Discovery of isoquinolinone and naphthyridinone-based inhibitors of poly(ADP-ribose) polymerase-1 (PARP1) as anticancer agents: Structure activity relationship and preclinical characterization

The exploitation of GLU988 and LYS903 residues in PARP1 as targets to design isoquinolinone (I & II) and naphthyridinone (III) analogues is described. Compounds of structure I have good biochemical and cellular potency but suffered from inferior PK. Constraining the linear propylene linker of structure I into a cyclopentene ring (II) offered improved PK parameters, while maintaining potency for PARP1. Finally, to avoid potential issues that may arise from the presence of an anilinic moiety, the nitrogen substituent on the isoquinolinone ring was incorporated as part of the bicyclic ring. This afforded a naphthyridinone scaffold, as shown in structure III. Further optimization of naphthyridinone series led to identification of a novel and highly potent PARP1 inhibitor 34, which was further characterized as preclinical candidate molecule. Compound 34 is orally bioavailable and displayed favorable pharmacokinetic (PK) properties. Compound 34 demonstrated remarkable antitumor efficacy both as a single-agent as well as in combination with chemotherapeutic agents in the BRCA1 mutant MDA-MB-436 breast cancer xenograft model. Additionally, compound 34 also potentiated the effect of agents such as temozolomide in breast cancer, pancreatic cancer and Ewing’s sarcoma models.     

Seemingly Unrelated Generalized Linear Models

By using deviance standardized residuals, the seemingly unrelated regression estimation procedure is extended to generalized linear models, and fitted by an iterative procedure. The matrix of cross products of standardized residuals is asymptotically multivariate normal, and can be used for further multivariate analyses and for hypothesis testing.     

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.     

Unravelling the coordination between leaf and stem economics spectra through local and global scale approaches

The existence of a coordination between leaf and stem economic spectra in woody species has been postulated repeatedly in the literature, with contrasting results. Here, we postulated that this coordination is conditioned by climate factors, being stronger in stressful environments. To test this hypothesis we explored the coordination between leaf and stem economic spectra in a seasonally dry forest in central Argentina and at the global scale, we analysed if the outcome of their coordination varies along a climatic gradient. At the local scale, we characterized leaf and stem economic spectra in 37 woody species by measuring six leaf and stem functional traits related to resource acquisition and use, and two functional traits used as proxies of water transport and use capacities. At the global scale, a meta‐regression was performed to analyse if the outcome of the coordination among leaf and stem traits varies along gradients of the mean precipitation of the driest quarter and of the minimum temperature of the coldest month. At the local scale, we observed a high integration among the measured leaf and stem traits, and this coordination seemed to be linked to hydraulic properties. At the global scale, we found not only that the overall weighted mean effect size of the correlation between specific leaf area and wood density was significant and negative but also that the coordination between leaf and stem traits seemed to be shaped by climate and tends to become stronger under harsh climate conditions. Furthermore, although our results seem to suggest that their coordination is context‐dependent, alternative strategies could be observed under stressful conditions.     

A Parameter-Elimination Method for Nonlinear Regression with Linear Parameters and Autocorrelated Errors

In this study, we are interested in the problem of estimating the parameters in a nonlinear regression model when the error terms are correlated. Throughout this work, we restrict ourselves to the special case when the error terms follow a pth order stationary autoregressive model (AR(p)). Following the idea of LAWTON and SYLVESTRE (1971) and GALLANT and GOEBEL (1976), a parameter-elimination method is proposed, which has the advantages that it is not sensitive to the initial values and convergence of the procedure may be more stable because of the reduced dimension of the problem. The parameter-elimination method is compared with the methods by GALLANT and GOEBEL (1976) and GLASBEY (1980) by Monte Carlo Simulation, and the results of applying the first two methods to the real data obtained from the Environmental Protection Administration of the Executive Yuan of the Republic of China are presented.     

Effects of Patch-Burn Management on Dickcissel Nest Success in a Tallgrass Prairie

Abstract Grassland birds have declined more than any other North American habitat-associated bird community. Because most species of grassland birds evolved within heterogeneous landscapes created by the interaction of fire and grazing, traditional rangeland management that promotes homogeneity, including annual dormant-season burning combined with early-intensive grazing, might be partly responsible for these declines, especially in some regions of the Great Plains, USA. Recently, an alternative grassland management practice known as patch-burning has been promoted as a means of restoring heterogeneity to grasslands by mimicking the grazing-fire interaction that once occurred on the prairie before European settlement. From 2003 to 2004, we examined effects of patch-burning and traditional management (annual burning followed by early-intensive grazing) on the reproductive success of dickcissels (Spiza americana) in tallgrass prairie in Oklahoma. We monitored 296 dickcissel nests and found that dickcissel nesting phenology differed between traditional and patch-burned pastures. Specifically, dickcissels tended to initiate their nests later in the traditional pasture. Mean number of eggs laid and fledglings produced were similar between the treatments, but nest densities were higher in traditional pastures. Predation was the predominant cause of nest failure and was higher in traditional pastures than in patch-burned pastures. Brown-headed cowbird (Molothrus ater) parasitism was higher in traditional pastures than in patch-burned pastures. Overall, dickcissel nest success was higher in patch-burned pastures than in traditional pastures. The positive response of dickcissel nest success to patch-burn management provides further evidence that this practice can be a useful tool for grassland bird conservation. By creating a mosaic of different stature vegetation, patch-burn management enhances productivity of grassland bird species by providing a refuge area in the unburned patches that affords dickcissels and other nesting grassland birds some protection from the direct (e.g., trampling) and indirect (e.g., cowbird parasitism and predation) effects of grazing, which are not available under traditional management. Patch-burn management should be encouraged as a conservation strategy for grassland birds throughout the Great Plains.     

拟似然非线性模型中的置信域：几何法

对拟似然非线性模型在欧氏内积实间建立了修改的Ｂａｔｅｓ＆Ｗａｔｔｓ几何结构，基于此几何结构，导出了参数和子集系数的与统计曲率有关的三种近似置信域，进一步推广和发展了Ｈａｍｉｌｔｏｎ ｅｔ ａｌ．（１９８２）。Ｈａｍｉｌｔｏｎ（１９８６）和Ｗｅｉ（１９９４，１９９８）等人的相应结果。