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31.
《Bioorganic & medicinal chemistry letters》2020,30(4):126949
The discovery of orally bioavailable FXIa inhibitors has been a challenge. Herein, we describe our efforts to address this challenge by optimization of our imidazole-based macrocyclic series. Our optimization strategy focused on modifications to the P2 prime, macrocyclic amide linker, and the imidazole scaffold. Replacing the amide of the macrocyclic linker with amide isosteres led to the discovery of substituted amine linkers which not only maintained FXIa binding affinity but also improved oral exposure in rats. Combining the optimized macrocyclic amine linker with a pyridine scaffold afforded compounds 23 and 24 that were orally bioavailable, single-digit nanomolar FXIa inhibitors with excellent selectivity against relevant blood coagulation enzymes. 相似文献
32.
Francisco J. Rodríguez‐Tovar Eulogio Pardo‐Igúzquiza Matias Reolid 《Lethaia: An International Journal of Palaeontology and Stratigraphy》2021,54(1):113-126
Cyclostratigraphical analysis of the foraminiferal assemblages from the Early Toarcian at the Mochras Farm Borehole (Wales) was conducted in order to evaluate the incidence of cyclic palaeoenvironmental changes on the foraminiferal community. Different variables such as type of morphogroup, evolutionary strategy, habitat, particular taxa, diversity and abundance were studied using the Lomb–Scargle periodogram implemented in the computer program SLOMBS. A well‐developed cyclostratigraphical pattern is recognized, with the presence of several cycles (in metres) at 3.4–4/7.2–7.5/10.1–10.6/32.1–33.3/104.2–111.2/128.2/166.7, belonging to the high‐, middle‐, middle‐/low‐, and low‐frequency bands. The incidence and relevance of the cycles is found to be related to particular variables marking the global and local character of the involved processes. Cyclic changes in the organic matter input are found to be the most relevant palaeoenvironmental factor, oxygenation being secondary. A correspondence with specific Milankovitch cycles is, at present, difficult to determine. 相似文献
33.
摘要 目的:探讨碱性成纤维细胞生长因子对激光烧伤大兔皮肤愈合的影响分析。方法:通过热辐射仪激光灼烧对大兔耳朵进行烧伤处理,根据实验需求,将其随机分为三组:对照组,bFGF组,bFGF + DAPT组。通过ImageJ软件测量伤口面积和疤痕组织的厚度,并定期计算残余伤口面积率和疤痕指数。通过组织学分析大兔伤口愈合的新血管生成量。通过蛋白印迹分析Notch1、Jagged1和Hes1的蛋白表达。通过免疫荧光分析愈合后的皮肤中α-SMA,Col I和Col III的相对蛋白水平。结果:bFGF组较对照组的疤痕指数降低(P<0.05),bFGF+DAPT组较bFGF组疤痕指数升高(P<0.05)。bFGF组较对照组的愈合面积增加(P<0.05),bFGF + DAPT组较bFGF组愈合面积降低(P<0.05)。与对照组相比,bFGF组的愈合时间明显缩短,较低的残余伤口面积和较低的疤痕指数(P<0.05),而bFGF + DAPT组表现出明显的愈合延迟和较高的疤痕指数(P<0.05)。bFGF组较对照组的新血管生成量增加(P<0.05),bFGF + DAPT组较bFGF组心血管生成量减少(P<0.05)。bFGF组较对照组的肉芽组织平均厚度增加,表皮间隙的闭合百分比升高(P<0.05),bFGF + DAPT组较bFGF组肉芽组织平均厚度增加、表皮间隙的闭合百分比减少(P<0.05)。H&E染色进行组织学分析发现,与对照组和bFGF + DAPT组相比,bFGF组出现明显的再上皮化和新血管形成,愈合效率较高(P<0.05)。bFGF组较对照组Notch1、Jagged1和Hes1的蛋白表达升高(P<0.05),bFGF + DAPT组较bFGF组Notch1、Jagged1和Hes1的蛋白表达降低(P<0.05)。bFGF组较对照组?琢-SMA,Col I和Col III的蛋白表达降低(P<0.05),bFGF + DAPT组较bFGF组表达升高(P<0.05)。结论:bFGF可以通过促进ESC的增殖并通过激活Notch1 / Jagged1途径抑制其向肌成纤维细胞(Myofibroblasts,MFB)的分化加快伤口愈合,减少疤痕形成。 相似文献
34.
Feng Qiu Chun‐hua Shi Jun Zheng Yu‐bin Liu 《Journal of biochemical and molecular toxicology》2013,27(7):364-369
This study was conducted to investigate the biological role of periostin in gastric cancer (GC) under hypoxia. Western blot analysis revealed that along with an upregulation of hypoxia‐inducible factor‐1alpha, there was a time‐dependent induction of periostin in MKN‐45 cells under hypoxia (2% O2), increasing by eightfold as compared to normoxic cells. Pretreatment with 30 µM PD98059, an inhibitor of ERK1/2, significantly reduced hypoxia‐stimulated periostin expression (P < 0.01). Periostin knockdown in MKN‐45 cells was achieved by specific small interfering RNA (siRNA). The conditioned medium from periostin siRNA‐transfected MKN‐45 cells induced significantly less (P < 0.01) endothelial tube formation than control siRNA‐transfected cells. Additionally, periostin silencing markedly decreased the mRNA expression and secretion of vascular endothelial growth factor (VEGF) in hypoxic MKN‐45 cells. Thus, our data suggest that periostin is a hypoxia‐response gene and mediates a cross talk between GC and endothelial cells under hypoxia, partially through regulation of the VEGF expression. © 2013 Wiley Periodicals, Inc. J BiochemMol Toxicol 27:364‐369, 2013; View this article online at wileyonlinelibrary.com . DOI 10.1002/jbt.21498 相似文献
35.
