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991.
992.
Takeshi Fukuda Takashi Ishiyama Takahiro Katagiri Kenjiro Ueda Sumie Muramatsu Masami Hashimoto Anri Aki Daichi Baba Kengo Watanabe Naoki Tanaka 《Bioorganic & medicinal chemistry letters》2018,28(20):3333-3337
Hepcidin has emerged as the central regulatory molecule in systemic iron homeostasis. The inhibition of hepcidin may be a favorable strategy for the treatment of anemia of chronic disease. Here, we have reported the design, synthesis, and structure–activity relationships (SAR) of a series of 4-aminopyrimidine compounds as inhibitors of hepcidin production. The optimization study of 1 led to the design of a potent and bioavailable inhibitor of hepcidin production, 34 (DS42450411), which showed serum hepcidin-lowering effects in a mouse model of interleukin-6-induced acute inflammation. 相似文献
993.
Miwa Fukuda Tomomi Sasaki Tomoko Hashimoto Hiroyuki Miyachi Minoru Waki Akira Asai Osamu Takikawa Osamu Ohno Kenji Matsuno 《Bioorganic & medicinal chemistry letters》2018,28(17):2846-2849
Kynurenine is biosynthesised from tryptophan catalysed by indoleamine 2,3-dioxygenase (IDO). The abrogation of kynurenine production is considered a promising therapeutic target for immunological cancer treatment. In the course of our IDO inhibitor programme, formal cyclisation of the isothiourea moiety of the IDO inhibitor 1 afforded the 5-Cl-benzimidazole derivative 2b-6, which inhibited both recombinant human IDO (rhIDO) activity and cellular kynurenine production. Further derivatisation of 2b-6 provided the potent inhibitor of cellular kynurenine production 2i (IC50?=?0.34?µM), which unexpectedly exerted little effect on the enzymatic activity of rhIDO. Elucidation of the mechanism of action revealed that compound 2i suppresses IDO expression at the protein level by inhibiting STAT1 expression in IFN-γ-treated A431 cells. The kynurenine-production inhibitor 2i is expected to be a promising starting point for a novel approach to immunological cancer treatment. 相似文献
994.
Yuta Murakami Koichi Takahashi Kyoka Hoshi Hiromi Ito Mayumi Kanno Kiyoshi Saito Kenneth Nollet Yoshiki Yamaguchi Masakazu Miyajima Hajime Arai Yasuhiro Hashimoto Tatsuo Mima 《Biochimica et Biophysica Acta (BBA)/General Subjects》2018,1862(8):1835-1842
Background
Spontaneous intracranial hypotension (SIH) is caused by cerebrospinal fluid (CSF) leakage. Definitive diagnosis can be difficult by clinical examinations and imaging studies.Methods
SIH was diagnosed with the following criteria: (i) evidence of CSF leakage by cranial magnetic resonance imaging (MRI) findings of intracranial hypotension and/or low CSF opening pressure; (ii) no recent history of dural puncture. We quantified CSF proteins by ELISA or Western blotting.Results
Comparing with non-SIH patients, SIH patients showed significant increase of brain-derived CSF glycoproteins such as lipocalin-type prostaglandin D synthase (L-PGDS), soluble protein fragments generated from amyloid precursor protein (sAPP) and “brain-type” transferrin (Tf). Serum-derived proteins such as albumin, immunoglobulin G, and serum Tf were also increased. A combination of L-PGDS and brain-type Tf differentiated SIH from non-SIH with sensitivity 94.7% and specificity 72.6%.Conclusion
L-PGDS and brain-type Tf can be biomarkers for diagnosing SIH.General significance
L-PGDS and brain-type Tf biosynthesized in the brain appears to be markers for abnormal metabolism of CSF. 相似文献995.
HMGB1‐induced inflammatory response promotes bone healing in murine tooth extraction socket 下载免费PDF全文
996.
Natalie J. Graham Mari Suontama Tony Pleasants Yongjun Li Martin K.-F. Bader Jaroslav Klápště Heidi S. Dungey Nari M. Williams 《Tree Genetics & Genomes》2018,14(4):55
Breeding for disease resistance or tolerance is a viable option for disease management programmes and is important for the continued success and resilience of planted forests. Red needle cast (RNC) is a disease that affects radiata pine (Pinus radiata) and is caused by Phytophthora pluvialis. Knowledge is still very limited regarding the potential for genetic tolerance to this pathogen. The application of controlled screening techniques is clearly required. Using a detached needle assay, we screened 392 clonally replicated individuals (clones) from an elite P. radiata population for quantitative tolerance to RNC. Data was highly skewed and required logarithmic data transformation and Poisson distributions for the estimation of best linear unbiased predictions. These estimates revealed a broad range in susceptibility/tolerance to RNC, and enabled the identification of clones that were clearly susceptible and clones that were clearly tolerant. There was a high correlation between the number and length of lesions that developed in response to inoculation with P. pluvialis. Broad-sense heritability estimates were low to moderate, indicating that there is potential for improving tolerance through breeding. These results provide evidence that breeding for tolerance to P. pluvialis is possible, although continued work into understanding and minimising causes for variance are required. 相似文献
997.
