Protective anti-gB neutralizing antibodies targeting two vulnerable sites for EBV-cell membrane fusion.

Epstein-Barr virus (EBV) infects more than 90% of the world's adult population and accounts for a significant cancer burden of epithelial and B cell origins. Glycoprotein B (gB) is the primary fusogen essential for EBV entry into host cells. Here, we isolated two EBV gB-specific neutralizing antibodies, 3A3 and 3A5; both effectively neutralized the dual-tropic EBV infection of B and epithelial cells. In humanized mice, both antibodies showed effective protection from EBV-induced lymphoproliferative disorders. Cryoelectron microscopy analyses identified that 3A3 and 3A5 bind to nonoverlapping sites on domains D-II and D-IV, respectively. Structure-based mutagenesis revealed that 3A3 and 3A5 inhibit membrane fusion through different mechanisms involving the interference with gB-cell interaction and gB activation. Importantly, the 3A3 and 3A5 epitopes are major targets of protective gB-specific neutralizing antibodies elicited by natural EBV infection in humans, providing potential targets for antiviral therapies and vaccines.

Fault Diagnosis of the Rolling Bearing by a Multi-Task Deep Learning Method Based on a Classifier Generative Adversarial Network.

Accurate fault diagnosis is essential for the safe operation of rotating machinery. Recently, traditional deep learning-based fault diagnosis have achieved promising results. However, most of these methods focus only on supervised learning and tend to use small convolution kernels non-effectively to extract features that are not controllable and have poor interpretability. To this end, this study proposes an innovative semi-supervised learning method for bearing fault diagnosis. Firstly, multi-scale dilated convolution squeeze-and-excitation residual blocks are designed to exact local and global features. Secondly, a classifier generative adversarial network is employed to achieve multi-task learning. Both unsupervised and supervised learning are performed simultaneously to improve the generalization ability. Finally, supervised learning is applied to fine-tune the final model, which can extract multi-scale features and be further improved by implicit data augmentation. Experiments on two datasets were carried out, and the results verified the superiority of the proposed method.

Vesicular Stomatitis Virus-Based Epstein-Barr Virus Vaccines Elicit Strong Protective Immune Responses.

Epstein-Barr virus (EBV), the first identified human tumor virus, is etiologically associated with various kinds of malignant and benign diseases, accounting for 265,000 cancer incident cases and 164,000 cancer deaths in 2017. EBV prophylactic vaccine development has been gp350 centered for several decades. However, clinical studies show that gp350-centered vaccines fail to prevent EBV infection. Advances in the EBV infection mechanisms shed light on gB and gHgL, the two key components of the infection apparatus. In this study, for the first time, we utilized recombinant vesicular stomatitis virus (VSV) to display EBV gB (VSV-ΔG-gB/gB-G) or gHgL (VSV-ΔG-gHgL). In vitro studies confirmed successful virion production and glycoprotein presentation on the virion surface. In mouse models, VSV-ΔG-gB/gB-G or VSV-ΔG-gHgL elicited potent humoral responses. Neutralizing antibodies elicited by VSV-ΔG-gB/gB-G were prone to prevent B cell infection, while those elicited by VSV-ΔG-gHgL were prone to prevent epithelial cell infection. Combinatorial vaccination yields an additive effect. The ratio of endpoint neutralizing antibody titers to the endpoint total IgG titers immunized with VSV-ΔG-gHgL was approximately 1. The ratio of IgG1/IgG2a after VSV-ΔG-gB/gB-G immunization was approximately 1 in a dose-dependent, adjuvant-independent manner. Taken together, VSV-based EBV vaccines can elicit a high ratio of epithelial and B lymphocyte neutralizing antibodies, implying their unique potential as EBV prophylactic vaccine candidates. IMPORTANCE Epstein-Barr virus (EBV), one of the most common human viruses and the first identified human oncogenic virus, accounted for 265,000 cancer incident cases and 164,000 cancer deaths in 2017 as well as millions of nonmalignant disease cases. So far, no prophylactic vaccine is available to prevent EBV infection. In this study, for the first time, we reported the VSV-based EBV vaccines presenting two key components of the EBV infection apparatus, gB and gHgL. We confirmed potent antigen-specific antibody generation; these antibodies prevented EBV from infecting epithelial cells and B cells, and the IgG1/IgG2a ratio indicated balanced humoral-cellular responses. Taken together, we suggest VSV-based EBV vaccines are potent prophylactic candidates for clinical studies and help eradicate numerous EBV-associated malignant and benign diseases.

