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Pd(II)-catalyzed E/Z isomerization of alkenes is a common process-yet its mechanism remains largely uncharacterized, particularly with non-conjugated alkenes. In this work, the mechanism of Pd(II)-catalyzed E/Z isomerization of unactivated olefins containing an aminoquinoline-based amide directing group is probed using in situ kinetic analysis, spectroscopic studies, kinetic modeling, and DFT calculations. The directing group allows for stabilization and monitoring of previously undetectable intermediates. Collectively, the data are consistent with isomerization occurring through a monometallic nucleopalladation mechanism.

To establish whether new indices on plain chest X-ray (CXR) can replace those on computed tomography (CT) for the follow-up of children who have undergone the Nuss procedure. The subjects of this retrospective study were 45 children who underwent the Nuss procedure between 2000 and 2016. The Haller index (HI) was measured by preoperative CT. Preoperative and postoperative chest deformities were evaluated by two CXR measurements: the concave rate on the lateral view (CR; the depth of the concavity divided by the anterior–posterior diameter of the rib cage) and the tracheal bifurcation angle (TBA) on the anterior view. Data are expressed as the median with range. The median age and HI of the children, when they underwent the Nuss procedure, was 9.3 (3.8–17.3) years and 4.5 (3.2–10.1), respectively. The preoperative CR was correlated significantly with the HI. The postoperative CR was significantly lower than the preoperative CR [pre: 0.17 (0.08–0.37), post: 0.09 (0.01–0.18), p

Objectives There is limited evidence on the infants' postoperative complications who have undergone surgical repair of duodenal atresia and stenosis. This study aimed to identify the factors associated with poor surgical outcomes after the initial repair. Methods We retrospectively reviewed the data of 82 patients who underwent surgery for duodenal atresia and stenosis between January 1994 and December 2013 at our institution. Gestational age, birth weight, fetal growth, and other associated anomalies were recorded. Multivariate regression analyses were used to identify the factors associated with surgical outcomes, including postoperative complications and time to full oral intake. Results The median gestational age was 37.6 weeks, with 30 (37%) preterm (37 weeks) and 11 (13%) early preterm (34 weeks) infants. The median birth weight was 2531 g, with 27 (33%) patients2000 g and 10 (12%) patients1500 g. Postoperative surgical complications were identified in 18 (22%) cases, of which 12 (15%) required additional operations. Multivariate regression analysis revealed that a combination of very low birth weight (1500 g) and early preterm was significantly associated with both surgical and non-surgical postoperative complications (p = 0.0028 and 0.021, respectively) and a prolonged time to full oral intake postoperatively (p = 0.013). Conclusion Very low birth weight and early preterm were significantly associated with postoperative complications and a prolonged time to full oral intake.

Pd(II)-catalyzed E/Z isomerization of alkenes is a common process—yet its mechanism remains largely uncharacterized, particularly with non-conjugated alkenes. In this work, the mechanism of Pd(II)-catalyzed E/Z isomerization of unactivated olefins containing an aminoquinoline-based amide directing group is probed using in situ kinetic analysis, spectroscopic studies, kinetic modeling, and DFT calculations. The directing group allows for stabilization and monitoring of previously undetectable intermediates. Collectively, the data are consistent with isomerization occurring through a monometallic nucleopalladation mechanism.

