Inhibitors of HCV NS5B polymerase: synthesis and structure-activity relationships of unsymmetrical 1-hydroxy-4,4-dialkyl-3-oxo-3,4-dihydronaphthalene benzothiadiazine derivatives

Substituted 1-hydroxy-4,4-dialkyl-3-oxo-3,4-dihydronaphthalene benzothiadiazine derivatives were investigated as inhibitors of genotype 1 HCV polymerase. Structure-activity relationship patterns for this class of compounds are discussed. It was found that the saturated alkane dialkyl units provided the most active analogs.     

Quinazolinones as γ-secretase modulators

Synthesis, SAR and evaluation of styrenyl quinazolinones as novel gamma secretase modulators are presented in this communication. Starting from literature and in-house leads we evaluated a range of quinazolinones which showed good modulation of γ-secretase activity.     

Direct measurements of the kinematics and dynamics of bat flight

Experimental measurements and analysis of the flight of bats are presented, including kinematic analysis of high-speed stereo videography of straight and turning flight, and measurements of the wake velocity field behind the bat. The kinematic data reveal that, at relatively slow flight speeds, wing motion is quite complex, including a sharp retraction of the wing during the upstroke and a broad sweep of the partially extended wing during the downstroke. The data also indicate that the flight speed and elevation are not constant, but oscillate in synchrony with both the horizontal and vertical movements of the wing. PIV measurements in the transverse (Trefftz) plane of the wake indicate a complex 'wake vortex' structure dominated by a strong wing tip vortex shed from the wing tip during the downstroke and either the wing tip or a more proximal joint during the upstroke. Data synthesis of several discrete realizations suggests a 'cartoon' of the wake structure during the entire wing beat cycle. Considerable work remains to be done to confirm and amplify these results.     

Mechanically stimulated osteocytes reduce the bone-metastatic potential of breast cancer cells in vitro by signaling through endothelial cells

Bone metastases occur in 65% to 75% of patients with advanced breast cancer and significantly worsen their survival and quality of life. We previously showed that conditioned medium (CM) from osteocytes stimulated with oscillatory fluid flow, mimicking bone mechanical loading during routine physical activities, reduced the transendothelial migration of breast cancer cells. Endothelial cells are situated at an ideal location to mediate signals between osteocytes in the bone matrix and metastasizing cancer cells in the blood vessels. In this study, we investigated the specific effects of flow-stimulated osteocytes on the interaction between endothelial cells and breast cancer cells in vitro. We observed that CM from flow-stimulated osteocytes reduced endothelial permeability by 15% and breast cancer cell adhesion onto endothelial monolayers by 18%. The difference in adhesion was abolished with anti-intercellular adhesion molecule 1 (ICAM-1) neutralizing antibodies. Furthermore, CM from endothelial cells conditioned in CM from flow-stimulated osteocytes significantly altered the gene expression in bone-metastatic breast cancer cells, as shown by RNA sequencing. Specifically, breast cancer cell expression of matrix metallopeptidase 9 (MMP-9) was downregulated by 62%, and frizzled-4 (FZD4) by 61%, when the osteocytes were stimulated with flow. The invasion of these breast cancer cells across Matrigel was also reduced by 47%, and this difference was abolished by MMP-9 inhibitors. In conclusion, we demonstrated that flow-stimulated osteocytes downregulate the bone-metastatic potential of breast cancer cells by signaling through endothelial cells. This provides insights into the capability of bone mechanical regulation in preventing bone metastases; and may assist in prescribing exercise or bone-loading regimens to patients with breast cancers.     

羊草与其主要伴生种竞争与共存的格局分析

在羊草种群与其它植物种群的交错区,应用频度、格避形式,格局强度指数对羊草及其主要伴生种之间的共存格局进行了分析。结果表明,羊草及其主要伴生种的格局呈多样化,集聚格局形式是羊草抵御外来物种入侵,或者是自身扩散的一种对策,羊草与其主要伴生种之间存在竞争与共存作用,羊草与芦苇之间通过拮抗作用实现竞争与共存,羊草与鸡儿肠通过竞争而实现共存,光稃茅香,碱茅以营养繁殖策略实现与羊草竞争,指子茅的生长受羊草竞争的抑制。     

Surface N balances and reactive N loss to the environment from global intensive agricultural production systems for the period 1970-2030

Data for the historical years 1970 and 1995 and the FAO-Agriculture Towards 2030 projection are used to calculate N inputs (N fertilizer, animal manure, biological N fixation and atmospheric deposition) and the N export from the field in harvested crops and grass and grass consumption by grazing animals. In most industrialized countries we see a gradual increase of the overall N recovery of the intensive agricultural production systems over the whole 1970-2030 period. In contrast, low N input systems in many developing countries sustained low crop yields for many years but at the cost of soil fertility by depleting soil nutrient pools. In most developing countries the N recovery will increase in the coming decades by increasing efficiencies of N use in both crop and livestock production systems. The surface balance surplus of N is lost from the agricultural system via different pathways, including NH3 volatilization, denitrification, N2O and NO emissions, and nitrate leaching from the root zone. Global NH3-N emissions from fertilizer and animal manure application and stored manure increased from 18 to 34 Tg·yr-1 between 1970 and 1995, and will further increase to 44 Tg·yr-1 in 2030. Similar developments are seen for N2O-N (2.0 Tg·yr-1 in 1970, 2.7 Tg·yr-1 in 1995 and 3.5 Tg·yr-1 in 2030) and NO-N emissions (1.1 Tg·yr-1 in 1970, 1.5Tg·yr-1 in 1995 and 2.0 Tg·yr-1 in 2030).     

Discovery of novel 4-amino-6-arylaminopyrimidine-5-carbaldehyde oximes as dual inhibitors of EGFR and ErbB-2 protein tyrosine kinases

We herein disclose a novel series of 4-aminopyrimidine-5-carbaldehyde oximes that are potent and selective inhibitors of both EGFR and ErbB-2 tyrosine kinases, with IC(50) values in the nanomolar range. Structure-activity relationship (SAR) studies elucidated a critical role for the 4-amino and C-6 arylamino moieties. The X-ray co-crystal structure of EGFR with 37 was determined and validated our design rationale.