A Category of Probability Spaces

We introduce a category \Prob of probability spaces whose objects are all probability spaces and whose arrows correspond to measurable functions satisfying an absolutely continuous requirement. We can consider a \Prob-arrow as an evolving direction of information. We introduce a contravariant functor $\mathcal{E}$ from \Prob to \Set, the category of sets. The functor $\mathcal{E}$ provides conditional expectations along arrows in \Prob, which are generalizations of the classical conditional expectations. For a \Prob-arrow $f^-$, we introduce two concepts $f^-$-measurability and $f^-$-independence and investigate their interaction with conditional expectations along $f^-$. We also show that the completion of probability spaces is naturally formulated as an endofunctor of \Prob

Mutation of the N-terminal proline 9 of BLMA from Streptomyces verticillus abolishes the binding affinity for bleomycin

AbstractA gene, blmA, from bleomycin (Bm)-producing Streptomyces verticillus, encodes a Bm-binding protein, designated BLMA. The expression of BLMA conferred resistance to Bm in the Escherichia coli host, whereas a mutant protein, designated Pro-9/Leu, with the N-terminal proline 9 residue in BLMA replaced by leucine, did not. We created a fusion protein between the maltose-binding protein (MBP) and a mutant protein Pro-9/Leu/Leu with Met-94 in Pro-9/Leu replaced by leucine. Pro-9/Leu/Leu from the fusion protein, obtained by digestion with CNBr digestion, did not inhibit DNA-cleaving and antibacterial activities of Bm. Native-polyacrylamide gel electrophoresis (PAGE) and gel filtration column chromatographic analysis showed that the molecular size of Pro-9/Leu/Leu is roughly half of that of BLMA, suggesting that the mutant protein cannot form dimeric structure. Furthermore, Far-UV circular dichroism (CD) spectrum of Pro-9/Leu/Leu was quite different from that of BLMA and similar to the spectra obtained from unordered proteins [Venyaminov, S.Y. and Vassilenko, K.S. (1994) Anal. Biochem. 222, 176–184], suggesting that the secondary structure of Pro-9/Leu/Leu is disrupted. These results indicate that the mutation abolishes not only dimer formation but also the secondary structure of BLMA, which results in the loss of its function as a Bm-resistance determinant

A reporter system evaluates tumorigenesis, metastasis, β-catenin/MMP regulation, and druggability

Cancer invasion, metastasis, and therapy resistance are the crucial phenomena in cancer malignancy. The high-expression of matrix metalloproteinase 9 (MMP9) is a biomarker as well as a causal factor of cancer invasiveness and metastatic activity. However, a regulatory mechanism underlying MMP9 expression in cancer is not clarified yet. Additionally, a new strategy for anti-cancer drug discovery is becoming an important clue. In the present study, we aimed (i) to develop a novel reporter system evaluating tumorigenesis, invasiveness, metastasis, and druggability with a combination of three-dimensional (3D) tumoroid model and Mmp9 promoter and (ii) to examine pharmacological actions of anti-cancer medications using this reporter system. High expression and genetic amplification of MMP9 were found in colon cancer cases. We found that proximal promoter sequences of MMP9 in murine and human contained conserved binding sites for transcription factors β-catenin/TCF/LEF, glucocorticoid receptor (GR), and NF-κB. The murine Mmp9 promoter (-569 to +19) was markedly activated in metastatic colon cancer cells and additionally activated by tumoroid formation and by β-catenin signaling stimulator lithium chloride (LiCl). The Mmp9 promoter-driven fluorescent reporter cells enabled the monitoring of activities of MMP9/gelatinase, tumorigenesis, invasion, and metastasis in allogeneic/syngenic transplantation experiments. We also demonstrated pharmacological actions as follows. ids Dexamethasone and hydrocortisone, steroidal medications binding to GR, inhibited the Mmp9 promoter but did not inhibit tumorigenesis. On the other hand, an antimetabolite 5-fluorouracil, a golden standard for colon cancer chemotherapy, inhibited tumoroid formation but did not inhibit Mmp9 promoter activity. Notably, anti-malaria medication artesunate inhibited both tumorigenesis and the Mmp9 promoter in vitro, potentially through inhibition of β-catenin/TCF/LEF signaling. Thus, this novel reporter system enabled monitoring tumorigenesis, invasiveness, metastasis, key regulatory signalings such as β-catenin/MMP9 axis, and druggability

Peptidylarginine deiminase is involved in maintaining the cornified oral mucosa of rats.

