Structure of the Endonuclease Domain of MutL: Unlicensed to Cut

DNA mismatch repair corrects errors that have escaped polymerase proofreading, increasing replication fidelity 100- to 1000-fold in organisms ranging from bacteria to humans. The MutL protein plays a central role in mismatch repair by coordinating multiple protein-protein interactions that signal strand removal upon mismatch recognition by MutS. Here we report the crystal structure of the endonuclease domain of Bacillus subtilis MutL. The structure is organized in dimerization and regulatory subdomains connected by a helical lever spanning the conserved endonuclease motif. Additional conserved motifs cluster around the lever and define a Zn2+-binding site that is critical for MutL function in vivo. The structure unveils a powerful inhibitory mechanism to prevent undesired nicking of newly replicated DNA and allows us to propose a model describing how the interaction with MutS and the processivity clamp could license the endonuclease activity of MutL. The structure also provides a molecular framework to propose and test additional roles of MutL in mismatch repair.American Cancer Society (Research Professor)Natural Sciences and Engineering Research Council of Canada (NSERC scholarship)National Institutes of Health (U.S.) (CA21615)National Institutes of Health (U.S.) (GM45190)Natural Sciences and Engineering Research Council of Canada (NSERC, 288295)Deutsche Forschungsgemeinschaft (FR-1495/4-1)University of Michigan (Start-up funds

Antigen presentation safeguards the integrity of the hematopoietic stem cell pool

Hematopoietic stem and progenitor cells (HSPCs) are responsible for the production of blood and immune cells. Throughout life, HSPCs acquire oncogenic aberrations that can cause hematological cancers. Although molecular programs maintaining stem cell integrity have been identified, safety mechanisms eliminating malignant HSPCs from the stem cell pool remain poorly characterized. Here, we show that HSPCs constitutively present antigens via major histocompatibility complex class II. The presentation of immunogenic antigens, as occurring during malignant transformation, triggers bidirectional interactions between HSPCs and antigen-specific CD4(+4) T cells, causing stem cell proliferation, differentiation, and specific exhaustion of aberrant HSPCs. This immunosurveillance mechanism effectively eliminates transformed HSPCs from the hematopoietic system, thereby preventing leukemia onset. Together, our data reveal a bidirectional interaction between HSPCs and CD4(+4) T cells, demonstrating that HSPCs are not only passive receivers of immunological signals but also actively engage in adaptive immune responses to safeguard the integrity of the stem cell pool

Integrated billing mechanisms in the Internet of Things to support information sharing and enable new business opportunities

The Internet of Things (IOT) concept and enabling technologies such as RFID offer the prospect of linking the real world of physical objects with the virtual world of information technology to improve visibility and traceability information within supply chains and across the entire lifecycles of products, as well as enabling more intuitive interactions and greater automation possibilities. There is a huge potential for savings through process optimization and profit generation within the IOT, but the sharing of financial benefits across companies remains an unsolved issue. Existing approaches towards sharing of costs and benefits have failed to scale so far. The integration of payment solutions into the IOT architecture could solve this problem. We have reviewed different possible levels of integration. Multiple payment solutions have been researched. Finally we have developed a model that meets the requirements of the IOT in relation to openness and scalability. It supports both hardware-centric and software-centric approaches to integration of payment solutions with the IOT. Different requirements concerning payment solutions within the IOT have been defined and considered in the proposed model. Possible solution providers include telcos, e-payment service providers and new players such as banks and standardization bodies. The proposed model of integrating the Internet of Things with payment solutions will lower the barrier to invoicing for the more granular visibility information generated using the IOT. Thus, it has the potential to enable recovery of the necessary investments in IOT infrastructure and accelerate adoption of the IOT, especially for projects that are only viable when multiple benefits throughout the supply chain need to be accumulated in order to achieve a Return on Investment (ROI). In a long-term perspective, it may enable IT-departments to become profit centres instead of cost centres. © 2010 - IOS Press and the authors. All rights reserved

A survey of literature on automated storage and retrieval systems from 2009 to 2019

This paper provides a literature review on automated storage and retrieval systems based on the Scopus database. The last comprehensive literature review that analyses the subject in its entirety dates back to 2009 by Roodbergen and Vis. Since then, the scientific community has provided many new efficient solutions, most of which are collected in Scopus. All these new published solutions need to be classified and summarised; thus, for this paper, more than one thousand scientific publications were analysed in order to classify the proposed solutions, deliver new academic insights to the field, and provide clear guidelines for researchers and practitioner

Architecture, application and implementation of a digital twin of the RFID-enabled material flow in real-time for automotive intralogistics

RFID is used in logistics in the automotive industry to automate processes and optimise material flow. However, the data generated by RFID installations during operation offer more potential for further analyses to collect even more benefits from the technology. Therefore, in this paper, RFID data will be used to create a digital twin of the RFID-enabled material flow (DTRMF) in real-time and to programme various big data analyses. The architecture of the DTRMF must meet various qualitative requirements. Since the big data and digital twin architectures available in the literature either do not optimally fulfil all these requirements, or they are not described in enough detail to support real applications, this paper presents a new digital twin architecture for RFID-enabled material flow. This architecture consists of the data ingestion layer, data processing and analyses layer, data storage layer, visualisation layer, and the optional semantic layer. In addition, suitable technologies for the implementation of the architecture are described, and the feasibility of the architecture is demonstrated and verified by means of a case study

Digilab4u: General architecture for a network of labs

The paper presents the architecture designed to create a network of remote and virtual laboratories, to integrate and enhance them with new technologies and methods for lab-based education, within five universities inside the Open Digital Lab For You (DigiLab4U) project. Many factors lead to an increase in interest in networks of labs. The main ones aim on increasing the exploitation of laboratory equipment, together with the increasing necessity of practical experience in students’ careers. Lead by this necessity, the network developed an education environment with a strong focus on Industry 4.0 and Industrial Internet of Things. Moreover, its aim is the integration of new technologies and alternative teaching methods within the environment through an iterative approach. Compliant with these objectives and considering the standards available for such concepts, a new architecture of a network has been created based on the Industrial Reference Internet Architecture. With respect to these standards, the general architecture has been built as a client-server architecture composed of three elements: (i) Client, (ii) Web server, and (iii) Local server. We also took into consideration that the project aims to enlarge the network in the future, making it accessible from different institutions all over the world, to enable the learners to perform new experiments and enhance their skills. Besides, it enables the integration of technologies such as Serious Games and Learning Analytics, as they are becoming more and more widespread and necessary for teaching and assessing the students. To ease the understanding and the scalability of the network, three different points of view architecture has been proposed, by splitting and describing it into software, hardware, and logical perspectives