Discovery of pyrazolo[3,4-d]pyrimidine derivatives as GPR119 agonists

We designed and synthesized a novel series of phenylamino- and phenoxy-substituted pyrazolo[3,4-d]pyrimidine derivatives as GPR119 agonists. SAR studies indicated that electron-withdrawing substituents on the phenyl ring are important for potency and full efficacy. Compound 26 combined good potency with a promising pharmacokinetic profile in mice, and lowered the glucose excursion in mice in an oral glucose-tolerance test.     

Structural Characterization of Tau in Fuzzy Tau:Tubulin Complexes

1. Download : Download high-res image (181KB)
2. Download : Download full-size image

     

Mean difference in live-weight per incremental difference in body condition score estimated in multiple sheep breeds and crossbreds

Body condition score (BCS) is a subjective assessment of the proportion of body fat an animal possesses and is independent of frame size. There is a growing awareness of the importance of mature animal live-weight given its contribution to the overall costs of production of a sector. Because of the known relationship between BCS and live-weight, strategies to reduce live-weight could contribute to the favouring of animals with lesser body condition. The objective of the present study was to estimate the average difference in live-weight per incremental change in BCS, measured subjectively on a scale of 1 to 5. The data used consisted of 19 033 BCS and live-weight observations recorded on the same day from 7556 ewes on commercial and research flocks; the breeds represented included purebred Belclare (540 ewes), Charollais (1484 ewes), Suffolk (885 ewes), Texel (1695 ewes), Vendeen (140 ewes), as well as, crossbreds (2812 ewes). All associations were quantified using linear mixed models with the dependent variable of live-weight; ewe parity was included as a random effect. The independent variables were BCS, breed (n=6), stage of the inter-lambing interval (n=6; pregnancy, lambing, pre-weaning, at weaning, post-weaning and mating) and parity (1, 2, 3, 4 and 5+). In addition, two-way interactions were used to investigate whether the association between BCS and live-weight differed by parity, a period of the inter-lambing interval or breed. The association between BCS and live-weight differed by parity, by a period of the inter-lambing interval and by breed. Across all data, a one-unit difference in BCS was associated with 4.82 (SE=0.08) kg live-weight, but this differed by parity from 4.23 kg in parity 1 ewes to 5.82 kg in parity 5+ ewes. The correlation between BCS and live-weight across all data was 0.48 (0.47 when adjusted for nuisance factors in the statistical model), but this varied from 0.48 to 0.53 by parity, from 0.36 to 0.63 by stage of the inter-lambing interval and from 0.41 to 0.62 by breed. Results demonstrate that consideration should be taken of differences in BCS when comparing ewes on live-weight as differences in BCS contribute quite substantially to differences in live-weight; moreover, adjustments for differences in BCS should consider the population stratum, especially breed.     

Stress integrated tests and cytological analyses reveal Brassica villosa subsp. drepanensis seed quality decrease upon long-term storage

Under stress integrated germination test (SIGT), seeds undergo osmo-saline stresses, which enable to detect differences in vigour of long-term stored seeds with high germination percentage (G%). The quality of Brassica villosa subsp. drepanensis seeds stored in a genebank (at ? 20°C for 16 years) was compared with seeds at harvest by standard germination tests (GT), SIGT and cytogenetic analysis. No differences were detected in G% and mean germination time under GT. Conversely, SIGT performed with NaCl ? 0.9 MPa osmotic potential did not influence G% at harvest but reduced that of stored seeds, SIGT at ? 1.4 MPa reduced G% of both. Cytogenetic analysis showed reduction of mitotic index, appearance of chromosomal aberrations and smaller nucleoli in stored seeds compared with harvest seeds germinated in water. SIGT at ? 0.9 MPa had no effect on mitotic index, but increased chromosome aberrations and nucleoli number. SIGT at ? 1.4 MPa inhibited G% of harvest and stored seeds, reduced mitoses in harvest and completely prevented it in stored seeds. The results indicate that GT does not faithfully reflect the quality of stored seeds, with misinterpretation of their vigour, whereas SIGT and cytogenetical parameters are sensitive, reliable and inexpensive methods for early prediction of genetic erosion in germplasm banks.     

