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Platinum resistance is one of the most challenging problems in ovarian cancer treatment. High-throughput functional siRNA screening identified tyrosine kinase with immunoglobulin-like and EGF-like domains 1 (TIE-1) as a gene that confers cells resistant to cisplatin. Conversely enforced over-expression of TIE-1 was validated to decrease cisplatin sensitivity in multiple ovarian cancer cell lines and up-regulation of TIE-1 was correlated with poor prognosis and cisplatin resistance in patients with ovarian cancer. Mechanistically, TIE-1 up-regulates the nucleotide excision repair (NER) system mediated by xeroderma pigmentosum complementation group C (XPC), thereby leading to decreased susceptibility to cisplatin-induced cell death without affecting cisplatin uptake and excretion. Importantly potentiation of therapeutic efficacy by TIE-1 inhibition was selective to DNA-adduct-type chemotherapeutic platinum reagents. Therefore, TIE-1 is suggested to promote XPC-dependent NER, rendering ovarian cancer cells resistant to platinum. Accompanied with novel findings, TIE-1 could represent as a novel therapeutic target for platinum-resistant ovarian cancer.

Fertilization-initiated development and adult-onset aging are standard features in the life history of eukaryotes. In Paramecium, the number of cell divisions after the birth of a new generation is an essential parameter of sexual phase transition and aging. However, the gene driving this process and its evolutionary origin have not yet been elucidated. Here we report several critical outcomes obtained by molecular genetics, immunofluorescence microscopy, transformation by microinjection, and enzymological analysis. The cloned immaturin gene induces sexual rejuvenation in both mature and senescent cells by microinjection. The immaturin gene originated from proteobacteria’s glutathione-S-transferase (GST) gene. However, immaturin has been shown to lose GST activity and instead acquire nuclease activity. In vitro substrates for immaturin-nuclease are single- and double-stranded DNA, linear and circular DNA, and single-stranded viral genome RNA such as coronavirus. Anti-immaturin antibodies have shown that the subcellular localizations of immaturin are the macronucleus, cytoplasm, cell surface area, and cilia. The phase transition of sexuality is related to a decrease in the intracellular abundance of immaturin. We propose that sexual maturation and rejuvenation is a process programmed by the immaturin gene, and the sexual function of each age is defined by both the abundance and the intracellular localization mode of the immaturin-nuclease.

Gaucher's disease is caused by defects in acid β-glucosidase 1 (GBA1) and has been also proposed as an inflammatory disease. GBA1 cleaves glucosylceramide to form ceramide, an established bioactive lipid, and defects in GBA1 lead to aberrant accumulation in glucosylceramide and insufficient formation of ceramide. We investigated if the pro-inflammatory kinase p38 is activated in Gaucher's disease, since ceramide has been proposed to suppress p38 activation. Three Gaucher's disease mouse models were employed, and p38 was found to be activated in lung and liver tissues of all Gaucher's disease mice. Most interestingly, neuronopathic Gaucher's disease type mice, but not non-neuronopathic ones, displayed significant activation of p38 and up-regulation of p38-inducible proinflammatory cytokines in brain tissues. In addition, all type of Gaucher's disease mice also showed increases in serum IL-6. As cellular signalling is believed to represent an in vivo inflammatory phenotype in Gaucher's disease, activation of p38 and possibly its-associated formation of proinflammatory cytokines were assessed in fibroblasts established from neuronopathic Gaucher's disease mice. In mouse Gaucher's disease cells, p38 activation and IL-6 formation by TNF-α treatment were enhanced as compared to those of wild type. Furthermore, human fibroblasts from Gaucher's disease patients also displayed increases in p38 activation and IL-6 formation as comparison to healthy counterpart. These results raise the potential that proinflammatory responses such as p38 activation and IL-6 formation are augmented in Gaucher's disease.

Targeting cell motility, which is required for dissemination and metastasis, has therapeutic potential for ovarian cancer metastasis, and regulatory mechanisms of cell motility need to be uncovered for developing novel therapeutics. Invasive ovarian cancer cells spontaneously formed protrusions, such as lamellipodia, which are required for generating locomotive force in cell motility. Short interfering RNA screening identified class II phosphatidylinositol 3-kinase C2β (PI3KC2β) as the predominant isoform of PI3K involved in lamellipodia formation of ovarian cancer cells. The bioactive sphingolipid ceramide has emerged as an antitumorigenic lipid, and treatment with short-chain C 6 -ceramide decreased the number of ovarian cancer cells with PI3KC2β-driven lamellipodia. Pharmacological analysis demonstrated that long-chain ceramide regenerated from C 6 -ceramide through the salvage/recycling pathway, at least in part, mediated the action of C 6 -ceramide. Mechanistically, ceramide was revealed to interact with the PIK-catalytic domain of PI3KC2β and affect its compartmentalization, thereby suppressing PI3KC2β activation and its driven cell motility. Ceramide treatment also suppressed cell motility promoted by epithelial growth factor, which is a prometastatic factor. To examine the role of ceramide in ovarian cancer metastasis, ceramide liposomes were employed and confirmed to suppress cell motility in vitro . Ceramide liposomes had an inhibitory effect on peritoneal metastasis in a murine xenograft model of human ovarian cancer. Metastasis of PI3KC2β knocked-down cells was insensitive to treatment with ceramide liposomes, suggesting specific involvement of ceramide interaction with PI3KC2β in metastasis suppression. Our study identified ceramide as a bioactive lipid that limits PI3KC2β-governed cell motility, and ceramide is proposed to serve as a metastasis-suppressor lipid in ovarian cancer. These findings could be translated into developing ceramide-based therapy for metastatic diseases.