Immunization with a Self-Assembled Nanoparticle Vaccine Elicits Potent Neutralizing Antibody Responses against EBV Infection.

Epstein-Barr virus (EBV) infection is a global health concern infecting over 90% of the population. However, there is no currently available vaccine. EBV primarily infects B cells, where the major glycoprotein 350 (gp350) is the main target of neutralizing antibodies. Given the advancement of nanoparticle vaccines, we describe rationally designed vaccine modalities presenting 60 copies of gp350 on self-assembled nanoparticles in a repetitive array. In a mouse model, gp350s on lumazine synthase (LS) and I3-01 adjuvanted with MF59 or aluminum hydroxide (Alhydrogel) elicited over 65- to 133-fold higher neutralizing antibody titers than the corresponding gp350 monomer to EBV. Furthermore, immunization with gp350D123-LS and gp350D123-I3-01 vaccine induced a Th2-biased response. For the nonhuman primate model, gp350D123-LS in MF59 elicited higher titers of total IgG and neutralizing antibodies than the monomeric gp350D123. Overall, these results support gp350D123-based nanoparticle vaccine design as a promising vaccine candidate for potent protection against EBV infection.

Optimization of High Temperature-Resistant Modified Starch Polyamine Anti-Collapse Water-Based Drilling Fluid System for Deep Shale Reservoir.

During drilling in deep shale gas reservoirs, drilling fluid losses, hole wall collapses, and additional problems occur frequently due to the development of natural fractures in the shale formation, resulting in a high number of engineering accidents such as drilling fluid leaks, sticking, mud packings, and buried drilling tools. Moreover, the horizontal section of horizontal well is long (about 1500 m), and the problems of friction, rock carrying, and reservoir pollution are extremely prominent. The performance of drilling fluids directly affects drilling efficiency, the rate of engineering accidents, and the reservoir protection effect. In order to overcome the problems of high filtration in deep shale formations, collapse of borehole walls, sticking of pipes, mud inclusions, etc., optimization studies of water-based drilling fluid systems have been conducted with the primary purpose of controlling the rheology and water loss of drilling fluid. The experimental evaluation of the adsorption characteristics of "KCl + polyamine" anti-collapse inhibitor on the surface of clay particles and its influence on the morphology of bentonite was carried out, and the mechanism of inhibiting clay mineral hydration expansion was discussed. The idea of controlling the rheology and water loss of drilling fluid with high temperature resistant modified starch and strengthening the inhibition performance of drilling fluid with "KCl + polyamine" was put forward, and a high temperature-resistant modified starch polyamine anti-sloughing drilling fluid system with stable performance and strong plugging and strong inhibition was optimized. The temperature resistance of the optimized water-based drilling fluid system can reach 180 °C. Applied to on-site drilling of deep shale gas horizontal wells, it effectively reduces the rate of complex accidents such as sticking, mud bagging, and reaming that occur when resistance is encountered during shale formation drilling. The time for a single well to trip when encountering resistance decreases from 2-3 d in the early stages to 3-10 h. The re-use rate of the second spudded slurry is 100 percent, significantly reducing the rate of complex drilling accidents and saving drilling costs. It firmly supports the optimal and rapid construction of deep shale gas horizontal wells.

Adiabatic evolution of optical beams in nonlocal nonlinear media of gradual nonlocality.

