Balancing oral exposure with Cyp3A4 inhibition in benzimidazole-based IGF-IR inhibitors

3-(Benzimidazol-2-yl)-pyridine-2-one-based ATP competitive inhibitors of Insulin-like Growth Factor 1 Kinase (IGF-IR) were optimized for reduced Cyp3A4 inhibition and improved oral exposure. The use of malonate as methyl anion synthon via S_NAr reaction and double decarboxylation under mild conditions is demonstrated.     

Potential chemical transformation of phosphinic acid derivatives and their applications in the synthesis of drugs

The chemical transformation of phosphinic acid is a well-considered mature area of research on account of the historical significant reactions such as Kabachnik–Fields, Mannich, Arbuzov, Michaelis–Becker, etc. Considerable advances have been made over last years especially in metal-catalyzed, free-radical processes and asymmetric synthesis using catalytic enantioselective. As a result, the aim of this synopsis is to make the reader familiar with advances in the approaches of phosphinic acids toward the synthesis of highly functionalized and valuable buildings blocks. Another purpose of this survey is to provide the current status of the applications of phosphinic acids in the synthesis of drugs.     

40Ar/39Ar dating in paleoanthropology and archeology

The potassium-argon (K-Ar) dating method has been widely used over the past 40 years to provide radioisotopic age control of hominid/hominoid evolutionary time scales. The wide appeal of the technique to paleoanthropology and archeology has been, in part, a result of its broad time range of applicability, from materials as young as a few thousand years old to an essentially unbounded upper age limit. Another reason for its appeal is the many geological circumstances in which datable materials are found. Beginning about two decades ago and accelerating into this decade, however, the conventional K-Ar technique has given way to ⁴⁰Ar/³⁹Ar dating as the method of preference. This technique is not only more precise and accurate when dating ideal materials, but also permits excellent ages to be obtained from situations that often stymie the conventional K-Ar technique, such as dating of contaminated tuffs and altered rocks. © 1998 Wiley-Liss, Inc.     

用组织光学特性鉴别诊断人离体的正常膀胱和膀胱癌组织

研究正常人膀胱和膀胱癌组织在Kube lka-Munk二流模型下对476.5 nm,514.5 nm和808 nm波长的激光的光学特性的差异。采用双积分球系统和Kube lka-Munk二流模型进行测量研究。实验结果表明,正常膀胱和膀胱癌组织在Kube lka-Munk二流模型下对476.5 nm,514.5 nm和808 nm波长的每一个波长的激光的吸收、散射、总衰减、有效衰减系数都有非常显著性的差异(P<0.01)。膀胱癌组织对476.5 nm,514.5 nm和808nm波长的激光的吸收系数明显地较正常膀胱组织对相应波长的激光的吸收系数要大(P<0.01),膀胱癌组织对476.5 nm和514.5 nm波长的激光的散射系数明显地较正常膀胱组织对相应波长的激光的散射系数要小(P<0.01),而膀胱癌组织对808 nm波长的激光的散射系数明显地较正常膀胱组织对同一波长的激光的散射系数要大(P<0.01)。膀胱癌组织对476.5 nm,514.5 nm和808 nm波长的激光的总衰减系数明显地较正常膀胱组织对相应波长的激光的总衰减系数要大(P<0.01),膀胱癌组织对476.5 nm,514.5 nm和808 nm波长的激光的有效衰减系数明显地较正常膀胱组织对相应波长的激光的有效衰减系数要大(P<0.01)。提示使用双积分球系统和Kube lka-Munk二流模型来确定离体的正常膀胱组织和膀胱癌组织对476.5 nm,514.5 nm和808nm波长的激光的光学特性的差异鉴别诊断病变的膀胱组织是一个有效的方法。     

Conodontes de la coupe de Reun Ar C'Hrank en Lanvéoc (Rade de Brest) emsien du massif Armoricain (France) corrélations biostratigraphiques

In the Reun ar C'Hrank section (Rade de Brest), the Conodonts from just above the base of the Beg an Arreun Formation of the Troaon Group in the Armorican Massif indicate the Polygnathus laticostatus Zone, which belongs to the highest Zlichvian and the base of the Dalejan. Species of Icriodus from the same beds indicate a correlation with the lower and middle part of the Hierges Formation, which represents the Upper Emsian in the Ardennes. Conodonts from Le Fret Formation are tentatively assigned an Upper Emsian/Dalejan age.     

