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91.
Small-angle X-ray scattering experiments were carried out to investigate the structural changes of cardiac thin filaments induced by the cardiomyopathy-causing E244D mutation in troponin T (TnT). We examined native thin filaments (NTF) from a bovine heart, reconstituted thin filaments containing human cardiac wild-type Tn (WTF), and filaments containing the E244D mutant of Tn (DTF), in the absence and presence of Ca2+. Analysis by model calculation showed that upon Ca2+-activation, tropomyosin (Tm) and Tn in the WTF and NTF moved together in a direction to expose myosin-binding sites on actin. On the other hand, Tm and Tn of the DTF moved in the opposite directions to each other upon Ca2+-activation. These movements caused Tm to expose more myosin-binding sites on actin than the WTF, suggesting that the affinity of myosin for actin is higher for the DTF. Thus, the mutation-induced structural changes in thin filaments would increase the number of myosin molecules bound to actin compared with the WTF, resulting in the force enhancement observed for the E244D mutation. 相似文献
92.
Irie O Kosaka T Kishida M Sakaki J Masuya K Konishi K Yokokawa F Ehara T Iwasaki A Iwaki Y Hitomi Y Toyao A Gunji H Teno N Iwasaki G Hirao H Kanazawa T Tanabe K Hiestand PC Malcangio M Fox AJ Bevan SJ Yaqoob M Culshaw AJ Hart TW Hallett A 《Bioorganic & medicinal chemistry letters》2008,18(19):5280-5284
We describe here orally active and brain-penetrant cathepsin S selective inhibitors, which are virtually devoid of hERG K(+) channel affinity, yet exhibit nanomolar potency against cathepsin S and over 100-fold selectivity to cathepsin L. The new non-peptidic inhibitors are based on a 2-cyanopyrimidine scaffold bearing a spiro[3.5]non-6-yl-methyl amine at the 4-position. The brain-penetrating cathepsin S inhibitors demonstrate potential clinical utility for the treatment of multiple sclerosis and neuropathic pain. 相似文献
93.
Katsutoshi Ando Fumiyuki Takahashi Motoyasu Kato Norihiro Kaneko Tokuhide Doi Yuichiro Ohe Fumiaki Koizumi Kazuto Nishio Kazuhisa Takahashi 《PloS one》2014,9(7)
Background
We previously reported the role of IL-6 in a murine model of cancer cachexia and currently documented a patient in whom tocilizumab, anti-IL-6 receptor antibody, dramatically improved cachexia induced by IL-6 over-expressing lung cancer. Despite this potential to alleviate cancer cachexia, tocilizumab has not been approved for this clinical use. Therefore, preceding our planned clinical trial of tocilizumab, we designed the two studies described here to evaluate the levels of IL-6 in patients with lung cancer and the effect of tocilizumab in a murine model of human cancer cachexia.Methods
First, we measured serum IL-6 levels in patients with lung cancer and analyzed its association with cachexia and survival. Next, we examined the effect of a rodent analog of tocilizumab (MR16-1) in the experimental cachexia model.Results
Serum IL-6 levels were higher in patients with cachexia than those without cachexia. In patients with chemotherapy-resistant lung cancer, a high IL-6 serum level correlated strongly with survival, and the cut-off level for affecting their prognosis was 21 pg/mL. Meanwhile, transplantation of IL-6-expressing Lewis Lung Carcinoma cells caused cachexia in mice, which then received either MR16-1 or 0.9% saline. Tumor growth was similar in both groups; however, the MR16-1 group lost less weight, maintained better food and water intake and had milder cachectic features in blood. MR16-1 also prolonged the survival of LLC-IL6 transplanted mice (36.6 vs. 28.5 days, p = 0.016).Conclusion
Our clinical and experimental studies revealed that serum IL-6 is a surrogate marker for evaluating cachexia and the prognosis of patients with chemotherapy resistant metastatic lung cancer and that tocilizumab has the potential of improving prognosis and ameliorating the cachexia that so devastates their quality of life. This outcome greatly encourages our clinical trials to evaluate the safety and efficacy of tocilizumab treatment for patients with increased serum IL-6. 相似文献94.
Effects of lactoferrin and lactoperoxidase‐containing food on the oral microbiota of older individuals 下载免费PDF全文
Manabu Nakano Hiroyuki Wakabayashi Hirosuke Sugahara Toshitaka Odamaki Koji Yamauchi Fumiaki Abe Jin‐Zhong Xiao Kohji Murakami Kentaro Ishikawa Shouji Hironaka 《Microbiology and immunology》2017,61(10):416-426
95.