Manousos Makridakis Maria G. Roubelakis Antonia Vlahou 《Biochimica et Biophysica Acta - Proteins and Proteomics》2013,1834(11):2380-2384
Stem cells have been considered as possible therapeutic vehicles for different health related problems such as cardiovascular and neurodegenerative diseases and cancer. Secreted molecules are key mediators in cell–cell interactions and influence the cross talk with the surrounding tissues. There is strong evidence supporting that crucial cellular functions such as proliferation, differentiation, communication and migration are strictly regulated from the cell secretome. The investigation of stem cell secretome is accumulating continuously increasing interest given the potential use of these cells in regenerative medicine. The scope of the review is to report the main findings from the investigation of stem cell secretome by the use of contemporary proteomics methods and discuss the current status of research in the field. This article is part of a Special Issue entitled: An Updated Secretome. 相似文献
36.
37.
Background and Aims
Anoxic conditions are seldom considered in root iron plaque induction of wetland plants in hydroponic experiments, but such conditions are essential for root iron plaque formation in the field. Although ferrous ion availability and root radial oxygen loss capacity are generally taken into account, neglect of anoxic conditions in root iron plaque formation might lead to an under- or over-estimate of their functional effects, such as blocking toxic metal uptake. This study hypothesized that anoxic conditions would influence root iron plaque formation characteristics and translocation of Zn and Cd by rice seedlings.Methods
A hydroponic culture was used to grow rice seedlings and a non-disruptive approach for blocking air exchange between the atmosphere and the induction solution matrix was applied for root iron plaque formation, namely flushing the headspace of the induction solution with N2 during root iron plaque induction. Zn and Cd were spiked into the solution after root iron plaque formation, and translocation of both metals was determined.Key Results
Blocking air exchange between the atmosphere and the nutrient solution by N2 flushing increased root plaque Fe content by between 11 and 77 % (average 31 %). The N2 flushing treatment generated root iron plaques with a smoother surface than the non-N2 flushing treatment, as observed by scanning electron microscopy, but Fe oxyhydroxides coating the rice seedling roots were amorphous. The root iron plaques sequestrated Zn and Cd and the N2 flushing enhanced this effect by approx. 17 % for Zn and 71 % for Cd, calculated by both single and combined additions of Zn and Cd.Conclusions
Blocking of oxygen intrusion into the nutrient solution via N2 flushing enhanced root iron plaque formation and increased Cd and Zn sequestration in the iron plaques of rice seedlings. This study suggests that hydroponic studies that do not consider redox potential in the induction matrices might lead to an under-estimate of metal sequestration by root iron plaques of wetland plants. 相似文献38.
Nenad Bukvic Carla CesaranoCaterina Ceccarini Marianna BrunoMaria Rosaria Lipsi Maria Grazia GallicchioMaria Assunta Carboni Lucia ValenteGiulia Cotoia Raffaele Antonetti 《Gene》2013
Herein, we describe a case of an infertile man detected in postnatal diagnosis with FISH characterization and array-CGH used for genome-wide screening which allowed the identification of a complex rearrangement involving sex chromosomes, apparently without severe phenotypic consequences. The deletion detected in our patient has been compared with previously reported cases leading us to propose a hypothetical diagnostic algorithm that would be useful in similar clinical situations, with imperative multi disciplinary approach integrated with genetic counseling. Our patient, uniquely of reproductive age, is one of six reported cases of duplication of Xp22.3 (~ 8.4 Mb) segment and contemporary deletion of Yq (~ 42.9 Mb) with final karyotype as follows:
- 46,X,der(Y),t(X;Y)(Ypter → Yq11.221::Xp22.33 → Xpter).ish der(Y) (Yptel+,Ycen+,RP11-529I21+,RP11-506M9-Yqtel −,Xptel +). arrXp22.33p22.31(702–8,395,963, 8,408,289x1), Yq11.221q12 (14,569,317x1, 14,587,321–57,440,839x0) 相似文献
39.
40.
Two syndromes are known to be associated with WNT7A mutations: Al-Awadi–Raas-Rothschild syndrome (AARRS) and Fuhrmann syndrome. Woods et al. (2006) showed that there is complete and partial loss of WNT7A function in these two syndromes respectively. Therefore, both syndromes have similar clinical features but the phenotype in Fuhrmann syndrome is less severe. The G204S mutation was previously reported to result in AARRS phenotype in three Saudi families. In the current communication, we report on a different unrelated Saudi patient with the same mutation but the patient had Fuhrmann syndrome phenotype. We believe this case is important because it questions the presence of a phenotype–genotype correlation in WNT7A mutations and because it demonstrates that the G204S mutation may be associated with both AARRS and Fuhrmann phenotypes. 相似文献