Disulfide by Design 2.0: a web-based tool for disulfide engineering in proteins

Abstract Background Disulfide engineering is an important biotechnological tool that has advanced a wide range of research. The introduction of novel disulfide bonds into proteins has been used extensively to improve protein stability, modify functional characteristics, and to assist in the study of protein dynamics. Successful use of this technology is greatly enhanced by software that can predict pairs of residues that will likely form a disulfide bond if mutated to cysteines. Results We had previously developed and distributed software for this purpose: Disulfide by Design (DbD). The original DbD program has been widely used; however, it has a number of limitations including a Windows platform dependency. Here, we introduce Disulfide by Design 2.0 (DbD2), a web-based, platform-independent application that significantly extends functionality, visualization, and analysis capabilities beyond the original program. Among the enhancements to the software is the ability to analyze the B-factor of protein regions involved in predicted disulfide bonds. Importantly, this feature facilitates the identification of potential disulfides that are not only likely to form but are also expected to provide improved thermal stability to the protein. Conclusions DbD2 provides platform-independent access and significantly extends the original functionality of DbD. A web server hosting DbD2 is provided at http://cptweb.cpt.wayne.edu/DbD2/

Computer assisted analysis of rock slope stability

Computers provide a powerful tool for the stability analysis of many physical scenarios. An area where advanced interactive computer analysis software has been relatively sparse is in the analysis of rock slopes. Interactive software aids in the analysis of rock slope stability in two main ways: first, by automating long and involved calculations, thus saving time and minimizing human error and second, by providing rapid visual feedback on how changing input parameters affects stability. In this way, the rock slope engineer can quickly get a feel for the factors critical to the problem at hand and the software thus becomes an effective learning tool, in addition to being an analysis tool. Three interactive computer programs which aid in the stability analysis of rock slopes have recently been developed at the Institute for Geotechnology, University of Tennessee, Knoxville under a research project funded by the Tennessee Department of Transportation. These programs are entitled PlaneSlip, WedgeSlip, and RockSlip and are collectively known as the ROCKSLIP package. PlaneSlip and WedgeSlip implement limiting equilibrium solutions for plane and wedge slides, respectively, while RockSlip implements an energy method to analyze the stability of curved or multi-plane failure surfacesApplication of these programs to the analysis of rock slopes in East Tennessee and Alabama will be demonstrated with some worked example problems. The worked examples are also included in a workbook which gives a condensed introduction to the programs and highlights major features of the programs with each of the example problems. These programs allow the user to interactively adjust the discontinuity geometry, slope geometry, water pressure, friction angle, cohesion, and slope reinforcement. Water pressure in PlaneSlip and RockSlip is governed by the combination of two parameters: the height of water in a tension crack and a parameter called drainage impedance, which controls the permeability of the discontinuities. In WedgeSlip there is an input value for the average water pressure on each plane which can be specified by the user or set to a default value based on slope geometry. Screen displays of the slope cross section and stereographic projections of the slope geometry and discontinuity data change in real time as the user adjusts the variables

In silico design of Phl p 6 variants with altered Fold-Stability significantly impacts antigen processing, immunogenicity and immune polarization

Introduction: Understanding, which factors determine the immunogenicity and immune polarizing properties of proteins, is an important prerequisite for designing better vaccines and immunotherapeutics. While extrinsic immune modulatory factors such as pathogen associated molecular patterns are well-understood, far less is known about the contribution of protein inherent features. Protein fold-stability represents such an intrinsic feature contributing to immunogenicity and immune polarization by influencing the amount of peptide-MHC II complexes (pMHCII). Here, we investigated how modulation of the fold-stability of the grass pollen allergen Phl p 6 affects its ability to stimulate immune responses and T cell polarization. Methods: MAESTRO software was used for in silico prediction of stabilizing or destabilizing point mutations. Mutated proteins were expressed in E. coli, and their thermal stability and resistance to endolysosomal proteases was determined. Resulting peptides were analyzed by mass spectrometry. The structure of the most stable mutant protein was assessed by X-ray crystallography. We evaluated the capacity of the mutants to stimulate T cell proliferation in vitro, as well as antibody responses and T cell polarization in vivo in an adjuvant-free BALB/c mouse model. Results: In comparison to wild-type protein, stabilized or destabilized mutants displayed changes in thermal stability ranging from −5 to +14°. While highly stabilized mutants were degraded very slowly, destabilization led to faster proteolytic processing in vitro. This was confirmed in BMDCs, which processed and presented the immunodominant epitope from a destabilized mutant more efficiently compared to a highly stable mutant. In vivo, stabilization resulted in a shift in immune polarization from TH2 to TH1/TH17 as indicated by higher levels of IgG2a and increased secretion of TNF-α, IFN-γ, IL-17, and IL-21. Conclusion: MAESTRO software was very efficient in detecting single point mutations that increase or reduce fold-stability. Thermal stability correlated well with the speed of proteolytic degradation and presentation of peptides on the surface of dendritic cells in vitro. This change in processing kinetics significantly influenced the polarization of T cell responses in vivo. Modulating the fold-stability of proteins thus has the potential to optimize and polarize immune responses, which opens the door to more efficient design of molecular vaccines

