Kinetic discrimination of self/non-self RNA by the ATPase activity of RIG-I and MDA5

International audienceAbstractBackgroundThe cytoplasmic RIG-like receptors are responsible for the early detection of viruses and other intracellular microbes by activating the innate immune response mediated by type I interferons (IFNs). RIG-I and MDA5 detect virus-specific RNA motifs with short 5′-tri/diphosphorylated, blunt-end double-stranded RNA (dsRNA) and >0.5–2 kb long dsRNA as canonical agonists, respectively. However, in vitro, they can bind to many RNA species, while in cells there is an activation threshold. As SF2 helicase/ATPase family members, ATP hydrolysis is dependent on co-operative RNA and ATP binding. Whereas simultaneous ATP and cognate RNA binding is sufficient to activate RIG-I by releasing autoinhibition of the signaling domains, the physiological role of the ATPase activity of RIG-I and MDA5 remains controversial.ResultsA cross-analysis of a rationally designed panel of RNA binding and ATPase mutants and truncated receptors, using type I IFN promoter activation as readout, allows us to refine our understanding of the structure-function relationships of RIG-I and MDA5. RNA activation of RIG-I depends on multiple critical RNA binding sites in its helicase domain as confirmed by functional evidence using novel mutations. We found that RIG-I or MDA5 mutants with low ATP hydrolysis activity exhibit constitutive activity but this was fully reverted when associated with mutations preventing RNA binding to the helicase domain. We propose that the turnover kinetics of the ATPase domain enables the discrimination of self/non-self RNA by both RIG-I and MDA5. Non-cognate, possibly self, RNA binding would lead to fast ATP turnover and RNA disassociation and thus insufficient time for the caspase activation and recruitment domains (CARDs) to promote downstream signaling, whereas tighter cognate RNA binding provides a longer time window for downstream events to be engaged.ConclusionsThe exquisite fine-tuning of RIG-I and MDA5 RNA-dependent ATPase activity coupled to CARD release allows a robust IFN response from a minor subset of non-self RNAs within a sea of cellular self RNAs. This avoids the eventuality of deleterious autoimmunity effects as have been recently described to arise from natural gain-of-function alleles of RIG-I and MDA5

Reflexion M\"ossbauer analysis of the in situ oxidation products hydroxycarbonate green rust

The purpose of this study is to determine the nature of the oxidation products of FeII-III hydroxycarbonate FeII4FeIII2(OH)12CO3~3H2O (green rust GR(CO32-)) by using the miniaturised M\"ossbauer spectrometer MIMOS II. Two M\"ossbauer measurements methods are used: method (i) with green rust pastes coated with glycerol and spread into Plexiglas sample holders, and method (ii) with green rust pastes in the same sample holders but introduced into a gas-tight cell with a beryllium window under a continuous nitrogen flow. Method (ii) allows us to follow the continuous deprotonation of GR(CO32-) into the fully ferric deprotonated form FeIII6O4(OH)8CO3~3H2O by adding the correct amount of H2O2, without any further oxidation or degradation of the samples

The Global Spread of English and the Teaching of English as a Foreign Language: Perspectives from Western Muslim Teachers of English as a Foreign Language in the Kingdom of Saudi Arabia

The global spread of English and the role played by TEFL in this phenomenon is a subject of debate among EFL educators and researchers; this study provides new insights into this complex situation in relation to the Islamic faith in a way that has not yet been addressed in the literature. There has been an increased interest among researchers concerning the relationship between faith and ELT; however, to this date, no empirical studies have been conducted with regards TEFL and Islam. The study is, therefore, providing rich insights into this area. In doing so, in light of the wider socio-political, ideological or religious issues connected to the spread of English, the study draws on the experiences of nine Western Muslim EFL teachers in the KSA by qualitatively investigating their views on TEFL and the global spread of English in the KSA with particular reference to their Islamic faith and its relationship with their profession The study also addresses how Islam relates to the perception of these processes and how it affects their professional practice. The study is, therefore, particularly significant as it can play a role in encouraging Muslim EFL teachers to relate the macro-level theoretical discourses and educational policies to the micro-level of classroom practice and contribute to the ongoing debate concerning the role played by TEFL in the KSA. The study also has the potential to raise awareness among Muslim educators in the KSA and other Muslim countries of the wider complex processes intertwined with the global spread of English and its impact on EFL education. This investigation as also shed light on a number of ethical questions in relation to how Western Muslims who have travelled to the KSA perceive the relationship between their faith and their role as EFL, which may open new ways for Muslim professionals to combine their faith with their profession. In-depth interviews were conducted with the participants and the data provided new insights into the perceptions of TEFL and the global spread of English. The participants not only described the global spread of English and TEFL as value-laden, politically and ideologically driven, but also as a facilitator in terms of communication and cross-cultural understanding and as a necessary tool to acquire in today’s world. The data collected also showed that the relationship between Islam and TEFL was not described in dichotomous terms, which meant that this conception was the result of the participants’ personal understandings of their faith. The findings also emphasised on the preponderant role of the participants’ Islamic faith on their personal and professional lives. The study’s main contribution relates to two essential notions that have been debated among applied linguists: ownership and appropriation of the English language. The research showed that Western Muslim EFL teachers appropriate and claim ownership of the English language in a way that has not yet been addressed in the literature. Finally, the study shows that language teaching issues are inextricably intertwined with broader issues such as religion, culture or politics and suggests that the links between Islam, politics and language need to be explicitly addressed within the ELT arena

Artistes et activistes : vers un plaidoyer commun ?