96.
There are two major modes for plant recognition of biotrophic microbial pathogens. In one mode, plant pattern recognition receptors (PRRs) recognize microbe associated molecular patterns (MAMPs, also called PAMPs), which are molecules such as flg22, a fragment of bacterial flagellin. In the other mode, the products of plant resistance (R) genes recognize pathogen effectors or host proteins modified by effectors. Salicylic acid (SA) -mediated defense responses are an important part of R gene-mediated resistance. It was not clear how these two signaling mechanisms interact with each other. Recently, we reported that treatment with flg22 triggered SA accumulation in Arabidopsis leaves. Disruptions of SA signaling components strongly affected MAMP-triggered gene expression responses. Flg22-triggered resistance to Pseudomonas syringae pv. tomato DC3000 (Pst DC3000) was partly dependent on SA signaling. Our results demonstrated the importance of SA signaling in flg22-triggered resistance and, at the same time, the importance of some other signaling mechanism(s) in this resistance. Here we discuss potential signaling components of flg22-triggered SA accumulation and other signaling mechanisms potentially contributing to flg22-triggered resistance to Pst DC3000.Key words: arabidopsis, expression profiling, MAMP, PAD4, PAMP, salicylic acid (SA), SID2 相似文献
97.
Ayako Furukawa Takashi Nagata Akimasa Matsugami Yuichirou Habu Ryuichi Sugiyama Fumiaki Hayashi Naohiro Kobayashi Shigeyuki Yokoyama Hiroshi Takaku Masato Katahira 《The EMBO journal》2009,28(4):440-451
Human APOBEC3G exhibits anti‐human immunodeficiency virus‐1 (HIV‐1) activity by deaminating cytidines of the minus strand of HIV‐1. Here, we report a solution structure of the C‐terminal deaminase domain of wild‐type APOBEC3G. The interaction with DNA was examined. Many differences in the interaction were found between the wild type and recently studied mutant APOBEC3Gs. The position of the substrate cytidine, together with that of a DNA chain, in the complex, was deduced. Interestingly, the deamination reaction of APOBEC3G was successfully monitored using NMR signals in real time. Real‐time monitoring has revealed that the third cytidine of the d(CCCA) segment is deaminated at an early stage and that then the second one is deaminated at a late stage, the first one not being deaminated at all. This indicates that the deamination is carried out in a strict 3′ → 5′ order. Virus infectivity factor (Vif) of HIV‐1 counteracts the anti‐HIV‐1 activity of APOBEC3G. The structure of the N‐terminal domain of APOBEC3G, with which Vif interacts, was constructed with homology modelling. The structure implies the mechanism of species‐specific sensitivity of APOBEC3G to Vif action. 相似文献
98.
Three forms of recombinant protein complexes comprising the human prorenin (hPro) and (pro)renin receptor (hPRR) (hPRR/prorenin)
were successfully expressed in the silkworm larvae using Bombyx mori nucleopolyhedrovirus (BmNPV) bacmids. They were localized in the fat body cells and formed a prorenin-bound hPRR complex.
The expressed levels of hPro and hPRR were similar judging from Western blotting. The hPRR/prorenin complex containing 40 μg
of hPRR (yield, 43%) and 30 μg of hPro (yield, 34%) was purified from 15 silkworm larvae by a series of purification using
anti-FLAG and Strep-Tactin affinity chromatography. The renin activity of the purified hPRR/prorenin complex was 3.8-fold
that of the mixture of hPRR and hPro expressed individually in vitro judging from the renin assay. These results show that
the unstable transmembrane protein, hPRR, was coexpressed stably with ligand, hPro, and formed a stable protein, hPRR/prorenin
complex that showed a high catalytic active form. 相似文献
99.
100.
Saito F Saito-Arai Y Nakamura-Okuma A Ikeda M Hagiwara H Masaki T Shimizu T Matsumura K 《Biochemical and biophysical research communications》2011,(2):494-369
α-Dystroglycan (α-DG) plays crucial roles in maintaining the stability of cells. We demonstrated previously that the N-terminal domain of α-DG (α-DG-N) is secreted by cultured cells into the culture medium. In the present study, to clarify its function in vivo, we generated a monoclonal antibody against α-DG-N and investigated the secretion of α-DG-N in human cerebrospinal fluid (CSF). Interestingly, we found that a considerable amount of α-DG-N was present in CSF. α-DG-N in CSF was a sialylated glycoprotein with both N- and O-linked glycan. These observations suggest that secreted α-DG-N may be transported via CSF and have yet unidentified effects on the nervous system. 相似文献