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"Takeshi Inoue"
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Memory B cells
Recent advances in studies of immune memory in mice and humans have reinforced the concept that memory B cells play a critical role in protection against repeated infections, particularly from variant viruses. Hence, insights into the development of high-quality memory B cells that can generate broadly neutralizing antibodies that bind such variants are key for successful vaccine development. Here, we review the cellular and molecular mechanisms by which memory B cells are generated and how these processes shape the antibody diversity and breadth of memory B cells. Then, we discuss the mechanisms of memory B cell reactivation in the context of established immune memory; the contribution of antibody feedback to this process has now begun to be reappreciated.Memory B cells are critical for protection against repeated infections, particularly with viral variants, and understanding their function and development is key for successful vaccine development. This Review discusses the cellular and molecular mechanisms of memory B cell generation and reactivation and how these processes shape antibody diversity and breadth.
Journal Article
Genetic and epigenetic basis of hepatoblastoma diversity
Hepatoblastoma (HB) is the most common pediatric liver malignancy; however, hereditary predisposition and acquired molecular aberrations related to HB clinicopathological diversity are not well understood. Here, we perform an integrative genomic profiling of 163 pediatric liver tumors (154 HBs and nine hepatocellular carcinomas) based on the data acquired from a cohort study (JPLT-2). The total number of somatic mutations is precious low (0.52/Mb on exonic regions) but correlated with age at diagnosis. Telomerase reverse transcriptase (
TERT)
promoter mutations are prevalent in the tween HBs, selective in the transitional liver cell tumor (TLCT, > 8 years old). DNA methylation profiling reveals that classical HBs are characterized by the specific hypomethylated enhancers, which are enriched with binding sites for ASCL2, a regulatory transcription factor for definitive endoderm in Wnt-pathway. Prolonged upregulation of ASCL2, as well as fetal-liver-like methylation patterns of
IGF2
promoters, suggests their “cell of origin” derived from the premature hepatoblast, similar to intestinal epithelial cells, which are highly proliferative. Systematic molecular profiling of HB is a promising approach for understanding the epigenetic drivers of hepatoblast carcinogenesis and deriving clues for risk stratification.
While hepatoblastoma is the most common pediatric liver cancer, its molecular background has not been fully characterised. Here, the authors perform genomic and epigenomic profiling of 163 untreated pediatric liver tumours and suggest the upregulation of ASCL2 and methylation patterns of IGF2 promoters in driving hepatoblast carcinogenesis.
Journal Article
Generation of High Quality Memory B Cells
Protection against pathogen re-infection is mediated, in large part, by two humoral cellular compartments, namely, long-lived plasma cells and memory B cells. Recent data have reinforced the importance of memory B cells, particularly in response to re-infection of different viral subtypes or in response with viral escape mutants. In regard to memory B cell generation, considerable advancements have been made in recent years in elucidating its basic mechanism, which seems to well explain why the memory B cells pool can deal with variant viruses. Despite such progress, efforts to develop vaccines that induce broadly protective memory B cells to fight against rapidly mutating pathogens such as influenza virus and HIV have not yet been successful. Here, we discuss recent advances regarding the key signals and factors regulating germinal center-derived memory B cell development and activation and highlight the challenges for successful vaccine development.
Journal Article
Digital financial inclusion, international remittances, and poverty reduction
Ensuring access to and usage of formal financial services through digital devices can be referred to as “digital financial inclusion” (DFI). In recent years, there has been a growing trend in the use of financial services, including money transfers through mobile phones. This study applies mobile phone subscriptions as a proxy to measure the degree of DFI and explores the individual effects of DFI and remittances and their interaction effects on poverty conditions in developing countries. Using panel data from 2000 to 2020 for 123 countries and employing the dynamic generalized method of moments estimation, the results reveal that DFI and remittance inflows help ameliorate poverty in developing countries. Furthermore, we find that the coefficient of the interaction term between DFI and remittances is statistically significant and positive, suggesting that the impact of DFI on poverty alleviation could weaken as remittance inflows increase in the remittance-receiving country and vice versa.
