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Vaccination for the prevention of severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) infection is considered the most promising approach to control the pandemic of coronavirus disease 2019 (COVID-19). Although various COVID-19 vaccines have been developed worldwide using several modalities, the vaccines that have shown the highest efficacy to date are mRNA vaccines. Despite their extensive usage, the mechanisms that stimulate the immune responses associated with their immunogenicity and reactogenicity remain largely unknown. In this review, we summarize and discuss current knowledge on immune responses to COVID-19 mRNA vaccines, including potential immune responses and correlating factors underlying the immunogenicity and reactogenicity of mRNA vaccines. We also describe recent trends in the optimization of lipid nanoparticles and vaccination routes. Further understanding of vaccine-elicited immune responses will guide the development of more effective and safe vaccines.

Funding Information: We acknowledge all the participants and researchers of the 23 biobanks that have contributed to the GBMI. Biobank-specific acknowledgments are included in the Data S3 . We thank H. Huang, A.R. Martin, B.M. Neale, Y. Okada, K. Tsuo, J.C. Ulirsch, Y. Wang, and all the members of Finucane and Daly labs for their helpful feedback. M.K. was supported by a Nakajima Foundation Fellowship and the Masason Foundation . H.K.F. was funded by NIH grant DP5 OD024582 . Publisher Copyright: © 2022 The Author(s) Meta-analysis is pervasively used to combine multiple genome-wide association studies (GWASs). Fine-mapping of meta-analysis studies is typically performed as in a single-cohort study. Here, we first demonstrate that heterogeneity (e.g., of sample size, phenotyping, imputation) hurts calibration of meta-analysis fine-mapping. We propose a summary statistics-based quality-control (QC) method, suspicious loci analysis of meta-analysis summary statistics (SLALOM), that identifies suspicious loci for meta-analysis fine-mapping by detecting outliers in association statistics. We validate SLALOM in simulations and the GWAS Catalog. Applying SLALOM to 14 meta-analyses from the Global Biobank Meta-analysis Initiative (GBMI), we find that 67% of loci show suspicious patterns that call into question fine-mapping accuracy. These predicted suspicious loci are significantly depleted for having nonsynonymous variants as lead variant (2.7×; Fisher's exact p = 7.3 × 10−4). We find limited evidence of fine-mapping improvement in the GBMI meta-analyses compared with individual biobanks. We urge extreme caution when interpreting fine-mapping results from meta-analysis of heterogeneous cohorts.

Intestinal inflammation can be accompanied by osteoporosis, but their relationship, mediated by immune responses, remains unclear. Here, we investigated a non-IgE-mediated food-allergic enteropathy model of ovalbumin (OVA) 23-3 mice expressing OVA-specific T-cell-receptor transgenes. Mesenteric lymph nodes (MLNs) and their pathogenic CD4+T cells were important to enteropathy occurrence and exacerbation when the mice were fed an egg-white (EW) diet. EW-fed OVA23-3 mice also developed bone loss and increased CD44hiCD62LloCD4+T cells in the MLNs and bone marrow (BM); these changes were attenuated by MLN, but not spleen, resection. We fed an EW diet to F1 cross offspring from OVA23-3 mice and a mouse line expressing the photoconvertible protein KikGR to track MLN CD4+T cells. Photoconverted MLN CD44hiCD62LloCD4+T cells migrated predominantly to the BM; pit formation assay proved their ability to promote bone damage via osteoclasts. Significantly greater expression of IL-4 mRNA in MLN CD44hiCD62LloCD4+T cells and bone was observed in EW-fed OVA23-3 mice. Anti-IL-4 monoclonal antibody injection canceled bone loss in the primary inflammation phase in EW-fed mice, but less so in the chronic phase. This novel report shows the specific inflammatory relationship, via Th2-dominant-OVA-specific T cells and IL-4 production, between MLNs and bone, a distant organ, in food-allergic enteropathy.

Although mRNA vaccines are more immunogenic than other vaccine modalities in primary series vaccination, their immunogenicity has not been well compared to different vaccine modalities in additional boosters. Here the longitudinal analysis reveals more sustained RBD-binding IgG titers and RBD-ACE2 binding inhibitory activities with the breadth to antigenically distinct Beta and Omicron BA.1 variants by the S-268019-b spike protein booster vaccination compared to BNT162b2 mRNA homologous booster on mRNA vaccinees. The differences in the durability and breadth of plasma antibodies between BNT162b2 and S-268019-b groups are pronounced in those without systemic adverse events and were associated with different trends in the number and breadth of memory B cells. High-dimensional immune profiling identifies early CD16+ natural killer cell dynamics with CCR3 upregulation, as one of the correlates for the distinct antibody responses by the S-268019-b booster. Our results illustrate the combinational effects of heterologous booster on the immune dynamics and the durability and breadth of recalled antibody responses against emerging virus variants.

