The Tungsten-Based Plasma-Facing Materials

The plasma-facing materials in fusion reactors will face very extreme servicing condition such as high temperatures, high thermal loads, extreme irradiation conditions induced by high-energy neutron, and high fluences of high-flux and low-energy plasma. Tungsten is considered as the most promising material for plasma-facing components (PFCs) in the magnetic confinement fusion devices, due to its high melting temperature, high thermal conductivity, low swelling, low tritium retention, and low sputtering yield. However, some important shortcomings such as the irradiation brittleness and high ductility-brittle transition temperature of pure tungsten limit its application. Focusing on this issue, various W alloys with enhanced performance have been developed. Among them, nanoparticle dispersion strengthening such as oxide particle dispersion-strengthened (ODS-W) and carbide particle dispersion-strengthened (CDS-W) tungsten alloys and W fiber-reinforced Wf/W composites are promising. This chapter mainly reviews the preparation, microstructure, properties, regulation, and service performance evaluation of ODS-W, CDS-W, and Wf/W materials, as well as future possible development is proposed

R2P: A Deep Learning Model from mmWave Radar to Point Cloud

Recent research has shown the effectiveness of mmWave radar sensing for object detection in low visibility environments, which makes it an ideal technique in autonomous navigation systems. In this paper, we introduce Radar to Point Cloud (R2P), a deep learning model that generates smooth, dense, and highly accurate point cloud representation of a 3D object with fine geometry details, based on rough and sparse point clouds with incorrect points obtained from mmWave radar. These input point clouds are converted from the 2D depth images that are generated from raw mmWave radar sensor data, characterized by inconsistency, and orientation and shape errors. R2P utilizes an architecture of two sequential deep learning encoder-decoder blocks to extract the essential features of those radar-based input point clouds of an object when observed from multiple viewpoints, and to ensure the internal consistency of a generated output point cloud and its accurate and detailed shape reconstruction of the original object. We implement R2P to replace Stage 2 of our recently proposed 3DRIMR (3D Reconstruction and Imaging via mmWave Radar) system. Our experiments demonstrate the significant performance improvement of R2P over the popular existing methods such as PointNet, PCN, and the original 3DRIMR design.Comment: arXiv admin note: text overlap with arXiv:2109.0918

Complete mapping of mutations to the SARS-CoV-2 spike receptor-binding domain that escape antibody recognition

Antibodies targeting the SARS-CoV-2 spike receptor-binding domain (RBD) are being developed as therapeutics and are a major contributor to neutralizing antibody responses elicited by infection. Here, we describe a deep mutational scanning method to map how all amino-acid mutations in the RBD affect antibody binding and apply this method to 10 human monoclonal antibodies. The escape mutations cluster on several surfaces of the RBD that broadly correspond to structurally defined antibody epitopes. However, even antibodies targeting the same surface often have distinct escape mutations. The complete escape maps predict which mutations are selected during viral growth in the presence of single antibodies. They further enable the design of escape-resistant antibody cocktails-including cocktails of antibodies that compete for binding to the same RBD surface but have different escape mutations. Therefore, complete escape-mutation maps enable rational design of antibody therapeutics and assessment of the antigenic consequences of viral evolution

A glycosylation risk score comprehensively assists the treatment of bladder neoplasm in the real-world cohort, including the tumor microenvironment, molecular and clinical prognosis

Background: Bladder cancer is a common urological cancer associated high significant morbidity and mortality rates. Immunotherapy has emerged as a promising treatment option, although response rates vary among patients. Glycosylation has been implicated in tumorigenesis and immune regulation. However, our current comprehensive understanding of the role of glycosylation in bladder cancer and its clinical implications is limited.Methods: We constructed a training cohort based on the downloaded TCGA-BLCA dataset, while additional datasets (Xiangya cohort, GSE32894, GSE48075, GSE31684, GSE69795 and E-MTAB-1803) from Xiangya hospital, GEO and ArrayExpress database were obtained and used as validation cohorts. To identify glycosylation-related genes associated with prognosis, univariate Cox regression and LASSO regression were performed. A Cox proportional hazards regression model was then constructed to develop a risk score model. The performance of the risk score was assessed in the training cohort using Kaplan-Meier survival curves and ROC curves, and further validated in multiple validation cohorts.Results: We classified patients in the training cohort into two groups based on glycosylation-related gene expression patterns: Cluster 1 and Cluster 2. Prognostic analysis revealed that Cluster 2 had poorer survival outcomes. Cluster 2 also showed higher levels of immune cell presence in the tumor microenvironment and increased activation in key steps of the cancer immune response cycle. We developed an independent prognostic risk score (p < 0.001) and used it to construct an accurate prognostic prediction nomogram. The high glycosylation risk score group exhibited higher tumor immune cell infiltration, enrichment scores in immune therapy-related pathways, and a tendency towards a basal subtype. Conversely, the low-risk score group had minimal immune cell infiltration and tended to have a luminal subtype. These findings were consistent in our real-world Xiangya cohort.Conclusion: This multi-omics glycosylation score based on these genes reliably confirmed the heterogeneity of bladder cancer tumors, predicted the efficacy of immunotherapy and molecular subtypes, optimizing individual treatment decisions

