Dual-active genome-editing reagents

Manipulation of complex genomes has many beneficial downstream applications in agriculture and human gene therapy. Precise genome-editing requires the introduction of a specific DNA double-stand break at a locus of interest, in turn inducing host DNA repair pathways to cause gene knockout through non-homologous end-joining or gene repair using homologous recombination and donor template. No matter the application, the field has depended on a few reagents to introduce precise double-strand breaks in host genomes. LAGLIDADG homing endonucleases or meganucleases harness the natural properties of these rare-cutting enzymes to target precise sequences in a complex genome. Other successful reagents are derived from a type IIS restriction endonuclease, FokI, fused to various DNA-binding architectures such as zinc finger domains and transcription activator-like effector domains. However, the discovery of clustered regularly interspaced short palindromic repeat-associated protein, CRISPR-Cas9, has dominated the field with its ease of design requiring a single RNA molecule to target the sequence of interest. Even with a handful of reagents to choose from, no one reagent is suitable for every application as every reagent has its own set of limitations and advantages. Here we present another potential genome-editing reagent derived from a GIY-YIG homing endonuclease, I-TevI, fused to all four DNA-targeting proteins described above. First, we demonstrate that I-TevI is a portable nuclease domain that can be targeted using Zinc-Fingers and LAGLIDADG proteins. Using these new reagents, we were able to further characterize I-TevI specificity using high throughput in vitro and in vivo screens to highlight important sequence requirements for targeting. Using this knowledge, we systematically engineered new I-TevI variants with altered specificity to broaden the number of targets available for I-TevI-derived reagents. We incorporated these new I-TevI variants into a more versatile dual-active nuclease, TevCas9, capable of introducing two double-strand breaks at a single target site. This dual cleavage event is capable of excising a short DNA fragment from the target site and is unique to I-TevI derived fusions. We envisioned that the monomeric, sequence-specific I-TevI catalytic domain would improve current tools by providing additional specificity and the ability to introduce dual-cleavage event would present unique applications for genome engineering

Derivation of a new mathematical framework for transmission system augmentation using von Stackelberg game

The market-based augmentation of the high voltage transmission systems as a legacy of the previous regulated regimes has been a challenging issue for the central transmission entities. The economic assessment framework for transmission upgrades or expansion projects, considering the interaction of the central transmission entity (CTE) with the electricity market management (MMC) company both as independent players needs to be addressed appropriately at least in the National Electricity Market, Australia. To assist in bridging this gap, this paper introduces a novel metric, namely, the L-Shape Area, for the economic assessment of the transmission expansion options. The proposed methodology employs a von Stackelberg game for the interaction modelling of the central transmission entity and the market management company. The upper subproblem minimises the objective of the CTE as the leader player and the lower subproblem solves the security-constrained economic dispatch as the follower subproblem. The bi-level programming problem has been solved by applying the Kuhn-Tucker optimality conditions to the follower subproblem and the use of a gradient search method to solve the resultant single level non-linear programming problem. A modified IEEE 14-bus test system has been used to show the effectiveness of the proposed formulation

Transmission Augmentation in an Oligopoly Electricity Market - Part II (Numerical Studies)

This paper proposes a Three-Stage Model for transmission augmentation in restructured electricity markets. The mathematical formulation of the model is developed based on the game theory. Transmission Network Service Provider, TNSP, Generating Companies, GenCos, and Market Management Company, MMC, are placed in different stages of the model. These stages are linked to each other using the Leader-followers game and the concept of Nash equilibriums. An increase in transmission capacity can have two benefits for the electricity market; firstly, efficiency benefit in terms of improving the social surplus of the electricity industry, and, secondly, competition benefit which leads to increasing competition among generating companies. The introduced Three-Stage Model can capture both benefits of transmission projects in electricity markets. An effective numerical method is designed for solving the developed Three-Stage Model. A modified IEEE 14 example system is employed to show the effectiveness of the methodology. This paper has been organized in two parts. First part deals with the mathematical formulation of the algorithm and second part deals with the numerical studies. What follows is the second part of the paper

Economic assessment of transmission expansion projects in competitive electricity markets - an analytical review

Restructuring of the electricity market has changed many aspects of the transmission system operation and planning. Reliability-Driven and Economic-Driven transmission expansion planning by regulated and private utilities are the substitutes of the traditional Cost-Driven transmission expansion planning. Reliability-based criteria for assessment of the transmission projects are almost well-developed while there exists a lack of a comprehensive framework for the economic evaluation of the transmission projects. Definition of a quantitative and monetary framework for economic evaluation of future transmission projects demands a detailed market analysis. In addition, specific characteristics and responsibilities of the transmission system in the open access structure must be understood comprehensively. To reaching the aforementioned goal, an analytical review on the existing economic assessment methodologies would be highly beneficial for the researchers in this area. Moreover, most of the review literatures on transmission investment in competitive electricity markets are general. These review literatures have tried to address all aspects of this challenging issue with devoting only few paragraphs to economic assessment of transmission projects. Given the aforementioned shortcomings, this article would bridge the gap by the following contributions: Firstly, reviewing available approaches for economic assessment of transmission projects based on research papers and industrial reports, Secondly, analysing the reviewed criteria critically by applying them to a modified Wood and Wollenberg 6-bus case study and Finally, summarizing the key components of a successful Economic Assessment Framework for transmission expansion or upgrade projects. Practical experiences of California Electricity Market, New England Electricity Market, Pennsylvania, New Jersey, and Maryland (PJM) and National Electricity Market, Australia have been accommodated in the article

The Nodal Market Power Index (NMP Index) for Modelling and Visualising Market Power

