記述言語：英語   掲載種別：研究論文（学術雑誌）  

Coinciding with the global outbreak of clade IIb mpox virus (MPXV), the Democratic Republic of the Congo (DRC) recently experienced a rapid surge in mpox cases with clade I MPXV. On 14 August 2024, the World Health Organization declared the continued cross-border spread of this clade in Africa a public health emergency of international concern (PHEIC). Clade I MPXV is known to be more fatal than clade IIb, but its clinical characteristics and prognosis differ between patients. Here, we used mathematical modeling to quantify temporal changes in total lesion counts during clade I MPXV infections, using data from a large cohort of patients with mpox in the DRC from 2007 to 2011. We further analyzed individuals' clinical data to explore predictive biomarkers of high lesion counts. Our analysis indicates that patients with clade I mpox can be stratified into two groups according to lesion severity and that viral load in peripheral blood at symptom onset may serve as a predictor for this classification [area under the curve (AUC) = 0.70]. Our estimates also suggest substantial individual heterogeneity in the time period during which patients have lesions, ranging from 20 to 65 days. Understanding the severity and duration of lesions in different patients, as characterized by our approach, may contribute to more tailored treatment strategies and control measures in ongoing clade I mpox outbreaks.

DOI： 10.1126/scitranslmed.ads4773

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Acute liver failure (ALF) is a serious disease that progresses from acute liver injury (ALI) and that often leads to multiorgan failure and ultimately death. Currently, effective treatment strategies for ALF, aside from transplantation, remain elusive, partly because ALI is highly heterogeneous. Furthermore, clinicians lack a quantitative indicator that they can use to predict which patients hospitalized with ALI will progress to ALF and the need for liver transplantation. In our study, we retrospectively analyzed data from 319 patients admitted to the hospital with ALI. By applying a machine-learning approach and by using the SHapley Additive exPlanations (SHAP) algorithm to analyze time-course blood test data, we identified prothrombin time activity percentage (PT%) as a biomarker reflecting individual ALI status. Unlike previous studies predicting the need for liver transplantation in patients with ALF, our study focused on PT% dynamics. Use of this variable allowed us to stratify the patients with highly heterogeneous ALI into six groups with distinct clinical courses and prognoses, i.e. self-limited, intensive care-responsive, or intensive care-refractory patterns. Notably, these groups were well predicted by clinical data collected at the time of admission. Additionally, utilizing mathematical modeling and machine learning, we assessed the predictability of individual PT% dynamics during the early phase of ALI. Our findings may allow for optimizing medical resource allocation and early introduction of tailored individualized treatment, which may result in improving ALF prognosis.

DOI： 10.1093/pnasnexus/pgaf004

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Quantification of intrahepatic covalently closed circular DNA (cccDNA) is a key for evaluating an elimination of hepatitis B virus (HBV) in infected patients. However, quantifying cccDNA requires invasive methods such as a liver biopsy, which makes it impractical to access the dynamics of cccDNA in patients. Although HBV RNA and HBV core-related antigens (HBcrAg) have been proposed as surrogate markers for evaluating cccDNA activity, they do not necessarily estimate the amount of cccDNA. Here, we employed a recently developed multiscale mathematical model describing intra- and intercellular viral propagation and applied it in HBV-infected patients under treatment. We developed a model that can predict intracellular HBV dynamics by use of extracellular viral markers, including HBsAg, HBV DNA, and HBcrAg in peripheral blood. Importantly, the model prediction of the amount of cccDNA in patients over time was confirmed to be well correlated with the data for quantified cccDNA by paired liver biopsy. Thus, our method combining classic and emerging surrogate markers enables us to predict the decay dynamics of cccDNA in patients undergoing treatment.

DOI： 10.1371/journal.pcbi.1012615

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Gravity has profoundly influenced life on Earth, yet how organisms adapt to changes in gravity remains largely unknown. This study examines vestibular plasticity, specifically how the vestibular system responds to altered gravity. We subjected male C57BL/6J mice to hypergravity (2 G) followed by normal gravity (1 G) to analyze changes in vestibular function and gene expression. Mice showed significant vestibular dysfunction, assessed by righting reflex tests, which persisted for days but reversed at 1 G after exposure to 2 G. Gene expression analysis in the vestibular ganglion identified significant changes in 212 genes out of 49,585 due to gravitational changes. Specifically, 25 genes were upregulated under 2 G and recovered at 1 G after 2 G exposure, while one gene showed the opposite trend. Key neural function genes like Shisa3, Slc25a37, Ntn4, and Snca were involved. Our results reveal that hypergravity-induced vestibular dysfunction is reversible and highlight genes critical for adaptation.