Innate immunity plays a major role in xenograft rejection. However, the majority of immunosuppressants focus on inhibiting acquired immunity and not innate immunity. Therefore, a novel immunosuppressant suitable for use in conjunction with xenografts continues to be needed. It has been reported that prenylated quinolinecarboxylic acid-18 (PQA-18), a p21-activated kinase 2 (PAK2) inhibitor, exerts an immunosuppressive function on T cells. Hence, the possibility exists that PQA-18 might be used in conjunction with xenografts, which prompted us to investigate the efficacy of PQA-18 on macrophages compared with Tofacitinib, a janus kinase (JAK) inhibitor. Initial experiments confirmed that PQA-18 is non-toxic to swine endothelial cells (SECs) and human monocytes. Both PQA-18 and Tofacitinib suppressed macrophage-mediated cytotoxicity in both the differentiation and effector phases. Both PQA-18 and tofacitinib suppressed the expression of HLA-ABC by macrophages. However, contrary to Tofacitinib, PQA-18 also significantly suppressed the expression of CD11b, HLA-DR and CD40 on macrophages. PQA-18 significantly suppressed CCR7 expression on day 3 and on day 6, but Tofacitinib-induced suppression only on day 6. In a mixed lymphocyte reaction (MLR) assay, PQA-18 was found to suppress Interleukin-2 (IL-2)-stimulated T cell proliferation to a lesser extent than Tofacitinib. However, PQA-18 suppressed xenogeneic-induced T cell proliferation more strongly than Tofacitinib on day 3 and the suppression was similar on day 7. In conclusion, PQA-18 has the potential to function as an immunosuppressant for xenotransplantation.

Pd(II)-catalyzed E/Z isomerization of alkenes is a common process—yet is largely uncharacterized, particularly with non-conjugated alkenes. In this work, the mechanism of Pd(II)-catalyzed E/Z isomerization of unactivated olefins containing an aminoquinoline-based amide directing group is probed using in situ kinetic analysis, spectroscopic studies, kinetic modeling, and DFT calculations. The directing group allows for stabilization and monitoring of previously undetectable intermediates. Collectively, the data are consistent with isomerization occurring through a monometallic nucleopalladation mechanism.

Selective carbon–carbon (C–C) bond formation in chemical synthesis generally requires pre-functionalized building blocks. However, the requisite pre-functionalization steps undermine the efficiency of multi-step synthetic sequences, which is particularly problematic in large-scale applications, such as in the commercial production of pharmaceuticals. Herein, we describe a selective and catalytic method for synthesizing 1,3-enynes without pre-functionalized building blocks. This method is facilitated by a tailored P,N-ligand that enables regioselective coupling and suppresses secondary E/Z-isomerization of the product. The transformation enables several classes of unactivated internal acceptor alkynes to be coupled with terminal donor alkynes to deliver 1,3-enynes in a highly regio- and stereoselective manner. The scope of compatible acceptor alkynes includes propargyl alcohols, (homo)propargyl amine derivatives, and (homo)propargyl carboxamides. The reaction is scalable and can operate effectively with 0.5 mol% catalyst loading. The products are versatile intermediates that can participate in various downstream transformations. We also present preliminary mechanistic experiments that are consistent with a redox-neutral Pd(II) catalytic cycle.

Selective carbon–carbon (C–C) bond formation in chemical synthesis generally requires pre-functionalized building blocks. However, the requisite pre-functionalization steps undermine the efficiency of multi-step synthetic sequences, which is particularly problematic in large-scale applications, such as in the commercial production of pharmaceuticals. Herein, we describe a selective and catalytic method for synthesizing 1,3-enynes without pre-functionalized building blocks. This method is facilitated by a tailored P,N-ligand that enables regioselective coupling and suppresses secondary E/Z-isomerization of the product. The transformation enables several classes of unactivated internal acceptor alkynes to be coupled with terminal donor alkynes to deliver 1,3-enynes in a highly regio- and stereoselective manner. The scope of compatible acceptor alkynes includes propargyl alcohols, (homo)propargyl amine derivatives, and (homo)propargyl carboxamides. The reaction is scalable and can operate effectively with 0.5 mol% catalyst loading. The products are versatile intermediates that can participate in various downstream transformations. We also present preliminary mechanistic experiments that are consistent with a redox-neutral Pd(II) catalytic cycle.