This study aimed to create an animal model of type Ia endoleak that creates persistent problems after thoracic endovascular aortic repair. In six swine, thoracic aortic aneurysms were created using the harvested jugular vein. We created a type Ia endoleak using a composite stent-graft comprising the first stent-graft (reverse-tapered: thicker part, 16 mm; thinner part, 10 mm) and the second stent-graft (tapered: thicker part, 18–20 mm; thinner part, 16 mm). This double-component stent-graft was deployed in the abdominal aorta and then moved upward to the proximal entry site of the thoracic aneurysm using the inflated balloon for precise positioning. After the surgical procedure and on postoperative day 8, aortography was performed to detect residual endoleak, and then the swine were euthanized. A stable aneurysm (mean size of all aneurysms, 16.8 ± 1.72 mm × 11.8 ± 2.32 mm) and type Ia endoleak were successfully observed in all swine. A single stent-graft was sufficient in one of the six swine. A novel technique to create a type Ia endoleak model can be successfully developed in swine.

HLA-A, -C, -B, and -DRB1 genotypes were analyzed in 178 Japanese COVID-19 patients to investigate the association of HLA with severe COVID-19. Analysis of 32 common HLA alleles at four loci revealed a significant association between HLA-DRB1*09:01 and severe COVID-19 (odds ratio [OR], 3.62; 95% CI, 1.57-8.35; p = 0.00251 [permutation p value = 0.0418]) when age, sex, and other common HLA alleles at the DRB1 locus were adjusted. The DRB1*09:01 allele was more significantly associated with risk for severe COVID-19 compared to preexisting medical conditions such as hypertension, diabetes, and cardiovascular diseases. These results indicate a potential role for HLA in predisposition to severe COVID-19.

Abstract An expanded myeloid cell compartment is a hallmark of severe coronavirus disease 2019 (COVID-19). However, data regarding myeloid cell expansion have been collected in Europe, where the mortality rate by COVID-19 is greater than those in other regions including Japan. Thus, characteristics of COVID-19-induced myeloid cell subsets remain largely unknown in the regions with low mortality rates. Here, we analyzed cellular dynamics of myeloid-derived suppressor cell (MDSC) subsets and examined whether any of them correlate with disease severity and prognosis, using blood samples from Japanese COVID-19 patients. We observed that polymorphonuclear (PMN)-MDSCs, but not other MDSC subsets, transiently expanded in severe cases but not in mild or moderate cases. Contrary to previous studies in Europe, this subset selectively expanded in survivors of severe cases and subsided before discharge, but such transient expansion was not observed in non-survivors in Japanese cohort. Analysis of plasma cytokine/chemokine levels revealed positive correlation of PMN-MDSC frequencies with IL-8 levels, indicating the involvement of IL-8 on recruitment of PMN-MDSCs to peripheral blood following the onset of severe COVID-19. Our data indicate that transient expansion of the PMN-MDSC subset results in improved clinical outcome. Thus, this myeloid cell subset may be a predictor of prognosis in cases of severe COVID-19 in Japan.

Reflected wave increases after endovascular aortic repair (EVAR) in patients with aortic aneurysm. This affects the left ventricular (LV) diastolic function and leads to a poor prognosis. This study aimed to evaluate the relationship between increased reflected wave amplitude and aortic diameter after EVAR. EVAR was performed in seven healthy goats. We assessed wave intensity (WI), aortic diameter, and stiffness parameter β. Moreover, we evaluated the relationship between negative reflected wave (NW, reflected waves toward the heart from the periphery by WI) and other parameters after EVAR. Results showed an increase in stiffness parameter β (3.5 ± 0.3 vs 15.9 ± 4.7, p = 0.018) and a decrease in the change of aortic diameter (6.9 ± 0.7 vs 2.7 ± 0.4%, p = 0.018) after EVAR. The NW was significantly amplified after EVAR from baseline (−589.8 ± 143.4 to − 1192.3 ± 303.7 mmHg-m/sec3, p = 0.043). The NW showed a significant correlation with maximum aortic diameter (R = 0.707, p = 0.038) and minimum aortic diameter (R = 0.724, p = 0.033). The reflected wave was enhanced after EVAR and was correlated to the aortic diameter at the stent-graft site. It is important to consider that patients with smaller aortic diameters in landing zone who undergo EVAR may develop LV dysfunction.

Multiple SARS-CoV-2 variants have mutations in the spike receptor binding domain (RBD) with potential to evade neutralizing antibody. In particular, the Beta and Omicron variants escape from antibody neutralizing activity in those who received two doses of BNT162b2 mRNA vaccine. Nonetheless, boosting with a third vaccine dose or by breakthrough infection improves the overall breadth of the neutralizing antibodies, but the mechanism remains unclear. Here, we longitudinally profiled the cellular composition of RBD-binding memory B cell subsets and their antibody binding and neutralizing activity against SARS-CoV-2 variants after the second dose of mRNA vaccine. Two doses of the mRNA vaccine elicited plasma neutralizing antibodies with a limited activity against Beta and Omicron but induced an expanded antibody breadth overtime, up to 4.9 months after vaccination. In contrast, more than one-third of RBD-binding IgG + memory B cells with a resting phenotype initially bound the Beta and Omicron variants and steadily increased the B cell receptor breadth overtime. As a result, a fraction of the resting memory B cell subset secreted Beta and Omicron-neutralizing antibody when stimulated in vitro. The neutralizing breadth of the resting memory B cell subset helps us understand the prominent recall of Omicron-neutralizing antibodies after an additional booster or breakthrough infection in fully vaccinated individuals.

