Systems-Based Design of Bi-Ligand Inhibitors of Oxidoreductases: Filling the Chemical Proteomic Toolbox

Genomics-driven growth in the number of enzymes of unknown function has created a need for better strategies to characterize them. Since enzyme inhibitors have traditionally served this purpose, we present here an efficient systems-based inhibitor design strategy, enabled by bioinformatic and NMR structural developments. First, we parse the oxidoreductase gene family into structural subfamilies termed pharmacofamilies, which share pharmacophore features in their cofactor binding sites. Then we identify a ligand for this site and use NMR-based binding site mapping (NMR SOLVE) to determine where to extend a combinatorial library, such that diversity elements are directed into the adjacent substrate site. The cofactor mimic is reused in the library in a manner that parallels the reuse of cofactor domains in the oxidoreductase gene family. A library designed in this manner yielded specific inhibitors for multiple oxidoreductases

Ruminococcal cellulosome systems from rumen to human

This article is protected by copyright. All rights reserved. The authors appreciate the kind assistance of Miriam Lerner (ImmunArray Ltd. Company, Rehovot, Israel) with experiments involving the MicroGrid II arrayer. This research was supported by a grant (No. 1349) to EAB also from the Israel Science Foundation (ISF) and a grant (No. 24/11) issued to RL by The Sidney E. Frank Foundation also through the ISF. Additional support was obtained from the establishment of an Israeli Center of Research Excellence (I-CORE Center No. 152/11) managed by the Israel Science Foundation, from the United States-Israel Binational Science Foundation (BSF), Jerusalem, Israel, by the Weizmann Institute of Science Alternative Energy Research Initiative (AERI) and the Helmsley Foundation. The authors also appreciate the support of the European Union, Area NMP.2013.1.1-2: Self-assembly of naturally occurring nanosystems: CellulosomePlus Project number: 604530 and an ERA-IB Consortium (EIB.12.022), acronym FiberFuel. HF and SHD acknowledge support from the Scottish Government Food Land and People programme and from BBSRC grant no. BB/L009951/1. In addition, EAB is grateful for a grant from the F. Warren Hellman Grant for Alternative Energy Research in Israel in support of alternative energy research in Israel administered by the Israel Strategic Alternative Energy Foundation (I-SAEF). E.A.B. is the incumbent of The Maynard I. and Elaine Wishner Chair of Bio-organic ChemistryPeer reviewedPostprin

TinkerCell: Modular CAD Tool for Synthetic Biology

Synthetic biology brings together concepts and techniques from engineering and biology. In this field, computer-aided design (CAD) is necessary in order to bridge the gap between computational modeling and biological data. An application named TinkerCell has been created in order to serve as a CAD tool for synthetic biology. TinkerCell is a visual modeling tool that supports a hierarchy of biological parts. Each part in this hierarchy consists of a set of attributes that define the part, such as sequence or rate constants. Models that are constructed using these parts can be analyzed using various C and Python programs that are hosted by TinkerCell via an extensive C and Python API. TinkerCell supports the notion of a module, which are networks with interfaces. Such modules can be connected to each other, forming larger modular networks. Because TinkerCell associates parameters and equations in a model with their respective part, parts can be loaded from databases along with their parameters and rate equations. The modular network design can be used to exchange modules as well as test the concept of modularity in biological systems. The flexible modeling framework along with the C and Python API allows TinkerCell to serve as a host to numerous third-party algorithms. TinkerCell is a free and open-source project under the Berkeley Software Distribution license. Downloads, documentation, and tutorials are available at www.tinkercell.com.Comment: 23 pages, 20 figure

Change, Coordination, and Capabilities

Empirical studies on coordination of economic activities focused on the two polar cases of governance mode, namely vertical integration and market exchanges. Whether firms should be vertically integrated or lever market exchanges in the face of change is, however, debated. Two positions have emerged. Some scholars argue that the vertically integrated firm is the appropriate mode of coordination when change occurs, while market exchanges are more appropriate for dealing with stable contexts (Teece, 1996). On the other hand, Harrigan (1984, 1985) contends that firms should rely on market exchanges when technological change renders upstream capabilities obsolete. Based on two case studies of the aircraft engine industry, this paper introduces the concept of systems integration as the primary coordination mechanism in-between markets and hierarchies that firms employ to cope with change. The focus is on multitechnology settings. Multitechnology, multicomponent products intensify the coordination efforts for firms developing them and therefore provide a vantage point to study coordination modes in the face of technological change. The paper argues that systems integration, as a coordination mechanism, comprises a set of different technological and organizational skills, ranging from component assembly through the understanding and integration of the technological disciplines underlying a product, to project management. It shows that from a competitive point of view, systems integration is most appropriately understood as knowledge integration. Systems integrating firms are understood as those organizations that set up the network of actors involved in the industry and lead it from an organizational and technological viewpoint.technological change, systems integration, knowledge integration, vertical integration, market exchanges

Gene content evolution in the arthropods

Arthropods comprise the largest and most diverse phylum on Earth and play vital roles in nearly every ecosystem. Their diversity stems in part from variations on a conserved body plan, resulting from and recorded in adaptive changes in the genome. Dissection of the genomic record of sequence change enables broad questions regarding genome evolution to be addressed, even across hyper-diverse taxa within arthropods. Using 76 whole genome sequences representing 21 orders spanning more than 500 million years of arthropod evolution, we document changes in gene and protein domain content and provide temporal and phylogenetic context for interpreting these innovations. We identify many novel gene families that arose early in the evolution of arthropods and during the diversification of insects into modern orders. We reveal unexpected variation in patterns of DNA methylation across arthropods and examples of gene family and protein domain evolution coincident with the appearance of notable phenotypic and physiological adaptations such as flight, metamorphosis, sociality, and chemoperception. These analyses demonstrate how large-scale comparative genomics can provide broad new insights into the genotype to phenotype map and generate testable hypotheses about the evolution of animal diversity

Logic Meets Algebra: the Case of Regular Languages

The study of finite automata and regular languages is a privileged meeting point of algebra and logic. Since the work of Buchi, regular languages have been classified according to their descriptive complexity, i.e. the type of logical formalism required to define them. The algebraic point of view on automata is an essential complement of this classification: by providing alternative, algebraic characterizations for the classes, it often yields the only opportunity for the design of algorithms that decide expressibility in some logical fragment. We survey the existing results relating the expressibility of regular languages in logical fragments of MSO[S] with algebraic properties of their minimal automata. In particular, we show that many of the best known results in this area share the same underlying mechanics and rely on a very strong relation between logical substitutions and block-products of pseudovarieties of monoid. We also explain the impact of these connections on circuit complexity theory.Comment: 37 page