Dynamic grasping of objects with a high-speed parallel robot

Underactuated grippers aim to simplify the control strategies for performing stable grasps due to their inherent shape adaptability. While at the beginning, the main research area was focused on developing human-like robotic hands for disabled people, in the last years, a new eld of application appeared with the constant evolution of the industry: the implementation of a single underactuated gripper as a replacement of diverse dedicated fully-actuated grippers. However, two main issues are restraining its use: the stability of the grasp and the speed of performance. The rst is an active topic as all underactuated grippers need to ensure the stability of the grasped object through an adequate kinematic design, while, the latter is not widely treated as there weren't many application elds where high-speed was required and, at the end, the quasi-static analysis must be also ensured. For this reason, the present research work has been focused on the speed of the grasping. In the rst place, an introduction to underactuated hands is made, and is followed by two main stability criteria. Then, the development of a model for an underactuated nger that allows analyzing the complete grasping sequence at high-speed along with a collision model are presented. Following, a design-based analysis to simplify the model is performed, and the graspstate volume tool is introduced in order to inspect the impact of the design variables on the proposed criteria. In the last chapter, an optimization over the design space is performed and a design is chosen, crosschecked with ADAMS software and prototyped. Finally, an overview remarking the strengths and gaps in the research is presented in the form of conclusions, and closing them, future works that could be interesting to develop

Banking on AI: mandating a proactive approach to AI regulation in the financial sector

Despite an emerging international consensus on principles of AI governance, lawmakers have so far failed to translate those principles into regulations in the financial sector. Perhaps, in order to remain competitive in the global race for AI supremacy without being typecast as stifling innovation, typically cautious financial regulators are unusually allowing the introduction of experimental AI technology into the financial sector, with few controls on the unprecedented risks to consumers and financial stability. Once an unregulated AI software causes serious economic harm, a public and regulatory backlash would lead to over-regulation that could harm innovation of this potentially beneficial technology. Artificial intelligence is rapidly influencing the financial sector with innumerable potential benefits, such as enhancing financial services and improving regulatory compliance. This article argues that the best way to encourage a sustainable future in AI innovation in the financial sector is to support a proactive regulatory approach prior to any financial harm occurring. This proactive approach should implement rational regulations that embody jurisdiction-specific rules in line with carefully construed international principles.NPRP11S-1119-17001

Análisis de procesos de inestabilidad en taludes mediante comparativo entre métodos de equilibrio límite y elementos finitos

Introduction: The article presents research results on the analysis of slope instability processes, conducted at the Universidad Pedagógica y Tecnológica de Colombia in 2019. Problem: Slope instability processes are permanently present in the state of Boyacá – Colombia. The stability analysis through the application of conventional limit equilibrium methods does not reflect the real conditions of mechanical resistance of the materials found. Aim: Analyze slope instability processes utilizing the finite element method in two critical spots located on the road that connects the city of Tunja with the town of Miraflores. Methods: Start with the search and compilation of information from critical spots with relevant geotechnical characterization on roads in the state, thereby permitting the identification of two unstable critical spots. With the use of geological, geotechnical and hydrological information, the mechanical behavior of the materials is modelled through the software Slide and Midas GTS NX. Results: The estimation of material stability through the finite element method shows more reliable results compared to the actual behavior of the studied locations and compared to the methods based on limit equilibrium. Conclusion:The use of this numerical simulation technique is recommended to replace conventional methods, being an affordable and effective tool for the analysis of instability processes. Originality: Most analyses of instability processes conducted in the state of Boyacá – Colombiado not use the finite element method. Limitations: The estimation of material stability is based on a constitutive model for soil and another for rock

European White Book on Real-Time Power Hardware in the Loop Testing : DERlab Report No. R- 005.0

The European White Book on Real-Time-Powerhardware-in-the-Loop testing is intended to serve as a reference document on the future of testing of electrical power equipment, with specifi c focus on the emerging hardware-in-the-loop activities and application thereof within testing facilities and procedures. It will provide an outlook of how this powerful tool can be utilised to support the development, testing and validation of specifi cally DER equipment. It aims to report on international experience gained thus far and provides case studies on developments and specifi c technical issues, such as the hardware/software interface. This white book compliments the already existing series of DERlab European white books, covering topics such as grid-inverters and grid-connected storag

Modelling of reduced GB transmission system in PSCAD/EMTDC

Energy and environmental issues are two of the greatest challenges facing the world today. In response to energy needs and environmental concerns, renewable energy technologies are now considered the future technologies of choice. Renewable energy is produced from natural sources that are clean and free; however, it is widely accepted that renewable energy is not a solution without challenges. An example of this can be seen in the UK, where there is much interest amongst generation developers in the construction of new large scale onshore and offshore wind farms, especially in Scotland. The stability of electric power systems is also an important issue. It is important to have full knowledge of the system and to be able to predict the behaviour under different situations is an important objective. As a result, several industrial grade power system simulator tools have been developed in order to estimate the behaviour of the electric power system under certain conditions. This paper presents a reduced Great Britain (GB) system model for stability analysis using PSCAD/EMTDC. The reduced model is based upon a future GB transmission system model and, hence, contains different types and mix of generation, HVDC transmission lines and additional interconnection. The model is based on the reduced DIgSILENT PowerFactory model developed by National Grid