Background: Wheat is known as the most widely consumed food all over the world. Although many types of wheat allergy have been recognized, their treatment still has a long way to go due to the complex pathogenesis. Oral immunotherapy (OIT) is under investigation for the treatment of wheat allergies. Previous studies have demonstrated that OIT using intact wheat allergens can induce tolerance, but is accompanied by a high risk of anaphylactic reactions. Objectives: Our objective was to prepare modified wheat allergens with hypoallergenic and tolerance-inducing properties to reduce adverse effects during immunotherapy. Methods: Wheat gliadin was degraded by hydrolysis with pepsin and trypsin, and then the hydrolysate was deamidated with hydrochloric acid. The IgE-binding capacity and T cell reactivity of the degraded gliadins were evaluated in vitro. Pepsin-digested gliadin (peptic-GLI) was applied in a mouse model to investigate whether it would induce oral tolerance. Results: Degradation with pepsin decreased IgE-binding capacity and maintained T cell reactivity. Oral administration of peptic-GLI to mice before sensitization and challenge with gliadin could significantly suppress the production of IgE, IgG1, and type 2 T helper cytokines. Moreover, the development of anaphylactic reactions and allergic responses of the small intestine induced by gliadin challenge were inhibited by oral administration of peptic-GLI. Conclusions: The findings of this study indicate that peptic-GLI with low allergenicity and potential for tolerance induction may become useful in wheat immunotherapy with less adverse effects.

Recently many researchers have revealed that certain lactic acid bacteria (LAB) have beneficial effects on the immune system. Understanding the mechanisms of how certain LAB induce immunomodulatory functions is important for the development of food ingredients that improve our health. Lactobacillus plantarum OLL2712 has been shown to induce production of interleukin (IL)-10, an anti-inflammatory cytokine, by murine in vitro-induced dendritic cells (DCs) and peritoneal macrophages. However, it is probable that in vitro-induced DCs have different properties compared with intestinal DCs, and the effects of the LAB on intestinal DCs are not fully understood. In this report, we investigated whether L. plantarum OLL2712 had efficacy for inducing intestinal DCs to produce IL-10 in vitro and whether oral administration of the bacteria induced the same effect. Co-culture of L. plantarum OLL2712 with purified DCs from the mesenteric lymph node (MLN) or Peyer's patch (PP) elevated IL-10 mRNA expression and protein production by both kinds of DCs. Addition of the LAB enhanced IL-10 production by T cells during antigen-specific responses in co-culture of MLN or PP DCs and T cells. Oral administration of L. plantarum OLL2712 for 6 days increased IL-10 gene expression in MLN DCs, and upregulated IL-10 gene expression in PP DCs was observed 12 hr after oral administration of the LAB. Our results suggested that L. plantarum OLL2712 could modulate immune responses by enhancing IL-10 production from intestinal DCs.

SARS-CoV-2 Beta and Omicron variants have multiple mutations in the receptor-binding domain (RBD) allowing antibody evasion. Despite the resistance to circulating antibodies in those who received two doses of mRNA vaccine, the third dose prominently recalls cross-neutralizing antibodies with expanded breadth to these variants. Herein, we longitudinally profiled the cellular composition of persistent memory B-cell subsets and their antibody reactivity against these variants following the second vaccine dose. The vaccination elicited a memory B-cell subset with resting phenotype that dominated the other subsets at 4.9 months. Notably, most of the resting memory subset retained the ability to bind the Beta variant, and the memory-derived antibodies cross-neutralized the Beta and Omicron variants at frequencies of 59% and 29%, respectively. The preservation of cross-neutralizing antibody repertoires in the durable memory B-cell subset likely contributes to the prominent recall of cross-neutralizing antibodies following the third dose of the vaccine.One Sentence SummaryFully vaccinated individuals preserve cross-neutralizing memory B-cells against the SARS-CoV-2 Omicron variant.

Pfizer/BioNTec BNT162b2 mRNA vaccine robustly elicits neutralizing antibodies against SARS-CoV-2 in clinical trials and real-world settings. However, booster vaccinations are frequently associated with self-limited adverse events. Here, by applying a high-dimensional immune profiling approach to peripheral blood, we linked early vaccine-induced immune dynamics with adverse events and neutralizing antibody responses. The dynamics of two dendritic cell subsets (DC3s and AS-DCs) were identified as the specific correlates for adverse events; the combination of these cell dynamics stratified the vaccinees with severe reactogenicity, while the stratification did not affect the neutralizing antibody titers. Furthermore, the NKT-like cell dynamics that correlated with adverse events and antibody titers were accounted for distinct magnitudes of both events by sex and age. The identified immune correlates for adverse events and antibody responses may pave the way for a rational vaccine strategy for reducing the reactogenicity of mRNA vaccines without compromising the immunogenicity.

