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Vaccine-induced T cells and neutralizing antibodies are essential for protection against SARS-CoV-2. Previously, we demonstrated that an antigen delivery system, pullulan nanogel (PNG), delivers vaccine antigen to lymph node medullary macrophages and thereby enhances the induction of specific CD8 + T cells. In this study, we revealed that medullary macrophage-selective delivery by PNG depends on its binding to a C-type lectin SIGN-R1. In a K18-hACE2 mouse model of SARS-CoV-2 infection, vaccination with a PNG-encapsulated receptor-binding domain of spike protein decreased the viral load and prolonged the survival in the CD8 + T cell- and B cell-dependent manners. T cell receptor repertoire analysis revealed that although the vaccine induced T cells at various frequencies, low-frequency specific T cells mainly promoted virus clearance. Thus, the induction of specific CD8 + T cells that respond quickly to viral infection, even at low frequencies, is important for vaccine efficacy and can be achieved by SIGN-R1 + medullary macrophage-targeted antigen delivery., (© 2024. The Author(s).)

Isolation of tumor-specific T cells and their antigen receptors (TCRs) from malignant pleural effusions (MPE) may facilitate the development of TCR-transduced adoptive cellular immunotherapy products for advanced lung cancer patients. However, the characteristics and markers of tumor-specific T-cells in MPE are largely undefined. To this end, to establish the phenotypes and antigen specificities of CD8 + T cells, we performed single-cell RNA and TCR sequencing of samples from three advanced lung cancer patients. Dimensionality reduction on a total of 4,983 CD8 + T cells revealed 10 clusters including naïve, memory, and exhausted phenotypes. We focused particularly on exhausted T cell clusters and tested their TCR reactivity against neoantigens predicted from autologous cancer cell lines. Four different TCRs specific for the same neoantigen and one orphan TCR specific for the autologous cell line were identified from one of the patients. Differential gene expression analysis in tumor-specific T cells relative to the other T cells identified CXCL13 , as a candidate gene expressed by tumor-specific T cells. In addition to expressing CXCL13 , tumor-specific T cells were present in a higher proportion of T cells co-expressing PDCD1 (PD-1)/ TNFRSF9 (4-1BB). Furthermore, flow cytometric analyses in advanced lung cancer patients with MPE documented that those with high PD-1/4-1BB expression have a better prognosis in the subset of 57 adenocarcinoma patients ( p  = .039). These data suggest that PD-1/4-1BB co-expression might identify tumor-specific CD8 + T cells in MPE, which are associated with patients' prognosis. (233 words)., Competing Interests: This study was partly funded by NEC Corporation., (© 2024 The Author(s). Published with license by Taylor & Francis Group, LLC.)

The range separation method for density functional theory (DFT) was extended to a two-component relativistic theory based on the unitary transformation of one- and two-electron operators and a density operator. In the framework of the spin-free infinite-order two-component Hamiltonian, we implemented several types of two-electron integrals of range-separated two-electron interactions arising from the unitary transformation. Numerical assessments were performed using long-range-corrected (LC)-DFT, which utilizes the range separation of an exchange functional. The present method successfully reproduced the reference values obtained by the four-component LC-DFT calculations when the whole unitary transformations of one-electron, full-range, and range-separated two-electron operators and a density operator were considered. An efficient scheme for the unitary transformation, which is termed the local unitary transformation (LUT), was also applied to the range-separated two-electron term and other operators. The LUT method reduced the computational costs of the LC-DFT calculations significantly without any loss of accuracy.

Background: The coronavirus disease 2019 (COVID-19) pandemic has caused significant structural changes in acute care hospitals. COVID-19-associated stroke has gained attention, with abnormal coagulation and vascular endothelial damage being recognized. While ischemic cases are commonly reported, hemorrhagic cases have also been reported. This report presents a case of ruptured vertebral artery dissection aneurysm associated with COVID-19, resulting in subarachnoid hemorrhage (SAH). The treatment course, challenges in managing cerebral vasospasm, and early recanalization achieved through endovascular therapy are described., Case Description: A 67-year-old male patient was brought to our hospital for emergency treatment of impaired consciousness that occurred while recovering from COVID-19. He underwent endovascular internal trapping using coils, and although the rupture did not recur, he required long-term tracheal management, which resulted in a cerebral infarction caused by cerebral vasospasm. In addition, early recanalization was seen, which required retreatment., Conclusion: This case highlights the challenges in managing COVID-19-associated SAH and emphasizes the need for infection control measures and proper postoperative care. Establishing protocols for detecting and managing cerebral vasospasm is essential., Competing Interests: There are no conflicts of interest., (Copyright: © 2023 Surgical Neurology International.)

