In contrast to a second dose of the SARS-CoV-2 mRNA vaccine, a third dose elicits potent neutralizing activity against the Omicron variant. To address the underlying mechanism for this differential ...antibody response, we examined spike receptor-binding domain (RBD)-specific memory B cells in vaccinated individuals. Frequency of Omicron-reactive memory B cells increased ∼9 mo after the second vaccine dose. These memory B cells show an altered distribution of epitopes from pre-second memory B cells, presumably due to an antibody feedback mechanism. This hypothesis was tested using mouse models, showing that an addition or a depletion of RBD-induced serum antibodies results in a concomitant increase or decrease, respectively, of Omicron-reactive germinal center (GC) and memory B cells. Our data suggest that pre-generated antibodies modulate the selection of GC and subsequent memory B cells after the second vaccine dose, accumulating more Omicron-reactive memory B cells over time, which contributes to the generation of Omicron-neutralizing antibodies elicited by the third vaccine dose.
Abstract
It was recently reported that hepatocellular carcinoma (HCC) patients with non-alcoholic steatohepatitis (NASH) are not responsive to immune-checkpoint inhibitor (ICI) treatment. The present ...study aimed to evaluate the therapeutic efficacy of lenvatinib in patients with non-alcoholic fatty liver disease (NAFLD)/NASH-related unresectable-HCC (u-HCC). Five hundred thirty u-HCC patients with Child–Pugh A were enrolled, and divided into the NAFLD/NASH (n = 103) and Viral/Alcohol (n = 427) groups. Clinical features were compared in a retrospective manner. Progression-free survival (PFS) was better in the NAFLD/NASH than the Viral/Alcohol group (median 9.3 vs. 7.5 months, P = 0.012), while there was no significant difference in overall survival (OS) (20.5 vs. 16.9 months, P = 0.057). In Cox-hazard analysis of prognostic factors for PFS, elevated ALT (≥ 30 U/L) (HR 1.247, P = 0.029), modified ALBI grade 2b (HR 1.236, P = 0.047), elevated AFP (≥ 400 ng/mL) (HR 1.294, P = 0.014), and NAFLD/NASH etiology (HR 0.763, P = 0.036) were significant prognostic factors. NAFLD/NASH etiology was not a significant prognostic factor in Cox-hazard analysis for OS (HR0.758, P = 0.092), whereas AFP (≥ 400 ng/mL) (HR 1.402, P = 0.009), BCLC C stage (HR 1.297, P = 0.035), later line use (HR 0.737, P = 0.014), and modified ALBI grade 2b (HR 1.875, P < 0.001) were significant. Lenvatinib can improve the prognosis of patients affected by u-HCC irrespective of HCC etiology or its line of treatment.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Control of ion arrangements in ionic liquids represents a major challenge owing to the presence of the predominant coulombic interactions between cationic and anionic ion species that forms the ...coulombic ordering. Here, water‐induced ion rearrangement in a room‐temperature ionic liquid (RT‐IL) metal complex, (1‐ethyl‐3‐methylimidazolium)2MnN(CN)4, is demonstrated through coordinative interactions between anions. Solidification occurred, which was associated with the formation of a “separated” structure consisting of cation columns and anionic cyanide‐bridged one‐dimensional coordination polymers. The energy diagram is in accord with the resultant RT‐IL incorporating mononuclear MnN(CN)42− molecules being a kinetic phase stabilized by inter‐ion repulsions of the anionic divalent metal complex moieties. Water acts to decrease the coulombic interactions, including repulsion, giving rise to breaking of the coulombic ordering arising from coordination bond formation in the IL phase.
Add water to get a solid: Water reduces the coulombic interaction in an ionic liquid (IL) metal complex, giving rise to the coordinative interaction to solidify the corresponding IL metal complex as a crystalline coordination polymer associated with the ion rearrangement.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Chromatin condensation state is the key for retrieving genetic information. High‐mobility group protein (HMG) proteins exhibit DNA‐binding and bending activities, playing an important role in the ...regulation of chromatin structure. We have shown that nucleosomes tightly packaged into heterochromatin undergo considerable dynamic histone H2A‐H2B maintenance via the direct interaction between HP1/Swi6 and facilitate chromatin transcription (FACT), which is composed of the Spt16/Pob3 heterodimer and Nhp6. In this study, we analyzed the role of Nhp6, an HMG box protein, in the FACT at heterochromatin. Pob3 mutant strains showed derepressed heterochromatin‐dependent gene silencing, whereas Nhp6 mutant strains did not show significant defects in chromatin regulation or gene expression, suggesting that these two modules play different roles in chromatin regulation. We expressed a protein fusing Nhp6 to the C‐terminus of Pob3, which mimics the multicellular FACT component Ssrp1. The chromatin‐binding activity of FACT increased with the number of Nhp6 fused to Pob3, and the heterochromatin formation rate was promoted more strongly. Furthermore, we demonstrated that this promotion of heterochromatinization inhibited the heterochromatic variegation caused by epe1+ disruption. Heterochromatic variegation can be observed in a variety of regulatory steps; however, when it is caused by fluctuations in chromatin arrangement, it can be eliminated through the strong recruitment of the FACT complex.