Epithelial cells derived from different regions exhibit marked differences in their differentiation capacity, allowing them to provide a suitable protective barrier. We aimed to clarify the role of peptidylarginine deiminase (PAD) in modifying the key epidermal proteins filaggrin (FLG) and keratin 1 (K1) during stratification of the rat palate and buccal mucosa.We performed immunofluorescence, immunoblotting, PAD activity assays and 2-dimensional electrophoresis, and developed an organotypic culture model.PAD1 expression was highest in the palate, whereas PAD2, PAD3 and PAD4 expression was highest in the skin, suggesting the tissue-specific expression of PAD isozymes that leads to differences in calcium dependency. Immunoblotting showed that the FLG monomer, as well as its degradation products and precursor (proFLG), were most abundantly expressed in the skin but had low expression in the palate, whereas only faint proFLG expression was detected in the buccal mucosa. FLG and K1 were colocalized with PAD1 and were likely to be citrullinated in the cornified layers of the skin; this colocalization was not detected on the palatal surface, and dot-like presence of proFLG that might be citrullinated and that of PAD1 were found in the granules of the palate. Organotypic models derived from the rat palate revealed that PAD inhibition reduced the breakdown of FLG, increased its association with K1 together with epithelial compaction, and decreased permeability in a dye permeability assay. Conversely, PAD stimulation had the opposite effects.Citrullination is likely a protein modification that plays an important role in maintaining the structure and function of oral cornified mucosa in a way that is distinctly different from that of the skin.福岡歯科大学2018年

Glyburide inhibits the bone resorption induced by traumatic occlusion in rats.

To examine whether glyburide inhibits bone destruction caused by traumatic occlusion in a rat occlusal trauma model.Excessive mechanical stress, such as traumatic occlusion, induces expression of IL-1β and may be involved in bone resorption. NLRP3 inflammasomes have been linked to IL-1β expression, but it is currently unclear whether glyburide, the inhibiter of NLRP3 inflammasome, suppresses occlusal trauma in rats.Male SD rats aged 7 weeks were used. In the trauma group, the occlusal surface of the maxillary first right molar was raised by attaching a metal wire to apply occlusal trauma to the mandibular first right molar. In the trauma + glyburide group, the NLRP3 inhibitor glyburide was administered orally every 24 hours from 1 day before induction of occlusal trauma. Rats were euthanized after 5 or 10 days, and the maxillary first molars were harvested with the adjacent tissues for histopathological investigation. Immunohistochemical expression of IL-1β, NLRP3, and RANKL was also assessed.On day 5, bone resorption was significantly greater in the trauma group compared with the control group or the trauma + glyburide group, and there were significantly higher numbers of osteoclasts and cells positive for IL-1β, NLRP3, and RANKL in the trauma group.In this study, glyburide inhibits bone resorption by traumatic occlusion in rats. It suggests that the NLRP3/IL-1β pathway might be associated with bone resorption induced by traumatic occlusion.福岡歯科大学2019年

Search for dark matter produced in association with bottom or top quarks in √s = 13 TeV pp collisions with the ATLAS detector

A search for weakly interacting massive particle dark matter produced in association with bottom or top quarks is presented. Final states containing third-generation quarks and miss- ing transverse momentum are considered. The analysis uses 36.1 fb−1 of proton–proton collision data recorded by the ATLAS experiment at √s = 13 TeV in 2015 and 2016. No significant excess of events above the estimated backgrounds is observed. The results are in- terpreted in the framework of simplified models of spin-0 dark-matter mediators. For colour- neutral spin-0 mediators produced in association with top quarks and decaying into a pair of dark-matter particles, mediator masses below 50 GeV are excluded assuming a dark-matter candidate mass of 1 GeV and unitary couplings. For scalar and pseudoscalar mediators produced in association with bottom quarks, the search sets limits on the production cross- section of 300 times the predicted rate for mediators with masses between 10 and 50 GeV and assuming a dark-matter mass of 1 GeV and unitary coupling. Constraints on colour- charged scalar simplified models are also presented. Assuming a dark-matter particle mass of 35 GeV, mediator particles with mass below 1.1 TeV are excluded for couplings yielding a dark-matter relic density consistent with measurements