Three-dimensional (3D) organoid culture holds great promises in cancer precision medicine. However, Matrigel and stem cell-stimulating supplements are necessary for culturing 3D organoid cells. It costs a lot of money and consumes more time and effort compared with 2D cultured cells. Therefore, the establishment of cheaper and Matrigel-free organoid culture that can maintain the characteristics of a part of 3D organoids is demanded. In the previous study, we established a dog bladder cancer (BC) 3D organoid culture system by using their urine samples. Here, we successfully isolated cells named “2.5D organoid” from multiple strains of dog BC 3D organoids using 2.5 organoid media. The cell proliferation speed of 2.5D organoids was faster than parental 3D organoid cells. The expression pattern of stem cell markers was close to 3D organoids. Injection of 2.5D organoid cells into immunodeficient mice formed tumors and showed the histopathological characteristics of urothelial carcinoma similar to the injection of dog BC 3D organoids. The 2.5D organoids had a similar sensitivity profile for anti-cancer drug treatment to their parental 3D organoids. These data suggest that our established 2.5D organoid culture method might become a reasonable and useful tool instead of 3D organoids in dog BC research and therapy.

Many slow slip events (SSEs) occur beneath the ocean, and continuous ocean‐bottom pressure gauge (OBP) observations provide useful data. OBPs record both oceanic variations and crustal movements, so we developed a multi‐channel singular spectrum analysis method to remove oceanic variations and applied our method to OBPs and oceanic model data. Then components of the oceanic model with good correlations to the OBP data were subtracted from the observed data. This method compensates for the incompleteness of the oceanic model and removes oceanic variations better than use of the original model. We applied the method to OBP data for the 2018 Boso, Japan, SSE to estimate its slip distribution. Comparing slip distributions obtained with and without the OBP data, we found that the distribution obtained using OBP data extended further offshore, and the offshore estimation error was smaller. Our study shows that offshore observations using OBPs are important for characterizing SSEs. Plain Language Summary Slow slip events (SSEs) occur when faults slip slowly without generating seismic waves. Because most SSEs occur under the ocean, continuous observations by ocean‐bottom pressure instruments (OBPs) provide useful data. OBPs record both oceanic changes and seafloor movements. To remove the oceanic changes and more clearly observe seafloor movements, we developed a signal processing method to extract similar components from multiple time series. We applied our method to OBP data and oceanic model data, then subtracted the components of the oceanic model that match the OBP data from the observed data. This method removed the oceanic changes from the OBP data better than use of the original oceanic model alone. We applied this method to OBP data for the 2018 Boso, Japan, SSE and used vertical motions in the OBP data to estimate the slip distribution. The distribution obtained with the OBP data extended further offshore and was more accurate than that obtained without the OBP data. This study shows that observations of the ocean bottom obtained with OBPs are important for characterizing SSEs. Key Points We removed oceanic variations from ocean‐bottom pressure data using a reconstructed oceanic model, achieving ±4 mm observed accuracy The reconstructed oceanic model includes only components with good correlations between observed data and the oceanic model Use of the ocean‐bottom pressure data and the proposed method improved the accuracy of the slow slip distribution in offshore areas

Biologically produced protein drugs are generally susceptible to degradation by proteases and often exhibit immunogenicity. To address this issue, mirror-image peptide/protein binders consisting of D -amino acids have been developed so far through the mirror-image phage display technique. Here, we develop a mirror-image protein binder derived from a monobody, one of the promising protein scaffolds, utilizing two notable technologies: chemical protein synthesis and TRAP display, an improved version of mRNA display. A sequential workflow of initial screening followed by affinity maturation, facilitated by TRAP display, generates an L -monobody with high affinity ( K D  = 1.3 nM) against monocyte chemoattractant protein-1 (MCP-1) D -enantiomer. The chemically synthesized D -monobody demonstrates strong and specific binding to L -MCP-1 and exhibits pharmaceutically favorable properties such as proteolytic resistance, minimal immune response, and a potent inhibitory effect on MCP-1-induced cell migration. This study elevates the value of mirror-image peptide/protein binders as an alternative modality in drug discovery. In this work, a mirror-image protein binder derived from a monobody targeting MCP-1 is generated via in vitro display technology and chemical synthesis. It exhibits pharmaceutically promising properties, including protease resistance, negligible immunogenicity, and a potent inhibitory effect on cell migration.