We theoretically investigate the evolution of optical beams in nonlocal nonlinear media of gradual nonlocality, which is governed by the nonlocal nonlinear Schrödinger equation with variable coefficient. With the variational approach, the evolution equation of beam width is derived. When the characteristic length of response function gradually changes with any functional forms, beams can exhibit a kind of adiabatic evolution. The variational results are well confirmed by numerical simulations.

Investigating behavior inhibition in obsessive-compulsive disorder: Evidence from eye movements.

We investigated the role of inhibition failure in Obsessive Compulsive Disorder (OCD) through an eye tracking experiment. Twenty-five subjects with OCD were recruited, as well as 25 with Generalized Anxiety Disorder (GAD) and 25 healthy controls. A 3 (group: OCD group, GAD group and control group) × 2 (target eccentricity: far and near) × 2 (saccade task: prosaccade and antisaccade) mixed design was used, with all participants completing two sets of tasks involving both prosaccade (eye movement towards a target) and antisaccade (eye movement away from a target). The main outcome was the eye movement index, including the saccade latency (the time interval from the onset of the target screen to the first saccade) and the error rate of saccade direction. The antisaccade latency and antisaccade error rates for OCDs were much higher than those for GADs and healthy controls. OCDs had longer latency and error rates for antisaccades than for prosaccades, and for far-eccentricity rather than near-eccentricity stimuli. These results suggest that OCDs experience difficulty with behavior inhibition, and that they have higher visual sensitivity to peripheral stimuli. In particular, they show greatest difficulty in inhibiting behavior directed towards peripheral stimuli.

Optimum Design and Application Research of Eddy Current Sensor for Measurement of TBM Disc Cutter Wear.

In view of the fact that the mature eddy current sensors on the market have a small measuring range and a certain requirement for the measured conductor area, which cannot meet the requirement of TBM disc cutter Wear monitoring, Ansoft Maxwell simulation was used to optimize the coil geometry parameters and circuit structure of eddy current sensor in this study. A special sensor for measuring disc cutter wear was designed, and the feasibility of the design was verified by measuring a 17-inch disc cutter. The results indicate that the linear range of the eddy current sensor is 35 mm under the condition that the measured blade width is 19 mm, which can meet the requirement of disc cutter wear measurement and provide monitoring data for real-time disc cutter wear monitoring system.

Superhydrophobic Coating for Antifouling of Chinese Paintings.

In the past 10 years, many studies on superhydrophobic (SH) papers have been reported. However, these works are rarely carried out on Chinese paintings. Compared with pure paper, the complexity of Chinese black ink and pigment, caused by including animal glue and fixatives allowing the nanoparticles to disperse in water, negatively affects the formation of SH coatings. In this work, we report the fabrication of SH coatings using fluorine silicon sol containing an epoxy group on Chinese paintings. Briefly, SiO2 nanoparticles were mixed with KH560 and FAS-17 and formed fluorine silicon sol. Then the sol was coated on the Chinese paintings. After drying, the SH coating was created. It can protect Chinese paintings and prevent them from being fouled by various liquids. Six types of beverages and ink can be repelled by the as-prepared SH coatings. Moreover, Chinese black ink can also be washed away from the SH coatings using water, without leaving any traces of ink behind. The SH coatings did not affect the appearance and internal structure of the Chinese paintings. Furthermore, due to covalent link, the SH coatings have good mechanical properties with regard to bending tests (120 times), finger pressing tests, and friction tests. The SH coatings also show an excellent high temperature resistance. This study has important applications for antifouling of Chinese paintings or oil paintings from dirty water.

Loss of function of KIF1B impairs oocyte meiotic maturation and early embryonic development in mice.

Kinesin family member 1B (KIF1B) is an important microtubule-dependent monomeric motor in mammals, although little is known about its role in meiosis. We profiled KIF1B expression and localization during oocyte maturation and early embryonic development in mice, revealing a dynamic pattern throughout meiotic progression. Depletion or inhibition of KIF1B leads to abnormal polar body extrusion, disordered spindle dynamics, defects in chromosome congression, increased aneuploidy, and impaired embryonic development. Further, KIF1B depletion affects the distribution of mitochondria and abundance of ATP. Taken together, our study demonstrates that mouse KIF1B is important for spindle assembly, chromosome congression, and mitochondrial distribution during oocyte maturation and early embryonic development. Mol. Reprod. Dev. 83: 1027-1040, 2016 © 2016 Wiley Periodicals, Inc.

