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Neural vasculature forms the blood–brain barrier against the delivery of systemically administered therapeutic drugs into parenchyma of neural tissues. Therefore, procedures to open the blood–brain barrier with minimal damage to tissues would lead to the great progress in therapeutic strategy for intractable neural diseases. In this study, through analyses with mouse in vitro brain microvascular endothelial cells and in vivo neural vasculature, we demonstrate that the administration of cyclophilin A (CypA), a ligand of basigin which is expressed in barrier-forming endothelial cells, realizes the artificial opening of blood–brain barrier. Monolayers of endothelial cells lost their barrier properties through the disappearance of claudin-5, an integral tight junction molecule, from cell membranes in a transient and reversible manner. Furthermore, the intravenous injection of a single dose of CypA into mice resulted in the opening of blood–brain barrier for a certain period which enabled the enhanced delivery of systemically administered doxorubicin into the parenchyma of neural tissues. These findings that the pre-injection of a single dose of CypA realizes an artificial, transient as well as reversible opening of blood–brain barrier are considered to be a great step toward the establishment of therapeutic protocols to overcome the intractability of neural diseases.

Methacrylic copolymers have high potential as matrix polymers for carbon fiber reinforced thermoplastics (CFRTPs) due to their superior mechanical properties and the versatility of the monomers. However, the methacrylic copolymers have low solvent resistance, compared to epoxy, polyamide, and polypropylene, due to their un-cross-linked amorphous structure. Therefore, an improvement of the solvent resistance by the introduction of metal salts into methacrylic copolymer matrices for CFRTPs was investigated. Infrared spectroscopy, dynamic mechanical analyses and small-angle X-ray scattering clarified that an ionic cross-linked structure was formed. Low-viscosity mixtures of the methacrylic monomers with the metal salts, as a precursor of the matrices for CFRTPs, were easily impregnated into CF fabrics and were then copolymerized within the CF fabrics. Both the flexural strength and shear adhesive strength of the CFRTPs using the in situ polymerized methacrylic ionomer cross-linked with sodium ions were sufficiently high, even after 12 h immersion in methyl ethyl ketone.

The k-omega SST turbulence model is extensively employed in Reynolds-averaged Navier–Stokes (RANS)-based Computational Fluid Dynamics (CFD) calculations. However, the accuracy of the estimation of viscous resistance and companion flow distribution for full-sized vessels is not sufficient. This study conducted a computational analysis of the flow around the Ryuko-maru at model-scale and full-scale Reynolds numbers utilizing the Reynolds stress turbulence model (RSM). The obtained Reynolds stress distribution from the model-scale computation was compared against experimental measurements to assess the capability of the RSM. Furthermore, full-scale computations were performed, incorporating the influence of hull surface roughness, with the resulting wake distributions juxtaposed with the actual ship measurements. The full-scale calculation employed the sand-grain roughness function, and an optimal roughness length scale was determined by aligning the computed wake distribution with Ryuko-maru’s measured data. The results of this study will allow for the direct performance estimation of full-scale ships and contribute to the design technology of performance.

Functional triblock copolymers (BCPs), i.e., poly(glycidyl methacrylate/methyl methacrylate)-b-poly(lauryl methacrylate)-b-poly(glycidyl methacrylate/methyl methacrylate) triblock copolymers [(P(GMA/MMA)-b-PLMA-bP(GMA/MMA)], were investigated as toughening modifiers for all-methacrylate polymer blends. Methyl methacrylate (MMA) was copolymerized with methacrylic acid (MAA) in the presence of the BCPs. Without MAA in the polymethacrylate matrices, the BCP blends formed micron-scale phase structures by polymerization-induced phase separation. In matrices copolymerized with MAA, self-assembled nanostructures, such as curved lamellae, worm-like cylindrical micelles, or spherical micelles were formed. The BCP blends with worm-like cylindrical nano-micelles achieved much higher fracture toughness than those with spherical nano-micelles. The toughening mechanisms were elucidated by transmission electron microscopy. Cavitation was initiated in worm-like cylindrical nano-micelles, and the aligned cavitation formed craze-like deformation with increased loads. This relieves hydrostatic tensile stress in front of the crack tip, forming a large shear yield zone within the craze-like deformation region, contributing to high toughness.