Background: CD8 + tumor infiltrating lymphocytes (TILs) are often observed in non-small cell lung cancers (NSCLC). However, the characteristics of CD8 + TILs, especially T-cell populations specific for tumor antigens, remain poorly understood., Methods: High throughput single-cell RNA sequencing and single-cell T-cell receptor (TCR) sequencing were performed on CD8 + TILs from three surgically-resected lung cancer specimens. Dimensional reduction for clustering was performed using Uniform Manifold Approximation and Projection. CD8 + TIL TCR specific for the cancer/testis antigen KK-LC-1 and for predicted neoantigens were investigated. Differentially-expressed gene analysis, Gene Set Enrichment Analysis (GSEA) and single sample GSEA was performed to characterize antigen-specific T cells., Results: A total of 6998 CD8 + T cells was analyzed, divided into 10 clusters according to their gene expression profile. An exhausted T-cell (exhausted T (Tex)) cluster characterized by the expression of ENTPD1 (CD39), TOX , PDCD1 (PD1), HAVCR2 (TIM3) and other genes, and by T-cell oligoclonality, was identified. The Tex TCR repertoire (Tex-TCRs) contained nine different TCR clonotypes recognizing five tumor antigens including a KK-LC-1 antigen and four neoantigens. By re-clustering the tumor antigen-specific T cells (n=140), it could be seen that the individual T-cell clonotypes were present on cells at different stages of differentiation and functional states even within the same Tex cluster. Stimulating these T cells with predicted cognate peptide indicated that TCR signal strength and subsequent T-cell proliferation and cytokine production was variable but always higher for neoantigens than KK-LC-1., Conclusions: Our approach focusing on T cells with an exhausted phenotype among CD8 + TILs may facilitate the identification of tumor antigens and clarify the nature of the antigen-specific T cells to specify the promising immunotherapeutic targets in patients with NSCLC., Competing Interests: Competing interests: This study was partly funded by NEC Corporation., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

This study elucidates that relativistic effect plays a key role in catalytic C-H activation using a cationic Ir complex. Experiments show that the cationic Ir(I)-diphosphine catalyst can be used for the deuterium substitution of N -phenylbenzamide, whereas a cationic Rh(I)-diphosphine catalyst is scarcely effective. Density functional theory calculations, including the relativistic effect, demonstrate a large difference in the reaction energy diagrams for the C-H activation of N -phenylbenzamide between the cationic Ir and Rh catalysts. In particular, the relatively low reaction barrier and considerably stabilized product obtained for the Ir catalysts are rationalized by strong Ir-C and Ir-H interactions, which originate from the relativistic self-consistent d-orbital expansion of Ir.

Traditionally, chemistry has been developed to obtain thermodynamically stable and isolable compounds such as molecules and solids by chemical reactions. However, recent developments in computational chemistry have placed increased importance on studying the dynamic assembly and disassembly of atoms and molecules formed in situ. This study directly visualizes the formation and dissociation dynamics of labile dimers and trimers at atomic resolution with elemental identification. The video recordings of many homo- and hetero-metallic dimers are carried out by combining scanning transmission electron microscopy (STEM) with elemental identification based on the Z-contrast principle. Even short-lived molecules with low probability of existence such as AuAg, AgCu, and AuAgCu are directly visualized as a result of identifying moving atoms at low electron doses., (© 2022. The Author(s).)

