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1.
《Bioorganic & medicinal chemistry letters》2014,24(19):4714-4723
Use of the tools of SBDD including crystallography led to the discovery of novel and potent 6,5 heterobicyclic MEKi’s [J. Med. Chem. 2012, 55, 4594]. The core change from a 5,6 heterobicycle to a 6,5 heterobicycle was driven by the desire for increased structural diversity and aided by the co-crystal structure of G-925 [J. Med. Chem. 2012, 55, 4594]. The key design feature was the shift of the attachment of the five-membered heterocyclic ring towards the B ring while maintaining the key hydroxamate and anilino pharamcophoric elements in a remarkably similar position as in G-925. From modelling, changing the connection point of the five membered ring heterocycle placed the H-bond accepting nitrogen within a good distance and angle to the Ser212 [J. Med. Chem. 2012, 55, 4594]. The resulting novel 6,5 benzoisothiazole MEKi G-155 exhibited improved potency versus aza-benzofurans G-925 and G-963 but was a potent inhibitor of cytochrome P450’s 2C9 and 2C19. Lowering the log D by switching to the more polar imidazo[1,5-a] pyridine core significantly diminished 2C9/2C19 inhibition while retaining potency. The imidazo[1,5-a] pyridine G-868 exhibited increased potency versus the starting point for this work (aza-benzofuran G-925) leading to deprioritization of the azabenzofurans. The 6,5-imidazo[1,5-a] pyridine scaffold was further diversified by incorporating a nitrogen at the 7 position to give the imidazo[1,5-a] pyrazine scaffold. The introduction of the C7 nitrogen was driven by the desire to improve metabolic stability by blocking metabolism at the C7 and C8 positions (particularly the HLM stability). It was found that improving on G-868 (later renamed GDC-0623) required combining C7 nitrogen with a diol hydroxamate to give G-479. G-479 with polarity distributed throughout the molecule was improved over G-868 in many aspects. 相似文献
2.
Henryk Brzeskwiniewicz 《Biometrical journal. Biometrische Zeitschrift》1995,37(2):191-198
We present the idea of using multiresponse incomplete block designs when not all responses can be observed in all experimental units. For a special class of such designs, in which partial designs are PBB designs, a method for estimating natural treatment contrast is given. We also consider the problem of testing the hypotheses concerning the natural and any estimable treatment contrasts. For testing this hypothesis the Wald statistics, being asymptotically chi-square distributed, is proposed. 相似文献
3.
《Journal of morphology》2017,278(2):215-227
Unlike most viviparous vertebrates, lamniform sharks develop functional teeth during early gestation. This feature is considered to be related to their unique reproductive mode where the embryo grows to a large size via feeding on nutritive eggs in utero. However, the developmental process of embryonic teeth is largely uninvestigated. We conducted X‐ray microcomputed tomography to observe the dentitions of early‐, mid‐, and full‐term embryos of the white shark Carcharodon carcharias (Lamniformes, Lamnidae). These data reveal the ontogenetic change of embryonic dentition of the species for the first time. Dentition of the early‐term embryos (∼45 cm precaudal length, PCL) is distinguished from adult dentition by 1) the presence of microscopic teeth in the distalmost region of the paratoquadrate, 2) a fang‐like crown morphology, and 3) a lack of basal concavity of the tooth root. The “intermediate tooth” of early‐term embryos is almost the same size as the adjacent teeth, suggesting that lamnoid‐type heterodonty (lamnoid tooth pattern) has not yet been established. We also discovered that mid‐term embryos (∼80 cm PCL) lack functional dentition. Previous studies have shown that the maternal supply of nutritive eggs in lamnoid sharks ceases during mid‐ to late‐gestation. Thus, discontinuation of functional tooth development is likely associated with the completion of the oophagous (egg‐eating) phase. Replacement teeth in mid‐term embryos include both embryonic and adult‐type teeth, suggesting that the embryo to adult transition in dental morphology occurs during this period. J. Morphol. 278:215–227, 2017. © 2016 Wiley Periodicals,Inc. 相似文献
4.