Funding Information: The work of the contributing biobanks was supported by numerous grants from governmental and charitable bodies. Biobank-specific acknowledgments and more detailed acknowledgments are included in Data S2. Initiative management, S.B.C. J.C. N.J.C. M.J.D. E.E.K. A.R.M. B.M.N. Y.O. A.V.P. D.A.v.H. R.G.W. C.J.W. W.Z. and S.Z.; individual biobank analysis, A.B. Y.B. B.M.B. C.D.B. S.C. T.-T.C. K.C. S.M.D. M.D. G.H.d.B. Y.D. N.J.D. M.-J.F. Y.-C.A.F. S.F. V.L.F. L.G.F. E.R.G. T.R.G. D.H.G. C.R.G. G.G.-A. S.E.G. L.A.G. C.H. J.B.H. W.E.H. H.H. K.H. N.I. A.I. R.J. M. Kurki, J.K. N.K. E.E.K. J.T.K. M. Kanai, T.L. K.L. M.H.L. S.L. K.L. Y.-F.L. V.L.F. R.J.F.L. E.A.L.-M. A.R.-M. S.M.-G. R.M. R.E.M. H.C.M. A.R.M. Y.M. H.M. S.E.M. I.Y.M. B.M. S.M. K.N. S.N. M.A.N.-A. K.N. Y.O. P.P. A.L.-P. A.P. B.P. S.P. M.H.P. D.J.R. N.R. M.D.R. A.R. C.S. S.S. S.S.S. J.A.S. P.S. I.S. T.T. R.T. K.T. J.U. D.A.v.H. B.V. M.V. Y.V. J.M.V. R.G.W. Y.W. S.J.W. B.N.W. K.-H.H.W. M.Z. X.Z. and S.Z.; individual biobank management, N.A. A.A.T. K.M.A.-D. P.A. K.C.B. M. Boehnke, M. Boezen, C.D.B. A.C. Z.C. C.-Y.C. J.C. N.J.C. S.M.D. S.F. Y.-C.A.F. S.F. E.F. T.G. C.R.G. C.J.G. Y.G. H.H. K.A.H. K.H. S.I.I. N.M.J. N.K. E.E.K. J.T.K. C.L. M.H.L. M.T.M.L. L.L. K.L. Y.-F.L. R.J.F.L. J.L. S.M. Y.M. K.M. I.Y.M. Y.O. C.M.O. A.V.P. B.P. D.J.P. D.J.R. M.D.R. S.S. J.W.S. H.S. K.S. T.T. U.T. R.C.T. D.A.v.H. M.V. R.G.W. D.C.W. C.W. J.W. M.Z. X.Z. and S.Z.; study design and interpretation of results, A.B. M. Boehnke, M. Boezen, B.M.B. T.-T.C. C.-Y.C. M.J.D. G.D.S. N.J.D. S.F. M.-J.F. H.K.F. E.R.G. A.G. T.G. J.B.H. J.H. K.H. R.J. M.K. E.E.K. T.K. C.M.L. V.L.F. E.A.L.-M. A.R.M. S.N. B.M.N. C.M.O. J.J.P. B.P. N.R. H.R. J.A.S. I.S. K.T. D.A.v.H. R.G.W. Y.W. D.C.W. S.J.W. C.J.W. B.N.W. J.W. K.-H.H.W. M.Z. H.Z. J.Z. W.Z. X.Z. and S.Z.; drafted and edited the paper, A.B. M. Boehnke, M. Boezen, M.J.D. G.H.d.B. N.J.D. T.R.G. J.B.H. N.I. N.M.J. M.K. V.L.F. S.M. A.R.M. H.M. S.N. B.M.N. C.M.O. B.P. H.R. C.S. J.A.S. J.W.S. K.T. Y.W. D.C.W. C.J.W. K.-H.H.W. H.Z. J.Z. W.Z. and S.Z.; primary meta-analysis and quality control, M.J.D. H.K.F. M. Kanai, J.K. J.T.K. M. Kurki, M.M. B.M.N. C.J.W. K.-H.H.W. and W.Z.; drug discovery: S.N. T.K. K.-H.H.W. W.Z. and Y.O.; fine mapping, M. Kanai, W.Z. M.J.D. and H.K.F.; polygenic risk score, Y.W. S.N. E.A.L.-M. S.K. K.T. K.L. M. Kanai, W.Z. K.W. M.-J.F. L.B. P.A. P.D. V.L.F. R.M. Y.M. B.B. S.S. J.U. E.R.G. N.J.C. I.S. Y.O. A.R.M. and J.B.H.; proteome-wide Mendelian randomization, H.Z. H.R. A.B. G.H. G.D.S. B.M.B. W.Z. B.M.N. T.R.G. and J.Z.; transcriptome-wide association study, A.B. J.B.H. W.Z. J.Z. M. Kanai, B.P. E.R.G. and N.J.C.; asthma, K.T. W.Z. Y.W. M. Kanai, S.N. Y.O. B.M.N. M.J.D. and A.R.M.; heart failure, K.