Journal Article
Prevalence of Circadian Rhythm Sleep-Wake Disorders and Associated Factors in Euthymic Patients with Bipolar Disorder
Recent studies have suggested that there are certain pathophysiological relationships between bipolar disorder (BD) and circadian rhythm dysfunction. However, apparently no studies have clarified the prevalence of circadian rhythm sleep-wake disorders (CRSWD) in patients with BD. This study was set out to investigate the prevalence of CRSWD and associated factors in patients with BD. One hundred four euthymic BD outpatients participated in this study. The subjects were asked to answer questionnaires including demographic variables, clinical course of BD, and family history of psychiatric disorders and suicide. Severity of BD was assessed by the Montgomery-Åsberg Depression Rating Scale and Young Mania Rating Scale. CRSWD was diagnosed by clinical interview, together with sleep logs, according to the International Classification of Sleep Disorders, third edition (ICSD-3). Thirty-five subjects (32.4%) met the criteria for CRSWD. The age at the time of investigation and that at the onset of BD were both lower in the CRSWD group than in the non-CRSWD group. The rates of family history of psychiatric disorders and suicide in the CRSWD group were higher than those in the non-CRSWD group. Multiple logistic regression analysis revealed that the presence of CRSWD was significantly associated with younger onset age of BD and family history of suicide. The prevalence of CRSWD could be quite high in BD patients. Younger onset age of BD and family history of suicide were associated with presence of CRSWD in BD patients.
Journal Article
CT-detected lymphadenopathy and prognostic markers in severe fever with thrombocytopenia syndrome: a retrospective study
Background
Severe fever with thrombocytopenia syndrome (SFTS) is a tick-borne viral disease with substantial mortality in endemic regions. CT findings, particularly lymphadenopathy with perinodal fat stranding, may be under-recognized. We evaluated CT findings and factors associated with in-hospital mortality in an endemic setting.
Methods
We retrospectively reviewed 16 RT-qPCR–confirmed SFTS patients treated at Ehime Prefectural Central Hospital and Kagawa University Hospital (January 2013–December 2024). CT images were reviewed by a board-certified diagnostic radiologist and an infectious diseases physician for lymphadenopathy and perinodal fat stranding. Clinical and laboratory variables were compared between non-survivors and survivors using permutation tests with bootstrap 95% confidence intervals; categorical factors were assessed by univariable analysis.
Results
Median age was 69 years (44–86), and 11 (68.8%) were male. CT showed lymphadenopathy with perinodal fat stranding in 15/16 (93.8%), with one case showing no lymphadenopathy. Two patients (12.5%) died in hospital. Lymph node size was not associated with mortality (difference [non-survivors − survivors], − 0.28 cm; 95% CI, − 0.54 to 0.84;
P
= 0.549). Non-survivors had higher aspartate aminotransferase (difference, 190.21 U/L; 95% CI, 37.36 to 343.50;
P
= 0.040) and lower platelet counts (difference, − 5.99 × 10³/µL; 95% CI, − 7.52 to − 4.40;
P
= 0.009). No categorical factor reached statistical significance (altered mental status, borderline;
P
= 0.050).
Conclusions
In this cohort, CT frequently revealed lymphadenopathy with perinodal fat stranding, an under-recognized pattern that may support earlier recognition of SFTS in patients with compatible clinical and epidemiological features. Additionally, elevated aspartate aminotransferase and decreased platelet counts were associated with in-hospital mortality in this cohort and may be useful as exploratory markers for early risk stratification.