DOI： 10.1186/s12576-024-00939-y

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

As we learned during the COVID-19 pandemic, vaccines are one of the most important tools in infectious disease control. To date, an unprecedentedly large volume of high-quality data on COVID-19 vaccinations have been accumulated. For preparedness in future pandemics beyond COVID-19, these valuable datasets should be analyzed to best shape an effective vaccination strategy. We are collecting longitudinal data from a community-based cohort in Fukushima, Japan, that consists of 2,407 individuals who underwent serum sampling two or three times after a two-dose vaccination with either BNT162b2 or mRNA-1273. Using the individually reconstructed time courses of the vaccine-elicited antibody response based on mathematical modeling, we first identified basic demographic and health information that contributed to the main features of the antibody dynamics, i.e., the peak, the duration, and the area under the curve. We showed that these three features of antibody dynamics were partially explained by underlying medical conditions, adverse reactions to vaccinations, and medications, consistent with the findings of previous studies. We then applied to these factors a recently proposed computational method to optimally fit an "antibody score", which resulted in an integer-based score that can be used as a basis for identifying individuals with higher or lower antibody titers from basic demographic and health information. The score can be easily calculated by individuals themselves or by medical practitioners. Although the sensitivity of this score is currently not very high, in the future, as more data become available, it has the potential to identify vulnerable populations and encourage them to get booster vaccinations. Our mathematical model can be extended to any kind of vaccination and therefore can form a basis for policy decisions regarding the distribution of booster vaccines to strengthen immunity in future pandemics.

DOI： 10.1371/journal.pdig.0000497

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

All tumour cells in a patient have shared and non-shared genetic alterations, and the diversity of mutations is described as intratumoural heterogeneity (ITH). Multiregion sequencing is a genome sequencing analytical technique used for multiple, spatially-separated biopsy tissues that may further our understanding of ITH and tumour evolution. Although genetic mutations in extramammary Paget's disease (EMPD) have recently been detected by next-generation sequencing analysis, there have been no reports of ITH based on multiregion sequencing in EMPD. Thus, we clarified the landscape of ITH and tumour evolution in EMPD. We performed whole-exome sequencing on 35 tissues (30 tumour tissues and five normal skin samples as a paired control), collected from five patients with EMPD. The rate of private mutations was significantly higher than that of ubiquitous and shared mutations. Ubiquitous mutations were not present in driver genes, and most driver genes exhibited private and shared mutations. The most frequent base substitution was C>T in almost all lesions, and most mutational signatures corresponded to signature 1, 2, 3, and 8. The types of proposed aetiology in most lesions were based on age and AID/APOBEC family and BRCA1/BRCA2 mutations. Evolutionary trees were characterized by short trunks and long branches due to the extremely high ratio of private mutations. In contrast, pathogenic factors, such as base substitutions, mutational signatures, and proposed aetiology, were shared. Tumour evolution in EMPD appears to be characterized by a high level of genetic ITH with shared background factors.

DOI： 10.1684/ejd.2024.4609

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Chronic infection with hepatitis B virus (HBV) is caused by the persistence of closed circular DNA (cccDNA) in the nucleus of infected hepatocytes. Despite available therapeutic anti-HBV agents, eliminating the cccDNA remains challenging. Thus, quantifying and understanding the dynamics of cccDNA are essential for developing effective treatment strategies and new drugs. However, such study requires repeated liver biopsy to measure the intrahepatic cccDNA, which is basically not accepted because liver biopsy is potentially morbid and not common during hepatitis B treatment. We here aimed to develop a noninvasive method for quantifying cccDNA in the liver using surrogate markers in peripheral blood. We constructed a multiscale mathematical model that explicitly incorporates both intracellular and intercellular HBV infection processes. The model, based on age-structured partial differential equations, integrates experimental data from in vitro and in vivo investigations. By applying this model, we roughly predicted the amount and dynamics of intrahepatic cccDNA within a certain range using specific viral markers in serum samples, including HBV DNA, HBsAg, HBeAg, and HBcrAg. Our study represents a significant step towards advancing the understanding of chronic HBV infection. The noninvasive quantification of cccDNA using our proposed method holds promise for improving clinical analyses and treatment strategies. By comprehensively describing the interactions of all components involved in HBV infection, our multiscale mathematical model provides a valuable framework for further research and the development of targeted interventions.