In a series of studies, using an identical rat intestinal transplantation model, we evaluated the effects of several drugs. FK-506 caused a significant attenuation in the proliferation of allogeneic CD4+ T cells and IFN-γ secreting effector functions. FYT720 resulted in a marked reduction in the numbers of lymphocytes, associated with a reduction of T cell recruitment, in grafts. An anti-MAdCAM antibody was next reported to significantly down-regulate CD4+ T cell infiltration in intestinal grafts by blocking the adhesion molecule, and could be useful as an induction therapy. Concerning TAK-779, this CCR5 and CXCR3 antagonist diminished the number of graft-infiltrating cells by suppressing the expression of their receptors in the graft. As a result, it reduced the total number of recipient T cells involved in graft rejection. As the next step, we focused on the participation of monocytes/ macrophages in this field. PQA-18 has been the focus of a novel immunosuppressant that attenuates not only the production of various cytokines, such as IL-2 & TNF-α, on T cells, but the differentiation of macrophages by inhibiting PAK2 as well. In this report, we summarize our previous studies not only regarding the above drugs, but on an anti-complement drug and a JAK inhibitor as well.

Objective Surfactant protein D (SP-D), which is secreted mainly in the lung, is an oligometric C type lectin that promotes phagocytosis by binding to carbohydrates on microbial surfaces. SP-D can also bind SIRPα, leading to a decrease in cytokine production by monocytes/macrophages. In the present study, we examined the possibility that SP-D suppresses macrophage-mediated xenogeneic cytotoxicity, by creating a membrane-type SP-D. Methods The cDNA for the carbohydrate recognition domain (CRD) of human SP-D was switched to that of a membrane-type protein, collectin placenta 1 (CL-P1), with a Flag-tag. The cDNA of CD47 was prepared as a control. The suppressive function of the membrane-type protein of the hybrid molecule, CL-SP-D, to monocytes/macrophages was then studied and the results compared with that for CD47. Results The expression of Flag-tagged CL-SP-D on the transfected SECs and the SIRPα on monocyte-like cells, THP-1 cells, was confirmed by FACS using anti-Flag Ab and anti-CD172a, respectively. The molecular size of the hybrid protein was next assessed by western blot. While significant cytotoxicity against SEC was induced in differentiated THP-1 cells, CL-SP-D significantly reduced THP-1-mediated cytotoxicity. In addition, phosphorylated SHP-1 was clearly detected in SEC/CL-SP-D in western blots. Moreover, IL-10 production was upregulated and IL-1β production was suppressed in the case of THP-1 and SEC/CL-SP-D, compared with naive SEC. Next, the cytotoxicity caused by the in vitro generated macrophage was assessed under the same conditions as were used for THP-1. CL-SP-D also showed the significant down-regulation on the macrophage. In addition, changes in IL-10 production by the macrophage confirmed the results. Conclusions These findings indicate that the membrane-type SP-D serve as an effective therapeutic strategy for inhibiting macrophage-mediated xenograft rejection in xenotransplantation.

While interest in the synthetic chemistry of radical cations continues to grow, controlling enantioselectivity in the reactions of these intermediates remains a challenge. Based on recent insights into the oxidation of tryptophan in enzymatic systems, we report a photocatalytic method for the generation of indole radical cations as hydrogen-bonded adducts with chiral phosphate anions. These non-covalent open-shell complexes can be intercepted by the stable nitroxyl radical TEMPO• to form alkoxyamine-substituted pyrroloindolines with high levels of enantioselectivity. Further elaboration of these optically-enriched adducts can be achieved via a catalytic single-electron oxidation/mesolytic cleavage sequence to furnish transient carbocation intermediates that may be intercepted by a wide range of nucleophiles. Taken together, this two-step sequence provides a simple catalytic method to access a wide range of substituted pyrroloindolines in enantioenriched form via a standard experimental protocol from a common synthetic intermediate. The design, development, mechanistic study, and scope of this process are presented, as are applications of this method to the synthesis of several dimeric pyrroloindoline natural products.

