Oxidation of SQSTM1/p62 mediates the link between redox state and protein homeostasis.

Cellular homoeostatic pathways such as macroautophagy (hereinafter autophagy) are regulated by basic mechanisms that are conserved throughout the eukaryotic kingdom. However, it remains poorly understood how these mechanisms further evolved in higher organisms. Here we describe a modification in the autophagy pathway in vertebrates, which promotes its activity in response to oxidative stress. We have identified two oxidation-sensitive cysteine residues in a prototypic autophagy receptor SQSTM1/p62, which allow activation of pro-survival autophagy in stress conditions. The Drosophila p62 homologue, Ref(2)P, lacks these oxidation-sensitive cysteine residues and their introduction into the protein increases protein turnover and stress resistance of flies, whereas perturbation of p62 oxidation in humans may result in age-related pathology. We propose that the redox-sensitivity of p62 may have evolved in vertebrates as a mechanism that allows activation of autophagy in response to oxidative stress to maintain cellular homoeostasis and increase cell survival

Oxidation of SQSTM1/p62 mediates the link between redox state and protein homeostasis

Cellular homoeostatic pathways such as macroautophagy (hereinafter autophagy) are regulated by basic mechanisms that are conserved throughout the eukaryotic kingdom. However, it remains poorly understood how these mechanisms further evolved in higher organisms. Here we describe a modification in the autophagy pathway in vertebrates, which promotes its activity in response to oxidative stress. We have identified two oxidation-sensitive cysteine residues in a prototypic autophagy receptor SQSTM1/p62, which allow activation of pro-survival autophagy in stress conditions. The Drosophila p62 homologue, Ref(2)P, lacks these oxidation-sensitive cysteine residues and their introduction into the protein increases protein turnover and stress resistance of flies, whereas perturbation of p62 oxidation in humans may result in age-related pathology. We propose that the redox-sensitivity of p62 may have evolved in vertebrates as a mechanism that allows activation of autophagy in response to oxidative stress to maintain cellular homoeostasis and increase cell survival.Peer reviewe

Neurodegenerative Diseases and Autophagy

Most neurodegenerative diseases are characterized by the accumulation of aggregated proteins within neurons. These aggregate-prone proteins cause toxicity, a phenomenon that is further exacerbated when there is defective protein clearance. Autophagy is an intracellular clearance pathway that can clear these protein aggregates and has been shown to be beneficial in the treatment of neurodegenerative diseases in a variety of model systems. Here, we introduce the key components of the autophagy machinery and signaling pathways that control this process and discuss the evidence that autophagic flux may be impaired and therefore a contributing factor in neurodegenerative disease pathogenesis. Finally, we review the use of autophagy upregulation as a therapeutic strategy to treat neurodegenerative disorders

Traitement des inconnus : une approche systématique de l'incomplétude lexicale

International audienceCet article aborde le phénomène de l'incomplétude des ressources lexicales, c'est-à-dire la problématique des inconnus, dans un contexte de traitement automatique. Nous proposons tout d'abord une définition opérationnelle de la notion d'inconnu. Nous décrivons ensuite une typologie des différentes classes d'inconnus, motivée par des considérations linguistiques et applicatives ainsi que par l'annotation des inconnus d'un petit corpus selon notre typologie. Cette typologie sera mise en œuvre et validée par l'annotation d'un corpus important de l'Agence France-Presse dans le cadre du projet EDyLex

Oxidation of SQSTM1/p62 mediates the link between redox state and protein homeostasis

Cellular homoeostatic pathways such as macroautophagy (hereinafter autophagy) are regulated by basic mechanisms that are conserved throughout the eukaryotic kingdom. However, it remains poorly understood how these mechanisms further evolved in higher organisms. Here we describe a modification in the autophagy pathway in vertebrates, which promotes its activity in response to oxidative stress. We have identified two oxidation-sensitive cysteine residues in a prototypic autophagy receptor SQSTM1/p62, which allow activation of pro-survival autophagy in stress conditions. The Drosophila p62 homologue, Ref(2)P, lacks these oxidation-sensitive cysteine residues and their introduction into the protein increases protein turnover and stress resistance of flies, whereas perturbation of p62 oxidation in humans may result in age-related pathology. We propose that the redox-sensitivity of p62 may have evolved in vertebrates as a mechanism that allows activation of autophagy in response to oxidative stress to maintain cellular homoeostasis and increase cell survival

The Amyotrophic Lateral Sclerosis M114T PFN1 Mutation Deregulates Alternative Autophagy Pathways and Mitochondrial Homeostasis

International audienceMutations in profilin 1 (PFN1) have been identified in rare familial cases of Amyotrophic Lateral Sclerosis (ALS). PFN1 is involved in multiple pathways that could intervene in ALS pathology. However, the specific pathogenic role of PFN1 mutations in ALS is still not fully understood. We hypothesized that PFN1 could play a role in regulating autophagy pathways and that PFN1 mutations could disrupt this function. We used patient cells (lymphoblasts) or tissue (post-mortem) carrying PFN1 mutations (M114T and E117G), and designed experimental models expressing wild-type or mutant PFN1 (cell lines and novel PFN1 mice established by lentiviral transgenesis) to study the effects of PFN1 mutations on autophagic pathway markers. We observed no accumulation of PFN1 in the spinal cord of one E117G mutation carrier. Moreover, in patient lymphoblasts and transfected cell lines, the M114T mutant PFN1 protein was unstable and deregulated the RAB9-mediated alternative autophagy pathway involved in the clearance of damaged mitochondria. In vivo, motor neurons expressing M114T mutant PFN1 showed mitochondrial abnormalities. Our results demonstrate that the M114T PFN1 mutation is more deleterious than the E117G variant in patient cells and experimental models and suggest a role for the RAB9-dependent autophagic pathway in ALS

A survey on automatic credibility assessment of textual credibility signals in the era of large language models.