Anthropogenic disturbance equalizes diversity levels in arbuscular mycorrhizal fungal communities 下载免费PDF全文
David García de León John Davison Mari Moora Maarja Öpik Huyuan Feng Inga Hiiesalu Teele Jairus Kadri Koorem Yongjun Liu Cherdchai Phosri Siim‐Kaarel Sepp Martti Vasar Martin Zobel 《Global Change Biology》2018,24(6):2649-2659
The arbuscular mycorrhizal (AM) symbiosis is a key plant–microbe interaction in sustainable functioning ecosystems. Increasing anthropogenic disturbance poses a threat to AM fungal communities worldwide, but there is little empirical evidence about its potential negative consequences. In this global study, we sequenced AM fungal DNA in soil samples collected from pairs of natural (undisturbed) and anthropogenic (disturbed) plots in two ecosystem types (10 naturally wooded and six naturally unwooded ecosystems). We found that ecosystem type had stronger directional effects than anthropogenic disturbance on AM fungal alpha and beta diversity. However, disturbance increased alpha and beta diversity at sites where natural diversity was low and decreased diversity at sites where natural diversity was high. Cultured AM fungal taxa were more prevalent in anthropogenic than natural plots, probably due to their efficient colonization strategies and ability to recover from disturbance. We conclude that anthropogenic disturbance does not have a consistent directional effect on AM fungal diversity; rather, disturbance equalizes levels of diversity at large scales and causes changes in community functional structure. 相似文献
998.
Cantharidin world in air: Spatiotemporal distributions of flying canthariphilous insects in the forest interior 下载免费PDF全文
The natural community in which the members interact using a toxic terpenoid cantharidin is named the “cantharidin world.” In previous studies, however, the members of this world have been surveyed only on the forest floor by setting pitfall traps with cantharidin as an attractant. In this study, we set cantharidin traps at various heights above the forest floor to investigate the structure and functional diversity of the canthariphilous flying insect community in the forest above‐ground space. A total of 3,168 arthropods were collected by the traps; among them, six species were more attracted to cantharidin than to control traps. Pseudopyrochroa brevitarsis and P. laticollis (Colecoptera: Pyrochroidae) both appeared for a short time during spring, but the latter species tended to use a lower layer of the forest. Clavicollis fugiens (Coleoptera: Anthicidae) also appeared in spring and flew near the ground. In these beetles, the attracted individuals were mostly males; they may use the obtained cantharidin for nuptial gifts to the female. Atrichopogon femoralis, A. insularis and Atrichopogon sp. (Diptera: Ceratopogonidae) were collected widely in the forest above‐ground space. These midges were almost females, probably because only females of these insects use chemical cues, including cantharidin, for searching for arthropods from which to suck hemolymph. 相似文献
999.
Kazutaka Miyamoto Mizuha Akiyama Fumiya Tamura Mari Isomi Hiroyuki Yamakawa Taketaro Sadahiro Naoto Muraoka Hidenori Kojima Sho Haginiwa Shota Kurotsu Hidenori Tani Li Wang Li Qian Makoto Inoue Yoshinori Ide Junko Kurokawa Tsunehisa Yamamoto Tomohisa Seki Masaki Ieda 《Cell Stem Cell》2018,22(1):91-103.e5
1000.
Janna Bednenko Rian Harriman Lore Mariën Hai M. Nguyen Alka Agrawal Ashot Papoyan 《MABS-AUSTIN》2018,10(4):636-650
Identifying monoclonal antibodies that block human voltage-gated ion channels (VGICs) is a challenging endeavor exacerbated by difficulties in producing recombinant ion channel proteins in amounts that support drug discovery programs. We have developed a general strategy to address this challenge by combining high-level expression of recombinant VGICs in Tetrahymena thermophila with immunization of phylogenetically diverse species and unique screening tools that allow deep-mining for antibodies that could potentially bind functionally important regions of the protein. Using this approach, we targeted human Kv1.3, a voltage-gated potassium channel widely recognized as a therapeutic target for the treatment of a variety of T-cell mediated autoimmune diseases. Recombinant Kv1.3 was used to generate and recover 69 full-length anti-Kv1.3 mAbs from immunized chickens and llamas, of which 10 were able to inhibit Kv1.3 current. Select antibodies were shown to be potent (IC50<10 nM) and specific for Kv1.3 over related Kv1 family members, hERG and hNav1.5. 相似文献