Novel genetic reassortants in H9N2 influenza A viruses and their diverse pathogenicity to mice

<p>Abstract</p> <p>Background</p> <p>H9N2 influenza A viruses have undergone extensive reassortments in different host species, and could lead to the epidemics or pandemics with the potential emergence of novel viruses.</p> <p>Methods</p> <p>To understand the genetic and pathogenic features of early and current circulating H9N2 viruses, 15 representative H9N2 viruses isolated from diseased chickens in northern China between 1998 and 2010 were characterized and compared with all Chinese H9N2 viruses available in the NCBI database. Then, the representative viruses of different genotypes were selected to study the pathogenicity in mice with the aim to investigate the adaptation and the potential pathogenicity of the novel H9N2 reassortants to mammals.</p> <p>Results</p> <p>Our results demonstrated that most of the 15 isolates were reassortants and generated four novel genotypes (B62-B65), which incorporated the gene segments from Eurasian H9N2 lineage, North American H9N2 branch, and H5N1 viruses. It was noteworthy that the newly identified genotype B65 has been prevalent in China since 2007, and more importantly, different H9N2 influenza viruses displayed a diverse pathogenicity to mice. The isolates of the 2008-2010 epidemic (genotypes B55 and B65) were lowly infectious, while two representative viruses of genotypes B0 and G2 isolated from the late 1990s were highly pathogenic to mice. In addition, Ck/SD/LY-1/08 (genotype 63, containing H5N1-like NP and PA genes) was able to replicate well in mouse lungs with high virus titers but caused mild clinical signs.</p> <p>Conclusion</p> <p>Several lines of evidence indicated that the H9N2 influenza viruses constantly change their genetics and pathogenicity. Thus, the genetic evolution of H9N2 viruses and their pathogenicity to mammals should be closely monitored to prevent the emergence of novel pandemic viruses.</p

Imprinted antibody responses against SARS-CoV-2 Omicron sublineages

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron sublineages carry distinct spike mutations resulting in escape from antibodies induced by previous infection or vaccination. We show that hybrid immunity or vaccine boosters elicit plasma-neutralizing antibodies against Omicron BA.1, BA.2, BA.2.12.1, and BA.4/5, and that breakthrough infections, but not vaccination alone, induce neutralizing antibodies in the nasal mucosa. Consistent with immunological imprinting, most antibodies derived from memory B cells or plasma cells of Omicron breakthrough cases cross-react with the Wuhan-Hu-1, BA.1, BA.2, and BA.4/5 receptor-binding domains, whereas Omicron primary infections elicit B cells of narrow specificity up to 6 months after infection. Although most clinical antibodies have reduced neutralization of Omicron, we identified an ultrapotent pan-variant-neutralizing antibody that is a strong candidate for clinical development

Longitudinal study after Sputnik V vaccination shows durable SARS-CoV-2 neutralizing antibodies and reduced viral variant escape to neutralization over time

Recent studies have shown a temporal increase in the neutralizing antibody potency and breadth to SARS-CoV-2 variants in coronavirus disease 2019 (COVID-19) convalescent individuals. Here, we examined longitudinal antibody responses and viral neutralizing capacity to the B.1 lineage virus (Wuhan related), to variants of concern (VOC; Alpha, Beta, Gamma, and Delta), and to a local variant of interest (VOI; Lambda) in volunteers receiving the Sputnik V vaccine in Argentina. Longitudinal serum samples

The poly(ADP-ribosyl)ation of BRD4 mediated by PARP1 promoted pathological cardiac hypertrophy

