Appearance of renal hemorrhage in adult mice after inoculation of patient-derived hantavirus

Background: Hemorrhagic fever with renal syndrome (HFRS) caused by hantavirus infection is characterized by fever, renal dysfunction and hemorrhage. An animal model mimicking symptoms of HFRS remains to be established. In this study, we evaluated the pathogenicity of an HFRS patient-derived Hantaan virus (HTNV) in adult mice. Methods: Five clones of HTNV strain KHF 83-61 BL (KHFV) that was derived from blood of an HFRS patient were obtained by plaque cloning. The pathogenicity of the virus clones was evaluated by using 6-week-old female BALB/c mice. Sequence analysis of the viral genome was performed by conventional methods. Results: All of the mice intravenously inoculated with KHFV clone (cl)-1, -2, -3 and -5 showed signs of disease such as transient body weight loss, ruffled fur, reduced activity and remarkably prominent hemorrhage in the renal medulla at 6 to 9 days post-inoculation (dpi) and then recovered. In contrast, mice intravenously inoculated with KHFV cl-4 did not show any signs of disease. We selected KHFV cl-5 and cl-4 as representative of high-pathogenic and low-pathogenic clones, respectively. Quantities of viral RNA in kidneys of KHFV cl-5-infected mice were larger than those in KHFV cl-4-infected mice at any time point examined (3, 6, 9 and 12 dpi). The quantities of viral RNA of KHFV cl-5 and cl-4 peaked at 3 dpi, which was before the onset of disease. Sequence analysis revealed that the amino acid at position 417 in the glycoprotein Gn was the sole difference in viral proteins between KHFV cl-5 and cl-4. The result suggests that amino acid at position 417 in Gn is related to the difference in pathogenicity between KHFV cl-5 and cl-4. When the inoculum of KHFV cl-5 was pretreated with a neutralizing antibody against HTNV strain 76-118, which belongs to the same serotype as KHFV clones, mice did not show any signs of disease, confirming that the disease was caused by KHFV infection. Conclusion: We found that an HFRS patient-derived HTNV caused renal hemorrhage in adult mice. We anticipate that this infection model will be a valuable tool for understanding the pathogenesis of HFRS

Contacts between the commissural axons and the floor plate cells are mediated by nectins

AbstractDuring development of the central nervous system (CNS), commissural axons grow toward the ventral midline. After crossing the floor plate, they abruptly change their trajectory from the circumferential to the longitudinal axis. The contacts between the commissural axons and the floor plate cells are involved in this axonal guidance, but their mechanisms or structures have not fully been understood. In this study, we found that nectin-1 and -3, immunoglobulin-like cell–cell adhesion molecules, asymmetrically localized at the contact sites between the commissural axons and the floor plate cells, respectively. In vitro perturbation of the endogenous trans-interaction between nectin-1 and -3 caused abnormal fasciculation of the commissural axons and impairment of the contacts, and resulted in failure in longitudinal turns of the commissural axons at the contralateral sites of the rat hindbrain. These results indicate that the contacts between the commissural axons and the floor plate cells are mediated by the hetero-trans-interaction between nectin-1 and -3 and involved in regulation of the trajectory of the commissural axons

Human NINEIN polymorphism at codon 1111 is associated with the risk of colorectal cancer

NINEIN serves an essential role in centrosome function as a microtubule organizing center, and in the reformation of the interphase centrosome architecture following mitosis. In the present study, the association between NINEIN Pro1111Ala (rs2236316), a missense single nucleotide polymorphism, and the risk of colorectal cancer (CRC), related to smoking and alcohol consumption habits in 200 patients with CRC and 1,141 cancer‑free control participants were assessed in a case‑control study performed in Japan. The results showed that the NINEIN Ala/Ala genotype compared with the Pro/Pro genotype was significantly more associated with an increased risk of CRC, and the males with the Ala/Ala genotype exhibited a significantly increased risk of CRC compared with those with Pro/Pro and Pro/Ala genotypes. Stratified analyses of the Ala/Ala genotype with CRC risk further showed an increased association in never/light drinkers (<23 g of ethanol/day), in male never/light drinkers and in male patients with rectal cancer. These findings suggest that the genetic variant of the NINEIN Pro1111Ala polymorphism has a significant effect on CRC susceptibility in the Japanese population

