42 research outputs found
Type II Kinase Inhibitors Targeting Cys-Gatekeeper Kinases Display Orthogonality with Wild Type and Ala/Gly-Gatekeeper Kinases
Analogue-sensitive (AS) kinases contain large to small mutations in the gatekeeper position rendering them susceptible to inhibition with bulky analogues of pyrazolopyrimidine-based Src kinase inhibitors (e.g., PP1). This âbump-holeâ method has been utilized for at least 85 of âŒ520 kinases, but many kinases are intolerant to this approach. To expand the scope of AS kinase technology, we designed type II kinase inhibitors, ASDO2/6 (analogue-sensitive âDFG-outâ kinase inhibitors 2 and 6), that target the âDFG-outâ conformation of Cys-gatekeeper kinases with submicromolar potency. We validated this system in vitro against Greatwall kinase (GWL), Aurora-A kinase, and cyclin-dependent kinase-1 and in cells using M110C-GWL-expressing mouse embryonic fibroblasts. These Cys-gatekeeper kinases were sensitive to ASDO2/6 inhibition but not AS kinase inhibitor 3MB-PP1 and vice versa. These compounds, with AS kinase inhibitors, have the potential to inhibit multiple AS kinases independently with applications in systems level and translational kinase research as well as the rational design of type II kinase inhibitors targeting endogenous kinases
Production and perception of situationally variable alarm calls in wild tufted capuchin monkeys (Cebus apella nigritus)
Many mammalian and avian species produce conspicuous vocalizations upon encountering a predator, but vary their calling based on risk urgency and/or predator type. Calls falling into the latter category are termed âfunctionally referentialâ if they also elicit predator-appropriate reactions in listeners. Functionally referential alarm calling has been well documented in a number of Old World monkeys and lemurs, but evidence among Neotropical primates is limited. This study investigates the alarm call system of tufted capuchin monkeys (Cebus apella nigritus) by examining responses to predator and snake decoys encountered at various distances (reflecting differences in risk urgency). Observations in natural situations were conducted to determine if predator-associated calls were given in additional contexts. Results indicate the use of three call types. âBarksâ are elicited exclusively by aerial threats, but the call most commonly given to terrestrial threats (the âhiccupâ) is given in nonpredatory contexts. The rate in which this latter call is produced reflects risk urgency. Playbacks of these two call types indicate that each elicits appropriate antipredator behaviors. The third call type, the âpeep,â seems to be specific to terrestrial threats, but it is unknown if the call elicits predator-specific responses. âBarksâ are thus functionally referential aerial predator calls, while âhiccupsâ are better seen as generalized disturbance calls which reflect risk urgency. Further evidence is needed to draw conclusions regarding the âpeep.â These results add to the evidence that functionally referential aerial predator alarm calls are ubiquitous in primates, but that noncatarrhine primates use generalized disturbance calls in response to terrestrial threats
Computer-based tools for decision support in agroforestry: Current state and future needs
âPumping ironââhow macrophages handle iron at the systemic, microenvironmental, and cellular levels
Alternatives to heparin and protamine anticoagulation for cardiopulmonary bypass in cardiac surgery
Computer-based tools for decision support in agroforestry: Current state and future needs
Successful design of agroforestry practices hinges on the ability to pull together very diverse and sometimes large sets of information (i.e., biophysical, economic and social factors), and then implementing the synthesis of this information across several spatial scales from site to landscape. Agroforestry, by its very nature, creates complex systems with impacts ranging from the site or practice level up to the landscape and beyond. Computer-based Decision Support Tools (DST) help to integrate information to facilitate the decision-making process that directs development, acceptance, adoption, and management aspects in agroforestry. Computer-based DSTs include databases, geographical information systems, models, knowledge-base or expert systems, and âhybridâ decision support systems. These different DSTs and their applications in agroforestry research and development are described in this paper. Although agroforestry lacks the large research foundation of its agriculture and forestry counterparts, the development and use of computer-based tools in agroforestry have been substantial and are projected to increase as the recognition of the productive and protective (service) roles of these tree-based practices expands. The utility of these and future tools for decision-support in agroforestry must take into account the limits of our current scientific information, the diversity of aspects (i.e. economic, social, and biophysical) that must be incorporated into the planning and design process, and, most importantly, who the end-user of the tools will be. Incorporating these tools into the design and planning process will enhance the capability of agroforestry to simultaneously achieve environmental protection and agricultural production goals