GSK3ß is a checkpoint for TNF-α-mediated impaired osteogenic differentiation of mesenchymal stem cells in inflammatory microenvironments.

BACKGROUND: The fate and differentiation of mesenchymal stem cells (MSCs) depend on various microenvironmental cues. In chronic inflammatory bone disease, bone regeneration is inhibited. The present study therefore sought to identify the underlying molecule mechanisms. METHODS: We isolated periodontal ligament stem cells (PDLSCs), a new population of MSCs, from the periodontal ligament tissues of periodontitis patients and healthy controls (p-PDLSCs and h-PDLSCs). The secretion of inflammatory cytokines, like TNF-α, IL-1ß, IL-6 and IL-8, after LPS stimulation was measured by ELISA. The expressions of p-GSK3ß and GSK3ß in two types of PDLSCs were detected by Western blot. TOPFlash was used to assay the Tcf/Lef transcriptional activity. Knockdown of GSK3ß by siRNA and over-expression of GSK3ß by adenoviruses were performed to confirm the role of GSK3ß in the impaired osteogenic differentiation of PDLSCs under inflammatory microenvironment. RESULTS: We demonstrated that p-PDLSCs displayed impaired osteogenic capacity than h-PDLSCs. Upon inflammatory stimulation, monocytes, but not PDLSCs, released inflammatory cytokines among which TNF-α directly act on PDLSCs and suppressed their osteogenic differentiation. TNF-α induced the phosphorylation of GSK3ß, the deactivated form of GSK3ß, which increased nuclear ß-catenin and Lef-1 accumulation, and eventually reduced the Runx2-associated osteogenesis in PDLSCs. Over-expression of GSK3ß rescued osteogenesis in TNF-α-stimulated PDLSCs, whereas inactivation of GSK3ß was sufficient to liberate the ß-catenin/Lef-1/Runx2 pathway. CONCLUSION: GSK3ß plays an obligatory role in the TNF-α-mediated inhibition of osteogenesis in MSCs. GENERAL SIGNIFICANCE: The strategy to target GSK3ß may provide a potential approach to bone regeneration in inflammatory microenvironments.

Investigating the Impact of Substrate Preheating on the Thermal Flow and Microstructure of Laser Cladding of Nickel-Based Superalloy.

The preheating of the substrate in laser additive superalloys can reduce residual stress and minimize cracking. However, this preheating process can lead to changes in the heat transfer conditions, ultimately affecting the resulting microstructure and mechanical properties. In order to explore the influence of substrate preheating on the formation of laser cladding, this research focuses on investigating the characteristics of Inconel 718, a nickel-based superalloy, as the subject of study. To simulate the temperature and flow field of laser cladding, a 3D computational fluid dynamics (CFD) model is employed. By varying the initial preheating conditions, an investigation is conducted into the distribution of the temperature field under different parameters. This leads to the acquisition of varying temperature gradients, G, and solidification speeds, R. Subsequently, an analysis is carried out on both the flow field and solidification microstructure in the melt pool. The results demonstrate that the preheating of the substrate results in a slower cooling rate, ultimately leading to the formation of a coarser microstructure.

Quantitative evaluation of acid flow behavior in fractures and optimization of design parameters based on acid wormhole filtration losses.

