1,721,058 research outputs found
Three-dimensional temperature distribution in laser surface hardening processes
No full textThis paper introduces a new analytical solution to predict transient temperature distributions in a finite thickness plate during laser surface hardening. This analytical solution was obtained by solving a transient three-dimensional heat conduction equation with convection boundary conditions at the surfaces of the workpiece. To calculate the temperature field numerically in laser surface hardening processes, laser beam absorptivity, one of the most important parameters, should first be determined. It was extremely difficult to find an accurate value for laser beam absorptivity owing to the use of coating material on the workpiece surfaces, essentially to improve the efficiency of laser beam power. Therefore, in this paper, absorptivities were measured experimentally under various hardening conditions, including variations in coating thickness, laser beam power and beam travel velocity. Thereafter, to prove the validity of the model, a series of laser surface hardening experiments was performed on medium-carbon steel under various hardening conditions. The hardened layer of the etched cross-sectional view was examined and compared with the isothermal lines predicted by the proposed analytical model, in which the values of the experimentally measured absorptivity were employed. The results showed that the solution predicted well the transient temperature distribution of finite plates with satisfactory accuracy. Also, owing to the simplicity of the solution method, the analytical model developed may be easily implemented for simulation work for analysis and prediction of laser surface hardening processes under various hardening conditions
Omicron: A Heavily Mutated SARS-CoV-2 Variant Exhibits Stronger Binding to ACE2 and Potently Escapes Approved COVID-19 Therapeutic Antibodies
Get PDFThe new SARS-CoV-2 variant of concern "Omicron" was recently spotted in South Africa and spread quickly around the world due to its enhanced transmissibility. The variant became conspicuous as it harbors more than 30 mutations in the Spike protein with 15 mutations in the receptor-binding domain (RBD) alone, potentially dampening the potency of therapeutic antibodies and enhancing the ACE2 binding. More worrying, Omicron infections have been reported in vaccinees in South Africa and Hong Kong, and that post-vaccination sera poorly neutralize the new variant. Here, we investigated the binding strength of Omicron with ACE2 and monoclonal antibodies that are either approved by the FDA for COVID-19 therapy or undergoing phase III clinical trials. Computational mutagenesis and free energy perturbation could confirm that Omicron RBD binds ACE2 ~2.5 times stronger than prototype SARS-CoV-2. Notably, three substitutions, i.e., T478K, Q493K, and Q498R, significantly contribute to the binding energies and almost doubled the electrostatic potential (ELE) of the RBD(Omic)-ACE2 complex. Omicron also harbors E484A substitution instead of the E484K that helped neutralization escape of Beta, Gamma, and Mu variants. Together, T478K, Q493K, Q498R, and E484A substitutions contribute to a significant drop in the ELE between RBD(Omic)-mAbs, particularly in etesevimab, bamlanivimab, and CT-p59. AZD1061 showed a slight drop in ELE and sotrovimab that binds a conserved epitope on the RBD; therefore, it could be used as a cocktail therapy in Omicron-driven COVID-19. In conclusion, we suggest that the Spike mutations prudently devised by the virus facilitate the receptor binding, weakening the mAbs binding to escape the immune response
Assessment of neutralization susceptibility of Omicron subvariants XBB.1.5 and BQ.1.1 against broad-spectrum neutralizing antibodies through epitopes mapping
Get PDFThe emergence of new variants of the SARS-CoV-2 virus has posed a significant challenge in developing broadly neutralizing antibodies (nAbs) with guaranteed therapeutic potential. Some nAbs, such as Sotrovimab, have exhibited varying levels of efficacy against different variants, while others, such as Bebtelovimab and Bamlanivimab-etesevimab are ineffective against specific variants, including BQ.1.1 and XBB. This highlights the urgent need for developing broadly active monoclonal antibodies (mAbs) providing prophylactic and therapeutic benefits to high-risk patients, especially in the face of the risk of reinfection from new variants. Here, we aimed to investigate the feasibility of redirecting existing mAbs against new variants of SARS-CoV-2, as well as to understand how BQ.1.1 and XBB.1.5 can evade broadly neutralizing mAbs. By mapping epitopes and escape sites, we discovered that the new variants evade multiple mAbs, including FDA-approved Bebtelovimab, which showed resilience against other Omicron variants. Our approach, which included simulations, endpoint free energy calculation, and shape complementarity analysis, revealed the possibility of identifying mAbs that are effective against both BQ.1.1 and XBB.1.5. We identified two broad-spectrum mAbs, R200-1F9 and R207-2F11, as potential candidates with increased binding affinity to XBB.1.5 and BQ.1.1 compared to the reference (Wu01) strain. Additionally, we propose that these mAbs do not interfere with Angiotensin Converting Enzyme 2 (ACE2) and bind to conserved epitopes on the receptor binding domain of Spike that are not-overlapping, potentially providing a solution to neutralize these new variants either independently or as part of a combination (cocktail) treatment
Molecular perspectives of SARS-CoV-2: Pathology, immune evasion, and therapeutic interventions
Get PDFThe outbreak of coronavirus disease 2019 (COVID-19) has not only affected human health but also diverted the focus of research and derailed the world economy over the past year. Recently, vaccination against COVID-19 has begun, but further studies on effective therapeutic agents are still needed. The severity of COVID-19 is attributable to several factors such as the dysfunctional host immune response manifested by uncontrolled viral replication, type I interferon suppression, and release of impaired cytokines by the infected resident and recruited cells. Due to the evolving pathophysiology and direct involvement of the host immune system in COVID-19, the use of immune-modulating drugs is still challenging. For the use of immune-modulating drugs in severe COVID-19, it is important to balance the fight between the aggravated immune system and suppression of immune defense against the virus that causes secondary infection. In addition, the interplaying events that occur during virus–host interactions, such as activation of the host immune system, immune evasion mechanism of the virus, and manifestation of different stages of COVID-19, are disjunctive and require thorough streamlining. This review provides an update on the immunotherapeutic interventions implemented to combat COVID-19 along with the understanding of molecular aspects of the immune evasion of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which may provide opportunities to develop more effective and promising therapeutics
