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Background Research has suggested an association between lower socioeconomic status (SES) and unhealthy dietary habits. However, differences in the effects of different SES indicators and age remain unclear. The current study addressed this research gap by investigating the relationship between SES and unhealthy dietary habits, specifically focusing on educational attainment and subjective financial status (SFS) among varied age groups. Methods Data were derived from a mail survey of 8,464 people living in a suburb of Tokyo, Japan. Participants were classified into three age groups (20–39 years: young adults; 40–64 years: middle-aged adults; and 65–97 years: older adults). SES was assessed based on individual educational attainment and SFS. Unhealthy dietary habits were defined as skipping breakfast and a low frequency of balanced meal consumption. Participants were asked how often they ate breakfast, and those who did not respond “every day” were categorized as “breakfast skippers.” Low frequency of balanced meal consumption was defined as eating a meal that included a staple meal, main dish, and side dishes at least twice a day for less than five days per week. Poisson regression analyses with robust variance adjusted for potential covariates were used to determine the interactive effects of educational attainment and SFS on unhealthy dietary habits. Results Individuals with lower educational attainment across all age groups skipped breakfast more frequently compared to those with higher educational attainment. For older adults, poor SFS was associated with skipping breakfast. Young adults with poor SFS and middle-aged adults with lower educational attainment tended to eat less balanced meals. In addition, an interaction effect was found in older adults, where those with lower education despite good SFS and those with poor SFS despite higher education were at a greater risk of falling into unhealthy diet. Conclusions The findings suggested that different SES indicators affect healthy dietary habits in different generations, and therefore, health policies should consider the potential influence of different SES on promoting healthier dietary habits.

Human papillomavirus 18 (HPV18) is a highly malignant HPV genotype among high‐risk HPVs, characterized by the difficulty of detecting it in precancerous lesions and its high prevalence in adenocarcinomas. The cellular targets and molecular mechanisms underlying its infection remain unclear. In this study, we aimed to identify the cells targeted by HPV18 and elucidate the molecular mechanisms underlying HPV18 replication. Initially, we established a lentiviral vector (HPV18LCR‐GFP vector) containing the HPV18 long control region promoter located upstream of EGFP. Subsequently, HPV18LCR‐GFP vectors were transduced into patient‐derived squamocolumnar junction organoids, and the presence of GFP‐positive cells was evaluated. Single‐cell RNA sequencing of GFP‐positive and GFP‐negative cells was conducted. Differentially expressed gene analysis revealed that 169 and 484 genes were significantly upregulated in GFP‐positive and GFP‐negative cells, respectively. Pathway analysis showed that pathways associated with cell cycle and viral carcinogenesis were upregulated in GFP‐positive cells, whereas keratinization and mitophagy/autophagy‐related pathways were upregulated in GFP‐negative cells. siRNA‐mediated luciferase reporter assay and HPV18 genome replication assay validated that, among the upregulated genes, ADNP, FHL2, and NPM3 were significantly associated with the activation of the HPV18 early promoter and maintenance of the HPV18 genome. Among them, NPM3 showed substantially higher expression in HPV‐related cervical adenocarcinomas than in squamous cell carcinomas, and NPM3 knockdown of HPV18‐infected cells downregulated stem cell‐related genes. Our new experimental model allows us to identify novel genes involved in HPV18 early promoter activities. These molecules might serve as therapeutic targets in HPV18‐infected cervical lesions. Using a combination of squamocolumnar junction organoids and HPV18LCR‐GFP lentivirus, we successfully identified three molecules that may be associated with the activation of the HPV18 early promoter and maintenance of the HPV18 genome. This novel approach could be a breakthrough in identifying the mechanism of initial HPV18 replication and the cellular origin of HPV18‐associated cervical cancer.

ABSTRACTBackgroundSocial isolation and homebound statuses are possible risk factors for increased mortality among older adults. However, no study has addressed the impact of accumulation of these two factors on mortality. The aim of this study was to examine whether such accumulation increased the risk of all-cause mortality. MethodsThe analyzed sample was drawn from a mail survey of 1,023 older adults without instrumental activities of daily living disability. Participants were classified into four groups according to the frequency of both face-to-face and non-face-to-face interactions with others (social isolation and non-social isolation) and the frequency of going outdoors (homebound and non-homebound). Social isolation and homebound statuses were defined as having a social interaction less than once a week and going outdoors either every few days or less, respectively. All-cause mortality information during a six-year follow-up was obtained. ResultsIn total, 78 (7.6%) participants were both socially isolated and homebound. During the follow-up period, 65 participants died, with an overall mortality rate of 10.6 per 1000 person-years. Cox proportional hazards regression analyses demonstrated that older adults who were socially isolated and homebound showed a significantly higher risk of subsequent all-cause mortality compared with healthy adults who were neither socially isolated nor homebound, independent of potential covariates (aHR, 2.19; 95% CI: 1.04–4.63). ConclusionOur results suggest that the co-existence of social isolation and homebound statuses may synergistically increase risk of mortality. Both active and socially integrated lifestyle in later life might play a major role in maintaining a healthy status.