A catalytic γ-selective syn-hydroarylation of alkenyl carbonyl compounds using arylboronic acids has been developed using a substrate directivity approach with a palladium(II) catalyst. This method tolerates a wide range of functionalized (hetero)arylboronic acids and a variety of substitution patterns on the alkene. Preliminary mechanistic studies suggest that transmetalation is rate-limiting.

Removable tridentate directing groups inspired by pincer ligands have been designed to stabilize otherwise kinetically and thermodynamically disfavored 6-membered alkyl palladacycle intermediates. This family of directing groups enables regioselective remote hydrocarbofunctionalization of several synthetically useful alkene-containing substrate classes, including 4-pentenoic acids, allylic alcohols, homoallyl amines, and bis-homoallylamines, under Pd(II) catalysis. In conjunction with previous findings, we demonstrate regiodivergent hydrofunctionalization of 3-butenoic acid derivatives to afford either Markovnikov or anti-Markovnikov addition products depending on directing group choice. Preliminary mechanistic and computational data are presented to support the proposed catalytic cycle.

Various strategies, such as the generation of alpha-1,3-galactosyltransferase knocked-out pigs and CD55 transgenic pigs, have been investigated to inhibit pig to human xenogeneic rejection. Our aim is to develop strategies to overcome the hurdle of not only hyper acute rejection, but also that of cellular xenogeneic rejection (CXR). Although macrophages have been well known to play a critical role in CXR, monocyte/macrophage-mediated xenogeneic rejection has not been well studied. In this study, we evaluated the effect of CD200 in xenogeneic rejection by macrophages. Naive swine endothelial cells (SEC) and SEC/CD200 were co-cultured with M0 macrophages and the cytotoxicity was measured by a WST-8 assay. The phagocytosis of SEC and SEC/CD200 by macrophages was analyzed by flow cytometry. While CD200 failed to suppress a significant amount of cytotoxicity against SEC by monocytes, M0 macrophage-mediated cytotoxicity was significantly suppressed by human CD200. The phagocytosis by M0 macrophages was also tested. The phagocytosis assay revealed that human CD200 suppresses M0 macrophage-mediated phagocytosis. Our findings indicate that human CD200 suppresses the xenogeneic rejection by CD200R+ macrophages and that the generation of hCD200 transgenic pigs for use in xenografts is very attractive for preventing the macrophage-mediated rejection.

We report a case of successful magnetic compression anastomosis (MCA) for obstructed cyst-jejunostomy in a young woman who had undergone surgery for type 1 biliary atresia (BA) on day 78 of life. A 16-year-old girl was admitted with obstructive jaundice. Jaundice resolved with percutaneous trans-hepatic cholangiodrainage (PTCD) but contrast medium injected from the PTCD tube did not flow through the anastomosis. Magnets were placed on each side of the anastomosis, in the cyst and the jejunum, to compress the partition. On postoperative day (POD) 6, the anastomosis was recanalized and the PTCD tube placed trans-anastomotically until POD 245. The patient remained free from jaundice after removal of the PTCD tube. MCA can be a useful and less invasive procedure for treating biliary tract anastomotic obstruction in patients with BA.

A catalytic γ-selective syn-hydroarylation of alkenyl carbonyl compounds using arylboronic acids has been developed using a substrate directivity approach with a palladium(II) catalyst. This method tolerates a wide range of functionalized (hetero)arylboronic acids and a variety of substitution patterns on the alkene.