Les associations ont de plus en plus souvent recours au monde artistique pour relayer et porter leurs sujets, leurs actions et leurs combats dans le champ des migrations et de l’immigration. La rencontre organisée au Musée national de l’histoire de l’immigration en partenariat avec l’Agence française de développement (AFD), dans le cadre de la Journée internationale des migrants en décembre 2022, interroge la façon dont la sphère artistique peut compléter, prolonger, relayer et favoriser l’action indispensable des associations

Do Gravity-Related Sensory Information Enable the Enhancement of Cortical Proprioceptive Inputs When Planning a Step in Microgravity?

International audienceWe recently found that the cortical response to proprioceptive stimulation was greater when participants were planning a step than when they stood still, and that this sensory facilitation was suppressed in microgravity. The aim of the present study was to test whether the absence of gravity-related sensory afferents during movement planning in microgravity prevented the proprioceptive cortical processing to be enhanced. We reestablished a reference frame in microgravity by providing and translating a horizontal support on which the participants were standing and verified whether this procedure restored the proprioceptive facilitation. The slight translation of the base of support (lateral direction), which occurred prior to step initiation, stimulated at least cutaneous and vestibular receptors. The sensitivity to proprioceptive stimulation was assessed by measuring the amplitude of the cortical somatosensory-evoked potential (SEP, over the Cz electrode) following the vibration of the leg muscle. The vibration lasted 1 s and the participants were asked to either initiate a step at the vibration offset or to remain still. We found that the early SEP (90–160 ms) was smaller when the platform was translated than when it remained stationary, revealing the existence of an interference phenomenon (i.e., when proprioceptive stimulation is preceded by the stimulation of different sensory modalities evoked by the platform translation). By contrast, the late SEP (550 ms post proprioceptive stimulation onset) was greater when the translation preceded the vibration compared to a condition without pre-stimulation (i.e., no translation). This suggests that restoring a body reference system which is impaired in microgravity allowed a greater proprioceptive cortical processing. Importantly, however, the late SEP was similarly increased when participants either produced a step or remained still. We propose that the absence of step-induced facilitation of proprioceptive cortical processing results from a decreased weight of proprioception in the absence of balance constraints in microgravity

Tim29 is a novel subunit of the human TIM22 translocase and is involved in complex assembly and stability

The TIM22 complex mediates the import of hydrophobic carrier proteins into the mitochondrial inner membrane. While the TIM22 machinery has been well characterised in yeast, the human complex remains poorly characterised. Here, we identify Tim29 (C19orf52) as a novel, metazoan-specific subunit of the human TIM22 complex. The protein is integrated into the mitochondrial inner membrane with it’s C-terminus exposed to the intermembrane space. Tim29 is required for the stability of the TIM22 complex and functions in the assembly of hTim22. Furthermore, Tim29 contacts the Translocase of the Outer Mitochondrial Membrane, TOM complex, enabling a mechanism for transport of hydrophobic carrier substrates across the aqueous intermembrane space. Identification of Tim29 highlights the significance of analysing mitochondrial import systems across phylogenetic boundaries, which can reveal novel components and mechanisms in higher organisms

Unified mechanisms for self-RNA recognition by RIG-I Singleton-Merten syndrome variants

The innate immune sensor retinoic acid-inducible gene I (RIG-I) detects cytosolic viral RNA and requires a conformational change caused by both ATP and RNA binding to induce an active signaling state and to trigger an immune response. Previously, we showed that ATP hydrolysis removes RIG-I from lower-affinity self-RNAs (Lassig et al., 2015), revealing how ATP turnover helps RIG-I distinguish viral from self-RNA and explaining why a mutation in a motif that slows down ATP hydrolysis causes the autoimmune disease Singleton-Merten syndrome (SMS). Here we show that a different, mechanistically unexplained SMS variant, C268F, which is localized in the ATP-binding P-loop, can signal independently of ATP but is still dependent on RNA. The structure of RIG-I C268F in complex with double-stranded RNA reveals that C268F helps induce a structural conformation in RIG-I that is similar to that induced by ATP. Our results uncover an unexpected mechanism to explain how a mutation in a P-loop ATPase can induce a gain-of-function ATP state in the absence of ATP

Racial Discrimination and TESOL

While the field of TESOL/TEFL claims to be inclusive given that it is composed of a myriad of sociocultural backgrounds and environments, racial discrimination is a common phenomenon, especially in the Kingdom of Saudi Arabia. Nonetheless, this issue has not been given enough attention by researchers, in that particular region at least. This article reports the findings of a small-scale qualitative study conducted in the Kingdom of Saudi Arabia drawing upon the experiences of six non-Saudi male English as a Foreign Language (EFL) lecturers. Open-ended questionnaires and interviews were used to collect data to explore the relationship between teachers' construction of their ethnic and racial identities and issues of discrimination within their professional environment. The study explored the participants' construction of their ethnic and cultural identity and its possible relation to discriminatory practices in their professional environment. The research showed how certain discriminatory practices affected how the participants projected their ethnic and cultural identity in their professional context.</jats:p

Tramor Quemeneur, Vivre en Algérie du XIXe au XXe siècle

Tramor Quemeneur est historien, spécialiste de la colonisation et de la guerre d’Algérie, et membre de la commission Mémoires et vérité mise en place à la suite du « rapport Stora ». Il est l’auteur de Vivre en Algérie du XIXe au XXe siècle, un livre aux apparences d’album photo. En effet, pour ce nouveau projet, Tramor Quemeneur a travaillé avec la base de données photo du Partnership for the Conservation of Amazon Biodiversity (PCAB), ainsi que la Bibliothèque nationale de France et les Arc..