蒙古中部湖泊之谷沉积岩-玄武岩共存的渐新世地层:蒙古-奥地利合作项目回顾(英文)

Taatsiin Gol和Taatsiin Tsagaan Nuur地区的渐新世沉积序列具有重要的地层学意义:这里出露的三达河组和Loh组沉积含有多个化石层和玄武岩夹层。在蒙古-奥地利合作项目中,从研究区域的33个剖面/化石地点的85个化石层中采集了289种化石(11种腹足类、2种两栖类、9种爬行类和267种哺乳类)。本文提供了所有地点的完整哺乳动物清单,并结合大、小哺乳动物的新资料,对蒙古非正式的生物带A,B,C和C1进行了更新。40Ar/39Ar测年给出了至少两组玄武岩年龄:早渐新世玄武岩I组大约31.5Ma,晚渐新世玄武岩II组大约28Ma。它们可以用作渐新世哺乳动物地层学的年代校正点。从早渐新世至晚渐新世,哺乳动物群发生了显著的变化,包括晚渐新世种数的明显减少。这种趋势在肉齿类、食肉类和反刍类中最为突出。     

Ar+诱变拟南芥雄性不育材料花器官表型分析及小孢子发生细胞形态学观察

利用低能氩离子作为诱变源诱变拟南芥种子,选用诱变剂量为1.5×1017ions/cm2,30 keV的能量。在其M2群体中根据有无果荚及其果荚是否异常,筛选出tc243不育突变体。用石蜡切片技术,在光学显微镜下观察拟南芥部分雄性不育材料小孢子发育过程和各时期的花形态特征,分析雄性不育的原因。从花表型上分析导致雄性不育的原因有三个方面:(1)柱头伸长过快;(2)花药生长过慢;(3)花药开裂晚。从小孢子发生的细胞形态学观察表明花粉败育主要发生在小孢子四分体时期,此时绒毡层正常,小部分四分体正常,大部分四分体外面的的胼胝体过早降解释放游离小孢子,此时的绒毡层还没解体不能提供小孢子发育所需要的营养物质,使过早释放的小孢子不能正常发育,导致最后形成大量没有活力的花粉粒。     

Sapropels and the age of hominins Omo I and II, Kibish, Ethiopia

The provenance and age of two Homo sapiens fossils (Omo I and Omo II) from the Kibish Formation in southern Ethiopia have been much debated. Here we confirm that Omo I and the somewhat more primitive-looking Omo II calvariae are from similar stratigraphic levels in Member I of the Kibish Formation. Based on (40)Ar/(39)Ar age measurements on alkali feldspar crystals from pumice clasts in the Nakaa'kire Tuff, a tuffaceous bed in Member I just below the hominin levels, we place an older limit of 198+/-14ka (weighted mean age=196+/-2ka) for the hominins. A younger limit of 104+/-7ka (weighted mean age=104+/-1ka) is provided by feldspars separated from pumice clasts in the Aliyo Tuff in Member III. Geological evidence indicates rapid deposition of each member of the Kibish Formation, concurrent with deposition of sapropels in the Mediterranean Sea. The (40)Ar/(39)Ar age measurements, together with correlations with sapropels, indicate that the hominin fossils are close in age to the older limit. Our preferred estimate of the age of the hominins is 195+/-5ka, making them the earliest well-dated anatomically modern humans yet described.     

High-precision Ar/Ar age for the Jehol Biota

Abundant fossils of the terrestrial Jehol Biota, including plants, insects, dinosaurs, birds, mammals and freshwater invertebrates, were discovered from the Yixian Formation and the overlying Jiufotang Formation in Inner Mongolia, Hebei Province and Liaoning Province, northeastern China. Because of the exceptional preservation of fossils, the Jehol Biota is one of the most important Mesozoic lagerstätten and is referred to as a “Mesozoic Pompeii”. The Jehol Biota has provided a rare opportunity to address questions about the origin of birds, the evolution of feathers and flight, the early diversification of angiosperms and the timing of placental mammal radiation. Six tuff samples and two basalt samples collected from the Tuchengzi, the Yixian and the Jiufotang formations near the classic outcrops in western Liaoning, NE China yielded high-precision ⁴⁰Ar/³⁹Ar ages. We obtain an age of 129.7 ± 0.5 Ma for a basaltic lava from the bottom of the Yixian Formation and an age of 122.1 ± 0.3 Ma for a tuff from the lowermost part of the overlying Jiufotang Formation. Our age results provide an age calibration of the whole Yixian Formation and show that the whole formation was deposited entirely within Early Cretaceous time over an interval of ~ 7 Ma.     

Mutagenicity of 22 N-nitrosamides and related compounds for Salmonella typhimurium TA1535.

Twenty-two N-nitrosamides and related compounds, including 14 nitrosoureas, 5 nitrosocarbamates, and one nitrosocyanamide, were tested at various concentrations for mutagenic activity towards Salmonella typhimurium TA1535 without the use of microsomes. The ether-water partition coefficient, solubility in water, and half-life in aqueous solution were also measured. Twenty compounds were mutagenic, with "standard mutagenic concentrations" (i.e. those producing 100 mutants/dish) of 0.0024--6500 micron. Standard mutagenic concentration was negatively correlated with the partition coefficient. Three compounds (ethyl 2-acetoxyethylnitrosocarbamate, nitrosocarbaryl, and methylnitrosobenzamide) were more active than the classic mutagen methylnitrosonitroguanidine. Nitrosocarbamates were at least 50 times more mutagenic than the corresponding nitrosoureas. Nitrosodihydrouracil and propylene-nitrosourea were more active than related compounds. Ethylnitrosocyanamide was 730 times more mutagenic than ethylnitrosourea. Fifteen of the test compounds (of which 14 were mutagenic) had previously been assayed in rats for carcinogenicity, all with positive results.