large-scale resequencing data for Sitopsis species will provide a valuable genomic resource for wheat genetic improvement and genomic studies.

A promoter is a short region of DNA that can bind RNA polymerase and initiate gene transcription. It is usually located directly upstream of the transcription initiation site. DNA promoters have been proven to be the main cause of many human diseases, especially diabetes, cancer or Huntington’s disease. Therefore, the classification of promoters has become an interesting problem and has attracted the attention of many researchers in the field of bioinformatics. Various studies have been conducted in order to solve this problem, but their performance still needs further improvement. In this research, we segmented the DNA sequence in a k-mers manner, then trained the word vector model, inputted it into long short-term memory(LSTM) and used the attention mechanism to predict. Our method can achieve 93.45% and 90.59% cross-validation accuracy in the two layers, respectively. Our results are better than others based on the same data set, and provided some ideas for accurately predicting promoters. In addition, this research suggested that natural language processing can play a significant role in biological sequence prediction.

Railway construction technology in China, especially of high-speed railway long-span bridge construction, has been developing rapidly since the beginning of the twenty-first century. To maintain the dynamic characteristics, travel safety and passenger comfort when the train travels over a bridge at high speed, and, at the same time, to meet the requirement of economical and technical viability of construction of the bridge—was a challenging problem. For solving this problem, many new types of bridge structure have been developed for railway and high-speed railway long-span bridges. The arch beam hybrid structure is one of the structures that have been widely used in China. It is normally made up of a prestressed concrete (PC) beam, a rigid frame, or V-shaped piers and a steel arch or concrete-filled steel tube arch.

Railway construction technology in China, especially of high-speed railway long-span bridge construction, has been developing rapidly since the beginning of the twenty-first century. To maintain the dynamic characteristics, travel safety and passenger comfort when the train travels over a bridge at high speed, and, at the same time, to meet the requirement of economical and technical viability of construction of the bridge—was a challenging problem. For solving this problem, many new types of bridge structure have been developed for railway and high-speed railway long-span bridges. The arch beam hybrid structure is one of the structures that have been widely used in China. It is normally made up of a prestressed concrete (PC) beam, a rigid frame, or V-shaped piers and a steel arch or concrete-filled steel tube arch.

Railway construction technology in China, especially of high-speed railway long-span bridge construction, has been developing rapidly since the beginning of the twenty-first century. To maintain the dynamic characteristics, travel safety and passenger comfort when the train travels over a bridge at high speed, and, at the same time, to meet the requirement of economical and technical viability of construction of the bridge—was a challenging problem. For solving this problem, many new types of bridge structure have been developed for railway and high-speed railway long-span bridges. The arch beam hybrid structure is one of the structures that have been widely used in China. It is normally made up of a prestressed concrete (PC) beam, a rigid frame, or V-shaped piers and a steel arch or concrete-filled steel tube arch.

Schistosomiasis is an important neglected tropical disease. Interactions between the host immune system and schistosomes are complex. Neutrophils contribute to clearance of large pathogens primarily by releasing neutrophil extracellular traps (NETs). However, the functional role of NETs in clearing schistosomes remains unclear. Herein, we report that extracellular vesicles (EVs) derived from the liver of Schistosoma japonicum-infected mice (IL-EVs) induce NET release by delivering miR-142a-3p to target WASL and block the development of S. japonicum. WASL knockout accelerated the formation of NETs that blocked further development of S. japonicum. miR-142a-3p and NETs upregulated the expression of CCL2, which recruits macrophages that block S. japonicumdevelopment. However, S. japonicuminhibited NET formation in wild-type mice by upregulating host interleukin-10 (IL-10) expression. In contrast, in WASL knockout mice, IL-10 expression was downregulated, and S. japonicum-mediated inhibition of NET formation was significantly reduced. IL-EV-mediated induction of NET formation is thus an anti-schistosome response that can be counteracted by S. japonicum.These findings suggest that IL-EV-mediated induction of NET formation plays a key role in schistosome infection and that WASL is a potential therapeutic target in schistosomiasis and other infectious diseases.

In this study, airflow and dust particle diffusion in the 3401 fully mechanized mining face of Xin’an Coal Mine considering the humidity field was numerically simulated. Based on the simulation results, the influence of relative humidity on dust migration and diffusion was revealed from two aspects, namely, dust concentration and dust diffusion distance. The following findings were obtained. Under seven relative humidity conditions, the degrees of dust pollution to the sidewalk vary notably. When the relative humidity is 45%, 55% and 65%, the dust concentration at the sidewalk ranges from 763 mg/m3to 1301 mg/m3. When the relative humidity is 95%, the dust concentration at the sidewalk is below 700 mg/m3, and the pollution is the slightest. As the relative humidity in the fully mechanized mining face rises, the dust diffusion distance generally shows a decreasing trend. Under different humidity conditions, the maximum differences of the dust diffusion distances at the sidewalk and the machine roadway are 20.36 m and 33.2 m, respectively. Finally, 75%− 85% is selected as the optimal relative humidity environment for coal mining, in accordance with the “people-centered” idea in ergonomics and the simulated dust pollution characteristics.

Diffraction gratings used in extreme UV are typically coated with periodic multilayer thin films. These coatings have a small bandwidth, thus leading to a narrow usable spectral region of multilayer gratings. Well-designed aperiodic multilayer coatings could provide high reflectivity over a much broader wavelength region, so they could broaden the usable spectral region of multilayer gratings. We designed and deposited an aperiodic Mo/Si multilayer coating onto a blazed grating substrate. At an incidence angle of 10°, the -2nd-order diffraction efficiency of the multilayer grating is ~10% through the wavelength range of 13-16 nm.