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•The mass campaign carried out by the emergency import of OPV in 1961 achieved great results for polio control in Japan.•School influenza vaccination in the 1960–80 s was discontinued without adequate and proper evaluation.•The judgment by the Tokyo High Court in 1992 and the discontinuation of the use of the MMR vaccine in 1993 were attributed for the creation of the so-called ‘vaccine gap.’•In the revision of the Immunization Act in 1994, a big change was added to individual vaccination by ‘obligation to make efforts.’•From around 2010, efforts have been made to bridge ‘vaccine gap’ and establish the global standard in vaccination. This paper reviews the administration related to vaccination in Japan after the enactment of the Immunization Act in 1948, under which vaccination was implemented mandatory for the public. To enhance the effectiveness of vaccination activities, the government implemented group vaccination, which is convenient for vaccinating recipients all at once. In 1976, Japan established the relief system for health damage after vaccination. While some projects, such as the mass administration of live oral polio vaccine in 1961, achieved excellent results, incidents leading to health damage occurred, such as the diphtheria toxoid immunization incident (1948) and frequent occurrence of aseptic meningitis owing to the measles, mumps, and rubella vaccine (1989). In December 1992, the Tokyo High Court sentenced that the onset of health damage after vaccination could be attributed to the negligence of the national government. In the revision of the Immunization Act in 1994, the “mandatory vaccination” enforced until then was changed to “recommended vaccination.” The Act was also changed to recommend “individual vaccination” in principle, which is performed after primary care physicians investigate the physical condition of individual recipients and carefully conduct preliminary examination. For approximately 20 years from the 1990s, a vaccine gap existed between Japan and other countries. From around 2010, efforts have been made to bridge this gap and establish the global standard in vaccination.

Significant technological advances in radiotherapy have been made in the past few decades. High-precision radiotherapy has recently become popular and is contributing to improvements in the local control of the irradiated target lesions and the reduction of adverse effects. Accordingly, for long-term survival, the importance of systemic cancer control, including at non-irradiated sites, is growing. Toward this challenge, the treatment methods in which anti-PD-1/PD-L1 antibodies that exert systemic effects by restoring anti-tumour immunity are combined with radiotherapy has attracted attention in recent years. Previous studies have reported the activation of anti-tumour immunity by radiotherapy, which simultaneously elevates PD-L1 expression, suggesting a potential for combination therapy. Radiotherapy induces so-called ‘immunogenic cell death’, which involves cell surface translocation of calreticulin and extracellular release of high-mobility group protein box 1 (HMGB-1) and adenosine-5′-triphosphate (ATP). Furthermore, radiotherapy causes immune activation via MHC class I upregulation and cGAS–STING pathway. In contrast, induction of immunosuppressive lymphocytes and the release of immunosuppressive cytokines and chemokines by radiotherapy contribute to immunosuppressive reactions. In this article, we review immune responses induced by radiotherapy as well as previous reports to support the rationale of combination of radiotherapy and anti-PD-1/PD-L1 antibodies. A number of preclinical and clinical studies have shown the efficacy of radiotherapy combined with immune checkpoint inhibition, hence combination therapy is considered to be an important future strategy for cancer treatment.

Accumulating evidence suggests that exogenous cellular stress induces PD-L1 upregulation in cancer. A DNA double-strand break (DSB) is the most critical type of genotoxic stress, but the involvement of DSB repair in PD-L1 expression has not been investigated. Here we show that PD-L1 expression in cancer cells is upregulated in response to DSBs. This upregulation requires ATM/ATR/Chk1 kinases. Using an siRNA library targeting DSB repair genes, we discover that BRCA2 depletion enhances Chk1-dependent PD-L1 upregulation after X-rays or PARP inhibition. In addition, we show that Ku70/80 depletion substantially enhances PD-L1 upregulation after X-rays. The upregulation by Ku80 depletion requires Chk1 activation following DNA end-resection by Exonuclease 1. DSBs activate STAT1 and STAT3 signalling, and IRF1 is required for DSB-dependent PD-L1 upregulation. Thus, our findings reveal the involvement of DSB repair in PD-L1 expression and provide mechanistic insight into how PD-L1 expression is regulated after DSBs. PD-L1 is upregulated in many cancers due to exogenous cellular stress. Here the authors show that PD-L1 is upregulated in response to DNA double strand breaks via STAT and IRF1 signalling.

