Peroxynitrite activates the NLRP3 inflammasome cascade in SOD1(G93A) mouse model of amyotrophic lateral sclerosis

Neuroinflammation, characterized by the appearance of reactive microglial and astroglial cells, is one of the several pathogenic mechanisms of amyotrophic lateral sclerosis (ALS), a fast-progressing and fatal neurodegenerative disease. Cerebrospinal fluid and spinal cord of ALS patients and SOD1 mutant mice show high concentrations of IL-1β. This interleukin, expressed as an inactive precursor, undergoes a proteolytic maturation by caspase1, whose activation, in turn, depends on inflammasomes. Whether and how inflammasome is activated in ALS models is still to be clarified. The mechanism of inflammasome activation was studied in murine microglial cells overexpressing hSOD1(G93A) and verified in the spinal cord of hSOD1(G93A) mice. Murine microglial hSOD1(G93A) cells express all the inflammasome components and LPS activates caspase1 leading to an increase in the secretion of IL-1β. By activating NF-κB, LPS increases ROS and NO levels that spontaneously react to form peroxynitrite, thus leading to protein nitration. Reduction in peroxynitrite levels results in a decrease in caspase1 activity. Protein nitration and caspase1 activity are concomitantly increased in the spinal cord of pre-symptomatic SOD1(G93A) mice. Oxidative/nitrosative stress induces peroxynitrite formation that may be a key trigger of caspase1/inflammasome activation. Peroxynitrite formation may play a critical role in inflammasome activation and might be exploited as potential therapeutic target for ALS

High order structure preserving explicit methods for solving linear-quadratic optimal control problems

[EN] We consider the numerical integration of linear-quadratic optimal control problems. This problem requires the solution of a boundary value problem: a non-autonomous matrix Riccati differential equation (RDE) with final conditions coupled with the state vector equation with initial conditions. The RDE has positive definite matrix solution and to numerically preserve this qualitative property we propose first to integrate this equation backward in time with a sufficiently accurate scheme. Then, this problem turns into an initial value problem, and we analyse splitting and Magnus integrators for the forward time integration which preserve the positive definite matrix solutions for the RDE. Duplicating the time as two new coordinates and using appropriate splitting methods, high order methods preserving the desired property can be obtained. The schemes make sequential computations and do not require the storrage of intermediate results, so the storage requirements are minimal. The proposed methods are also adapted for solving linear-quadratic N-player differential games. The performance of the splitting methods can be considerably improved if the system is a perturbation of an exactly solvable problem and the system is properly split. Some numerical examples illustrate the performance of the proposed methods.The author wishes to thank the University of California San Diego for its hospitality where part of this work was done. He also acknowledges the support of the Ministerio de Ciencia e Innovacion (Spain) under the coordinated project MTM2010-18246-C03. The author also acknowledges the suggestions by the referees to improve the presentation of this work.Blanes Zamora, S. (2015). High order structure preserving explicit methods for solving linear-quadratic optimal control problems. 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Defective extracellular matrix remodeling in brown adipose tissue is associated with fibro-inflammation and reduced diet-induced thermogenesis

© 2023 The Authors. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).The relevance of extracellular matrix (ECM) remodeling is reported in white adipose tissue (AT) and obesity-related dysfunctions, but little is known about the importance of ECM remodeling in brown AT (BAT) function. Here, we show that a time course of high-fat diet (HFD) feeding progressively impairs diet-induced thermogenesis concomitantly with the development of fibro-inflammation in BAT. Higher markers of fibro-inflammation are associated with lower cold-induced BAT activity in humans. Similarly, when mice are housed at thermoneutrality, inactivated BAT features fibro-inflammation. We validate the pathophysiological relevance of BAT ECM remodeling in response to temperature challenges and HFD using a model of a primary defect in the collagen turnover mediated by partial ablation of the Pepd prolidase. Pepd-heterozygous mice display exacerbated dysfunction and BAT fibro-inflammation at thermoneutrality and in HFD. Our findings show the relevance of ECM remodeling in BAT activation and provide a mechanism for BAT dysfunction in obesity.This work is supported by the Wellcome strategic award (100574/Z/12/Z); MRC MDU: MC_UU_12012/2 and MC_UU_12012/5 (The Disease Model Core, Biochemistry Assay Lab, Histology Core, and the Genomics and Transcriptomics Core); the Wellcome grant 10953/Z/15/Z (I.S.); the Wellcome Cambridge Trust scholarship (E.F.-J.); the Spanish Ministry of Economy and Competitiveness (SAF2017-88908-R) and PT17/0009/0006 from the ISCIII (C.Ç. and J.D.B.); the Academy of Finland (grants 259926, 265204, 292839, 314456, and 335446), the Paulo Foundation, the Finnish Cultural Foundation Southwest Finland Regional Fund, the Turku University Hospital Research Funds, and the European Union (EUFP7 project 278373; DIABAT) (K.A.V. and M.U.-D.); the Fundación Ramón Areces (BEVP32P01S10090) and subsequently by a Sir Henry Wellcome postdoctoral fellowship (222748/Z/21/Z) (S.R.-F.); We thank the Wellcome-Trust Sanger Institute Mouse Genetics Project (Sanger MGP) and its funders for providing the mutant mouse line (Pepd<tm1a[KOMP]Wtsi). Funding and associated primary phenotypic information may be found at www.sanger.ac.uk/mouseportal.Peer reviewe

