The lectin‐like domain of thrombomodulin is a drug candidate for both prophylaxis and treatment of liver ischemia and reperfusion injury in mice

Ischemia and reperfusion injury (IRI) can occur in any tissue or organ. With respect to liver transplantation, the liver grafts from donors by definition experience transient ischemia and subsequent blood reflow. IRI is a problem not only in organ transplantation but also in cases of thrombosis or circulatory disorders such as mesenteric ischemia, myocardial, or cerebral infarction. We have reported that recombinant human soluble thrombomodulin (rTM), which is currently used in Japan to treat disseminated intravascular coagulation (DIC), has a protective effect and suppresses liver IRI in mice. However, rTM may not be fully safe to use in humans because of its inherent anticoagulant activity. In the present study, we used a mouse liver IRI model to explore the possibility that the isolated lectin-like domain of rTM (rTMD1), which has no anticoagulant activity, could be effective as a therapeutic modality for IRI. Our results indicated that rTMD1 could suppress ischemia and reperfusion-induced liver damage in a dose-dependent manner without concern of associated hemorrhage. Surprisingly, rTMD1 suppressed the liver damage even after IR insult had occurred. Taken together, we conclude that rTMD1 may be a candidate drug for prevention of and therapy for human liver IRI without the possible risk of hemorrhage

Influence of petrographic textures on the shapes of impact experiment fine fragments measuring several tens of microns: Comparison with Itokawa regolith particles

In 2010, fine regolith particles on asteroid Itokawa were recovered by the Hayabusa mission. The three-dimensional microstructure of 48 Itokawa particles smaller than 120 µm was examined in previous studies. The shape distribution of Itokawa particles is distributed around the mean values of the axial ratio 2:√2:1, which is similar to laboratory impact fragments larger than several mm created in catastrophic disruptions. Thus, the Itokawa particles are considered to be impact fragments on the asteroid's surface. However, there have never been any laboratory impact experiments investigating the shapes of fine fragments smaller than 120 µm, and little is known about the relation between the shapes of fine fragments and the petrographic textures within those fragments. In this study, in order to investigate the relation between the petrographic textures and the shapes of fine fragments by impacts, the shapes of 2163 fine fragments smaller than 120 µm are examined by synchrotron radiation-based microtomography at SPring-8. Most samples are fine fragments from basalt targets, obtained in previous laboratory impact experiments by Michikami et al. (2016). Moreover, two impacts into L5 chondrite targets were carried out and the shapes of their fine fragments are examined for comparison. The results show that the shape distributions of fine fragments in basalt targets are similar regardless of impact energy per target mass (in contract to the shape distribution of relatively large fragments, which are affected by impact energy), and are similar to those in L5 chondrite targets and Itokawa regolith particles. The physical process producing these fine fragments would be due to multiple rarefaction waves in the target. Besides, the petrographic textures do not significantly affect the shapes of fine fragments in our experiments. On the other hand, according to Molaro et al. (2015), the shapes of the fragments produced by thermal fatigue by the day-night temperature cycles on the asteroid surface are influenced by the petrographic textures. Therefore, we conclude that the Itokawa particles are not the products of thermal fatigue but impact fragments on the asteroid surface

Factors Predicting Difficult Biliary Cannulation during Endoscopic Retrograde Cholangiopancreatography for Common Bile Duct Stones

Background/Aims Difficult biliary cannulation is an important risk factor for post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP). Therefore, this study aimed to identify the factors that predict difficult cannulation for common bile duct stones (CBDS) to reduce the risk for PEP. Methods This multicenter retrospective study included 1,406 consecutive patients with native papillae who underwent ERCP for CBDS. Factors predicting difficult cannulation for CBDS were identified using univariate and multivariate analyses. Results Univariate analysis showed that six factors significantly predicted difficult cannulation: ERCP performed by non-expert endoscopists, low-volume center, absence of acute cholangitis, normal serum bilirubin, intradiverticular papilla, and type of major duodenal papilla. Multivariate analysis identified ERCP performed by non-expert endoscopists (odds ratio [OR], 2.5; p<0.001), low-volume center (OR, 1.6; p<0.001), intradiverticular papilla (OR, 1.3; p=0.007), normal serum bilirubin (OR, 1.3; p=0.038), and absence of acute cholangitis (OR, 1.3; p=0.049) as factors significantly predicting difficult cannulation for CBDS. Conclusions Initial cannulation by an experienced endoscopist, early rescue cannulation, or early takeover by an experienced endoscopist should be considered when performing ERCP for CBDS in the presence of factors predicting difficult cannulation

