Structure based design of novel 6,5 heterobicyclic mitogen-activated protein kinase kinase (MEK) inhibitors leading to the discovery of imidazo[1,5-a] pyrazine G-479

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.     

A Nuclear Marker for Mammalian Cells and Its Use with Intracerebral Transplants

The Hoechst dye staining method has been successfully applied to the central nervous system in mammals and its use has been demonstrated in intracerebral transplantation. The technique is rapid, simple and based on intrinsic nuclear properties. It was found to be permanent and valid whatever the animal strains or ages, allowing the distinction of rat cells from those of mouse, studied either separately or in a cross-transplantation model. It permitted the detection of grafted cells in the area of transplantation and the observation of early dispersion around the implantation site. Moreover, it can be combined with immunohistochemistry as demonstrated by a myelin marker in a relevant model. Immunodetection can thus help to directly observe grafted cells, at distance from the locus of transplantation, confirming their presence in the graft-type myelin patches.

Because of its rapid performance, this technique can be used systematically after transplantation to check for the presence of grafted cells in the host.     

On the PBB Designs for Multiresponse Experiments

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.     

On Connectedness of a Two-way Elimination of Heterogeneity Design

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.     

唐古拉山以北地区生态资产核算

生态系统核算可以为生态文明建设提供定量性的决策依据,包括生态资产核算和生态系统服务核算两个方面,生态资产指生产和提供生态系统产品和服务的生态系统。以唐古拉山以北地区(简称唐北地区)为研究对象对其生态资产进行了核算,建立生态资产实物量及变化核算表、损益表,提出了生态资产综合指数。2015年唐北地区草地生态资产面积为21800.01 km~2,其中良级比重最高达68.46%,湿地生态资产面积为4763.01 km~2,其中优级比例最高为59.72%,野生动植物共有138种,其中重点保护动物10种。2015年唐北地区生态资产综合指数为79.77,比2000年降低了3.60%。2000—2015年,湿地、草地生态资产分别增加了164.23、2.82 km~2。2000—2015年湿地生态资产存量增加202.90 km~2,其中由湿地恢复导致面积增加最大为200.50 km~2,存量减少38.63 km~2,其中湿地退化是导致存量减少的主要原因,面积为36.23 km~2,草地存量增加了39.18 km~2,主要是由于湿地退化导致的草地扩张,存量减少36.26 km~2,主要由湿地恢复和荒漠化引起。研究中不同生态资产质量等级的核算以及生态资产综合指数的提出利于生态资产的全面核算和比较,对于建立离任责任制、生态文明建设意义重大。     

Design and Analysis of Field Experiments Incorporating Local and Remote Effects of Treatments

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.     

Physical associations of microglia and the vascular blood-brain barrier and their importance in development,health, and disease

Brain endothelial cells (BEC) of the vascular blood-brain barrier (BBB) interact with many different cell types in the brain, including microglia, the brain's resident immune cells. Physical associations of microglia with the BBB and the importance of these interactions in health and disease are an emerging area of study and likely involved in neuroimmune communication. In this mini-review, we consider how microglia and the BBB are intrinsically linked in the developing brain, discuss possible mechanisms that attract microglia to the vasculature in healthy physiological conditions, and examine the known microglial-vascular associated changes in systemic infection and various disease states. Our findings shed light on the complexities of microglial-vascular interactions and highlight the contributions of microglia to the functions of the neurovascular unit.     

Adsorption of DNA by Bacteria and Their Composites with Minerals

Previous studies revealed the thermodynamic properties of DNA adsorption on pure minerals or biomasses; however, there has been little attempt to develop such studies on bacteria–mineral composites. Equilibrium adsorption experiments, attenuated total reflectance Fourier transform infrared spectroscopy, and isothermal titration calorimetry were employed to investigate the adsorption of DNA by Bacillus subtilis, Pseudomonas putida, and their composites with minerals. Similar capacity and affinity were observed for DNA adsorption on two bacterial cells. However, different patterns were found in the adsorption of DNA by bacteria–mineral composites. The Gram-positive bacterium B. subtilis enhanced the adsorption of DNA on its mineral composites compared with their individual components, while the composites of Gram-negative bacterial cells with kaolinite and goethite bound lower amounts of DNA than the predicted values. The thermodynamic parameters and the Fourier transform infrared spectra showed that van der Waals force and hydrogen bonding are responsible for the DNA adsorption on B. subtilis–minerals and P. putida–kaolinite. By contrast, the entropy increases of excluded water rearrangement and dehydration effect play key roles in the interaction between DNA and P. putida–montmorillonite/goethite composites.