Heterochromatic variegation was suppressed by Ssrp1‐like FACT.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
H3K9 methylation (H3K9me) is a conserved marker of heterochromatin, a transcriptionally silent chromatin structure. Knowledge of the mechanisms for regulating heterochromatin distribution is limited. ...The fission yeast JmjC domain-containing protein Epe1 localizes to heterochromatin mainly through its interaction with Swi6, a homologue of heterochromatin protein 1 (HP1), and directs JmjC-mediated H3K9me demethylation in vivo. Here, we found that loss of epe1 (epe1Δ) induced a red-white variegated phenotype in a red-pigment accumulation background that generated uniform red colonies. Analysis of isolated red and white colonies revealed that silencing of genes involved in pigment accumulation by stochastic ectopic heterochromatin formation led to white colony formation. In addition, genome-wide analysis of red- and white-isolated clones revealed that epe1Δ resulted in a heterogeneous heterochromatin distribution among clones. We found that Epe1 had an N-terminal domain distinct from its JmjC domain, which activated transcription in both fission and budding yeasts. The N-terminal transcriptional activation (NTA) domain was involved in suppression of ectopic heterochromatin-mediated red-white variegation. We introduced a single copy of Epe1 into epe1Δ clones harboring ectopic heterochromatin, and found that Epe1 could reduce H3K9me from ectopic heterochromatin but some of the heterochromatin persisted. This persistence was due to a latent H3K9me source embedded in ectopic heterochromatin. Epe1H297A, a canonical JmjC mutant, suppressed red-white variegation, but entirely failed to remove already-established ectopic heterochromatin, suggesting that Epe1 prevented stochastic de novo deposition of ectopic H3K9me in an NTA-dependent but JmjC-independent manner, while its JmjC domain mediated removal of H3K9me from established ectopic heterochromatin. Our results suggest that Epe1 not only limits the distribution of heterochromatin but also controls the balance between suppression and retention of heterochromatin-mediated epigenetic diversification.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
It is important to achieve herd immunity by vaccinating as many people as possible to end the COVID-19 pandemic. We investigated the relationship between willingness to receive vaccination and ...sources of health information among those who did not want to be vaccinated against COVID-19.
This prospective cohort study collected data using a self-administered questionnaire survey. The baseline survey was conducted during December 22-25, 2020, and the follow-up survey during February 18-19, 2021. Participants were aged 20-65 years and worked at the time of the baseline survey (N = 33,087). After excluding 6,051 invalid responses, we included responses from 27,036 participants at baseline. In total, 19,941 people responded to the follow-up survey (74% follow-up rate). We excluded 7,415 participants who answered "yes" to the question "If a COVID-19 vaccine becomes available, would you like to get it?" in the baseline survey. We finally analyzed 12,526 participants.
The odds ratio for change in willingness to be vaccinated from "no" to "yes" differed by source of health information. Compared with workers that used TV as a source of information, significantly fewer people who reported getting information from the Internet and friends/colleagues were willing to get the vaccine.
It is important to approach workers who do not watch TV when implementing workplace vaccination programs. It is likely that willingness to be vaccinated can be increased through an active company policy whereby the top management recommend vaccination, coupled with an individual approach by occupational health professionals.
Not applicable.
The subcommissural organ (SCO) is a part of the circumventricular organs located in the dorsocaudal region of the third ventricle at the entrance of the aqueduct of Sylvius. The SCO comprises ...epithelial cells and produces high molecular weight glycoproteins, which are secreted into the third ventricle and become part of Reissner's fibre in the cerebrospinal fluid. Abnormal development of the SCO has been linked with congenital hydrocephalus, a condition characterized by excessive accumulation of cerebrospinal fluid in the brain. In the present study, we characterized the SCO cells in the adult mouse brain to gain insights into the possible role of this brain region. Immunohistochemical analyses revealed that expression of Pax6, a transcription factor essential for SCO differentiation during embryogenesis, is maintained in the SCO at postnatal stages from P0 to P84. SCO cells in the adult brain expressed known neural stem/progenitor cell (NSPC) markers, Sox2 and vimentin. The adult SCO cells also expressed proliferating marker PCNA, although expression of another proliferation marker Ki67, indicating a G2/M phase, was not detected. The SCO cells did not incorporate BrdU, a marker for DNA synthesis in the S phase. Therefore, the SCO cells have a potential for proliferation but are quiescent for cell division in the adult. The SCO cells also expressed GFAP, a marker for astrocytes or NSPCs, but not NeuN (for neurons). A few cells positive for Iba1 (microglia), Olig2 (for oligodendrocytes) and PDGFRα (oligodendrocyte progenitors) existed within or on the periphery of the SCO. These findings revealed that the SCO cells have a unique feature as secretory yet immature neuroepithelial cells in the adult mouse brain.