-H.H.W. N.J.D. B.N.W. I.S. S.E.G. J.B.H. N.J.C. M.P. R.J.F.L. M.J.D. B.M.N. W.Z. W.E.H. and C.J.W.; idiopathic pulmonary fibrosis, J.J.P. W.Z. M.J.D. J.T.K. N.J.C. and J.B.H.; primary open-angle glaucoma, V.L.F. A.B. W.Z. Y.W. K.L. M. Kanai, E.A.L.-M. P.S. R.T. X.Z. S.N. S.S. Y.O. N.I. S.M. H.S. I.S. C.W. A.R.M. E.R.G. N.M.J. N.J.C. and J.B.H.; stroke, I.S. K.-H.H.W. W.H. B.N.W. W.Z. J.E.H. A.P. B.B. A.H.S. M.E.G. R.G.W. K.H. C.K. S.Z. M.J.D. B.M.N. and C.J.W.; venous thromboembolism, B.N.W. I.S. K.-H.H.W. B.B. V.L.F. K.T. M.D. B.N. W.Z. J.A.S. and C.J.W. All authors reviewed the manuscript. M.J.D. is a founder of Maze Therapeutics. B.M.N. is a member of the scientific advisory board at Deep Genomics and a consultant for Camp4 Therapeutics, Takeda Pharmaceutical, and Biogen. The spouse of C.J.W. works at Regeneron Pharmaceuticals. C.-Y.C. is employed by Biogen. C.R.G. owns stock in 23andMe, Inc. T.R.G. has received research funding from various pharmaceutical companies to support the application of Mendelian randomization to drug target prioritization. E.E.K. has received speaker fees from Regeneron, Illumina, and 23andMe and is a member of the advisory board for Galateo Bio. R.E.M. has received speaker fees from Illumina and is a scientific advisor to the Epigenetic Clock Development Foundation. G.D.S. has received research funding from various pharmaceutical companies to support the application of Mendelian randomization to drug target prioritization. K.S. and U.T. are employed by deCODE Genetics/Amgen, Inc. J.Z. has received research funding from various pharmaceutical companies to support the application of Mendelian randomization to drug target prioritization. S.M. is a co-founder of and holds stock in Seonix Bio. Publisher Copyright: © 2022 Biobanks facilitate genome-wide association studies (GWASs), which have mapped genomic loci across a range of human diseases and traits. However, most biobanks are primarily composed of individuals of European ancestry. We introduce the Global Biobank Meta-analysis Initiative (GBMI)—a collaborative network of 23 biobanks from 4 continents representing more than 2.2 million consented individuals with genetic data linked to electronic health records. GBMI meta-analyzes summary statistics from GWASs generated using harmonized genotypes and phenotypes from member biobanks for 14 exemplar diseases and endpoints. This strategy validates that GWASs conducted in diverse biobanks can be integrated despite heterogeneity in case definitions, recruitment strategies, and baseline characteristics. This collaborative effort improves GWAS power for diseases, benefits understudied diseases, and improves risk prediction while also enabling the nomination of disease genes and drug candidates by incorporating gene and protein expression data and providing insight into the underlying biology of human diseases and traits.