Aim Clinical attention to and understanding of women with impaired fetal bonding is important for early therapeutic intervention. This study aimed to clarify the clinical characteristics of women belonging to groups derived by cluster analysis of impaired maternal–fetal bonding. Methods A mixed‐method approach was adopted. We conducted a two‐wave internet survey targeting pregnant women less than 36 gestational weeks by using a questionnaire (33‐item Dimensional Assessment of Mother Baby Organization Questionnaire [DAMBO Q33]) with subsequent online interviews (Dimensional Assessment of Mother and Baby Organization‐Research Version). The maternal–fetal bonding disorder items in the DAMBO Q33 were entered into a two‐step cluster analysis. Two representative cases from each of the clusters, except for the positive bonding cluster, were selected to describe their clinical pictures. Finally, quantitative data and qualitative data were integrated and interpreted. Results A two‐step cluster analysis elicited four clusters: bonding disorder (n = 101), ambivalent bonding (n = 156), positive bonding (n = 173), and lack of bonding emotions (n = 122). Women in the bonding disorder cluster were characterized by seriously negative feelings towards the fetus. Women in the ambivalent bonding cluster wished to be pregnant but were not sufficiently ready for the transition into parenthood. Women in the lack of bonding emotions cluster were characterized by a lack of strong interest in pregnancy and the fetus. Conclusion Patterns of impaired maternal–fetal bonding were identified. We should not think of a pathological category of mental illness among them but recognize that such parents are targets for professional assessments and supportive (therapeutic) interventions. Understanding the meaning of getting pregnant and difficulties in the process of maternal role attainment is required. Four clusters of pregnant women were identified in terms of maternal–fetal emotions. The women in each cluster had different clinical features. Early intervention and treatment tailored to clinical features should be provided by frontline staff caring for pregnant women.

In human and dogs, bladder cancer (BC) is the most common neoplasm affecting the urinary tract. Dog BC resembles human muscle‐invasive BC in histopathological characteristics and gene expression profiles, and could be an important research model for this disease. Cancer patient‐derived organoid culture can recapitulate organ structures and maintains the gene expression profiles of original tumor tissues. In a previous study, we generated dog prostate cancer organoids using urine samples, however dog BC organoids had never been produced. Therefore we aimed to generate dog BC organoids using urine samples and check their histopathological characteristics, drug sensitivity, and gene expression profiles. Organoids from individual BC dogs were successfully generated, expressed urothelial cell markers (CK7, CK20, and UPK3A) and exhibited tumorigenesis in vivo. In a cell viability assay, the response to combined treatment with a range of anticancer drugs (cisplatin, vinblastine, gemcitabine or piroxicam) was markedly different in each BC organoid. In RNA‐sequencing analysis, expression levels of basal cell markers (CK5 and DSG3) and several novel genes (MMP28, CTSE, CNN3, TFPI2, COL17A1, and AGPAT4) were upregulated in BC organoids compared with normal bladder tissues or two‐dimensional (2D) BC cell lines. These established dog BC organoids might be a useful tool, not only to determine suitable chemotherapy for BC diseased dogs but also to identify novel biomarkers in human muscle‐invasive BC. In the present study, for the 1st time, dog BC organoids were generated and several specifically upregulated organoid genes were identified. Our data suggest that dog BC organoids might become a new tool to provide fresh insights into both dog BC therapy and diagnostic biomarkers. In the present study, we for the first time generated dog bladder cancer (BC) organoids and identified several genes specifically upregulated in the organoids. Our data suggest that dog BC organoids might become a new tool to provide new insights for both dog BC therapy and diagnostic markers.

Bat is considered a natural reservoir of various important pathogens, including severe acute respiratory syndrome coronavirus (SARS-CoV), SARS-CoV-2, Ebola virus, and Nipah virus. To study these viruses’ pathogenicity and proliferation efficacy and viral tolerance mechanisms in bats, bat-derived cell lines, and primary cultured cells are used. However, these do not adequately reflect the exact biology of bats, and establishing new bat-related research models is necessary. Organoid culture can recapitulate organ structure, functions, and diseases. The respiratory tract is one of the primary routes of viral infection, and the establishment of bat lung organoids (BLO) is necessary to study the viral susceptibility in bats. Therefore, we aimed to establish a culture method of BLO from Rousettus leschenaultia that died of natural causes. The generated BLO successfully recapitulated the characteristics of pulmonary epithelial structure and morphology. BLO expressed the entry receptors for coronavirus, Angiotensin-converting enzyme 2 (ACE2), and Transmembrane Protease Serine 2 (TMPRSS2), and alveolar type 2 cells were successfully sorted from BLO, which has an important role for the development of viral infection in the respiratory system. Furthermore, we showed that BLO had no susceptibility to Pteropine orthoreovirus (PRV) compared to bat intestinal organoids. Collectively, our established bat organoid culture models including this BLO might become promising in vitro biomaterials to study the biology of bat-derived infectious diseases.