Spin dynamics and spin freezing behavior in the two-dimensional antiferromagnet NiGa2_{2}S4_{4} revealed by Ga-NMR, NQR and μ\muSR measurements

We have performed $^{69,71}$Ga nuclear magnetic resonance (NMR) and nuclear quadrupole resonance (NQR) and muon spin rotation/resonance on the quasi two-dimensional antiferromagnet (AFM) NiGa$_2$S$_4$, in order to investigate its spin dynamics and magnetic state at low temperatures. Although there exists only one crystallographic site for Ga in NiGa$_2$S$_4$, we found two distinct Ga signals by NMR and NQR. The origin of the two Ga signals is not fully understood, but possibly due to stacking faults along the c axis which induce additional broad Ga NMR and NQR signals with different local symmetries. We found the novel spin freezing occurring at $T_{\rm f}$, at which the specific heat shows a maximum, from a clear divergent behavior of the nuclear spin-lattice relaxation rate $1/T_{1}$ and nuclear spin-spin relaxation rate $1/T_{2}$ measured by Ga-NQR as well as the muon spin relaxation rate $\lambda$. The main sharp NQR peaks exhibit a stronger tendency of divergence, compared with the weak broader spectral peaks, indicating that the spin freezing is intrinsic in NiGa$_2$S$_4$. The behavior of these relaxation rates strongly suggests that the Ni spin fluctuations slow down towards $T_{\rm f}$, and the temperature range of the divergence is anomalously wider than that in a conventional magnetic ordering. A broad structureless spectrum and multi-component $T_1$ were observed below 2 K, indicating that a static magnetic state with incommensurate magnetic correlations or inhomogeneously distributed moments is realized at low temperatures. However, the wide temperature region between 2 K and $T_{\rm f}$, where the NQR signal was not observed, suggests that the Ni spins do not freeze immediately below $T_{\rm f}$, but keep fluctuating down to 2 K with the MHz frequency range.Comment: 14 pages, 14 figures. To appear in Phys. Rev.

マウス肝虚血再灌流障害におけるトロンボモデュリンのToll-Like Receptor 4依存性の抗炎症効果の解明

京都大学0048新制・課程博士博士(医学)甲第20267号医博第4226号新制||医||1021(附属図書館)京都大学大学院医学研究科医学専攻(主査)教授 妹尾 浩, 教授 坂井 義治, 教授 竹内 理学位規則第4条第1項該当Doctor of Medical ScienceKyoto UniversityDGA

Microbiota in organ transplantation: An immunological and therapeutic conundrum?

The gastrointestinal (GI) tract microbiota is an environmental factor that regulates host immunity in allo-transplantation (allo-Tx). It is required for the development of resistance against pathogens and the stabilization of mucosa-associated lymphoid tissue. The gut-microbiota axis may also precipitate allograft rejection by producing metabolites that activate host cell-mediated and humoral immunity. Here, we discuss new insights into microbial immunomodulation, highlighting ongoing attempts to affect commensal colonization in an attempt to ameliorate allograft rejection cascade. Recent progress on the use of antibiotics to modulate GI microbiota diversity and innate-adaptive immune interface are discussed. Our focus on the microbiota's influence of endoplasmic reticulum (ER) stress and autophagy signaling through hepatic EP4/CHOP/LC3B platforms reveals a novel molecular pathway and potential biomarkers determining the progression of allo-Tx damage. Understanding and harnessing the potential of microbiome/bacteriophage therapies may offer safe and effective means for personalized treatment to reduce risks of infections and immunosuppression in allo-Tx