Spatial transcriptome analysis of formalin-fixed paraffin-embedded (FFPE) tissues using RNA-sequencing (RNA-seq) provides interactive information on morphology and gene expression, which is useful for clinical applications. However, despite the advantages of long-term storage at room temperature, FFPE tissues may be severely damaged by methylene crosslinking and provide less gene information than fresh-frozen tissues. In this study, we proposed a sensitive FFPE micro-tissue RNA-seq method that combines the punching of tissue sections (diameter: 100 μm) and the direct construction of RNA-seq libraries. We evaluated a method using mouse liver tissues at two years after fixation and embedding and detected approximately 7000 genes in micro-punched tissue-spots (thickness: 10 μm), similar to that detected with purified total RNA (2.5 ng) equivalent to the several dozen cells in the spot. We applied this method to clinical FFPE specimens of lung cancer that had been fixed and embedded 6 years prior, and found that it was possible to determine characteristic gene expression in the microenvironment containing tumor and non-tumor cells of different morphologies. This result indicates that spatial gene expression analysis of the tumor microenvironment is feasible using FFPE tissue sections stored for extensive periods in medical facilities.

Spatial transcriptomics is useful for understanding the molecular organization of a tissue and providing insights into cellular function in a morphological context. In order to obtain reproducible results in spatial transcriptomics, we have to maintain tissue morphology and RNA molecule stability during the image acquisition and biomolecule collection processes. Here, we developed a tissue processing method for robust and reproducible RNA-seq from tissue microdissection samples. In this method, we suppressed RNA degradation in fresh-frozen tissue specimens by dehydration fixation and effectively collected a small amount of RNA molecules from microdissection samples by magnetic beads. We demonstrated the spatial transcriptome analysis of the mouse liver and brain in serial microdissection samples (100 μm in a diameter and 10 μm in thickness) produced by a microdissection punching system. Using our method, we could prevent RNA degradation at room temperature and effectively produce a sequencing library with Smart-seq2. This resulted in reproducible sequence read mapping in exon regions and the detection of more than 2000 genes compared to non-fixed samples in the RNA-seq analysis. Our method would be applied to various transcriptome analyses, providing the information for region specific gene expression in tissue specimens.

Gene expression analysis at the single-cell level by next-generation sequencing has revealed the existence of clonal dissemination and microheterogeneity in cancer metastasis. The current spatial analysis technologies can elucidate the heterogeneity of cell–cell interactions in situ. To reveal the regional and expressional heterogeneity in primary tumors and metastases, we performed transcriptomic analysis of microtissues dissected from a triple-negative breast cancer (TNBC) cell line MDA-MB-231 xenograft model with our automated tissue microdissection punching technology. This multiple-microtissue transcriptome analysis revealed three cancer cell-type clusters in the primary tumor and axillary lymph node metastasis, two of which were cancer stem cell (CSC)-like clusters (CD44/MYC-high, HMGA1-high). Reanalysis of public single-cell RNA-sequencing datasets confirmed that the two CSC-like populations existed in TNBC xenograft models and in TNBC patients. The diversity of these multiple CSC-like populations could cause differential anticancer drug resistance, increasing the difficulty of curing this cancer.

The cellular origins of cervical cancer and the histological differentiation of human papillomavirus (HPV)‐infected cells remain unexplained. To gain new insights into the carcinogenesis and histological differentiation of HPV‐associated cervical cancer, we focused on cervical cancer with mixed histological types. We conducted genomic and transcriptomic analyses of cervical cancers with mixed histological types. The commonality of the cellular origins of these cancers was inferred using phylogenetic analysis and by assessing the HPV integration sites. Carcinogenesis was estimated by analyzing human gene expression profiles in different histological types. Among 42 cervical cancers with known HPV types, mixed histological types were detected in four cases, and three of them were HPV18‐positive. Phylogenetic analysis of these three cases revealed that the different histological types had a common cell of origin. Moreover, the HPV‐derived transcriptome and HPV integration sites were common among different histological types, suggesting that HPV integration could occur before differentiation into each histological type. Human gene expression profiles indicated that HPV18‐positive cancer retained immunologically cold components with stem cell properties. Mixed cervical cancer has a common cellular origin among different histological types, and progenitor cells with stem‐like properties may be associated with the development of HPV18‐positive cervical cancer. To gain new insights into the carcinogenesis and histological differentiation of human papillomavirus (HPV)‐associated cervical cancer, we conducted genomic and transcriptomic analyses of cervical cancer with mixed histological types. The results suggest that mixed cervical cancer has a common cellular origin among different histological types, and progenitor cells with stem‐like properties may be associated with the development of HPV18‐positive cervical cancer. In addition, cells with stem‐like properties are immunologically cold.