Activation of Cdc42 by trans interactions of the cell adhesion molecules nectins through c-Src and Cdc42-GEF FRG

Nectins, Ca2+-independent immunoglobulin-like cell–cell adhesion molecules, initiate cell–cell adhesion by their trans interactions and recruit cadherins to cooperatively form adherens junctions (AJs). In addition, the trans interactions of nectins induce the activation of Cdc42 and Rac small G proteins, which increases the velocity of the formation of AJs. We examined here how nectins induce the activation of Cdc42 in MDCK epithelial cells and L fibroblasts. Nectins recruited and activated c-Src at the nectin-based cell–cell adhesion sites. FRG, a GDP/GTP exchange factor specific for Cdc42, was then recruited there, tyrosine phosphorylated by c-Src, and activated, causing an increase in the GTP-bound active form of Cdc42. Inhibition of the nectin-induced activation of c-Src suppressed the nectin-induced activation of FRG and Cdc42. Inhibition of the nectin-induced activation of FRG or depletion of FRG by RNA interference suppressed the nectin-induced activation of Cdc42. These results indicate that nectins induce the activation of Cdc42 through c-Src and FRG locally at the nectin-based cell–cell adhesion sites

Currency Invoicing and Foreign Exchange Risk Management: A Case Study of Japanese Firms (Japanese)

This paper, through interviews with 12 major Japanese firms, has revealed new "stylized facts" of the Japanese firms' strategy of currency invoicing, foreign exchange risk managements, and price-setting in recent years. It is also investigated whether these stylized facts are consistent with what has been theoretically and empirically found in the literature. First, the amendment of Foreign Exchange and Foreign Trade Control Law in 1998 had significant impact on the foreign exchange risk management of Japanese firms. Electronics and automobile companies pursue the most efficient settlements of trade transactions under the amended law, and currency invoicing is one of the most important strategic variables to optimize their foreign exchange risk managements. Second, as intra-firm trade has been increasingly a major part of their external trade, Japanese electronics and automobile companies have a strong tendency to choose local currency invoicing in exports to advanced countries, while U.S. dollar invoicing has been increasing when exporting to East Asian countries. Such an invoicing strategy aims at stabilizing the local currency (or U.S. dollar) price of their exports in local markets, which conforms to the pricing-to-market (PTM) behavior discussed in the literature. Third, the recent increase in U.S. dollar invoicing in East Asia can be attributed to (i) U.S. dollar's dominant role of world financial and foreign exchange transactions, (ii) the importance of the U.S. markets as a final export destination, and (iii) the increasing intra-firm transactions as Japanese firms has established regional production networks. Fourth, the currency invoicing and price-setting strategies are affected by competitors in global markets where it is hard to pass-through exchange rate risks to importers due to the strong market competition. Since U.S. dollar invoicing is now dominant in the East Asian markets, not only Japanese parent companies but also local affiliates in East Asia will take exchange rate risks against the U.S. dollar if the dollar fluctuates unstably. As the intra-regional trade keeps growing, it will become more important for East Asian countries including Japan to stabilize the exchange rate not vis-a-vis the U.S. dollar but between the regional currencies. This aspect will have important implications for new strategy of optimal exchange rate risk management and, hence, establishing regional currency arrangements such as a common currency basket in East Asia.

Significant growth suppression of synovial sarcomas by the histone deacetylase inhibitor FK228 in vitro and in vivo

About 97% of synovial sarcomas harbor the SYT-SSX fusion gene by chromosomal translocation. We found that the histone deacetylase (HDAC) inhibitor FK228 significantly suppressed the growth of synovial sarcoma cells as compared with that of osteosarcoma. The 50% growth inhibition IC50 value we obtained for FK228 was 0.02-0.2 nM, and it indicates that its suppression effect on synovial sarcoma cells is the highest of any of the HDAC inhibitors yet reported. It was not likely that the growth suppression of FK228 depends on the doubling time of these cells. Introduction of SYT-SSX cDNA into HEK293 cells enhanced the sensitivity of the cells for FK228. Immunostaining of the FK228-treated cells using an anti-acetyl-histone H3 antibody showed that FK228 inhibits deacetylation of histone. In a mice assay, the growth of synovial sarcoma cells was markedly inhibited by FK228 treatment, and the invasion of tumors into surrounding tissues was suppressed. These results suggest that FK228 may be useful in developing therapeutic strategies to treat synovial sarcoma