The bromodomain and extraterminal (BET) family member BRD4 is pivotal in the pathogenesis of cardiac hypertrophy. BRD4 induces hypertrophic gene expression by binding to the acetylated chromatin, facilitating the phosphorylation of RNA polymerases II (Pol II) and leading to transcription elongation. The present study identified a novel post-translational modification of BRD4: poly(ADP-ribosyl)ation (PARylation), that was mediated by poly(ADP-ribose)polymerase-1 (PARP1) in cardiac hypertrophy. BRD4 silencing or BET inhibitors JQ1 and MS417 prevented cardiac hypertrophic responses induced by isoproterenol (ISO), whereas overexpression of BRD4 promoted cardiac hypertrophy, confirming the critical role of BRD4 in pathological cardiac hypertrophy. PARP1 was activated in ISO-induced cardiac hypertrophy and facilitated the development of cardiac hypertrophy. BRD4 was involved in the prohypertrophic effect of PARP1, as implied by the observations that BRD4 inhibition or silencing reversed PARP1-induced hypertrophic responses, and that BRD4 overexpression suppressed the anti-hypertrophic effect of PARP1 inhibitors. Interactions of BRD4 and PARP1 were observed by co-immunoprecipitation and immunofluorescence. PARylation of BRD4 induced by PARP1 was investigated by PARylation assays. In response to hypertrophic stimuli like ISO, PARylation level of BRD4 was elevated, along with enhanced interactions between BRD4 and PARP1. By investigating the PARylation of truncation mutants of BRD4, the C-terminal domain (CTD) was identified as the PARylation modification sites of BRD4. PARylation of BRD4 facilitated its binding to the transcription start sites (TSS) of hypertrophic genes, resulting in enhanced phosphorylation of RNA Pol II and transcription activation of hypertrophic genes. The present findings suggest that strategies targeting inhibition of PARP1-BRD4 might have therapeutic potential for pathological cardiac hypertrophy

SIRT6 Suppresses NFATc4 Expression and Activation in Cardiomyocyte Hypertrophy

NFATc4, a member from the Nuclear Factor of Activated T cells (NFATs) transcription factor family, plays a pivotal role in the development of cardiac hypertrophy. NFATc4 is dephosphorylated by calcineurin and translocated from the cytoplasm to the nucleus to regulate the expression of hypertrophic genes, like brain natriuretic polypeptide (BNP). The present study identified SIRT6, an important subtype of NAD+ dependent class III histone deacetylase, to be a negative regulator of NFATc4 in cardiomyocyte hypertrophy. In phenylephrine (PE)-induced hypertrophic cardiomyocyte model, overexpression of SIRT6 by adenovirus infection or by plasmid transfection repressed the protein and mRNA expressions of NFATc4, elevated its phosphorylation level, prevented its nuclear accumulation, subsequently suppressed its transcriptional activity and downregulated its target gene BNP. By contrast, mutant of SIRT6 without deacetylase activity (H133Y) did not demonstrate these effects, suggesting that the inhibitory effect of SIRT6 on NFATc4 was dependent on its deacetylase activity. Moreover, the effect of SIRT6 overexpression on repressing BNP expression was reversed by NFATc4 replenishment, whereas the effect of SIRT6 deficiency on upregulating BNP was recovered by NFATc4 silencing. Mechanistically, interactions between SIRT6 and NFATc4 might possibly facilitate the deacetylation of NFATc4 by SIRT6, thereby preventing the activation of NFATc4. In conclusion, the present study reveals that SIRT6 suppresses the expression and activation of NFATc4. These findings provide more evidences of the anti-hypertrophic effect of SIRT6 and suggest SIRT6 as a potential therapeutic target for cardiac hypertrophy

Analysis of tumor-related features of non-small cell lung cancer based on TCR repertoire workflow

Objective·To explore the immune-related characteristics of non-small cell lung cancer (NSCLC), discover potential tumor markers in V-J genes, and lay the foundation for establishing a TCR-antigen recognition prediction model.Methods·A total of 704 NSCLC samples were collected to establish a comprehensive T-cell receptor (TCR) repertoire analysis workflow. The upstream analysis included steps such as raw data processing, quality control, filtering, TCR sequence identification, and extraction. The downstream analysis included repertoire clone distribution, clone typing, V-J gene sharing, CDR3 distribution characteristics, and clone tracking. The sample clone distribution was analyzed by using indices such as Shannon-Weiner index and Chao1 index. Clone typing was performed based on the number of clone amplifications to explore differences among different types. The degree of V-J gene segment sharing was analyzed, and the sharing of low-frequency clone types was determined through clone amplification weight analysis of V-J genes by using two samples of papillary thyroid carcinoma. Finally, analysis of the distribution characteristics of V genes and high-frequency clone type CDR3, and clone tracking analysis were conducted to monitor changes in tumor immune clone frequencies before and after analysis, aiming to identify potential tumor markers.Results·① Significant differences were observed in clone distribution and clone typing among different NSCLC tissues, as well as among different ages and genders. ② Specific highly-shared V-J genes were identified in the analysis of V-J gene sharing, and non-normal distribution of high-clone V genes and amino acid high-frequency clone types were found in the CDR3 distribution analysis. ③ In the analysis of high-frequency clone type clone tracking, highly expressed or newly expressed high-frequency clone types were observed in NSCLC, suggesting that these clone types could serve as potential tumor-associated antigens or bind with CDR3 reference sequences of new antigens. ④ It was found that the expression frequency of TRBJ2-5 gene, originally low-expressed, significantly increased, indicating its potential role as a key low-frequency gene in tumor immune response.Conclusion·The TRAV21 and TRBV6.5 genes show high clone amplification in NSCLC and could serve as potential tumor biomarkers