Journal Article
3D reconstruction of neuronal allometry and neuromuscular projections in asexual planarians using expansion tiling light sheet microscopy
The intricate coordination of the neural network in planarian growth and regeneration has remained largely unrevealed, partly due to the challenges of imaging the CNS in three dimensions (3D) with high resolution and within a reasonable timeframe. To address this gap in systematic imaging of the CNS in planarians, we adopted high-resolution, nanoscale imaging by combining tissue expansion and tiling light-sheet microscopy, achieving up to fourfold linear expansion. Using an automatic 3D cell segmentation pipeline, we quantitatively profiled neurons and muscle fibers at the single-cell level in over 400 wild-type planarians during homeostasis and regeneration. We validated previous observations of neuronal cell number changes and muscle fiber distribution. We found that the increase in neuron cell number tends to lag behind the rapid expansion of somatic cells during the later phase of homeostasis. By imaging the planarian with up to 120 nm resolution, we also observed distinct muscle distribution patterns at the anterior and posterior poles. Furthermore, we investigated the effects of β-catenin-1 RNAi on muscle fiber distribution at the posterior pole, consistent with changes in anterior-posterior polarity. The glial cells were observed to be close in contact with dorsal-ventral muscle fibers. Finally, we observed disruptions in neural-muscular networks in inr-1 RNAi planarians. These findings provide insights into the detailed structure and potential functions of the neural-muscular system in planarians and highlight the accessibility of our imaging tool in unraveling the biological functions underlying their diverse phenotypes and behaviors.
Journal Article
DNA Methylation Profiles of the Brain-Derived Neurotrophic Factor (BDNF) Gene as a Potent Diagnostic Biomarker in Major Depression
Major depression, because of its recurring and life-threatening nature, is one of the top 10 diseases for global disease burden. Major depression is still diagnosed on the basis of clinical symptoms in patients. The search for specific biological markers is of great importance to advance the method of diagnosis for depression. We examined the methylation profile of 2 CpG islands (I and IV) at the promoters of the brain-derived neurotrophic factor (BDNF) gene, which is well known to be involved in the pathophysiology of depression. We analyzed genomic DNA from peripheral blood of 20 Japanese patients with major depression and 18 healthy controls to identify an appropriate epigenetic biomarker to aid in the establishment of an objective system for the diagnosis of depression. Methylation rates at each CpG unit was measured using a MassArray® system (SEQUENOM), and 2-dimensional hierarchical clustering analyses were undertaken to determine the validity of these methylation profiles as a diagnostic biomarker. Analyses of the dendrogram from methylation profiles of CpG I, but not IV, demonstrated that classification of healthy controls and patients at the first branch completely matched the clinical diagnosis. Despite the small number of subjects, our results indicate that classification based on the DNA methylation profiles of CpG I of the BDNF gene may be a valuable diagnostic biomarker for major depression.
Journal Article
Cognitive complaints mediate childhood parental bonding influence on presenteeism
Childhood parental bonding and cognitive complaints (CCs) affect a worker's mental health (MH), and CCs affect presenteeism. However, the impact of childhood parental bonding on presenteeism and the mediating effect of CCs with respect to the association among childhood parental bonding and presenteeism remain poorly understood.
We aimed to investigate the mediating role of CCs on the relationship between childhood parental bonding and presenteeism to better understand the influence of childhood parental bonding on adulthood presenteeism.
A total of 440 Japanese adult workers recruited using convenience sampling were evaluated.
The Parental Bonding Instrument, Cognitive Complaints in Bipolar Disorder Rating Assessment and Work Limitations Questionnaire 8 were used to assess childhood parental bonding, CCs, and presenteeism, respectively. We performed Spearman's correlation analysis and path analysis to investigate the relationship among the variables.
Path analysis revealed that childhood parental bonding and CCs significantly affected presenteeism. More specifically, CCs fully and partially mediated the effect of paternal and maternal care on presenteeism, respectively. Moreover, CCs partially mediated the effects of both paternal and maternal overprotection on presenteeism.
The mediating role of CCs on the relationship between childhood parental bonding and presenteeism was shown in this study. In occupational MH, evaluating the mediating effect of CCs may be useful for addressing adulthood presenteeism associated with childhood parental bonding.
Journal Article