DOI： 10.1371/journal.pcbi.1011238

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Infectious virus shedding from individuals infected with severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) is used to estimate human-to-human transmission risk. Control of SARS-CoV-2 transmission requires identifying the immune correlates that protect infectious virus shedding. Mucosal immunity prevents infection by SARS-CoV-2, which replicates in the respiratory epithelium and spreads rapidly to other hosts. However, whether mucosal immunity prevents the shedding of the infectious virus in SARS-CoV-2-infected individuals is unknown. We examined the relationship between viral RNA shedding dynamics, duration of infectious virus shedding, and mucosal antibody responses during SARS-CoV-2 infection. Anti-spike secretory IgA antibodies (S-IgA) reduced viral RNA load and infectivity more than anti-spike IgG/IgA antibodies in infected nasopharyngeal samples. Compared with the IgG/IgA response, the anti-spike S-IgA post-infection responses affected the viral RNA shedding dynamics and predicted the duration of infectious virus shedding regardless of the immune history. These findings highlight the importance of anti-spike S-IgA responses in individuals infected with SARS-CoV-2 for preventing infectious virus shedding and SARS-CoV-2 transmission. Developing medical countermeasures to shorten S-IgA response time may help control human-to-human transmission of SARS-CoV-2 infection and prevent future respiratory virus pandemics.

DOI： 10.1073/pnas.2314808120

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

The 3-dose COVID-19 vaccine (booster vaccination) has been offered worldwide. As booster vaccinations continue, it is important to understand the antibody dynamics elicited by booster vaccination in order to evaluate and develop vaccination needs and strategies. Here, we investigated longitudinal data by monitoring IgG antibodies against the receptor binding domain (RBD) in health care workers. We extended our previously developed mathematical model to booster vaccines and successfully fitted antibody titers over time in the absence and presence of past SARS-CoV-2 infection. Quantitative analysis using our mathematical model indicated that anti-RBD IgG titers increase to a comparable extent after booster vaccination, regardless of the presence or absence of infection, but infection history extends the duration of antibody response by 1.28 times. Such a mathematical modeling approach can be used to inform future vaccination strategies on the basis of an individual's immune history. Our simple quantitative approach can be extended to any kind of vaccination and therefore can form a basis for policy decisions regarding the distribution of booster vaccines to strengthen immunity in future pandemics.

DOI： 10.1016/j.vaccine.2023.11.040

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Although studies have demonstrated that infections with various viruses, bacteria, and parasites can modulate the immune system, no study has investigated changes in antibodies against microbial antigens after the COVID-19 mRNA vaccination. IgG antibodies against microbial antigens in the blood of vaccinees were comprehensively analyzed using microbial protein microarrays that carried approximately 5000 microbe-derived proteins. Changes in antibodies against microbial antigens were scrutinized in healthy participants enrolled in the Fukushima Vaccination Community Survey conducted in Fukushima Prefecture, Japan, after their second and third COVID-19 mRNA vaccinations. Antibody profiling of six groups stratified by antibody titer and the remaining neutralizing antibodies was also performed to study the dynamics of neutralizing antibodies against SARS-CoV-2 and the changes in antibodies against microbial antigens. The results showed that changes in antibodies against microbial antigens other than SARS-CoV-2 antigens were extremely limited after COVID-19 vaccination. In addition, antibodies against a staphylococcal complement inhibitor have been identified as microbial antigens that are associated with increased levels of neutralizing antibodies against SARS-CoV-2. These antibodies may be a predictor of the maintenance of neutralizing antibodies following the administration of a COVID-19 mRNA vaccine.

DOI： 10.3390/vaccines11111694

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Natural killer (NK) cells are innate immune cells critical for protective immune responses against infection and cancer. Although NK cells differentiate in the bone marrow (BM) in an interleukin-15 (IL-15)-dependent manner, the cellular source of IL-15 remains elusive. Using NK cell reporter mice, we show that NK cells are localized in the BM in scattered and clustered manners. NK cell clusters overlap with monocyte and dendritic cell accumulations, whereas scattered NK cells require CXCR4 signaling. Using cell-specific IL-15-deficient mice, we show that hematopoietic cells, but not stromal cells, support NK cell development in the BM through IL-15. In particular, IL-15 produced by monocytes and dendritic cells appears to contribute to NK cell development. These results demonstrate that hematopoietic cells are the IL-15 niche for NK cell development in the BM and that BM NK cells are present in scattered and clustered compartments by different mechanisms, suggesting their distinct functions in the immune response.