The technique of matrix acidification or acid fracturing is commonly utilized to establish communication with natural fractures during reservoir reconstruction. However, this process often encounters limitations due to filtration, which restricts the expansion of the primary acid-etching fracture. To address this issue, a computational model has been developed to simulate the expansion of an acid-etching wormhole by considering various factors such as formation process, injection duration, pressure build-up, and time-varying acid percolation rate. By analyzing the pumping displacement of acid-etching wormholes, this model provides valuable insights into the time-dependent quantities of acid percolation. It has been revealed that the filtration rate of acid-etching wormholes is strongly influenced by pumping displacement, viscosity, and concentration of the acid fluid used in stimulation as well as physical properties of the reservoir itself. Notably, viscosity plays a significant role in determining the effectiveness of acid fracturing especially in low-viscosity conditions. Acid concentration within 15% to 20% exhibits maximum impact on successful acid fracturing while concentrations below 15% or above 20% show no obvious effect. Furthermore, it was found that pumping displacement has a major influence on effective fracturing. However, beyond a certain threshold (> 5.0 m3/min), increased pumping displacement leads to slower etching distance for acids used in construction purposes. The simulation also provides real-time distribution analysis for acidity levels within eroded fractures during matrix-acidification processes and quantifies extent of chemical reactions between acids and rocks within these fractures thereby facilitating optimization efforts for design parameters related to matrix-acidification.

Serum analysis based on SERS combined with 2D convolutional neural network and Gramian angular field for breast cancer screening.

Breast cancer is a significant cause of death among women worldwide. It is crucial to quickly and accurately diagnose breast cancer in order to reduce mortality rates. While traditional diagnostic techniques for medical imaging and pathology samples have been commonly used in breast cancer screening, they still have certain limitations. Surface-enhanced Raman spectroscopy (SERS) is a fast, highly sensitive and user-friendly method that is often combined with deep learning techniques like convolutional neural networks. This combination helps identify unique molecular spectral features, also known as "fingerprint", in biological samples such as serum. Ultimately, this approach is able to accurately screen for cancer. The Gramian angular field (GAF) algorithm can convert one-dimensional (1D) time series into two-dimensional (2D) images. These images can be used for data visualization, pattern recognition and machine learning tasks. In this study, 640 serum SERS from breast cancer patients and healthy volunteers were converted into 2D spectral images by Gramian angular field (GAF) technique. These images were then used to train and test a two-dimensional convolutional neural network-GAF (2D-CNN-GAF) model for breast cancer classification. We compared the performance of the 2D-CNN-GAF model with other methods, including one-dimensional convolutional neural network (1D-CNN), support vector machine (SVM), K-nearest neighbor (KNN) and principal component analysis-linear discriminant analysis (PCA-LDA), using various evaluation metrics such as accuracy, precision, sensitivity, F1-score, receiver operating characteristic (ROC) curve and area under curve (AUC) value. The results showed that the 2D-CNN model outperformed the traditional models, achieving an AUC value of 0.9884, an accuracy of 98.13%, sensitivity of 98.65% and specificity of 97.67% for breast cancer classification. In this study, we used conventional nano-silver sol as the SERS-enhanced substrate and a portable laser Raman spectrometer to obtain the serum SERS data. The 2D-CNN-GAF model demonstrated accurate and automatic classification of breast cancer patients and healthy volunteers. The method does not require augmentation and preprocessing of spectral data, simplifying the processing steps of spectral data. This method has great potential for accurate breast cancer screening and also provides a useful reference in more types of cancer classification and automatic screening.

Exercise-induced calf muscle hyperemia quantified with dynamic blood oxygen level-dependent (BOLD) imaging.