Gas sensing by using the transmission surface plasmon resonance (T-SPR) technique was demonstrated. Polyacrylic acid (PAA)/5-nm-thick gold/40-nm-thick silver/polycarbonate grating substrate...

Macrophages are classified into classically activated M1 macrophages and alternatively activated M2 macrophages, and the two phenotypes of macrophages are present during the development of various chronic diseases, including obesity-induced inflammation. In the present study, β-elemene, which is contained in various plant substances, is predicted to treat high-fat diet (HFD)-induced macrophage dysfunction based on the Gene Expression Omnibus (GEO) database and experimental validation. β-elemene impacts the imbalance of M1-M2 macrophages by regulating pro-inflammatory cytokines in mouse white adipose tissue both in vitro and in vivo. In addition, the RAW 264 cell line, which are macrophages from mouse ascites, is used to identify the effects of β-elemene on inhibiting bacterial endotoxin lipopolysaccharide (LPS)-induced phosphorylation of mitogen-activated protein kinase (MAPK) pathways. These pathways both induce and are activated by pro-inflammatory cytokines, and they also participate in the process of obesity-induced inflammation. The results highlight that β-elemene may represent a possible macrophage-mediated therapeutic medicine.

Antibody titers against SARS-CoV-2 slowly wane over time. Here, we examined how time affects antibody potency. To assess the impact of antibody maturation on durable neutralizing activity against original SARS-CoV-2 and emerging variants of concern (VOCs), we analyzed receptor binding domain (RBD)-specific IgG antibodies in convalescent plasma taken 1–10 months after SARS-CoV-2 infection. Longitudinal evaluation of total RBD IgG and neutralizing antibody revealed declining total antibody titers but improved neutralization potency per antibody to original SARS-CoV-2, indicative of antibody response maturation. Neutralization assays with authentic viruses revealed that early antibodies capable of neutralizing original SARS-CoV-2 had limited reactivity toward B.1.351 (501Y.V2) and P.1 (501Y.V3) variants. Antibodies from late convalescents exhibited increased neutralization potency to VOCs, suggesting persistence of cross-neutralizing antibodies in plasma. Thus, maturation of the antibody response to SARS-CoV-2 potentiates cross-neutralizing ability to circulating variants, suggesting that declining antibody titers may not be indicative of declining protection., Graphical abstract, Antigenic drifts in SARS-CoV-2 variants permit escape from neutralizing antibody in COVID-19 convalescent plasma. Moriyama et al. reveal the evolution of serological immunity with time that counters SARS-CoV-2 variants via affinity maturation and durable elicitation of IgG antibodies that are resistant to viral escape.

Background This study investigated the effect of outpatient cardiac rehabilitation (OCR) and physical activity on the estimated glomerular filtration rate based on serum cystatin C (eGFRcys) in patients with heart disease (HD) aged ≥75 years.Methods and Results:This non-randomized prospective intervention study involved 136 patients (non-OCR group, n=66; OCR group, n=70), 55 of whom were aged ≥75 years (non-OCR group, n=29; OCR group, n=26). Renal function (eGFRcys) was evaluated at discharge and 3 months thereafter. A linear mixed model (LMM) was used to assess changes in renal function over time. The hospital readmission rate within 3 months after discharge was also evaluated. LMM analysis showed that the change in eGFRcys was -2.27 and +0.48 mL/min/1.73 m2in the non-OCR and OCR groups, respectively (F=2.960, P=0.022). Further, among patients aged ≥75 years in the non-OCR and OCR groups, the change in eGFRcys was -3.83 and -1.08 mL/min/1.73 m2, respectively (F=2.719, P=0.039). The proportion of patients aged ≥75 years who were rehospitalized due to exacerbation of HD was 16.9% (n=10) and 6.7% (n=2) in the non-OCR and OCR groups, respectively. Conclusions Among patients with HD aged ≥75 years, participation in OCR reduces the decline in renal function and hospital readmission rates.

SARS-CoV-2 variants have raised concerns regarding resistance to neutralizing antibodies elicited by the parental virus. In the present study, we monitored multiple parameters of neutralizing antibodies in convalescent plasma up to 10 months after the symptom onset. In contrast to marked decline of neutralizing antibody titers, the neutralization potency per antibody increased with time. The antigenic drift of B.1.351 (501Y.V2) and P.1 (501Y.V3) variants conferred resistance to neutralization by convalescent plasma in the early phase; however, the resistance of these variants was attenuated by progressive increase of neutralization potency and breadth over time. Furthermore, this increase in the neutralization potency/breadth were highly correlated with the affinity maturation of IgG antibodies that target virus conserved sites with extended half-lives. Despite a quantitative decline in the neutralizing antibody titers, the serological immunity shapes the neutralization potency and breadth with time, thereby acquiring persistent neutralizing activity toward SARS-CoV-2 variants. Declaration of Interest: All authors declare that they have no competing interests. Ethical Approval: All studies were approved by the Institutional Review Board of the National Institute of Infectious Diseases (#1127, #1132, and #1197). This study was performed in accordance with the Declaration of Helsinki. All volunteers provided written informed consent prior to enrollment.

Summary The role of the intestinal immune system in the inhibition of fat tissue-related inflammation by dietary material is yet to be elucidated. Oral administration of β-elemene, contained in various foodstuffs, downregulated expressions of inflammatory cytokines and increased Foxp3+CD4+ T cells in adipose tissue of obese mice. However, β-elemene did not affect the inflammatory response of adipose tissue in vitro, suggesting that the inhibition observed in vivo was not due to direct interactions of adipose tissue with β-elemene. Instead, β-elemene increased Foxp3+CD4+ T cell population enhancing gene expressions of transforming growth factor β 1, retinaldehyde dehydrogenase 2, integrin αvβ8, and interleukin-10 in intestinal dendritic cells (DCs) in vivo and in vitro. Taken together, this study suggested the therapeutic effects of β-elemene on treating experimental obesity-induced chronic inflammation by adjusting the balance of immune cell populations in fat tissue through the generation of regulatory T cells in the intestinal immune system by modulating DC function., Graphical abstract, Highlights • β-elemene downregulated inflammatory cytokines of adipose tissue of obese mice • β-elemene increased Tregs of adipose tissue of obese mice • β-elemene enhanced the expression of molecules for Treg induction in intestinal DCs, Human Metabolism; Immunology

