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Concerns about bioterrorism and outbreaks of zoonotic orthopoxvirus require safe and efficacious smallpox vaccines. We previously reported the clinical efficacy and safety profiles of LC16m8, a live, attenuated, cell culture-derived, smallpox vaccine, examined in over 3000 healthy Japanese adults with various vaccination histories. In this study, serum of approximately 200 subjects pre and post LC16m8 vaccination were subjected to a vaccinia virus-specific protein array to evaluate the proteome-wide immunogenicity. The relationships between antigen-specific antibodies and plaque reduction neutralization titers were analyzed. LC16m8 induced antibodies to multiple vaccinia antigens in primary-vaccinated individuals and yielded effective booster responses in previously vaccinated individuals, demonstrating similar antibody profiles to those reported for other vaccinia virus strains. Several immunodominant antigens were indicated to be important for neutralization of the intracellular mature virion. The similarity of antibody profiles between LC16m8 and other smallpox vaccine strains supports the immunogenicity and protective efficacy of LC16m8.

The phenotype of an attenuated live vaccine depends on gene mutation achieved by, for example, many passages in cultured cells. Viral clones with preferable phenotypes are selected and the causative genetic mutation(s) are later identified. LC16m8 is an example of a highly attenuated smallpox vaccine that was developed and licensed in Japan in the 1970s. LC16m8 was obtained by the passaging of Lister strain, with indicators of small plaque formation and temperature sensitivity as virus phenotypes. This strain can replicate in mammalian cells and provides robust cellular and humoral immunity, as well as long-term immune memory. Recent studies using proteome-wide antigen arrays have revealed that antibody production against LC16m8 and other VACVs differs largely among individuals. Moreover, associations between SNPs in immune-related genes and immune outcomes have been increasingly found. These results lead to predicting adverse events of a vaccine, which is a purpose of vaccinomics. Studies on VACV will continue to contribute to the understanding of host-pathogen interactions and to development of a vaccine for other infectious and non-infectious diseases. Here, we review studies of VACV, including our recent research on LC16m8, with a focus on the phenotype and genotype, and we discuss future research directions.

LC16m8 is a live, attenuated, cell-cultured smallpox vaccine that was developed and licensed in Japan in the 1970s, but was not used in the campaign to eradicate smallpox. In the early 2000s, the potential threat of bioterrorism led to reconsideration of the need for a smallpox vaccine. Subsequently, LC16m8 production was restarted in Japan in 2002, requiring re-evaluation of its safety and efficacy. Approximately 50,000 children in the 1970s and about 3500 healthy adults in the 2000s were vaccinated with LC16m8 in Japan, and 153 adults have been vaccinated with LC16m8 or Dryvax in phase I/II clinical trials in the USA. These studies confirmed the safety and efficacy of LC16m8, while several studies in animal models have shown that LC16m8 protects the host against viral challenge. The World Health Organization Strategic Advisory Group of Experts on Immunization recommended LC16m8, together with ACAM2000, as a stockpile vaccine in 2013. In addition, LC16m8 is expected to be a viable alternative to first-generation smallpox vaccines to prevent human monkeypox.

We examined the antimicrobial effects of human β-defensin-2 (hBD-2) on 17 species of oral streptococci to investigate the involvement of antimicrobial peptide activity in oral microflora development and the clinical use of the antimicrobial peptide for oral microflora control. Oral streptococci exhibit diverse levels of susceptibility to human β-defensin-2 (hBD-2). Two major cariogenic bacterial species, Streptococcus mutans (S. mutans) and S. sobrinus, were found to be susceptible to the peptide, indicating that it is a potential therapeutic agent for preventing dental caries. S. mitis exhibited the lowest susceptibility to the peptide. S. mitis is a major indigenous bacterium in the oral microflora, and our results suggest that it might possess a certain resistance mechanism against hBD-2.[PUBLICATION ABSTRACT]

We examined the antimicrobial effects of human beta-defensin-2 (hBD-2) on 17 species of oral streptococci to investigate the involvement of antimicrobial peptide activity in oral microflora development and the clinical use of the antimicrobial peptide for oral microflora control. Oral streptococci exhibit diverse levels of susceptibility to human beta-defensin-2 (hBD-2). Two major cariogenic bacterial species, Streptococcus mutans ( S. mutans) and S. sobrinus, were found to be susceptible to the peptide, indicating that it is a potential therapeutic agent for preventing dental caries. S. mitis exhibited the lowest susceptibility to the peptide. S. mitis is a major indigenous bacterium in the oral microflora, and our results suggest that it might possess a certain resistance mechanism against hBD-2.

