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Dissecting an Allosteric Switch in Caspase-7 Using Chemical and Mutational Probes *
No full textApoptotic caspases, such as caspase-7, are stored as inactive protease zymogens, and when activated, lead to a fate-determining switch to induce cell death. We previously discovered small molecule thiol-containing inhibitors that when tethered revealed an allosteric site and trapped a conformation similar to the zymogen form of the enzyme. We noted three structural transitions that the compounds induced: (i) breaking of an interaction between Tyr-223 and Arg-187 in the allosteric site, which prevents proper ordering of the catalytic cysteine; (ii) pinning the L2 loop over the allosteric site, which blocks critical interactions for proper ordering of the substrate-binding groove; and (iii) a hinge-like rotation at Gly-188 positioned after the catalytic Cys-186 and Arg-187. Here we report a systematic mutational analysis of these regions to dissect their functional importance to mediate the allosteric transition induced by these compounds. Mutating the hinge Gly-188 to the restrictive proline causes a massive ϳ6000-fold reduction in catalytic efficiency. Mutations in the Arg-187-Tyr-223 couple have a far less dramatic effect (3-20-fold reductions). Interestingly, although the allosteric couple mutants still allow binding and allosteric inhibition, they partially relieve the mutual exclusivity of binding between inhibitors at the active and allosteric sites. These data highlight a small set of residues critical for mediating the transition from active to inactive zymogen-like states. Caspases are a family of dimeric cysteine proteases whose members control the ultimate steps for apoptosis (programmed cell death) or innate inflammation among others (for reviews, see Refs. 1 and 2). During apoptosis, the upstream initiator caspases (caspase-8 and -9) activate the downstream executioner caspases (caspase-3, -6, and-7) via zymogen maturation (3). The activated executioner caspases then cleave upwards of 500 key proteins (4 -6) and DNA, leading to cell death. Due to their pivotal role in apoptosis, the caspases are involved both in embryonic development and in dysfunction in diseases including cancer and stroke (7). The 11 human caspases share a common active site cysteine-histidine dyad (8), and derive their name, cysteine aspartate proteases, from their exquisite specificity for cleaving substrate proteins after specific aspartate residues (9 -13). Thus, it has been difficult to develop active site-directed inhibitors with significant specificity for one caspase over the others Caspase-7 has been a paradigm for understanding the structure and dynamics of the executioner caspases (15-21). The substrate-binding site is composed of four loops; L2, L3, and L4 are contributed from one-half of the caspase dimer, and L2Ј is contributed from the other half of the caspase dimer A potential alternative to active site inhibitors are allosteric inhibitors that have been seeded by the discovery of selective cysteine-tethered allosteric inhibitors for either apoptotic executioner caspase-3 or apoptotic executioner caspase-7 (23) as well as the inflammatory caspase-1 (24). These thiol-containing compounds bind to a putative allosteric site through disulfide bond formation with a thiol in the cavity at the dimer interface Here, using mutational analysis and small molecule inhibitors, we assess the importance of these three structural units t
Undertaking phenomenological research in Cyprus: the nature and impact of Aristotle's emotions in the Higher Education workplace
Get PDFAbstract The following paper discusses an exploratory study that the author undertakes as part of her doctoral research. This research refers to a phenomenological investigation of Aristotle's fourteen emotions as they were first introduced in his Rhetoric (1984) and aims to understand how these emotions are experienced by the Higher Education academics of Cyprus, at work. Inspired by Aristotle's human emotions, the study examines the nature and impact of anger, calmness, love, hate, fear, confidence, shame, shamelessness, benevolence, selfishness, pity, indignation, envy, and emulation into academics' workdays, using storytelling. The emphasis is placed on the interpretive phenomenological approach being taken to this topic and discusses how the research of emotions can be conceived from this perspective, and why this conception can facilitate the development of the research
THE STATUS OF THE FERMILAB DATA STORAGE SYSTEM. STRUCTURE OF THE SYSTEM AND ITS MAJOR FEATURES
No full textAbstract This document describes the Fermilab Data Storage System Enstore, its design concepts, structure, and current status. Enstore provides storage of the data in robotic tape libraries according to requirements of the experiments. High fault tolerance and availability, as well as multilevel priority based request processing allows experiments to effectively store and access data in the Enstore. Amount of data stored in the system currently approaches 2 PBytes. The Enstore system includes 5 robotic tape libraries, more than 100 PC nodes, and 90 tape drives. The distributed structure and modularity of Enstore allows scaling of the system and adding of more storage equipment as the requirements and needs grow. Users access data in Enstore directly using a special command. They can also use ftp, GridFtp, and SRM interfaces to the dCache caching and buffering system [1], which uses Enstore as its lower layer storage. STRUCTURE OF THE SYSTEM AND ITS MAJOR FEATURES The Enstore project was started as a preparation for the Fermilab Collider Run II experiments. The estimated storage requirements were 250 Mbytes/s of aggregate throughput sustained for a month of uninterrupted work. Estimated capacity of the storage was several petabytes. The storage system had to provide a centralized primary data store for all kinds of data including online and analysis. This required grouping of data sets according to certain criteria, prioritized request processing, and resource allocation. The storage system had to be very reliable to provide uninterrupted operations over