Significance: Claudin-1(CLDN1), which is thought to be a key gene for human skin disease, especially atopic dermatitis (AD), encodes the dominant claudin responsible for the paracellular barrier at tight junctions in the epidermis. Although decreasedCLDN1expression levels are reported in AD patients, it has been difficult to study how CLDN1 contributes to AD development, mainly becauseCldn1knock-out mice die within 1 d after birth from dehydration. In this report, we reproduced features of human AD in mice, by systematically regulating theCldn1expression level. Our experimental approach contributes to the understanding of AD’s etiology and suggests a therapeutic target for this disorder.

Acute myeloid leukemia (AML) cells are highly dependent on oxidative phosphorylation (OxPhos) for survival, and they continually adapt to fluctuations in nutrient and oxygen availability in the bone marrow (BM) microenvironment. We investigated how the BM microenvironment affects the response to OxPhos inhibition in AML by using a novel complex I OxPhos inhibitor, IACS-010759. Cellular adhesion, growth, and apoptosis assays, along with measurements of expression of mitochondrial DNA and generation of mitochondrial reactive oxygen species indicated that direct interactions with BM stromal cells triggered compensatory activation of mitochondrial respiration and resistance to OxPhos inhibition in AML cells. Mechanistically, inhibition of OxPhos induced transfer of mitochondria derived from mesenchymal stem cells (MSCs) to AML cells via tunneling nanotubes under direct-contact coculture conditions. Inhibition of OxPhos also induced mitochondrial fission and increased functional mitochondria and mitophagy in AML cells. Mitochondrial fission is known to enhance cell migration, so we used electron microscopy to observe mitochondrial transport to the leading edge of protrusions of AML cells migrating toward MSCs. We further demonstrated that cytarabine, a commonly used antileukemia agent, increased mitochondrial transfer of MSCs to AML cells triggered by OxPhos inhibition. Our findings indicate an important role of exogenous mitochondrial trafficking from BM stromal cells to AML cells as well as endogenous mitochondrial fission and mitophagy in the compensatory adaptation of leukemia cells to energetic stress in the BM microenvironment.

Neutrophils respond to invading bacteria by adopting a polarized morphology, migrating in the correct direction, and engulfing the bacteria. How neutrophils establish and precisely orient this polarity toward pathogens remains unclear. Here we report that in resting neutrophils, the ERM (ezrin, radixin, and moesin) protein moesin in its active form (phosphorylated and membrane bound) prevented cell polarization by inhibiting the small GTPases Rac, Rho, and Cdc42. Attractant-induced activation of myosin phosphatase deactivated moesin at the prospective leading edge to break symmetry and establish polarity. Subsequent translocation of moesin to the trailing edge confined the formation of a prominent pseudopod directed toward pathogens and prevented secondary pseudopod formation in other directions. Therefore, both moesin-mediated inhibition and its localized deactivation by myosin phosphatase are essential for neutrophil polarization and effective neutrophil tracking of pathogens.

Limited nationally representative evidence is available on temporal trends in physical fitness (PF) for children and adolescents during the coronavirus disease 2019 (COVID-19) pandemic. The primary aim was to examine the temporal trends in PF for Japanese children and adolescents before and during the COVID-19 pandemic. The secondary aim was to estimate the concurrent trends in body size (measured as body mass and height) and movement behaviors (exercise, screen, and sleep time). Census PF data for children in Grade 5 (aged 10–11 years) and adolescents in Grade 8 (aged 13–14 years) were obtained for the years 2013–2021 from the National Survey of Physical Fitness, Athletic Performance, and Exercise Habits in Japan (n = 16,647,699). PF and body size were objectively measured, and movement behaviors were self-reported. Using sample-weighted linear regression, temporal trends in mean PF were calculated before the pandemic (2013–2019) and during the pandemic (2019–2021) with adjustments for age, sex, body size, and exercise time. When adjusted for age, sex, body size, and exercise time, there were significant declines in PF during the pandemic, with the largest declines observed in 20-m shuttle run (standardized (Cohen's) effect size (ES) = −0.109 per annum (p.a.)) and sit-ups performance (ES = −0.133 p.a.). The magnitude of the declines in 20-m shuttle run and sit-ups performances were 18- and 15-fold larger, respectively, than the improvements seen before the pandemic (2013–2019), after adjusting for age, sex, body size, and exercise time. During the pandemic, both body mass and screen time significantly increased, and exercise time decreased. Declines in 20-m shuttle run and sit-ups performances suggest corresponding declines in population health during the COVID-19 pandemic.

Epithelial cells are joined by tight junctions (TJs) to form a cell sheet. In the stomach, epithelial cell sheet forms an essential barrier against gastric material, including gastric acid. Although the decreased expression of stomach-type claudin-18 (stCldn18), a TJ protein, is generally observed in human gastritis and gastric cancer, its pathological roles are not fully understood. We previously reported that mice lacking stCldn18 (stCldn18-/-) exhibit gastric acid leakage through TJs, which induces active gastritis at a young age. Here, we examined the gastric pathologies in mice after long-term stCldn18 deficiency. The gastric pathologies in stCldn18-/- mice were sequentially analyzed from youth to old age, and compared to those in humans. To examine the relationship between stCldn18 deficiency-induced gastric pathologies and Wnt-dependent tumorigenesis, we generated Wnt1-overexpressing stCldn18-/- mice. StCldn18-/- mice developed chronic active gastritis at middle age, with expression of the chemoattractant CCL28. At old age, 20-30% of these mice developed gastric tumors with CXCL5 expression, indicative of EMT. In this process, spasmolytic polypeptide-expressing metaplasia (SPEM) cells appeared. Increased expressions of CD44-variants, TLR2, and CXCL5 indicated age-dependent changes in cell characteristics. Some features of the stCldn18-/- mouse gastric tumorigenesis resembled H pylori-infection-related human carcinogenesis. The gastric tumorigenesis was accelerated in Wnt1-overexpressing stCldn18-/- mice, indicating that Wnt is involved in the stCldn18-/- mouse gastric tumorigenesis. StCldn18 deficiency induced gastric tumorigenesis in mice without H pylori infection. Our findings revealed that several signaling networks, including the cytokine-, stemness-, and Wnt-signaling pathways, may be activated under the stCldn18-deficiency-induced chronic active gastritis to accelerate the gastric tumorigenesis.