Two doses of Pfizer/BioNTec BNT162b2 mRNA vaccine elicit robust SARS-CoV-2-neutralizing antibodies with frequent adverse events. Here, by applying a high-dimensional immune profiling on 92 vaccinees, we identified six vaccine-induced immune dynamics that correlated with the amounts of neutralizing antibodies, the severity of adverse events, or both. The early dynamics of natural killer/monocyte subsets and two dendritic cell subsets were revealed as the distinct cell correlates for neutralizing antibody titers and adverse events, respectively. Indeed, the combination of two dendritic cell dynamics classified a subgroup of vaccinees with more severe adverse events but with equivalent antibody titers. Among the six cell dynamics, there were multiple dynamics that varied with gender and age, suggesting the possible linkages with gender/age-dependent responses. The identified immune correlates may pave the way for a rational strategy for optimizing an immune balance between the immunogenicity and reactogenicity of the vaccine. Funding: This work was supported by Japan Agency for Medical Research and Development grant (grant number JP20fk0108534 to T.M. and Y.T.). Declaration of Interests: N.S. is an employee of KOTAI Biotechnologies, Inc. K.Y. is a founder, shareholder and board director of KOTAI Biotechnologies, Inc. All other authors declare they have no competing interests. Ethics Approval Statement: All studies were approved by the Institutional Review Board of the National Institute of Infectious Diseases and Tokyo Shinagawa Hospital (Permit 24 numbers: 1292 and 20-A-33). This study was performed in accordance with the principles of the Declaration of Helsinki. All volunteers provided written informed consent prior to enrollment.

An expanded myeloid cell compartment is a hallmark of severe coronavirus disease 2019 (COVID-19); however, it remains unclear whether myeloid cells are beneficial or detrimental to the clinical outcome. Here, we tracked cellular dynamics of myeloid-derived suppressor cell (MDSC) subsets and examined whether any of them correlate with disease severity and prognosis by flow cytometric analysis of blood samples from COVID-19 patients. We observed that polymorphonuclear (PMN)-MDSCs, rather than other MDSC subsets, transiently expanded in severe cases but not in mild or moderate cases. Notably, this subset was selectively expanded in survivors of severe cases and diminished during recovery. Analysis of plasma cytokines/chemokines revealed that interleukin-8 increased prior to PMN-MDSC expansion in survivors and returned to basal levels during the recovery phase. In contrast, interleukin-6 and interferon--induced protein 10 were abundantly induced in non-survivors, suggesting possible downstream targets for the immunosuppressive effects of the MDSC subset. Our data indicate that increased cellularity of PMN-MDSCs might be beneficial for the clinical outcome and could be useful as a possible predictor of prognosis in cases of severe COVID-19.

An expanded myeloid cell compartment is a hallmark of severe coronavirus disease 2019 (COVID-19). However, data regarding myeloid cell expansion have been collected in Europe, where the mortality rate by COVID-19 is greater than those in other regions including Japan. Thus, characteristics of COVID-19-induced myeloid cell subsets remain largely unknown in the regions with low mortality rates. Here, we analyzed cellular dynamics of myeloid-derived suppressor cell (MDSC) subsets and examined whether any of them correlate with disease severity and prognosis, using blood samples from Japanese COVID-19 patients. We observed that polymorphonuclear (PMN)-MDSCs, but not other MDSC subsets, transiently expanded in severe cases but not in mild or moderate cases. Contrary to previous studies in Europe, this subset selectively expanded in survivors of severe cases and subsided before discharge, but such transient expansion was not observed in non-survivors in Japanese cohort. Analysis of plasma cytokine/chemokine levels revealed positive correlation of PMN-MDSC frequencies with interleukin 8 (IL-8) levels prior to the cell expansion, indicating the involvement of IL-8 on recruitment of PMN-MDSCs to peripheral blood following the onset of severe COVID-19. Thus, our data indicates that transient expansion of the PMN-MDSC subset results in improved clinical outcome. Thus, this myeloid cell subset may be a predictor of prognosis in cases of severe COVID-19 in Japan.

As a kind of metabolically triggered inflammation, obesity influences the interplay between the central nervous system and the enteral environment. The present study showed that β-elemene, which is contained in various plant substances, had effects on recovering the changes in metabolites occurring in high-fat diet (HFD)-induced obese C57BL/6 male mice brains, especially in the prefrontal cortex (PFC) and hippocampus (HIP). β-elemene also partially reversed HFD-induced changes in the composition and contents of mouse gut bacteria. Furthermore, we evaluated the interaction between cerebral metabolites and intestinal microbiota via Pearson correlations. The prediction results suggested that Firmicutes were possibly controlled by neuron integrity, cerebral inflammation, and neurotransmitters, and Bacteroidetes in mouse intestines might be related to cerebral aerobic respiration and the glucose cycle. Such results also implied that Actinobacteria probably affected cerebral energy metabolism. These findings suggested that β-elemene has regulatory effects on the imbalanced microbiota-gut-brain axis caused by obesity and, therefore, would contribute to the future study in on the interplay between cerebral metabolites from different brain regions and the intestinal microbiota of mice.