Testing parameter sensitivities and uncertainty analysis of Biome-BGC model in simulating carbon and water fluxes in broadleaved-Korean pine forests

生态过程模型的发展为研究者在长时间序列和区域尺度的研究提供了便利, 但模型模拟的准确性受到模型自身结构、模型参数估计合理性的影响。敏感性分析能够定量或定性筛选出对模型模拟结果影响较大的敏感参数, 是模型参数校准过程中的重要工具, 也是建模和应用的先决条件。该文以阔叶红松林为研究对象, 采用全局敏感性分析方法——傅里叶幅度灵敏度检验扩展法(EFAST)对Biome-BGC模型的生理生态参数进行了敏感性分析, 分别分析了红松(Pinus koraiensis)和阔叶树的净初级生产力(NPP)、蒸散(ET)对参数变化的敏感性。结果表明: (1)模拟红松NPP的不确定性高于阔叶树, 但二者的模拟ET的不确定性均较小。阔叶树的NPP和ET对生理生态参数的敏感性总体上都小于红松。(2)无论是红松、阔叶或其他植被类型, 模拟NPP均表现出对叶片碳氮比、细根碳氮比、比叶面积(SLA)和冠层截留系数的敏感性, 这4个参数的高敏感性主要是由模型自身结构所决定的, 与植被类型和研究地区的关系较小。对模拟ET而言, 细根与叶片碳分配比、新茎与新叶碳分配比和SLA均是影响红松和阔叶树ET的敏感参数, 但红松ET主要受参数与参数间的二阶或多阶交互作用的间接影响, 而阔叶树ET则主要是受到敏感参数直接效应的影响。(3)除了上述影响红松和阔叶树碳水通量的共性参数外, 诸如核酮糖-1,5-二磷酸羧化酶中叶氮含量、叶片与细根周转率、所有叶面积与投影叶面积之比等也是对模拟结果有影响的重要参数, 但是其敏感程度随物种不同和研究区不同而不同, 所以这类参数可以根据具体情况进行参数本地化, 对于其他不敏感参数则可以采用模型缺省值。     

The energetics of middle-distance running

In order to assess the relative contribution of aerobic processes to running velocity (v), 27 male athletes were selected on the basis of their middle-distance performances over 800, 1500, 3000 or 5000 m, during the 1987 track season. To be selected for study, the average running velocity (v) corresponding to their performances had to be superior to 90% of the best French v of the season. Maximum O2 consumption (VO2max) and energy cost of running (C) had been measured within the 2 months preceding the track season, which, together with oxygen consumption at rest (VO2rest) allowed us to calculate the maximal v that could be sustained under aerobic conditions: vamax = (VO2max - VO2rest) x C-1. The treadmill running v corresponding to a blood lactate of 4 mmol.l-1 (vla4), was also calculated. In the whole group, C was significantly related to height (r = -0.43; P less than 0.03). Neither C nor VO2max (with, in this case, the exception of the 3000 m athletes) were correlated to v. On the other hand, vamax was significantly correlated to v over distances longer than 800 m. These v were also correlated to vla4. However vla4 occurred at 87.5% SD 3.3% of vamax, this relationship was interpreted as being an expression of the correlation between vamax and v. Calculation of vamax provided a useful means of analysing the performances. At the level of achievement studied, v sustained over 3000 m corresponded to vamax.(ABSTRACT TRUNCATED AT 250 WORDS)     

The intersectional hybrid between Weigela hortensis and W. maximowiczii (Caprifoliaceae)

Morphologically intermediate plants between Weigela hortensis (Siebold & Zucc.) K.Koch and W. maximowiczii (S.Moore) Rehder have been found in Miyagi and Yamagata Pref., northern Japan. Quantitative character analyses of flowers, pollen stainability and molecular analyses indicated that the intermediate plants were hybrids of those two species. This is the first record of an intersectional hybrid with W. maximowiczii (sect. Weigelastrum ) as one of the parent species. The morphological differences among hybrid individuals imply the possibility of backcrosses or formation of second or later generations of hybrids, although those may be quite rare because of a low frequency of viable pollen grains. Causes of hybridization between two distantly-related species in Weigela are discussed. © 2002 The Linnean Society of London, Botanical Journal of the Linnean Society , 2002, 138 , 369–380.     

Microsecond Dynamics During the Binding-induced Folding of an Intrinsically Disordered Protein

Tau is an intrinsically disordered protein implicated in many neurodegenerative diseases. The repeat domain fragment of tau, tau-K18, is known to undergo a disorder to order transition in the presence of lipid micelles and vesicles, in which helices form in each of the repeat domains. Here, the mechanism of helical structure formation, induced by a phospholipid mimetic, sodium dodecyl sulfate (SDS) at sub-micellar concentrations, has been studied using multiple biophysical probes. A study of the conformational dynamics of the disordered state, using photoinduced electron transfer coupled to fluorescence correlation spectroscopy (PET-FCS) has indicated the presence of an intermediate state, I, in equilibrium with the unfolded state, U. The cooperative binding of the ligand (L), SDS, to I has been shown to induce the formation of a compact, helical intermediate (IL₅) within the dead time (∼37 µs) of a continuous flow mixer. Quantitative analysis of the PET-FCS data and the ensemble microsecond kinetic data, suggests that the mechanism of induction of helical structure can be described by a U ↔ I ↔ IL₅ ↔ FL₅ mechanism, in which the final helical state, FL₅, forms from IL₅ with a time constant of 50–200 µs. Finally, it has been shown that the helical conformation is an aggregation-competent state that can directly form amyloid fibrils.