Background Accumulating social capital in urban areas is essential to improve community health. Previous studies suggested that intergenerational contact may be effective for enhancing social capital. However, no study has examined the effect of intergenerational contact on social capital through a population-based evaluation. This study aimed to investigate the effects of a community-based intervention to increase the frequency of intergenerational contact on social capital among adults aged 25–84 years. Methods This study used a non-randomized controlled trial design to conduct a community-based intervention (from March 2016 to March 2019). The study area was Tama ward, Kawasaki city, Kanagawa, Japan. The area comprises five districts; one district was assigned as the intervention group and the other four districts as the control group. We provided the intervention to residents in the intervention group. The intervention comprised three phases: Phase 1 was the preparation term (organizing the project committee); Phase 2 was the implementation term (trained volunteer staff members, conducted the intergenerational greeting campaign, and held intergenerational contact events); and Phase 3 was the transition term (surrendering the lead role of the project to the city hall field workers). In the control group, field workers provided public health services as usual. We conducted mail surveys in September 2016 and November 2018 to assess the effects of the intervention on social capital during Phase 2. Eligible participants were randomly selected from community-dwelling adults aged 25–84 years according to age (10,620 control group individuals and 4479 intervention group individuals). We evaluated social trust, norm of reciprocity, and social support as outcome variables. Results In total, 2518 participants completed both surveys and were analyzed (control group: 1727; intervention group: 791). We found that social trust (coefficient = 0.065; 95% confidence interval [CI]: 0.006, 0.125) and norm of reciprocity (coefficient = 0.084; 95% CI: 0.020, 0.149) positively changed in the intervention group compared with the control group. Conclusions This community-based intervention may contribute to sustaining and improving social capital among community-dwelling adults. Trial registration : UMIN000046769 (UMIN-CTR); first registered on January 28, 2022 (retrospectively registered).

This study aims to identify the independent influence of face-to-face contact (FFC) and non-face-to-face contact (NFFC) on the subsequent decline in self-rated health and mental health status by age. A total of 12,000 participants were randomly selected among residents in the study area, and 1751 of them responded to both the 2016 and 2018 mail surveys. The participants were subsequently classified into three age groups (25–49: Young adults; 50–64: Mid-aged adults; and 65–84: Older adults). Social contact was assessed by computing the frequencies of FFC and NFFC. Multiple logistic regression analysis showed the risk of social contact on the decline in self-rated health and World Health Organization-Five Well-Being Index. Both FFC and NFFC were significantly associated with maintaining mental health; however, the impacts of FFC on mental health were more significant than that of NFFC among older adults and young adults. Compared with the no contact group, FFC was significantly associated with maintaining self-rated health in mid-aged adults. The influence of FFC and NFFC on health differed by age group.

Humanized mouse models are attractive experimental models for analyzing the development and functions of human dendritic cells (DCs) in vivo . Although various types of DC subsets, including DC type 3 (DC3s), have been identified in humans, it remains unclear whether humanized mice can reproduce heterogeneous DC subsets. CD14, classically known as a monocyte/macrophage marker, is reported as an indicator of DC3s. We previously observed that some CD14 + myeloid cells expressed CD1c, a pan marker for bona fide conventional DC2 (cDC2s), in humanized mouse models in which human FLT3L and GM-CSF genes were transiently expressed using in vivo transfection (IVT). Here, we aimed to elucidate the identity of CD14 + CD1c + DC-like cells in humanized mouse models. We found that CD14 + CD1c + cells were phenotypically different from cDC2s; CD14 + CD1c + cells expressed CD163 but not CD5, whereas cDC2s expressed CD5 but not CD163. Furthermore, CD14 + CD1c + cells primed and polarized naïve CD4 + T cells toward IFN-γ + Th1 cells more profoundly than cDC2s. Transcriptional analysis revealed that CD14 + CD1c + cells expressed several DC3-specific transcripts, such as CD163, S100A8, and S100A9, and were clearly segregated from cDC2s and monocytes. When lipopolysaccharide was administered to the humanized mice, the frequency of CD14 + CD1c + cells producing IL-6 and TNF-α was elevated, indicating a pro-inflammatory signature. Thus, humanized mice are able to sustain development of functional CD14 + CD1c + DCs, which are equivalent to DC3 subset observed in humans, and they could be useful for analyzing the development and function of DC3s in vivo .