Dendritic cells (DCs) in mesenteric lymph nodes (MLNs) induce Foxp3+ regulatory T cells to regulate immune responses to beneficial or non-harmful agents in the intestine, such as commensal bacteria and foods. Several studies in MLN DCs have revealed that the CD103+ DC subset highly induces regulatory T cells, and another study has reported that MLN DCs from programmed death ligand 1 (PD-L1) -deficient mice could not induce regulatory T cells. Hence, the present study investigated the expression of these molecules on MLN CD11c+ cells. Four distinct subsets expressing CD103 and/or PD-L1 were identified, namely CD11b+ CD103+ PD-L1High , CD11b- CD103+ PD-L1High , CD11b- CD103+ PD-L1Low and CD11b+ CD103- PD-L1Int . Among them, the CD11b- CD103+ PD-L1High DC subset highly induced Foxp3+ T cells. This subset expressed Aldh1a2 and Itgb8 genes, which are involved in retinoic acid metabolism and transforming growth factor-β (TGF-β) activation, respectively. Exogenous TGF-β supplementation equalized the level of Foxp3+ T-cell induction by the four subsets whereas retinoic acid did not, which suggests that high ability to activate TGF-β is determinant for the high Foxp3+ T-cell induction by CD11b- CD103+ PD-L1High DC subset. Finally, this subset exhibited a migratory DC phenotype and could take up and present orally administered antigens. Collectively, the MLN CD11b- CD103+ PD-L1High DC subset probably takes up luminal antigens in the intestine, migrates to MLNs, and highly induces regulatory T cells through TGF-β activation.

An 84-year-old woman was referred to our hospital with a suspected cardiac tumor detected by transthoracic echocardiography performed as a preoperative examination of gastric cancer. In addition to a tumor in the left atrium, we found on cardiac ultrasound a 15-mm mobile tumor that adhered to the aortic valve. Gross findings and histological examination confirmed that the tumor in the left atrium was a cardiac myxoma, and that the tumor adhered to the aortic valve was a papillary fibroelastoma. We experienced a rare case where preoperative examination before gastrectomy accidentally revealed concomitant cardiac tumors.

Papillary fibroelastoma is a rare, benign cardiac tumor. Surgical resection is indicated to prevent embolization. We herein report a case of a 78-year-old asymptomatic man who was found to have a mobile left ventricular papillary fibroelastoma anchoring deep in the left ventricle by incidental transthoracic echocardiography. The tumor was resected under visualization by a video-assisted rigid endoscope with a flexible head inserted through the aortic valve into the left ventricle. Intraoperative frozen section analysis provided a pathological diagnosis of papillary fibroelastoma. The postoperative course was uneventful. This technique is recommended for the observation and resection of a tumor anchoring deep in the left ventricle and is helpful for avoiding the adverse effects of left ventriculotomy.

A 74-year-old man with multiple aortic aneurysms and shaggy aorta was simultaneously treated by conventional open repair for an abdominal aortic aneurysm and endoluminal stent grafting for a thoracic aortic aneurysm. We performed intermittent clamping of the visceral and carotid arteries under an extracorporeal circulation circuit without a blood flow pump, which lead to the avoidance of embolization in spite of the disadvantage of endoluminal stent grafting for atheromatous aorta.

高温加熱を受ける高強度コンクリートの耐火性能の向上を目的とし，ポリプロピレン繊維，鋼繊維，およびこれらを混合したハイブリット繊維で補強した高強度コンクリートについて，比較的温度の低い領域での耐火性能を調べるために約600℃の加熱によるセメント硬化体の化学的変化，微細構造の劣化および透水性挙動などの物理的性質および残存強度特性，じん性劣化挙動ならびに爆裂に関する耐火性能を明らかにした． その結果，400℃までの加熱ではC-S-Hの結晶体群は完全結晶体に近づき，また，爆裂現象にはCa(OH)2の脱水分解が影響している可能性を示した．ハイブリット繊維補強高強度コンクリートは鋼繊維ならびにポリプロピレン繊維補強高強度コンクリートの短所を補う耐火性を示すことを明らかにした．

Many of saccular aortic arch aneurysms exist near left subclabian artery(LSA). The thoracic endovascular aneurysm repair( TEVAR) landing on zone 2 is a less invasive and suitable procedure for this type of aneurysm. However, there are several cases with the aneurysm located close to LSA necessitate landing TEVAR on zone 1 or zone 0, otherwise the aneurysm could not be sealed completely. And this procedure seems to increase the invasiveness. In order to complete the sealing of the aneurysm and also keep the less invasiveness, we performed TEVAR using an axillo-axillary bypass or simple occlusion of LSA followed by an embolization using metal coil and NBCA through the catheter which detained in the saccular aneurysm beforehand. We report our experience of seven cases have been successfully treated by this procedure with good results.

In vivo oxygen measurement is the key to understanding how biological systems dynamically adapt to reductions in oxygen supply. High spatial resolution oxygen imaging is of particular importance because recent studies address the significance of within-tissue and within-cell heterogeneities in oxygen concentration in health and disease. Here, we report a new technique for in vivo molecular imaging of oxygen in organs using green fluorescent protein (GFP). GFP-expressing COS-7 cells were briefly photoactivated with a strong blue light while lowering the oxygen concentration from 10% to 580 nm) appeared after photoactivation at