This paper deals with a systematic way for modelling and visualising market power in liberalised electricitymarkets. The paper first introduces a new index termed the “Nodal Market Power” index, the NMP index. The NMP index is calculated based on the concept of “social welfare” in economics and the game theory in applied mathematics. The oligopoly electricity market is modelled through a non-cooperative game and the solution concept of the Nash equilibrium. The solution concept of Nash equilibrium is reformulated as an optimisation problem. To tackle the multiple Nash equilibria problem, the worst Nash equilibrium in terms of the social cost to the society is selected. Then after, the NMP index is calculated for each node of power system. A colour contour map is used for visualising the market power using the NMP index

Design and study of a switch reactor for Central Queensland SWER system

Single Wire Earth Return (SWER) systems are awidely applied, low cost electrification method used inmany rural areas. In Central Queensland a single SWERsystem supplying approximately 100kW may extend morethan 300km. Many SWER systems include shunt reactorsto control the effects of the line charging capacitance. Oneeffect, the Ferranti effect, causes the line voltage to risewith the distance. In three phase distribution systems thiseffect is not visible but in SWER systems, this effect makesit difficult to maintain the consumers supply within theacceptable regulation range. As the second effect, theloading of the SWER system supply transformer increases.Controllable shunt reactors are used as one solution to theaforementioned problems.Stanage Bay feeder in Central Queensland area has beenchosen for the installation of the designed shunt reactor.Stange Bay feeder is supplied by an isolating transformerwith the total capacity of 150kVA and the voltage level of22kV.Using the Stanage Bay feeder, this paper details theprocess of design and simulation of a suitable switchreactor. This step has been carried out by firstly, thedesign of the switch reactor and secondly, the propermodelling of the designed reactor for the voltageregulation studies

Functional protection by acute phase proteins alpha(1)-acid glycoprotein and alpha(1)-antitrypsin against ischemia/reperfusion injury by preventing apoptosis and inflammation.

BACKGROUND: Ischemia followed by reperfusion (I/R) causes apoptosis, inflammation, and tissue damage leading to organ malfunction. Ischemic preconditioning can protect against such injury. This study investigates the contribution of the acute phase proteins alpha(1)-acid glycoprotein (AGP) and alpha(1)-antitrypsin (AAT) to the protective effect of ischemic preconditioning in the kidney. METHODS AND RESULTS: Exogenous AGP and AAT inhibited apoptosis and inflammation after 45 minutes of renal I/R in a murine model. AGP and AAT administered at reperfusion prevented apoptosis at 2 hours and 24 hours, as evaluated by the presence of internucleosomal DNA cleavage, terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling, and the determination of renal caspase-1- and caspase-3-like activity. AGP and AAT exerted anti-inflammatory effects, as reflected by reduced renal tumor necrosis factor-alpha expression and neutrophil influx after 24 hours. In general, these agents improved renal function. Similar effects were observed when AGP and AAT were administered 2 hours after reperfusion but to a lesser extent and without functional improvement. Moreover, I/R elicited an acute phase response, as reflected by elevated serum AGP and serum amyloid P (SAP) levels after 24 hours, and increased hepatic acute phase protein mRNA levels after 18 hours of renal reperfusion. CONCLUSIONS: We propose that the antiapoptotic and anti-inflammatory effects of AGP and AAT contribute to the delayed type of protection associated with ischemic preconditioning and other insults. This mechanism is potentially involved in the course of many clinical conditions associated with I/R injury. Moreover, exogenous administration of these proteins may provide new therapeutic means of treatmen

An executable interface specification for industrial embedded system design.

Nowadays, designers resort to abstraction techniques to conquer the complexity of industrial embedded systems during the design process. However, due to the large semantic gap between the abstractions and the implementation, the designers often fails to apply the abstraction techniques. In this paper, an EIS-based (executable interface specification) approach is proposed for the embedded system design.The proposed approach starts with using interface state diagrams to specify system architectures. A set of rules is introduced to transfer these diagrams into an executable model (EIS model) consistently. By making use of simulation/verification techniques, many architectural design errors can be detected in the EIS model at an early design stage. In the end, the EIS model can be systematically transferred into an interpreted implementation or a compiled implementation based on the constraints of the embedded platform. In this way, the inconsistencies between the high-level abstractions and the implementation can largely be reduced

Economic Transmission Augmentation With Explicit Modeling of the Competition Benefit

This paper derives and evaluates a mathematical structure for identifying economically-efficient transmission augmentations. The mathematical structure is based on the concepts of sequential-move and simultaneous-move games in applied mathematics. The Nash equilibrium solution concept has been reformulated as an optimization problem in the proposed structure. The problem of multiple Nash equilibria is managed by introducing the concept of the worst-case Nash equilibrium. Both the economic concepts of the "efficiency benefit" and "competition benefit" of the transmission capacity are explicitly modeled in the proposed structure. A simple three-bus example system and Garver's example system are employed and modified to suit the purpose of analysis. A thorough economic study of these example systems is presented to highlight the concept and operation of the proposed mathematical structure from different perspectives. The results demonstrate the utility of the proposed structure for measuring the total economic efficiency benefit of additional transmission capacity

Derivation of a mathematical structure for market-based transmission augmentation in oligopoly electricity markets using multilevel programming

In this paper, we derive and evaluate a new mathematical structure for market-based augmentation of the transmission system. The closed-form mathematical structure can capture both the efficiency benefit and competition benefit of the transmission capacity. The Nash solution concept is employed to model the price-quantity game among GenCos. The multiple Nash equilibria of the game are located through a characterisation of the problem in terms of minima of the R function. The worst Nash equilibrium is used in the mechanism of transmission augmentation. The worst Nash equilibrium is defined as the one which maximises the social cost, total generation cost + total value of lost load. Thorough analysis of a simple three-node network is presented to clearly highlight the mechanism of the derived mathematical structure from different perspectives