Rasmussen encephalitis associated with SCN1A mutation

Mutations in the SCN 1 A gene, encoding the neuronal voltage-gated sodium channel alpha1 subunit, cause SMEI, GEFS+, and related epileptic syndromes. We herein report the R1575C-SCN 1 A mutation identified in a patient with Rasmussen encephalitis. R1575C were constructed in a recombinant human SCN 1 A and then heterologously expressed in HEK293 cells along with the human beta1 and beta2 sodium channel accessory subunits. Whole-cell patch-clamp recording was used to define biophysical properties. The R1575C channels exhibited increased channel availability and an increased persistent sodium current in comparison to the wild-type. These defects of electrophysiological properties can result in neuronal hyperexitability. The seizure susceptibility allele may influence the pathogenesis of Rasmussen encephalitis in this case

Analysis of bis(trifluoromethylsulfonyl)imide-doped paramagnetic graphite intercalation compound using F-19 very fast magic angle spinning nuclear magnetic resonance

F atoms bonding to paramagnetic/conductive graphene layers in accepter-type graphite intercalation compounds (GICs) are analyzed using very fast magic angle spinning nuclear magnetic resonance, which is applied for the first time on F-19 nuclei to investigate paramagnetic materials. In the bis(trifluoromethylsulfonyl)imide(TFSI)-doped GIC, C-F bonds between fluorine atoms and graphene layers conform to a weak bonding of F to the graphene sheets. TFSI anions intercalated in the GIC do not show overall molecular motion; even at room temperature only the CF3 groups rotate

大腸癌患者における術前血清インターロイキン6 が全身性炎症反応に与える影響についての検討

背景：全身性炎症反応は担癌患者における免疫応答を反映し，予後と関連することが報告されている．目的：血清インターロイキン6（IL-6）と臨床背景因子，とりわけ全身炎症性反応との関連について大腸癌患者を対象として検討すること．方法：大腸癌患者20 人の術前IL-6 濃度を測定し，L 群（低IL-6 群，11 人；IL-6＜10 pg/ml）とH 群（高IL-6 群，9 人；IL-6 ≥ 10 pg/ml）の2 群に分けて臨床背景因子との関連について検討した．結果：血清C-reactive protein（CRP）値＞1.0 mg/dl（P＝0.038），血沈；9±7 versus 31±24（mm/ hr , P＝0.031）が2 群間で有意差を認めたが，血小板数・血清アルブミン値・Glasgow Prognostic Score・好中球リンパ比に2 群間で有意差は認めなかった．2 群間の生存曲線による解析は，H 群はL 群に比べて予後不良の傾向を認めたが，統計学的な有意差は認められなかった．結論：高IL-6 血症は大腸癌術前患者における高CRP 値，血沈の亢進といった全身性炎症反応と相関し，予後との関連を示唆するものであった．Purpose：To investigate the relationship between preoperative serum interleukin-6（IL-6）level and clinical characteristics, including systemic inflammatory response（SIR）related characteristics, in colorectal cancer（CRC）patients undergoing surgery. Patients and methods：Twenty CRC patients who had undergone curative surgery were divided into two groups as follows：Group A（n＝9）；patients with low serum IL-6 level（＜10 pg/ml）and Group B（n＝11）；patients with high serum IL-6 level（≥ 10 pg/ml）. Chi squared test and Mann-Whitney test were performed to compare the clinical characteristics of two groups. Kaplan-Meier analysis and log rank test were used to compare the two groups in relation to overall survival. Results：Among a lot of clinical characteristics, there were significant differences between the two groups in serum C-reactive protein（CRP）level（0.2±0.1 versus 2.9 ±4.9 mg/dl, mean± SD, P＝0.016）and erythrocyte sedimentation rate（ESR）（9±7 versus 31±24 mm/hr, mean ± SD, P＝0.031）. However, there was no significant difference between the two groups in overall survival. Conclusion：There is a close relationship between preoperative serum IL-6 level and SIR related clinical characteristics such as serum CRP level and ESR in CRC patients