We show that the subcommissural organ maintains features of neuroepithelial cells in the adult mouse. The subcommissural organ expressed Pax6 and two other neural stem cell markers, Sox2 and vimentin, and a proliferation marker PCNA, suggesting proliferating capability. Our results suggest that the SCO has similar features of quiescent neural stem cells in the adult mouse brain.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Objective
The appropriate timing of aortic repair in patients with bicuspid aortic valve-related aortopathy remains controversial. We describe the changes in diameter of the non-aneurysmal ascending ...aorta after aortic valve replacement for bicuspid or tricuspid aortic valve stenosis.
Methods
This retrospective review included 189 patients who had undergone aortic valve replacement for severe stenotic aortic valve with a non-aneurysmal ascending aorta diameter of 45 mm or less between January 2008 and December 2018. A linear mixed-effect model was used to analyze and compare the enlargement rates of the non-aneurysmal ascending aorta at the tubular portion after aortic valve replacement in bicuspid and tricuspid aortic valve patients.
Results
The enlargement rate of the non-aneurysmal ascending aorta after aortic valve replacement was significantly greater in the bicuspid aortic valve group than in the tricuspid aortic valve group (0.36 mm/year vs. 0.09 mm/year,
p
< 0.001). The specific form of bicuspid aortic valve also affected aorta diameter enlargement: the enlargement rate of 0.85 mm/year in the Type 0 (according to Sievers’ classification) group was approximately five times that in the Non-Type 0 group (
p
< 0.001). No aortic events were observed, and no patients needed reoperations for the ascending aorta, in either the bicuspid or tricuspid aortic valve groups.
Conclusion
The persistent possibility of progressive ascending aortic dilatation after aortic valve replacement for bicuspid aortic valve stenosis, especially in Type 0 bicuspid aortic valve patients, demands careful post-procedural evaluation of the ascending aorta.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Few studies have examined the details of nutritional status in patients with unresectable hepatocellular carcinoma (u-HCC) undergoing systemic chemotherapy with lenvatinib. We evaluated the ...prognostic/predictive value of nutritional status using Onodera's prognostic nutritional index (O-PNI) for overall survival among patients with u-HCC treated with lenvatinib.
Three-hundred and seventy-five u-HCC patients treated with lenvatinib were enrolled (median age 72 years; Child-Pugh class A/B/C: n = 312/60/3; BCLC stage A/B/C/D: n = 2/159/212/2). We examined median survival time (MST) and time to progression (TTP) in all patients (n = 375), prognosis according to the O-PNI (high/low: >40/≤40) in 298 patients with lymphocyte findings, and the prognostic/predictive values of Child-Pugh stage, albumin-bilirubin (ALBI)/modified ALBI (mALBI) grade, and O-PNI for Chemotherapy grade (OPNIC grade 1/2/3: O-PNI >40/≤40 to >36/≤36).
The MST and TTP were 16.6 and 8.0 months, respectively. The MST and TTP according to the O-PNI (>40/≤40) were "not reached" (NR)/12.4 months (p < 0.001) and 10.0/6.1 months (p = 0.012), respectively. There was a good correlation noted between ALBI score and O-PNI (r = -0.939, p < 0.001). The predictive value of the O-PNI for mALBI grade 2a was 36.0 (specificity/sensitivity = 0.894/0.942; area under the curve AUC = 0.978), while that for mALBI grade 1 was 39 (specificity/sensitivity = 0.920/0.929; AUC = 0.972), which was very similar to a high O-PNI. The MST analyzed with the OPNIC in the 298 patients was NR/16.2/10.4 months for OPNIC grade 1/2/3 (p < 0.001), respectively, and the c-index was 0.632, the same as that for mALBI grade (0.632), while that for Child-Pugh class was 0.571.
OPNIC grading might have a potential for easy substitution of mALBI grading. A good nutritional status (OPNIC grade 1) or mALBI grade 1 is the best indication for lenvatinib use, while with an OPNIC grade 3, lenvatinib might be not suitable.
Objectives
The number of hemodialysis patients requiring aortic valve replacement (AVR) is increasing. Although bioprosthetic valves are increasingly popular, they are associated with a risk of ...structural valve deterioration (SVD). The aim of this study is to examine the outcomes of bioprosthetic valves in hemodialysis patients undergoing AVR and to identify treatment strategies that can decrease the risk of SVD.
Methods
Between February 2010 and November 2019, 61 patients on hemodialysis underwent AVR using bioprosthetic valves at our hospital. Five patients died while still in the hospital. Kaplan–Meier estimates of overall survival and univariate Cox proportional hazards regression analyses were performed for the remaining 56 patients.
Results
During follow-up, there were six SVD events (10.7%) related to the bioprosthetic valves. The survival rate was 67.9% at 3 years and 39.5% at 5 years. In all SVD cases, SVD was caused by aortic stenosis. The mean interval between AVR and the discovery of SVD was 41.5 months. The SVD-free rate was 88.6% at 3 years and 65.3% at 5 years. Preoperative phosphorus levels are associated with SVD risk. High preoperative phosphorus concentration is associated with elevated SVD risk.
Conclusions
In this study, we determined that the risk of SVD can be influenced by preoperative phosphorus level. Strict control of the phosphorus concentration of hemodialysis patients may decrease structural valve deterioration after aortic valve replacement.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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