The Reynolds-averaged Navier–Stokes (RANS)-based computational fluid dynamics (CFD) calculation using a two-equation turbulence model, such as the k–omega shear-stress transport (SST) model, is a mainstream method with sufficient accuracy for the estimation of integral hydrodynamic forces and moment at both the model-scale and full scale. This paper confirmed that the Reynolds stress model (RSM) has sufficient estimation accuracy of viscous resistance and wake distribution at the hull design stage. Herein, the ability of RSMs to estimate the viscous resistance and wake distribution of a JBC ship is evaluated. Specifically, the verification and validation (V&V) method is employed to indicate the numerical and model uncertainties of each turbulence model used to estimate the viscous resistance. The RSMs showed higher numerical uncertainty than the k–omega SST. However, the uncertainty of the experimental measurements is generally smaller than the numerical uncertainty. Moreover, the linear pressure–strain (LPS) and the linear pressure–strain two-layer (LPST) models show less comparison error of the viscous resistance than the k–omega SST. Furthermore, the LPST and k–omega SST models are applied to twenty ships with various full and fine hull forms to calculate the viscous resistance and compare it with the experimental results. The viscous resistance of the LPST model showed a small difference when employed in experimental fluid dynamics (EFD) and CFD calculations. Using the LPST model, the viscous resistance can be estimated with high accuracy in our setting. For industrial use, this study could provide an important insight into the designing of various types of vessels.

Mast cells are one of major players in allergic responses. Mast cell activation via the high affinity IgE receptor (FcεRI) causes degranulation and release of de novo synthesized proinflammatory cytokines in a process that involves vesicle trafficking. Considering that the GTPase ADP-ribosylation factor 1 (Arf1) orchestrates and maintains membrane traffic and organelle structure, it seems likely that Arf1 contributes to mast cell activation. Actually, it has been reported that pharmaceutical blockade of the Arf1 pathway suppresses cytokine secretion and mast cell degranulation. However, physiological roles of Arf1 in mast cells remain elusive. Here, by using a genetic approach, we demonstrate that Arf1 is required for optimal mTORC1 activation upon IL-3 and facilitates mast cell proliferation. On the other hand, contrary to our expectation, Arf1-deficiency had little impact on FcεRI-induced degranulation nor cytokine secretion. Our findings reveal an unexpected role of Arf1 in mast cell expansion and its potential as a therapeutic target in the mast cell proliferative disorders.

Mastitis and breast abscesses are most common in lactating women but can also be observed in non-lactating women, adolescent girls, and neonates. However, breast abscesses are extremely rare in young boys. Herein, we report the case of a three-year-old boy with a swollen and painful right nipple, later diagnosed with a breast abscess. In this case, we suspected that the patient's inverted nipple was the possible site of the infection. To our best knowledge, this is the first case report of breast abscess in a young boy after the neonatal period. Although is the most common pathogen, our patient showed three rare bacteria, namely, , , and , in the culture of the aspirated pus. Furthermore, this case study is the first report of a breast abscess caused by .