In the current era of social media and generative AI, an ability to automatically assess the credibility of online social media content is of tremendous importance. Credibility assessment is fundamentally based on aggregating credibility signals, which refer to small units of information, such as content factuality, bias, or a presence of persuasion techniques, into an overall credibility score. Credibility signals provide a more granular, more easily explainable and widely utilizable information in contrast to currently predominant fake news detection, which utilizes various (mostly latent) features. A growing body of research on automatic credibility assessment and detection of credibility signals can be characterized as highly fragmented and lacking mutual interconnections. This issue is even more prominent due to a lack of an up-to-date overview of research works on automatic credibility assessment. In this survey, we provide such systematic and comprehensive literature review of 175 research papers while focusing on textual credibility signals and Natural Language Processing (NLP), which undergoes a significant advancement due to Large Language Models (LLMs). While positioning the NLP research into the context of other multidisciplinary research works, we tackle with approaches for credibility assessment as well as with 9 categories of credibility signals (we provide a thorough analysis for 3 of them, namely: 1) factuality, subjectivity and bias, 2) persuasion techniques and logical fallacies, and 3) claims and veracity). Following the description of the existing methods, datasets and tools, we identify future challenges and opportunities, while paying a specific attention to recent rapid development of generative AI

Decreased motivation in the use of insecticide-treated nets in a malaria endemic area in Burkina Faso

<p>Abstract</p> <p>Background</p> <p>The use of insecticide-treated nets (ITN) is an important tool in the Roll Back Malaria (RBM) strategy. For ITNs to be effective they need to be used correctly. Previous studies have shown that many factors, such as wealth, access to health care, education, ethnicity and gender, determine the ownership and use of ITNs. Some studies showed that free distribution and public awareness campaigns increased the rate of use. However, there have been no evaluations of the short- and long-term impact of such motivation campaigns. A study carried out in a malaria endemic area in south-western Burkina Faso indicated that this increased use declined after several months. The reasons were a combination of the community representation of malaria, the perception of the effectiveness and usefulness of ITNs and also the manner in which households are organized by day and by night.</p> <p>Methods</p> <p>PermaNet 2.0^®and Olyset^®were distributed in 455 compounds at the beginning of the rainy season. The community was educated on the effectiveness of nets in reducing malaria and on how to use them. To assess motivation, qualitative tools were used: one hundred people were interviewed, two hundred houses were observed directly and two houses were monitored monthly throughout one year.</p> <p>Results</p> <p>The motivation for the use of bednets decreased after less than a year. Inhabitants' conception of malaria and the inconvenience of using bednets in small houses were the major reasons. Acceptance that ITNs were useful in reducing malaria was moderated by the fact that mosquitoes were considered to be only one of several factors which caused malaria. The appropriate and routine use of ITNs was adversely affected by the functional organization of the houses, which changed as between day and night. Bednets were not used when the perceived benefits of reduction in mosquito nuisance and of malaria were considered not to be worth the inconvenience of daily use.</p> <p>Conclusion</p> <p>In order to bridge the gap between possession and use of bednets, concerted efforts are required to change behaviour by providing accurate information, most particularly by convincing people that mosquitoes are the only source of malaria, whilst recognising that there are other diseases with similar symptoms, caused in other ways. The medical message must underline the seriousness of malaria and the presence of the malaria vector in the dry season as well as the wet, in order to encourage the use of bednets whenever transmission can occur. Communities would benefit from impregnated bednets and other vector control measures being better adapted to their homes, thus reducing the inconvenience of their use.</p

Neuroprotective activity of ursodeoxycholic acid in CHMP2B Intron5 models of frontotemporal dementia

Frontotemporal dementia (FTD) is one of the most prevalent forms of early-onset dementia. It represents part of the FTD-Amyotrophic Lateral Sclerosis (ALS) spectrum, a continuum of genetically and pathologically overlapping disorders. FTD-causing mutations in CHMP2B, a gene encoding a core component of the heteromeric ESCRT-III Complex, lead to perturbed endosomal-lysosomal and autophagic trafficking with impaired proteostasis. While CHMP2B mutations are rare, dysfunctional endosomal-lysosomal signalling is common across the FTD-ALS spectrum. Using our established Drosophila and mammalian models of CHMP2BIntron5 induced FTD we demonstrate that the FDA-approved compound Ursodeoxycholic Acid (UDCA) conveys neuroprotection, downstream of endosomal-lysosomal dysfunction in both Drosophila and primary mammalian neurons. UDCA exhibited a dose dependent rescue of neuronal structure and function in Drosophila pan-neuronally expressing CHMP2BIntron5. Rescue of CHMP2BIntron5 dependent dendritic collapse and apoptosis with UDCA in rat primary neurons was also observed. UDCA failed to ameliorate aberrant accumulation of endosomal and autophagic organelles or ubiquitinated neuronal inclusions in both models. We demonstrate the neuroprotective activity of UDCA downstream of endosomal-lysosomal and autophagic dysfunction, delineating the molecular mode of action of UDCA and highlighting its potential as a therapeutic for the treatment of FTD-ALS spectrum disorders