Muscle hyperemia in exercise is usually the combined result of increased cardiac output and local muscle vasodilation, with the latter reflecting muscle's capacity for increased blood perfusion to support exercise. In this study, we aim to quantify muscle's vasodilation capability with dynamic BOLD imaging. A deoxyhemoglobin-kinetics model is proposed to analyze dynamic BOLD signals acquired during exercise recovery, deriving a hyperemia index (HI) for a muscle group of interest. We demonstrated the method's validity with calf muscles of healthy subjects who performed plantar flexion for muscle stimulation. In a test with exercise load incrementally increasing from 0 to 16 lbs., gastrocnemius HI showed considerable variance among the 4 subjects, but with a consistent trend, i.e. low at light load (e.g. 0-6 lbs) and linearly increasing at heavy load. The high variability among different subjects was confirmed with the other 10 subjects who exercised with a same moderate load of 8 lbs., with coefficient of variance among subjects' medial gastrocnemius 87.8%, lateral gastrocnemius 111.8% and soleus 132.3%. These findings align with the fact that intensive exercise induces high muscle hyperemia, but a comparison among different subjects is hard to make, presumably due to the subjects' different rate of oxygen utilization. For the same 10 subjects who exercised with load of 8 lbs., we also performed dynamic contrast enhanced (DCE) MRI to measure muscle perfusion (F). With a moderate correlation of 0.654, HI and F displayed three distinctive responses of calf muscles: soleus of all the subjects were in the cluster of low F and low HI, and gastrocnemius of most subjects had high F and either low or high HI. This finding suggests that parameter F encapsulates blood flow through vessels of all sizes, but BOLD-derived HI focuses on capillary flow and therefore is a more specific indicator of muscle vasodilation. In conclusion, the proposed hyperemia index has the potential of quantitatively assessing muscle vasodilation induced with exercise.

Potent human monoclonal antibodies targeting Epstein-Barr virus gp42 reveal vulnerable sites for virus infection.

Epstein-Barr virus (EBV) is linked to various malignancies and autoimmune diseases, posing a significant global health challenge due to the lack of specific treatments or vaccines. Despite its crucial role in EBV infection in B cells, the mechanisms of the glycoprotein gp42 remain elusive. In this study, we construct an antibody phage library from 100 EBV-positive individuals, leading to the identification of two human monoclonal antibodies, 2B7 and 2C1. These antibodies effectively neutralize EBV infection in vitro and in vivo while preserving gp42's interaction with the human leukocyte antigen class II (HLA-II) receptor. Structural analysis unveils their distinct binding epitopes on gp42, different from the HLA-II binding site. Furthermore, both 2B7 and 2C1 demonstrate potent neutralization of EBV infection in HLA-II-positive epithelial cells, expanding our understanding of gp42's role. Overall, this study introduces two human anti-gp42 antibodies with potential implications for developing EBV vaccines targeting gp42 epitopes, addressing a critical gap in EBV research.

Deciduous dental pulp stem cells are involved in osteoclastogenesis during physiologic root resorption.

Multipotent mesenchymal stem cells are derived from the dental pulps of permanent teeth and exfoliated deciduous teeth, and are known to induce bone and dentin generation. However, the role of deciduous dental pulp stem cells (DDPSCs) in physiologic root resorption remains unclear. In this study, dental pulp stem cells (DPSCs) in permanent teeth (P) were retrieved and compared to DDPSCs from deciduous incisors at different root resorption stages: stable (S), middle (M), and final (F). Decalcified teeth sections showed that osteoclasts and resorption lacunae were most prevalent in the M resorption stage. DDPSC proliferation rate was also highest in the M stage. DDPSCs in the F stage produced more calcified nodules than those in the S or M stages. Alkaline phosphatase (ALP) expression was highest in the F stage, indicating that DDPSCs promote mineralization. In addition, the ratio of receptor activator of nuclear factor kappa B ligand (RANKL) and osteoprotegerin (OPG) expression was significantly higher in the M stage, indicating that DDPSCs promote resorption. Dickkopf 1 (Dkk1) expression was remarkably higher in the F and P groups, suggesting that the Wnt pathway is inhibited during the resorption process. Interestingly, despite the fact that Wnt3a down-regulated OPG in osteogenic induction medium and up-regulated RANKL in medium with 1,25-dihydroxy vitamin D3 (VD(3) ), the RANKL/OPG ratio was reduced only with VD(3) . Collectively, our data indicate that DDPSCs influence osteoclastogenesis during the physiologic root resorption process, and that the canonical Wnt pathway can change the RANKL/OPG expression ratio in DDPSCs.

Enhanced Mechanical Property of Polyamide-6/Graphite Sheet Composites with Segregated 3D Network Binary Structure for High Thermal Conductivity.