Mid-domain effect (MDE) models predict that the random placement of species’ ranges within a bounded geographical area leads to increased range overlap and species richness in the center of the bounded area. These models are frequently applied to study species-richness patterns of macroorganisms, but the MDE in relation to microorganisms is poorly understood. In this study, we examined the characteristics of the MDE in richness patterns of ectomycorrhizal (EM) fungi, an ecologically important group of soil symbionts. We conducted intensive soil sampling to investigate overlap among species ranges and the applicability of the MDE to EM fungi in four temperate forest stands along an elevation gradient on Mount Fuji, Japan. Molecular analyses using direct sequencing revealed 302 EM fungal species. Of 73 EM fungal species found in multiple stands, 72 inhabited a continuous range along the elevation gradient. The maximum overlap in species range and the highest species richness occurred at elevations in the middle of the gradient. The observed richness pattern also fit within the 95% confidence interval of the mid-domain null model, supporting the role of the MDE in EM fungal richness. Deviation in observed richness from the mean of the mid-domain null estimation was negatively correlated with some environmental factors, including precipitation and soil C/N, indicating that unexplained richness patterns could be driven by these environmental factors. Our results clearly support the existence of microbial species’ ranges along environmental gradients and the potential applicability of the MDE to better understand microbial diversity patterns.

Abstract Photons, such as X- or γ-rays, induce DNA damage (distributed throughout the nucleus) as a result of low-density energy deposition. In contrast, particle irradiation with high linear energy transfer (LET) deposits high-density energy along the particle track. High-LET heavy-ion irradiation generates a greater number and more complex critical chromosomal aberrations, such as dicentrics and translocations, compared with X-ray or γ irradiation. In addition, the formation of >1000 bp deletions, which is rarely observed after X-ray irradiation, has been identified following high-LET heavy-ion irradiation. Previously, these chromosomal aberrations have been thought to be the result of misrepair of complex DNA lesions, defined as DNA damage through DNA double-strand breaks (DSBs) and single-strand breaks as well as base damage within 1–2 helical turns (<3–4 nm). However, because the scale of complex DNA lesions is less than a few nanometers, the large-scale chromosomal aberrations at a micrometer level cannot be simply explained by complex DNA lesions. Recently, we have demonstrated the existence of clustered DSBs along the particle track through the use of super-resolution microscopy. Furthermore, we have visualized high-level and frequent formation of DSBs at the chromosomal boundary following high-LET heavy-ion irradiation. In this review, we summarize the latest findings regarding the hallmarks of DNA damage structure and the repair pathway following heavy-ion irradiation. Furthermore, we discuss the mechanism through which high-LET heavy-ion irradiation may induce dicentrics, translocations and large deletions.

In the fight against the pandemic of COVID-19, it is important to ascertain the status and trend of the infection spread quickly and accurately. The purpose of our study is to formulate a new and simple indicator that represents the COVID-19 spread rate by using publicly available data. The new indicator K is a backward difference approximation of the logarithmic derivative of the cumulative number of cases with a time interval of 7 days. It is calculated as a ratio of the number of newly confirmed cases in a week to the total number of cases. The analysis of the current status of COVID-19 spreading over countries showed an approximate linear decrease in the time evolution of the K value. The slope of the linear decrease differed from country to country. In addition, it was steeper for East and Southeast Asian countries than for European countries. The regional difference in the slope seems to reflect both social and immunological circumstances for each country. The approximate linear decrease of the K value indicates that the COVID-19 spread does not grow exponentially but starts to attenuate from the early stage. The K trajectory in a wide range was successfully reproduced by a phenomenological model with the constant attenuation assumption, indicating that the total number of the infected people follows the Gompertz curve. Focusing on the change in the value of K will help to improve and refine epidemiological models of COVID-19.

Lypd8 protein derived from intestinal epithelial cells binds to flagellated bacteria to reduce their motility, which limits the entry of Gram-negative bacteria into the inner colonic mucus and prevents invasion of colonic epithelia. Lypd8 separates microbiota from epithelia This paper shows that the intestinal epithelial cell derived protein Lypd8, a member of member of the Ly6/PLAUR superfamily, binds to flagellated bacteria. In doing so it reduces the bacteria's motility, limits the entry of Gram-negative bacteria into the inner colonic mucus, and prevents invasion into colonic epithelium. Colonic epithelial cells are covered by thick inner and outer mucus layers 1 , 2 . The inner mucus layer is free of commensal microbiota, which contributes to the maintenance of gut homeostasis 3 , 4 , 5 , 6 . In the small intestine, molecules critical for prevention of bacterial invasion into epithelia such as Paneth-cell-derived anti-microbial peptides and regenerating islet-derived 3 (RegIII) family proteins have been identified 7 , 8 , 9 , 10 , 11 . Although there are mucus layers providing physical barriers against the large number of microbiota present in the large intestine, the mechanisms that separate bacteria and colonic epithelia are not fully elucidated. Here we show that Ly6/PLAUR domain containing 8 (Lypd8) protein prevents flagellated microbiota invading the colonic epithelia in mice. Lypd8, selectively expressed in epithelial cells at the uppermost layer of the large intestinal gland, was secreted into the lumen and bound flagellated bacteria including Proteus mirabilis . In the absence of Lypd8, bacteria were present in the inner mucus layer and many flagellated bacteria invaded epithelia. Lypd8 −/− mice were highly sensitive to intestinal inflammation induced by dextran sulfate sodium (DSS). Antibiotic elimination of Gram-negative flagellated bacteria restored the bacterial-free state of the inner mucus layer and ameliorated DSS-induced intestinal inflammation in Lypd8 −/− mice. Lypd8 bound to flagella and suppressed motility of flagellated bacteria. Thus, Lypd8 mediates segregation of intestinal bacteria and epithelial cells in the colon to preserve intestinal homeostasis.