Background Xenotransplantation is an appealing alternative to human allotransplantation because of a worldwide shortage of organs. One of the obstacles for xenografts is cellular rejection by the innate immune system, comprised of NK cells, monocytes, and macrophages. In this study the inhibitory function of HLA-G1, a MHC Ib molecule, on macrophage-mediated cytotoxicity was examined. Furthermore, this study also evaluates the suppressive effect of cytokine production by macrophages. Methods The expression of inhibitory receptors that interact with HLA-G1, immunoglobulin-like transcript 2 (ILT2), ILT4 and KIR2DL4 (CD158d) on in vitro generated macrophages were examined by flow cytometry. Complementary DNA (cDNA) of HLA-G1, HLA-E and human β2-microglobulin (hβ2m) were prepared and transfected into swine endothelial cells (SECs). The expression of the transgenic genes was evaluated by flow cytometry, and macrophage-mediated SEC cytolysis was assessed using the macrophages. Results In vitro generated macrophages expressed not only ILT2 and ILT4 but CD158d as well. The transgenic HLA-G1 on SECs indicated significant suppression in macrophage-mediated cytotoxicity, which was equivalent to that of transgenic HLA-E. Furthermore, the results on real time PCR and ELISA revealed that transgenic HLA-G1 induces the anti-inflammatory cytokines, such as IL-10 and TGF-β, and suppresses iNOS mRNA expression, indicating that transgenic HLA-G1 has suppressive effects in a broad range of transplant rejection. Conclusion These results indicate that generating HLA-G1 transgenic pigs can protect porcine grafts from macrophage-mediated cytotoxicity.

We diagnosed a primipara woman with anMYH9disorder during her pregnancy. A peripheral blood smear with an immunofluorescence analysis is the established method of diagnosingMYH9disorders. We provided genetic counseling, as required, which included apprising the woman of the inheritance pattern, the importance of a genetic analysis, and the potential delivery risks for the patient and her offspring. Given that the potential delivery risks are reportedly low, special perinatal management is not necessary for patients with anMYH9disorder whose platelet count is above 5.0 × 104/μL, except for rapid blood access.

Background Xenotransplantation is one of the promising strategies for overcoming the shortage of organs available for transplant. However, many immunological obstructions need to be overcome for practical use. Increasing evidence suggests that neutrophils contribute to xenogeneic cellular rejection. Neutrophils are regulated by activation and inhibitory signals to induce appropriate immune reactions and to avoid unnecessary immune reactivity. Therefore, we hypothesized that the development of neutrophil-targeted therapies may have the potential for increased graft survival in xenotransplantation. Methods A plasmid containing a cDNA insert encoding the human CD31 gene was transfected into swine endothelial cells (SEC). HL-60 cells were differentiated into neutrophil-like cells by culturing them in the presence of 1.3% dimethyl sulfoxide for 48 hours. The cytotoxicity of the differentiated HL-60 cells (dHL-60) and peripheral blood-derived neutrophils was evaluated by WST-8 assays. To investigate the mechanism responsible for hCD31-induced immunosuppression, citrullinated histone 3 (cit-H3) and phosphorylation of SHP-1 were detected by a cit-H3 enzyme-linked immunosorbent assay (ELISA) and Western blotting, respectively. Results A significant decrease in dHL-60 and neutrophil-mediated cytotoxicity in SEC/hCD31 compared with SEC was seen, as evidenced by a cytotoxicity assay. Furthermore, the suppression of NETosis and the induction of SHP-1 phosphorylation in neutrophils that had been co-cultured with SEC/CD31 were confirmed by cit-H3 ELISA and Western blotting with an anti-phosphorylated SHP-1. Conclusion These data suggest that human CD31 suppresses neutrophil-mediated xenogenic cytotoxicity via the inhibition of NETosis. As CD31 is widely expressed in a variety of inflammatory cells, human CD31-induced suppression may cover the entire xenogeneic cellular rejection, thus making the generation of human CD31 transgenic pigs very attractive for use in xenografts.