DOI： 10.1016/j.celrep.2023.113127

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.3389/fcvm.2023.1093576

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND AND AIMS: The coronavirus disease 2019 (COVID-19) pandemic precipitated lifestyle changes. We aimed to clarify whether COVID-19-induced lifestyle changes affected the development of metabolic dysfunction-associated fatty liver disease (MAFLD). METHODS: This retrospective longitudinal study included 973 participants who underwent health check-ups between 2018 and 2020. We used data from the MedCity21 health examination registry. Participants' clinical characteristics and lifestyle habits were investigated. Independent lifestyle predictors of MAFLD development before the pandemic (2018-2019) and during the pandemic (2019-2020) were identified using logistic regression analysis. RESULTS: In 2018, 261 (27%) patients were diagnosed with MAFLD. Before the pandemic, 22 patients developed new MAFLD. During this time, routine late-night meals were identified as an independent lifestyle predictor of MAFLD development (hazard ratio [HR] 2.54, 95% confidence interval [CI] 1.02-6.36, P = .046). In contrast, 44 patients developed new MAFLD during the pandemic. During this time, higher daily alcohol intake was identified as an independent lifestyle predictor of MAFLD development (HR 1.03, 95% CI 1.01-1.05, P = .008). In participants aged <60 years, daily alcohol intake and the proportion of participants who ate 2 times/day were significantly higher in patients who developed MAFLD during the pandemic than in those who did not. In participants aged ≥60 years, no lifestyle habits were associated with MAFLD development before or during the pandemic. CONCLUSIONS: New MAFLD diagnoses increased during the COVID-19 pandemic. Changes in lifestyle factors, particularly in those aged <60 years, must be monitored and addressed as the pandemic continues.

DOI： 10.1111/liv.15158

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Frontiers Media SA  

Background

There is currently no subjective, definitive evaluation method for therapeutic indication other than symptoms in aortic regurgitation. Energy loss, a novel parameter of cardiac workload, can be visualized and quantified using echocardiography vector flow mapping. The purpose of the present study was to evaluate whether energy loss in patients with chronic aortic regurgitation can quantify their subjective symptoms more clearly than other conventional metrics.

Methods

We studied 15 patients undergoing elective aortic valve surgery for aortic regurgitation. We divided the patients into symptomatic and asymptomatic groups using their admission records. We analyzed the mean energy loss in one cardiac cycle using transesophageal echocardiography during the preoperative period. The relationships between symptoms, energy loss, and other conventional metrics were statistically analyzed.

Results

There were seven and eight patients in the symptomatic and asymptomatic groups, respectively. The mean energy loss of one cardiac cycle was higher in the symptomatic group (121 mW/m [96–184]) than in the asymptomatic group (87 mW/m [80–103]) (p = 0.040), whereas the diastolic diameter was higher in the asymptomatic group (65 mm [59–78]) than in the symptomatic group (57 mm [51–57]) (p = 0.040). There was no significant difference between the symptomatic and asymptomatic groups in terms of other conventional metrics.

Conclusions

An energy loss can quantify patients' subjective symptoms more clearly than other conventional metrics. The small sample size is the primary limitation of our study, further studies assessing larger cohort of patients are warranted to validate our findings.

DOI： 10.3389/fsurg.2022.739743

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Hepatocellular carcinoma (HCC) is the third leading cause of cancer death worldwide. Additionally, the efficacy of targeted molecular therapies with multiple tyrosine kinase inhibitors is limited. In this study, we focused on the cellular signaling pathways common to diverse HCC cells and used quantitative reverse phase protein array (RPPA) and statistical analyses to elucidate the molecular mechanisms determining its malignancy. We examined the heterogeneity of 17 liver cancer cell lines by performing cluster analysis of their expression of CD90 and EpCAM cancer stem cell markers. Gaussian mixture model clustering identified three dominant clusters: CD90-positive and EpCAM-negative (CD90+), EpCAM-positive and CD90-negative (EpCAM+) and EpCAM-negative and CD90-negative (Neutral). A multivariate analysis by partial least squares revealed that the former two cell populations showed distinct patterns of protein expression and phosphorylation in the EGFR and EphA2 signaling pathways. The CD90+ cells exhibited higher abundance of AKT, EphA2 and its phosphorylated form at Ser897, whereas the EpCAM+ cells exhibited higher abundance of ERK, RSK and its phosphorylated form. This demonstrates that pro-oncogenic, ligand-independent EphA2 signaling plays a dominant role in CD90+ cells with higher motility and metastatic activity than EpCAM+ cells. We also showed that an AKT inhibitor reduced the proliferation and survival of CD90+ cells but did not affect those of EpCAM+ cells. Taken together, our results suggest that AKT activation may be a key pro-oncogenic regulator in HCC.