Polycystic kidney disease (PKD) is a common genetic disorder arising from developmental and postnatal processes. Defects in primary cilia and their signaling (eg, mTOR) underlie the pathogenesis. However, how mTOR regulates tubular integrity remains unclear. The paucity of faithful models has limited our understanding of pathogenesis and, therefore, the refinement of therapeutic targets. To understand the role of mTOR in early cystogenesis, we studied an in-house mouse model, Cd79a-Cre;Tsc1ff. (Cd79a-Tsc1 KO hereafter), recapitulating human autosomal-dominant PKD histology. Cre-mediated Tsc1 depletion driven by the promoter for Cd79a, a known B-cell receptor, activated mTORC1 exclusively along the distal nephron from embryonic day 16 onward. Cysts appeared in the distal nephron at 1 weeks of age and mice developed definite PKD by 4 weeks. Cd79a-Tsc1 KO tubule cells proliferated at a rate comparable to controls after birth but continued to divide even after postnatal day 14 when tubulogenesis is normally completed. Apoptosis occurred only after 9 weeks. During postnatal days 7–11, pre-cystic Cd79a-Tsc1 KO tubule cells showed cilia elongation, aberrant cell intercalation, and mitotic division, suggesting that defective cell planar polarity (PCP) may underlie cystogenesis. mTORC1 was activated in a portion of cyst-lining cells and occasionally even when Tsc1 was not depleted, implying a non-autonomous mechanism. Our results indicate that mTORC1 overactivation in developing distal tubules impairs their postnatal narrowing by disrupting morphogenesis, which orients an actively proliferating cell toward the elongating axis. The interplay between mTOR and cilium signaling, which coordinate cell proliferation with PCP, may be essential for cystogenesis.

Protein phosphatase 6 is a Ser/Thr protein phosphatase and its catalytic subunit is Ppp6c. Ppp6c is thought to be indispensable for proper growth of normal cells. On the other hand, loss of Ppp6c accelerates growth of oncogenic Ras‐expressing cells. Although it has been studied in multiple contexts, the role(s) of Ppp6c in cell proliferation remains controversial. It is unclear how oncogenic K‐Ras overcomes cell proliferation failure induced by Ppp6c deficiency; therefore, in this study, we attempted to shed light on how oncogenic K‐Ras modulates tumor cell growth. Contrary to our expectations, loss of Ppp6c decreased proliferation, anchorage‐independent growth in soft agar, and tumor formation of oncogenic Ras‐expressing mouse embryonic fibroblasts (MEFs). These findings show that oncogenic K‐RasG12V cannot overcome proliferation failure caused by loss of Ppp6c in MEFs. Protein phosphatase 6 is a Ser/Thr protein phosphatase and its catalytic subunit is Ppp6c. Ppp6c is thought to be indispensable for proper growth of normal cells. On the other hand, loss of Ppp6c accelerates growth of oncogenic Ras‐expressing cells. Here we showed that oncogenic K‐RasG12V cannot overcome proliferation failure caused by loss of Ppp6c in mouse embryonic fibroblasts.

mTOR is an evolutionarily conserved kinase that plays a critical role in sensing and responding to environmental determinants. Recent studies have shown that fine-tuning of the activity of mTOR complexes contributes to organogenesis and tumorigenesis. Although rapamycin, an allosteric mTOR inhibitor, is an effective immunosuppressant, the precise roles of mTOR complexes in early T-cell development remain unclear. Here we show that mTORC1 plays a critical role in the development of both early T-cell progenitors and leukemia. Deletion of Raptor, an essential component of mTORC1, produced defects in the earliest development of T-cell progenitors in vivo and in vitro. Deficiency of Raptor resulted in cell cycle abnormalities in early T-cell progenitors that were associated with instability of the Cyclin D2/D3-CDK6 complexes; deficiency of Rictor, an mTORC2 component, did not have the same effect, indicating that mTORC1 and -2 control T-cell development in different ways. In a model of myeloproliferative neoplasm and T-cell acute lymphoblastic leukemia (T-ALL) evoked by Kras activation, Raptor deficiency dramatically inhibited the cell cycle in oncogenic Kras-expressing T-cell progenitors, but not myeloid progenitors, and specifically prevented the development of T-ALL. Although rapamycin treatment significantly prolonged the survival of recipient mice bearing T-ALL cells, rapamycin-insensitive leukemia cells continued to propagate in vivo. In contrast, Raptor deficiency in the T-ALL model resulted in cell cycle arrest and efficient eradication of leukemia. Thus, understanding the cell-contextdependent role of mTORC1 illustrates the potential importance of mTOR signals as therapeutic targets.