Internet of Things Privacy, Security and Governance

Internet of Things (IoT) is broad term, which indicates the concept that increasingly pervasive communication and connected devices (“Things”) will support various applications to enhance the awareness and the capabilities of users. The adoption of IoT essentially depends upon trust. Moreover this trust must be established and maintained with respect to a broad group of stakeholders otherwise IoT will face, to some degree or other, challenges which may restrict adoption scope or delay its timing. Without sufficient IoT security it is highly likely that some applications will more resemble the Intranet of Things rather than the Internet of Things as users seek to place their own proprietary protection barriers and thus frustrating broad interoperability. Many of the device connections to the Internet today more closely resemble the Intranet of Things which differs dramatically from the vision for the Internet of Things, the latter being a much more open and interoperable environment allowing in theory the connection with many more objects and with their multiple IoT compatible devices. One specific challenge in IoT is the control on the information collected and distributed by mobile devices, which are increasingly small and pervasive like RFID or future micro-nano sensors, which can be worn or distributed in the environment. In most cases, such devices have the capability of being wireless connected and accessible. In this context, the challenge is to ensure that the information collected and stored by the devices should be visible and distributed only to authorized users. Finally, one aspect which often gets overlooked particularly frequently by those of us who entered adulthood before the year 2000 is the importance of the virtual-world. IoT is capable of establishing an important bridge between the two. This bridge is likely to grow and become more relevant in the life of the citizens in the future. The book chapter describes how the FP7 projects iCore, BUTLER, GAMBAS and IoT@Work have addressed the issues identified above and identified related mitigation approaches.JRC.G.7-Digital Citizen Securit

IERC Activity Chain 05 – IoT Privacy, Security and Governance

Internet of Things (IoT) is a broad term which indicates the concept of increasingly pervasive connected devices (embedded within, attached to or related to “Things”) supporting various applications to enhance the awareness and the capabilities of users. The adoption of IoT essentially depends upon trust. Moreover this trust must be established and maintained with respect to a broad group of stakeholders otherwise IoT will face, to some degree or other, challenges which may restrict adoption scope or delay its timing. Without sufficient IoT security it is highly likely that some applications will more resemble the Intranet of Things rather than the Internet of Things as users seek to place their own proprietary protection barriers and thus frustrating broad interoperability. Many of the device connections to the Internet today more closely resemble the Intranet of Things which differs dramatically from the vision for the Internet of Things, the latter being a much more open and interoperable environment allowing in theory the connection with many more objects and, with their multiple IoT compatible devices. One specific challenge within IoT is the control exercised over information collected by increasingly small and pervasive mobile devices, like RFID or future micro-nano sensors which can be ingested, implanted, worn or distributed elsewhere within the environment. In most cases, such devices have the capability of being wireless connected and accessible at all times and by anyone. In this context, the challenge is to ensure that the information collected and stored by the devices should be visible and distributed only by those legally permitted and authorized, acknowledging that permissions and authorizations may change throughout a devices or objects life or lives. This element of IoT represents one of a number of perceived and real concerns which are grouped under the title of IoT privacy. One aspect which often gets overlooked particularly frequently by those of us who entered adulthood before the year 1990 is the importance of the virtual-world. The Internet is a virtual environment. IoT is capable of establishing an important new bridge between the real and virtual-worlds. This bridge is likely to grow and become more relevant to the lives of citizens in the future allowing real-world augmentation of virtual-worlds and conversely allow the virtual-world to be enhanced by real-world information. Noteworthy is that IoT devices may be real or, virtual or, include aspects of both, either instantaneously or one or the other over a device’s or thing’s lifetime. IoT not only supports the exchange of information it nourishes the creation of greater automation. When IoT delivers this automation often reference is made to “smart” e.g. smart-city, smart-healthcare, etc. Trusted IoT therefore extends to confident and appropriate outcomes and not only the aggregation of clear dependable and timely information. Similar such “smart” automation has been widely used for investment banking transactions which has shown how a small change can cause an almost instantaneous and unstoppable global avalanche of stock values which was neither intended nor justified and resulting in severe penalties for a large number of stakeholders. IoT and “smart” applications effects need careful consideration and possibly some form of permanent monitoring to identity potential risks and oversee the development and introduction of suitably appropriate measures. A future IoT governance model has a role in overseeing such measures are put in place to protect IoT users and reinforce trust and confidence in “smart” applications. This chapter provides an overview of how the FP7 projects iCore, BUTLER, GAMBAS and IoT@Work within IERC Activity Chain 05 have approached IoT – security, privacy and governance