DOI： 10.3390/ijms22168652

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記述言語：英語  

DOI： 10.1038/s10038-020-00890-x

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担当区分：筆頭著者   記述言語：日本語   掲載種別：研究論文（学術雑誌）  

DOI： 10.11540/bjsiam.31.3_28

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担当区分：筆頭著者   記述言語：日本語   掲載種別：研究論文（学術雑誌）  

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記述言語：英語   掲載種別：研究論文（国際会議プロシーディングス）   出版者・発行元：Springer  

DOI： 10.1007/978-981-16-4866-3_21

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Elsevier BV  

BACKGROUND: We evaluated the association between survival and bystandercardiopulmonary resuscitation (CPR) with or without dispatcher instructions (DI) considering the time from emergency call receipt by the dispatch center to emergency medical services (EMS) personnel's contact with the patient (i.e. time to EMS arrival). METHODS: This prospective study conducted in Osaka City, Japan, from 2009 to 2015 included patients with medical cause-related out-of-hospital cardiac arrest who were ≥18 years old. The primary outcome was one-month favorable neurological survival. Using multiple logistic regression models, the adjusted odds ratios (AOR) of independent and DI-dependent CPR for the primary outcome were compared with no CPR. Adjustments were made for patients' age, sex, activities of daily living before the cardiac arrest, year of cardiac arrest, location, presence or absence of witnesses, etiology of cardiac arrest, and the time from EMS contact with the patient to patient's arrival at the hospital. The effective estimated "time to EMS arrival" was also calculated. RESULTS: For analyses 10,925 individuals were eligible. Independent CPR had a significantly higher one-month favorable neurological survival than no CPR whereas there was no significant difference between DI-dependent CPR and no CPR (AOR, 1.90 [1.47-2.46] and 1.16 [0.91-1.47], respectively). The estimated "time to EMS arrival" for a one-month favorable neurological survival after independent CPR was ≤13min. CONCLUSIONS: Bystander CPR that did not need DI was associated with significantly higher one-month favorable neurological survival than no CPR, with an effective estimated "time to EMS arrival" of ≤13min.

DOI： 10.1016/j.jjcc.2019.08.007

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Japanese Society for Artificial Intelligence  

DOI： 10.1527/tjsai.d-j13

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記述言語：英語   出版者・発行元：Cold Spring Harbor Laboratory  

<title>Abstract</title>Computational cytometry methods are now frequently used in flow and mass cytometric data analyses. However, systematic bias-free methodologies to assess inter-sample variability have been lacking, thereby hampering efficient data mining from a large set of samples. Here, we devised a computational method termed LAVENDER (<italic>l</italic>atent <italic>a</italic>xes disco<italic>ve</italic>ry from multiple cytometry samples with <italic>n</italic>onparametric <italic>d</italic>ivergence <italic>e</italic>stimation and multidimensional scaling <italic>r</italic>econstruction). It measures the Jensen-Shannon distances between samples using the <italic>k</italic>-nearest neighbor density estimation and reconstructs samples in a new coordinate space, called the LAVENDER space. The axes of this space can then be compared against other omics measurements to obtain biological information. Application of LAVENDER to multidimensional flow cytometry datasets of 301 Japanese individuals immunized with a seasonal influenza vaccine revealed an axis related to baseline immunological characteristics of each individual. This axis correlated with the proportion of plasma cells and the neutrophil-to-lymphocyte ratio, a clinical marker of the systemic inflammatory response. The same method was also applicable to mass cytometry data with more molecular markers. These results demonstrate that LAVENDER is a useful tool for identifying critical heterogeneity among similar, yet different, single-cell datasets.

DOI： 10.1101/673434

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1186/s12872-017-0612-4

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1093/icvts/ivx033

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1186/s12872-016-0444-7

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1002/jemt.22773

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1523/JNEUROSCI.3487-15.2015

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

添付ファイル： Nakamura-Shibata2015_Article_BifurcationAnalysisOfASelf-org (1).pdf

DOI： 10.1007/s13160-015-0185-5

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1038/msb.2009.6

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