Background: Mumps vaccination coverage is low in Japan, partly because of its voluntary nature. Although pediatric cases of mumps virus infection are captured by the National Epidemiological Surveillance of Infectious Diseases program under the Infectious Disease Law, there are currently no data regarding the occurrence of mumps and its complications in adults.Methods: We investigated the annual incidence rates of mumps and its complications based on health insurance reimbursement data for 5,209,660 individuals aged 0–64 years for 2005–2017, obtained from JMDC Inc., to estimate the mumps-related disease burden during this period.Results: There were three mumps outbreaks (2006, 2010, and 2016) during 2005–2017. The annual incidence of mumps was highest in individuals aged 0–5 years (808–3,792 per 100,000 persons), followed by those aged 6–15 years (658–2,141 per 100,000 persons). The incidence of mumps was higher in females than in males (male/female ratio, 0.90). Among mumps-related complications, the overall incidence (per 1,000 mumps cases) was highest for orchitis (6.6), followed by meningitis (5.8), deafness (1.3), pancreatitis (0.5), and encephalitis (0.3). No cases of oophoritis were noted. The overall incidence of mumps-related complications was 2.5 times higher in males than in females.Conclusions: This study revealed the disease burden due to mumps and its complications in Japan during 2005–2017. These data suggest the need for mumps-prevention measures in adolescents and adults, as well as in children.

Background: Mumps deafness causes serious problems, and incidence data are needed to identify its disease burden. However, such data are limited, and the reported incidence is highly variable. Nationwide studies in Japan with a large age range are lacking.Methods: This was a retrospective observational investigation of the 2005–2017 mumps burden using employment-based health insurance claims data. Data were analyzed for 5,190,326 people aged 0–64 years to estimate the incidence of mumps deafness.Results: Of 68,112 patients with mumps (36,423 males; 31,689 females), 102 (48 males; 54 females) developed mumps deafness—an incidence of 15.0 per 10,000 patients (1 in 668 patients). Fifty-four (52.9%) patients had mumps deafness in childhood (0–15 years), and 48 (47.1%) had mumps deafness in adolescence and adulthood (16–64 years); most cases occurred in childhood, the peak period for mumps onset. The incidence of mumps deafness per 10,000 patients was 73.6 in adolescence and adulthood, 8.4 times higher than the incidence of 8.8 in childhood (P < 0.001). In childhood, the incidence of mumps deafness was 7.2 times higher among 6–15-year-olds (13.8; 95% CI, 10.2–18.2) than among 0–5-year-olds (1.9; 95% CI, 0.6–4.5), and this difference was statistically significant (P < 0.001). No sex difference was observed.Conclusions: The incidence of mumps deafness per 10,000 patients aged 0–64 years was 15.0 (1 in 668 patients). A secondary risk of deafness following mumps virus infection was identified not only for children, but also for adolescents and adults.

Point clouds from laser scanners have been widely used in recent research on indoor modeling methods. Currently, particularly in data-driven modeling methods, data preprocessing for dividing structural components and nonstructural components is required before modeling. In this paper, we propose an indoor modeling method without the classification of structural and nonstructural components. A pre-mesh is generated for constructing the adjacency relations of point clouds, and plane components are extracted using planar-based region growing. Then, the distance fields of each plane are calculated, and voxel data referred to as a surface confidence map are obtained. Subsequently, the inside and outside of the indoor model are classified using a graph-cut algorithm. Finally, indoor models with watertight meshes are generated via dual contouring and mesh refinement. The experimental results showed that the point-to-mesh error ranged from approximately 2 mm to 50 mm depending on the dataset. Furthermore, completeness—measured as the proportion of original point-cloud data successfully reconstructed into the mesh—approached 1.0 for single-room datasets and reached around 0.95 for certain multiroom and synthetic datasets. These results demonstrate the effectiveness of the proposed method in automatically removing non-structural components and generating clean structural meshes.