Engineering a Dimeric Caspase-9: A Re-evaluation of the Induced Proximity Model for Caspase Activation

Caspases are responsible for the execution of programmed cell death (apoptosis) and must undergo proteolytic activation, in response to apoptotic stimuli, to function. The mechanism of initiator caspase activation has been generalized by the induced proximity model, which is thought to drive dimerization-mediated activation of caspases. The initiator caspase, caspase-9, exists predominantly as a monomer in solution. To examine the induced proximity model, we engineered a constitutively dimeric caspase-9 by relieving steric hindrance at the dimer interface. Crystal structure of the engineered caspase-9 closely resembles that of the wild-type (WT) caspase-9, including all relevant structural details and the asymmetric nature of two monomers. Compared to the WT caspase-9, this engineered dimer exhibits a higher level of catalytic activity in vitro and induces more efficient cell death when expressed. However, the catalytic activity of the dimeric caspase-9 is only a small fraction of that for the Apaf-1-activated caspase-9. Furthermore, in contrast to the WT caspase-9, the activity of the dimeric caspase-9 can no longer be significantly enhanced in an Apaf-1-dependent manner. These findings suggest that dimerization of caspase-9 may be qualitatively different from its activation by Apaf-1, and in conjunction with other evidence, posit an induced conformation model for the activation of initiator caspases

Discovering Argumentative Patterns in Energy Polylogues: A Macroscope for Argument Mining

A macroscope is proposed and tested here for the discovery of the unique argumentative footprint that characterizes how a collective (e.g., group, online community) manages differences and pursues disagreement through argument in a polylogue. The macroscope addresses broader analytic problems posed by various conceptualizations of large-scale argument, such as fields, spheres, communities, and institutions. The design incorporates a two-tier methodology for detecting argument patterns of the arguments performed in arguing by an interactive collective that produces views, or topographies, of the ways that issues are generated in the making and defending of standpoints. The design premises for the macroscope build on insights about argument patterns from pragma-dialectical theory by incorporating research and theory on disagreement management and the Argumentum Model of Topics. The design reconceptualizes prototypical and stereotypical argument patterns for characterizing large-scale argumentation. A prototype of the macroscope is tested on data drawn from six threads about oil-drilling and fracking from the subreddit Changemyview. The implementation suggests the efficacy of the macroscope’s design and potential for identifying what communities make controversial and how the disagreement space in a polylogue is managed through stereotypical argument patterns in terms of claims/premises, inferential relations, and presentational devices

First World Consensus Conference on pancreas transplantation: Part II - recommendations.

Funder: Fondazione Pisa, Pisa, Italy; Id: http://dx.doi.org/10.13039/100007368Funder: Tuscany Region, Italy; Id: http://dx.doi.org/10.13039/501100009888Funder: Pisa University Hospital, Pisa, ItalyFunder: University of Pisa, Pisa, Italy; Id: http://dx.doi.org/10.13039/501100007514The First World Consensus Conference on Pancreas Transplantation provided 49 jury deliberations regarding the impact of pancreas transplantation on the treatment of diabetic patients, and 110 experts' recommendations for the practice of pancreas transplantation. The main message from this consensus conference is that both simultaneous pancreas-kidney transplantation (SPK) and pancreas transplantation alone can improve long-term patient survival, and all types of pancreas transplantation dramatically improve the quality of life of recipients. Pancreas transplantation may also improve the course of chronic complications of diabetes, depending on their severity. Therefore, the advantages of pancreas transplantation appear to clearly surpass potential disadvantages. Pancreas after kidney transplantation increases the risk of mortality only in the early period after transplantation, but is associated with improved life expectancy thereafter. Additionally, preemptive SPK, when compared to SPK performed in patients undergoing dialysis, appears to be associated with improved outcomes. Time on dialysis has negative prognostic implications in SPK recipients. Increased long-term survival, improvement in the course of diabetic complications, and amelioration of quality of life justify preferential allocation of kidney grafts to SPK recipients. Audience discussions and live voting are available online at the following URL address: http://mediaeventi.unipi.it/category/1st-world-consensus-conference-of-pancreas-transplantation/246