Myeloid-derived suppressor cells (MDSCs) were initially found to contribute to immunosuppression in tumor patients and have recently been recognized as a subset of innate immune cells. They are a heterogeneous population composed of monocytic MDSCs (M-MDSCs) and granulocytic MDSCs (G-MDSCs). In addition, MDSCs have been reported to induce immunological tolerance and prolong the graft survival in transplantation. In mouse CD11b+ Gr-1+ cells, MDSCs have been reported to exhibit immunosuppressive functions under various inflammatory conditions. On the other hand, human MDSCs do not have a universal marker and have not been well defined. Furthermore, while mouse CD11b+ Gr-1+ MDSCs account for 20-30% of bone marrow cells, human peripheral blood includes only a few percent of MDSCs. Hence, further investigations of human MDSCs and the development of strategies for isolating human MDSCs are mandatory for their use in the clinic for transplantation. We previously established a new strategy to generate monocytic MDSCs in vitro and to isolate them from human peripheral blood mononuclear cells (PBMC). Based on these studies, we have concluded that they have great potential for suppressing cytotoxic T lymphocyte (CTL) – mediated xenocytotoxicity and NK-mediated xenocytotoxicity. Furthermore, they also suppress macrophage-mediated xenocytotoxicity significantly. Here, we review the therapeutic potential of MDSCs in transplantation.

Background Hypercalcemia has been observed in patients after liver transplantation. However, it is rare that the hypercalcemia induced disseminated tissue calcification and heart failure. Case Report We report a rare case of heart failure caused by disseminated metastatic tissue calcification that involved extensive progressive myocardial calcification after liver transplantation. A 20-year-old man with end-stage liver disease due to biliary atresia underwent ABO-incompatible living donor liver transplantation. After successful transplantation, he suffered from antibody-mediated rejection. Subsequently, ABO-matched cadaveric liver retransplantation was successfully performed. Hypercalcemia developed gradually following the second transplantation. His serum calcium level increased to 18.3 mg/dL with sudden onset of ventricular tachycardia. Although he was resuscitated with a cardiopulmonary support device, he died of heart and liver failure. Histopathologic examination revealed systemic disseminated metastatic tissue calcification, including massive myocardial calcification. Conclusion Progressive worsening of hypercalcemia resulted in disseminated metastatic tissue calcification and massive metastatic myocardial calcification, which led to heart failure after liver transplantation. Because hypercalcemia after liver transplantation can cause fatal tissue calcification, early intervention for hypercalcemia should be considered.

The inhibitory function of HLA-G1, a class Ib molecule, on monocyte/macrophage−mediated cytotoxicity was examined. The expression of inhibitory receptors that interact with HLA-G, immunoglobulin-like transcript 2 (ILT2), ILT4, and KIR2DL4 (CD158d) on in vitro−generated macrophages obtained from peripheral blood mononuclear cells and the phorbol 12-myristate 13-acetate (PMA)-activated THP-1 cells were examined by flow cytometry. cDNAs of HLA-G1, HLA-G3, HLA-E, and human β2-microglobulin were prepared, transfected into pig endothelial cells (PECs), and macrophage- and the THP-1 cell−mediated PEC cytolysis was then assessed. In vitro−generated macrophages expressed not only ILT2 and ILT4 but CD158d as well. The transgenic HLA-G1 on PEC indicated a significant suppression in macrophage-mediated cytotoxicity, which was equivalent to that of transgenic HLA-E. HLA-G1 was clearly expressed on the cell surface of PEC, whereas the levels of HLA-G3 were much lower and remained in the intracellular space. On the other hand, the PMA-activated THP-1 cell was less expressed these inhibitory molecules than in vitro−generated macrophages. Therefore, the HLA-G1 on PECs showed a significant but relatively smaller suppression to THP-1 cell−mediated cytotoxicity compared to in vitro−generated macrophages. These results indicate that by generating HLA-G1, but not HLA-G3, transgenic pigs can protect porcine grafts from monocyte/macrophage-mediated cytotoxicity.