I. Siatkowski 《Biometrical journal. Biometrische Zeitschrift》1993,35(3):283-289
For some subclass of a two-way elimination of heterogeneity design, necessary and sufficient conditions are established for row-connectedness and column-connectedness of a design to imply its connectedness. 相似文献
5.
P. S. Gill 《Biometrical journal. Biometrische Zeitschrift》1993,35(3):343-354
Design and analysis of field experiments in the presence of local and remote treatment effects are considered. The design criteria are optimality and balance for estimating local and remote effects. A nonlinear model, where remote effects are assumed to be proportional to the local effects, has been discussed. 相似文献
6.
7.
R.T. Hanlon C.-C. Chiao L.M. M?thger A. Barbosa K.C. Buresch C. Chubb 《Philosophical transactions of the Royal Society of London. Series B, Biological sciences》2009,364(1516):429-437
Individual cuttlefish, octopus and squid have the versatile capability to use body patterns for background matching and disruptive coloration. We define—qualitatively and quantitatively—the chief characteristics of the three major body pattern types used for camouflage by cephalopods: uniform and mottle patterns for background matching, and disruptive patterns that primarily enhance disruptiveness but aid background matching as well. There is great variation within each of the three body pattern types, but by defining their chief characteristics we lay the groundwork to test camouflage concepts by correlating background statistics with those of the body pattern. We describe at least three ways in which background matching can be achieved in cephalopods. Disruptive patterns in cuttlefish possess all four of the basic components of ‘disruptiveness’, supporting Cott''s hypotheses, and we provide field examples of disruptive coloration in which the body pattern contrast exceeds that of the immediate surrounds. Based upon laboratory testing as well as thousands of images of camouflaged cephalopods in the field (a sample is provided on a web archive), we note that size, contrast and edges of background objects are key visual cues that guide cephalopod camouflage patterning. Mottle and disruptive patterns are frequently mixed, suggesting that background matching and disruptive mechanisms are often used in the same pattern. 相似文献
8.
城市景观生态风险评估框架与实践——以北京天坛地区为例 总被引:3,自引:0,他引:3
当前,城市景观生态风险研究缺少科学合理、方便实用的评估框架。作者基于景观生态风险评估基本范式,明确了城市景观生态服务价值的测算方法,分析了引起生态损害的自然因素和人类活动因素,形成了城市景观生态风险评估的技术框架和参数体系;继而以北京天坛地区为研究区,开展了典型城市景观生态风险的定量评估。结果表明:(1)天坛地区景观生态价值总量约为2.41亿元。区域的历史文化价值最高,教育和美学景观价值紧随其后。(2)城市景观生态受损概率呈现"北高南低"的空间分布格局。生态受损概率的高值区面积占整个区域总面积的22.2%,主要分布在珠市口、磁器口和崇文门附近区域。(3)城市景观生态风险呈现"北低南高"的空间分布格局。高风险区主要分布在天坛公园内的文物建筑周边。本研究提供了一个可参考的城市景观生态风险评估应用框架,对生态风险评估中的不确定性进行了讨论,研究针对天坛案例区的具体结论有助于城市管理者避免潜在的风险。 相似文献
9.
10.
Alicia A. Gil de Pertierra 《Zoologischer Anzeiger》2005,243(4):307-304
The surface of the tegument of the scolex and the immature proglottides of Monticellia belavistensis, M. ventrei, Nomimoscolex chubbi, and N. lopesi is described using scanning electron microscopy. Only blade-like spiniform microtriches and filiform microtriches were observed in the species studied. The types, size and density of microtriches on the apical region surface of the scolex, central cavity surface of suckers, marginal ring surface of suckers, non-adherent surface of suckers, proliferation zone surface, and immature proglottis surface were compared among these species. The distribution pattern of the microtriches was not a reliable feature to discriminate among the genera considered in this study. It varied in each of the species of Monticellia examined, and did not permit to split the heterogeneous genus Nomimoscolex. However, the microthrix pattern can be regarded as an additional diagnostic feature to distinguish among species of proteocephalideans. Further comparative research involving other species of proteocephalid taxa is needed to elucidate the systematic value of the tegumental morphology. 相似文献