Meclozine has been developed as an inhibitor of fibroblast growth factor receptor 3 (FGFR3) to treat achondroplasia (ACH). Extracellular signal regulated kinase (ERK) phosphorylation was attenuated by meclozine in FGF2-treated chondrocyte cell line, but the site of its action has not been elucidated. Although orally administered meclozine promoted longitudinal bone growth in a mouse model of ACH, its effect on craniofacial bone development during the early stage remains unknown. Herein, RNA-sequencing analysis was performed using murine chondrocytes from FGF2-treated cultured tibiae, which was significantly elongated by meclozine treatment. Gene set enrichment analysis demonstrated that FGF2 significantly increased the enrichment score of mitogen-activated protein kinase (MAPK) family signaling cascades in chondrocytes; however, meclozine reduced this enrichment. Next, we administered meclozine to FGF2-treated larval zebrafish from 8 h post-fertilization (hpf). We observed that FGF2 significantly increased the number of ossified vertebrae in larval zebrafish at 7 days post-fertilization (dpf), while meclozine delayed vertebral ossification in FGF2-induced zebrafish. Meclozine also reversed the FGF2-induced upregulation of ossified craniofacial bone area, including ceratohyal, hyomandibular, and quadrate. The current study provided additional evidence regarding the inhibitory effect of meclozine on the FGF2-induced upregulation of MAPK signaling in chondrocytes and FGF2-induced development of craniofacial and vertebral bones., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Takemoto, Matsushita, Okamoto, Ito, Matsuura, Takashima, Chen-Yoshikawa, Ebi, Imagama, Kitoh, Ohno and Hosono.)

Superoxide dismutase 1 (SOD1) is a metalloenzyme with high structural stability, but a lack of Cu and Zn ions decreases its stability and enhances the likelihood of misfolding, which is a pathological hallmark of amyotrophic lateral sclerosis (ALS). A growing body of evidence has demonstrated that misfolded SOD1 has prion-like properties such as transmissibility between cells and intracellular propagation of misfolding of natively folded SOD1. Recently, we found that SOD1 is misfolded in the cerebrospinal fluid of sporadic ALS patients, providing a route by which misfolded SOD1 spreads via the extracellular environment of the central nervous system. Unlike intracellular misfolded SOD1, it is unknown which extracellular misfolded species is most relevant to prion-like properties. Here, we determined a conformational feature of extracellular misfolded SOD1 that is linked to prion-like properties. Using culture media from motor neuron-like cells, NSC-34, extracellular misfolded wild-type, and four ALS-causing SOD1 mutants were characterized as a metal-free, disulfide oxidized form of SOD1 (apo-SOD1 S-S ). Extracellular misfolded apo-SOD1 S-S exhibited cell-to-cell transmission from the culture medium to recipient cells as well as intracellular propagation of SOD1 misfolding in recipient cells. Furthermore, culture medium containing misfolded apo-SOD1 S-S exerted cytotoxicity to motor neuron-like cells, which was blocked by removal of misfolded apo-SOD1 S-S from the medium. We conclude that misfolded apo-SOD1 S-S is a primary extracellular species that is linked to prion-like properties.

From January, 1988 to October, 1995, 96 patients with operable breast cancer were treated by breast conserving treatment (BCT) including wide excision and axillary dissection followed by breast radiation. During the same period, 188 patients were treated by modified radical mastectomy (MRM) with or without breast reconstruction. In order to compare the survival of BCT and MRM groups, univariate and multivariate analyses were performed in this retrospective study. Univariate analysis revealed that the 5-year survival rates in the BCT and MRM groups were 97% +/- 2% and 87% +/- 3%, respectively (p < 0.05 with the Cox-Mantel test). However, the baseline variables were different between the groups. The adjusted Cox regression analysis revealed that the results of BCT were almost equivalent with those of MRM. Moreover, no breast recurrence was found in the BCT group. Therefore, it is suggested that our technique of BCT is as effective as modified radical mastectomy in treating operable breast cancer in Japanese patients.

The diagnostic value of frozen section was evaluated in the histologic assessment of surgical margins obtained by wide excision of breast tumors. There were 87 patients with unilateral breast cancer, and 5 with bilateral breast cancers. The periphery of the excised breast tissue was peeled like an orange and histologically examined by frozen and permanent section. If either in situ or infiltrating microscopic tumor was found at the margin, it was considered positive. Using frozen sections, the margin was judged histologically positive or suspicious in 30 tumors (31%) and negative in 67(69%) tumors. Positive surgical margins were histologically confirmed by permanent section in 20(67%) of the 30 tumors diagnosed as positive or suspicious on frozen section. Another 10 tumors had negative margins. In 4 tumors, however, while the initial or re-excised margin was negative on frozen section, the margins were positive by permanent section. These surgical margins were positive due exclusively to the presence of ductal carcinoma in situ (DCIS). Evaluation of surgical margins in breast cancer by frozen section, thus exhibited a diagnostic accuracy of 86&prtcnt;, a sensitivity of 83%, and a specificity of 86%. It is concluded that frozen sections are useful in the determination of involvement of surgical margins after the wide excision of breast cancer. It must be pointed out that frozen sections will ofter overestimate involvement of the surgical margins.