A pericardial cyst is a rare condition in childhood. We report on a 10-year-old girl who presented with an intrathoracic mass detected on a chest X-ray performed during a routine medical examination. She had no symptoms and a physical examination revealed no abnormalities. Ultrasonography, computed tomography and magnetic resonance imaging showed a multiloculated cystic mass in the right upper thorax. The cyst was resected using a thoracoscopic procedure. Histologically, the findings were consistent with a pericardial cyst. Thoracoscopic surgery was an effective surgical technique even for such a young patient and the results successfully reduced the morbidity. A pericardial cyst, a rare condition in childhood, was treated successfully by video-assisted thoracoscopic surgery.

Microglia are the immune cells of the central nervous system that play important roles in brain pathologies. Microglia also help shape neuronal circuits during development, via phagocytosing weak synapses and regulating neurogenesis. Using in vivo multiphoton imaging of layer 2/3 pyramidal neurons in the developing somatosensory cortex, we demonstrate here that microglial contact with dendrites directly induces filopodia formation. This filopodia formation occurs only around postnatal day 8–10, a period of intense synaptogenesis and when microglia have an activated phenotype. Filopodia formation is preceded by contact-induced Ca 2+ transients and actin accumulation. Inhibition of microglia by genetic ablation decreases subsequent spine density, functional excitatory synapses and reduces the relative connectivity from layer 4 neurons. Our data provide the direct demonstration of microglial-induced spine formation and provide further insights into immune system regulation of neuronal circuit development, with potential implications for developmental disorders of immune and brain dysfunction. Microglia contribute to shaping neural circuits in the developing brain. Here, the authors show that microglial contact with pyramidal neuron dendrites induces synapse formation in the developing somatosensory cortex, and ablation of microglia reduces synaptic connections from L4 to L2/3 neurons.

Forensic dentistry identifies deceased individuals by comparing postmortem dental charts, oral-cavity pictures and dental X-ray images with antemortem records. However, conventional forensic dentistry methods are time-consuming and thus unable to rapidly identify large numbers of victims following a large-scale disaster. Our goal is to automate the dental filing process by using intraoral scanner images. In this study, we generated and evaluated an artificial intelligence-based algorithm that classified images of individual molar teeth into three categories: (1) full metallic crown (FMC); (2) partial metallic restoration (In); or (3) sound tooth, carious tooth or non-metallic restoration (CNMR). A pre-trained model was created using oral-cavity pictures from patients. Then, the algorithm was generated through transfer learning and training with images acquired from cadavers by intraoral scanning. Cross-validation was performed to reduce bias. The ability of the model to classify molar teeth into the three categories (FMC, In or CNMR) was evaluated using four criteria: precision, recall, F-measure and overall accuracy. The average value (variance) was 0.952 (0.000140) for recall, 0.957 (0.0000614) for precision, 0.952 (0.000145) for F-measure, and 0.952 (0.000142) for overall accuracy when the algorithm was used to classify images of molar teeth acquired from cadavers by intraoral scanning. We have created an artificial intelligence-based algorithm that analyzes images acquired with an intraoral scanner and classifies molar teeth into one of three types (FMC, In or CNMR) based on the presence/absence of metallic restorations. Furthermore, the accuracy of the algorithm reached about 95%. This algorithm was constructed as a first step toward the development of an automated system that generates dental charts from images acquired by an intraoral scanner. The availability of such a system would greatly increase the efficiency of personal identification in the event of a major disaster.

Background It is known that the circadian rhythm phase in adults can be advanced in a natural light-dark cycle without electrical lighting. However, the effect of advanced sleep-wake timing according to the natural light-dark cycle on children’s circadian phase is unclear. We investigated the effects of approximately 2 weeks of camping life with little access to artificial lighting on children’s circadian phases. We also conducted an exploratory examination on the effects of wake time according to natural sunrise time on the manner of the advance of their circadian phases. Methods Twenty-one healthy children (mean ± SD age, 10.6 ± 1.4 years) participated in a camping program with wake time (4:00) being earlier than sunrise time (EW condition), and 21 healthy children (10.4 ± 1.1 years) participated in a camping program with wake time (5:00) being almost matched to sunrise time (SW condition). Salivary dim light melatonin onset (DLMO) before the camping program and that after approximately 2 weeks of camping were compared. Results DLMO was advanced by approximately 2 h after the camping program compared with the circadian phase in daily life in both conditions. In addition, the advances in DLMO were significantly correlated with mid-sleep points before the camp in both conditions (EW: r = 0.72, p < 0.01, SW: r = 0.70, p < 0.01). These correlations mean that the phase advance was greater for the children with delayed sleep habits in daily life. Furthermore, in the EW condition, mean DLMO after the camp (18:09 ± 0:33 h) was earlier than natural sunset time and there was no significant decrease in interindividual variability in DLMO. On the other hand, in the SW condition, mean DLMO after the camp (18:43 ± 0:20 h) matched natural sunset time and interindividual variability in DLMO was significantly lower than that before the camp. Conclusions Camping with advanced sleep and wake timing under natural sunlight advances children’s circadian phases. However, DLMO earlier than sunset in an early waking condition may lead to large interindividual variability in the circadian rhythm phase.