an extended period of time. Failure of one or more hardware elements could not lead to the failure of the whole system. The system should support the addition of new equipment to scale its capacity and rates, as well as new types of equipment. The low cost of the system and its operation was also one of the major requirements. We evaluated storage systems which existed at that time. Most of the them were designed as backup systems. They could not group stored data according to experiment needs. They did not map to the specific needs of high energy physics data processing. They could not sustain a constant data flow at a very high rate of uninterrupted work over a substantial time period. The ratio cost/effectiveness was not satisfactory. Most of the systems were strongly coupled to the hardware, reducing flexibility in the selection of machines and robotic libraries. It was also difficult to get the code modified to meet user requirements. Fermilab then decided to develop its own data storage system to satisfy requirements of high energy experiments and general storage needs. This system is highly reliable, scalable, flexible mass storage system. It uses inexpensive computers and has the capability to select between a wide range of robotic libraries and tape drives.The Enstore project started in July 1998 and the major components of the system were developed and put into test production in approximately 1 year. The structure of the Enstore software is presented in All Enstore components communicate using IPC based on UDP. Great care has been taken to provide reliable communications under extreme load conditions. The user command, encp, retries in case of an internal Enstore error
Special Section on Pediatric Drug Disposition and Pharmacokinetics-Commentary Challenges and Opportunities for Increasing the Knowledge Base Related to Drug Biotransformation and Pharmacokinetics during Growth and Development
Get PDFABSTRACT It is generally acknowledged that there is a need and role for informative pharmacokinetic models to improve predictions and simulation as well as individualization of drug therapy in pediatric populations of different ages and developmental stages. This special issue contains more than 20 papers responding to the challenge of providing new information on scaling factors, ontogeny functions for drug metabolizing enzymes and transporters, the mechanisms underlying the observed developmental trajectories for these gene products, age-dependent changes in physiologic processes affecting drug disposition in children, as well as in vitro and in vivo studies describing the relative contribution of ontogeny and genetic factors as sources of variability in drug disposition in children. Considered together, these contributions serve to illustrate some of the current limitations regarding sample availability, number, and quality, but also provide a framework that allows for the potential value of the results of a given study to be interpreted within the context of these limitations. Among the challenges for the future are improving our understanding of the mechanisms regulating age-dependent changes in factors influencing drug disposition and response, thereby facilitating generalization to systems lacking detailed data, better integrating age-dependent changes in pharmacokinetics with age-dependent changes in pharmacodynamics, and allowing better predictability and individualization of drug disposition and response across the pediatric age spectrum
Fixed Point Results for Generalized Chatterjea Type Contractive Conditions in Partially Ordered -Metric Spaces
Get PDFIn the framework of ordered -metric spaces, fixed points of maps that satisfy the generalized ( , )-Chatterjea type contractive conditions are obtained. The results presented in the paper generalize and extend several well known comparable results in the literature
A Strong Lexical Matching Method for the Machine Comprehension Test
Get PDFAbstract Machine comprehension of text is the overarching goal of a great deal of research in natural language processing. The Machine Comprehension Tes
Myth and reality: A response to Lynn on the determinants of Italy's North-South imbalances ☆
No full textIn his article "In Italy, North-South differences in IQ predict differences in income, education, infant mortality, stature, and literacy," Richard Lynn claims to have found the reason causing the divergence between the Northern and the Southern regions of Italy. This article identifies the four main hypotheses formulated in his paper and presents significant evidence against each one of them. We claim that the evidence presented by the author is not sufficient to say that the IQ of Southern Italians is lower than the one of Northern Italians; that his analysis does not prove that there is any causal link between what he defines as IQ and any of the variables mentioned; that there is no evidence that the alleged differences in IQ are persistent in time and, therefore, attributable to genetic factors
Time-Frequency Coupled Proportional Fair Scheduler with Multicarrier Awareness for LTE Downlink
Get PDFAbstract-Proportional fair schedulers have been thoroughly used in Long Term Evolution (LTE) due to their ability to provide a good trade-off between cell spectral efficiency and user fairness. Current algorithms provide suboptimum solutions at a low computational cost, but present several drawbacks. This paper proposes a Coupled and Multicarrier Aware PFS (CMA-PFS) for LTE downlink that increases efficiency as compared with current algorithms with independent time and frequency domain scheduling, referred to as Decoupled PFS (D-PFS). The proposed algorithm includes new features such as tight coupling between time and frequency domain scheduling and multicarrier transmission awareness. Simulations have been conducted using an International Mobile Telecommunications Advanced (IMT-Advanced) compliant semi-static simulator. Results show that the CMA-PFS improves proportional fairness as compared with D-PFS that is reflected both in an increase of cell spectral efficiency (around +2%) and a higher cell-edge user spectral efficiency (around +10%) in a Single User MIMO (SU-MIMO) system