Optimization of vision transformer-based detection of lung diseases from chest X-ray images
Get PDFBackground: Recent advances in Vision Transformer (ViT)-based deep learning have significantly improved the accuracy of lung disease prediction from chest X-ray images. However, limited research exists on comparing the effectiveness of different optimizers for lung disease prediction within ViT models. This study aims to systematically evaluate and compare the performance of various optimization methods for ViT-based models in predicting lung diseases from chest X-ray images. Methods: This study utilized a chest X-ray image dataset comprising 19,003 images containing both normal cases and six lung diseases: COVID-19, Viral Pneumonia, Bacterial Pneumonia, Middle East Respiratory Syndrome (MERS), Severe Acute Respiratory Syndrome (SARS), and Tuberculosis. Each ViT model (ViT, FastViT, and CrossViT) was individually trained with each optimization method (Adam, AdamW, NAdam, RAdam, SGDW, and Momentum) to assess their performance in lung disease prediction. Results: When tested with ViT on the dataset with balanced-sample sized classes, RAdam demonstrated superior accuracy compared to other optimizers, achieving 95.87%. In the dataset with imbalanced sample size, FastViT with NAdam achieved the best performance with an accuracy of 97.63%. Conclusions: We provide comprehensive optimization strategies for developing ViT-based model architectures, which can enhance the performance of these models for lung disease prediction from chest X-ray images
Tumor suppressor RBM24 inhibits nuclear translocation of CTNNB1 and TP63 expression in liver cancer cells
No full textRNA-binding protein 24 (RBM24) has been shown to play tumor-suppressive functions in various types of cancer. The present study aimed to investigate the role of RBM24 in liver cancers and its downstream mechanisms. The present study demonstrated that RBM24 functioned as a tumor suppressor in liver cancer cells, and inhibited nuclear translocation of β-catenin and tumor protein 63 expression by immunocytochemistry. In addition, RBM24 could suppress sphere formation in a multicellular tumor spheroid model of liver cancer cells. In conclusion, it is hypothesized that RBM24 is a tumor suppressor of liver cancer cells, which could be a potential novel therapeutic target for treatment of patients with liver cancer
Endoplasmic reticulum stress induces cap2 expression promoting epithelial-mesenchymal transition in liver cancer cells
No full textCyclase-associated protein 2 (CAP2) has been addressed as a candidate biomarker in various cancer types. Previously, we have shown that CAP2 is expressed during multi-step hepatocarcinogenesis; however, its underlying mechanisms in liver cancer cells are not fully elucidated yet. Here, we demonstrated that endoplasmic reticulum (ER) stress induced CAP2 expression, and which promoted migration and invasion of liver cancer cells. We also found that the ER stressinduced CAP2 expression is mediated through activation of protein kinase C epsilon (PKCε) and the promotor binding of activating transcription factor 2 (ATF2). In addition, we further demonstrated that CAP2 expression promoted epithelial-mesenchymal transition (EMT) through activation of Rac1 and ERK. In conclusion, we suggest that ER stress induces CAP2 expression promoting EMT in liver cancer cells. Our results shed light on the novel functions of CAP2 in the metastatic process of liver cancer cells
Challenges and considerations in multi-epitope vaccine design surrounding toll-like receptors
No full textEpitope-based peptide vaccines elicit targeted immune responses, making them effective for diseases requiring focused immune activation, such as targeting cancer-associated antigens. Strategies like peptide cocktails and mRNA-based epitope vaccines have revolutionized the field; however, the term ‘multi-epitope peptide vaccine’ has been overextended, especially concerning the use of toll-like receptors (TLRs), their ligands, and peptide linkers. TLRs are often conflated with T cell receptors (TCRs) and B cell receptors (BCRs), which recognize immunogenic peptides within vaccines. This Opinion clarifies the role of TLRs and highlights challenges linked to their indiscriminate use in multi-epitope vaccine design. While peptide linkers are crucial in creating multivalent vaccines, their unsupervised application is increasing and warrants attention. After highlighting their role in advancing peptide vaccines, we discuss critical factors in linker implementation and caution against their misuse, which could undermine vaccines’ efficacy
Structural insights into antibody-based immunotherapy for hepatocellular carcinoma
No full textHepatocellular carcinoma (HCC) is one of the most common types of primary liver cancer and remains a leading cause of cancer-related deaths worldwide. While traditional approaches like surgical resection and tyrosine kinase inhibitors struggle against the tumor's immune evasion, monoclonal antibody (mAb)-based immunotherapies have emerged as promising alternatives. Several therapeutic antibodies that counter the immunosuppressive tumor microenvironment have demonstrated efficacy in clinical trials, leading to FDA approvals for advanced HCC treatment. A crucial aspect of advancing these therapies lies in understanding the structural interactions between antibodies and their targets. Recent findings indicate that mAbs and bispecific antibodies (bsAbs) can target different, non-overlapping epitopes on immune checkpoints such as PD-1 and CTLA-4. This review delves into the epitope-paratope interactions of structurally unresolved mAbs and bsAbs, and discusses the potential for combination therapies based on their non-overlapping epitopes. By leveraging this unique feature, combination therapies could enhance immune activation, reduce resistance, and improve overall efficacy, marking a new direction for antibody-based immunotherapy in HCC
- …