Background The purpose of this study was to produce molecules that can precisely regulate the complement and coagulation system and to assess the expression of such molecules in transgenic animals. Methods The CTDM gene, which is composed of the delta-1-99 amino acid (aa) C1-INH, EGF domain 4-6 of thrombomoduline (TM), short consensus repeat (SCR) 2-4 of DAF(CD55), and SCR 2-4 of MCP(CD46) was established. The codon usage for expression in mammals was adopted. The cDNA of CTDM was subcloned into the pCPI site (the human insulin promoter and a cytomegalovirus enhancer). pCPI-CTDM was transfected into pig endothelial cells (PEC). The expression of the molecule was clearly assessed by means of flow cytometry. Results BD3F1 female mice were induced to superovulate and were then crossed with BD3F1 males. Micro-injection and embryo transfer were performed by standard methods, thus generating transgenic mice that express CTDM. The mice carried the CTDM plasmid, as verified by PCR. Tissue expression levels in transgenic mouse lines generated with the constructs were follows: pancreas, 1.0; brain, 5.4; thymus, 0.3; heart, 0.2; lung, 1.2; liver, 0.1; kidney, 0.1; intestine, 0.4; and spleen, 1.6. A naive control mouse was also analyzed in the exact manner as for the transgenic mice. Conclusions A synthetic CTDM gene with codon usage optimized to the mammalian system represents a critical factor in the development of transgenic animals.

Background Xenotransplantation is considered to be one of the most attractive strategies for overcoming the worldwide shortage of organs. However, many obstructions need to be overcome before it will achieve clinical use in patients. One such obstacle is the development of an effective immunosuppressive strategy. We previously reported that myeloid-derived suppressor cells (MDSCs), a heterogeneous population of progenitor and immature myeloid cells, suppress xenogenic CTL-mediated cytotoxicity. Because of their heterogeneous nature, MDSC can function via several suppressive mechanisms that disrupt both innate and adaptive immunity. Since macrophages play a pivotal role in the rejection of a xenograft, in this study, we evaluated the suppressive effects of MDSC against macrophage-mediated xenogenic rejection. Materials and methods To evaluate the effect of monocyte-derived MDSCs on xenogenic immune reactions, a CFSE(carboxyfluorescein diacetate, succinimidyl ester)assay was employed to assess cytotoxicity. Results While, in the absence of activation, primed MDSCs had no detectable effect on macrophage-induced cytotoxicity against SEC cells, LPS-activated MDSCs were found to significantly suppress xenogenic cytotoxicity. A CFSE cytotoxicity assay revealed that MDSCs significantly suppressed macrophage-induced cytotoxicity. Furthermore, an indoleamine 2,3 dioxygenase (IDO) inhibitor, 1-methyl tryptophan (1-MT), abolished the MDSC-induced suppression of macrophage-mediated xeno-rejection, indicating that MDSCs may suppress macrophage-mediated cytotoxicity in an IDO-dependent manner. Conclusion These findings indicate that MDSCs have great potential for immunosuppressing macrophage-mediated xeno-rejection.

In the original publication, the fifth author name was erroneously published as "Patmika Jiaravuthiasan". The correct author name should read as, "Patmika Jiaravuthisan". The original article was corrected.

America came to stage of political issue before Holland to involve Japan to new relationship of international treaties. But making good use of vested rights of contnuing trade at Nagasaki under the control of Tokugawa government, Holland intended to make a treaty of commerce, before America. Holland had an advantage because Japan consulted Holland for the establishment of the Japanese Navy. This paper begins with historical research of time when Pels Rijcken started training the Japanese Navy at Nagasaki. Secondly, relating to the above research, it brings into focus that captain Fabius, at the same time, mysteriously acted on the treaties issue. Lastly it states that Kattendijke was the last instructor for the Japanese Navy by a Duch man. He was seriously anxious about a military British treat to Japan and visited Shanghai to obtain information. It shows that Naval War Captain in those days should be a good politician as well. Although Holland did not succed to make a teraty of commerce before America did, it devoted itself to make political efforts to oppose British and American threat to Japan and to educate the Japanese Navy. As a result, Hollandhad peculiar influence to Japanese Naval students such as katsu Kaisyuu.