Segregated conductive polymer composites exhibit excellent electrical properties with a low percolation threshold. However, the mechanical properties of the segregated conductive polymer composites were always poor because the conductive fillers at the interfaces hinder polymer chain diffusion and thus lead to weak interfacial interaction between the conductive fillers and the polymer matrix. In this paper, polyamide-6 and polyamide-612 microspheres were synthesized via the in situ anionic ring opening of caprolactam and laurolactam. Segregated graphite sheets/polyamide-6(GS/PA6) and polyamide-612(PA612) composites with good mechanical properties were realized via high-pressure solid-phase compression molding. The microstructures of the composite samples were observed by scanning electron microscopy, which showed that the formation of a GS-conductive network at the PA6 granule interfaces in the segregated conductive structures and the adopting of PA612 considerably improved the interfacial adhesion of the composites. A superior impact strength of 5.1 kJ/m2 was achieved with 50 wt% PA612 loading owing to improvements in the interface compatibility between PA6 and GS. The composites possessed an ultralow percolation threshold, which was ascribed to the segregated network structure being successfully constructed inside the material. As for GS/PA6 composites, the combination of segregated GS-conductive networks achieved an ultralow percolation of 2.8 vol%. The percolation of 80PA6/20PA612-GS composites was slightly higher, measuring up to 3.2 vol%. Moreover, the thermal conductivity of the 80PA6/20PA612-GS composites increased from 0.26 to around 0.5 W/(m·K), which was 1.9 times larger than the pure polyamide.

Prediction of Primary Dendrite Arm Spacing of the Inconel 718 Deposition Layer by Laser Cladding Based on a Multi-Scale Simulation.

Primary dendrite arm spacing (PDAS) is a crucial microstructural feature in nickel-based superalloys produced by laser cladding. In order to investigate the effects of process parameters on PDAS, a multi-scale model that integrates a 3D transient heat and mass transfer model with a quantitative phase-field model was proposed to simulate the dendritic growth behavior in the molten pool for laser cladding Inconel 718. The values of temperature gradient (G) and solidification rate (R) at the S/L interface of the molten pool under different process conditions were obtained by multi-scale simulation and used as input for the quantitative phase field model. The influence of process parameters on microstructure morphology in the deposition layer was analyzed. The result shows that the dendrite morphology is in good agreement with the experimental result under varying laser power (P) and scanning velocity (V). PDAS was found to be more sensitive to changes in laser scanning velocity, and as the scanning velocity decreased from 12 mm/s to 4 mm/s, the PDAS increased by 197% when the laser power was 1500 W. Furthermore, smaller PDAS can be achieved by combining higher scanning velocity with lower laser power.

mRNA-based Vaccines Targeting the T-cell Epitope-rich Domain of Epstein Barr Virus Latent Proteins Elicit Robust Anti-Tumor Immunity in Mice.

Epstein-Barr virus (EBV) is associated with various malignancies and infects >90% of the global population. EBV latent proteins are expressed in numerous EBV-associated cancers and contribute to carcinogenesis, making them critical therapeutic targets for these cancers. Thus, this study aims to develop mRNA-based therapeutic vaccines that express the T-cell-epitope-rich domain of truncated latent proteins of EBV, including truncatedlatent membrane protein 2A (Trunc-LMP2A), truncated EBV nuclear antigen 1 (Trunc-EBNA1), and Trunc-EBNA3A. The vaccines effectively activate both cellular and humoral immunity in mice and show promising results in suppressing tumor progression and improving survival time in tumor-bearing mice. Furthermore, it is observed that the truncated forms of the antigens, Trunc-LMP2A, Trunc-EBNA1, and Trunc-EBNA3A, are more effective than full-length antigens in activating antigen-specific immune responses. In summary, the findings demonstrate the effectiveness of mRNA-based therapeutic vaccines targeting the T-cell-epitope-rich domain of EBV latent proteins and providing new treatment options for EBV-associated cancers.