Activation of proteinase-activated receptor 2 in human osteoarthritic cartilage upregulates catabolic and proinflammatory pathways capable of inducing cartilage degradation: a basic science study

Proteinase-activated receptors (PARs) belong to a family of G protein-coupled receptors. PARs are activated by a serine-dependent cleavage generating a tethered activating ligand. PAR-2 was shown to be involved in inflammatory pathways. We investigated the in situ levels and modulation of PAR-2 in human normal and osteoarthritis (OA) cartilage/chondrocytes. Furthermore, we evaluated the role of PAR-2 on the synthesis of the major catabolic factors in OA cartilage, including metalloproteinase (MMP)-1 and MMP-13 and the inflammatory mediator cyclooxygenase 2 (COX-2), as well as the PAR-2-activated signalling pathways in OA chondrocytes. PAR-2 expression was determined using real-time reverse transcription-polymerase chain reaction and protein levels by immunohistochemistry in normal and OA cartilage. Protein modulation was investigated in OA cartilage explants treated with a specific PAR-2-activating peptide (PAR-2-AP), SLIGKV-NH2 (1 to 400 μM), interleukin 1 beta (IL-1β) (100 pg/mL), tumor necrosis factor-alpha (TNF-α) (5 ng/mL), transforming growth factor-beta-1 (TGF-β1) (10 ng/mL), or the signalling pathway inhibitors of p38 (SB202190), MEK1/2 (mitogen-activated protein kinase kinase) (PD98059), and nuclear factor-kappa B (NF-κB) (SN50), and PAR-2 levels were determined by immunohistochemistry. Signalling pathways were analyzed on OA chondrocytes by Western blot using specific phospho-antibodies against extracellular signal-regulated kinase 1/2 (Erk1/2), p38, JNK (c-jun N-terminal kinase), and NF-κB in the presence or absence of the PAR-2-AP and/or IL-1β. PAR-2-induced MMP and COX-2 levels in cartilage were determined by immunohistochemistry. PAR-2 is produced by human chondrocytes and is significantly upregulated in OA compared with normal chondrocytes (p < 0.04 and p < 0.03, respectively). The receptor levels were significantly upregulated by IL-1β (p < 0.006) and TNF-α (p < 0.002) as well as by the PAR-2-AP at 10, 100, and 400 μM (p < 0.02) and were downregulated by the inhibition of p38. After 48 hours of incubation, PAR-2 activation significantly induced MMP-1 and COX-2 starting at 10 μM (both p < 0.005) and MMP-13 at 100 μM (p < 0.02) as well as the phosphorylation of Erk1/2 and p38 within 5 minutes of incubation (p < 0.03). Though not statistically significant, IL-1β produced an additional effect on the activation of Erk1/2 and p38. This study documents, for the first time, functional consequences of PAR-2 activation in human OA cartilage, identifies p38 as the major signalling pathway regulating its synthesis, and demonstrates that specific PAR-2 activation induces Erk1/2 and p38 in OA chondrocytes. These results suggest PAR-2 as a potential new therapeutic target for the treatment of OA

Ultralight vector dark matter search using data from the KAGRA O3GK run

Among the various candidates for dark matter (DM), ultralight vector DM can be probed by laser interferometric gravitational wave detectors through the measurement of oscillating length changes in the arm cavities. In this context, KAGRA has a unique feature due to differing compositions of its mirrors, enhancing the signal of vector DM in the length change in the auxiliary channels. Here we present the result of a search for U(1)B−L gauge boson DM using the KAGRA data from auxiliary length channels during the first joint observation run together with GEO600. By applying our search pipeline, which takes into account the stochastic nature of ultralight DM, upper bounds on the coupling strength between the U(1)B−L gauge boson and ordinary matter are obtained for a range of DM masses. While our constraints are less stringent than those derived from previous experiments, this study demonstrates the applicability of our method to the lower-mass vector DM search, which is made difficult in this measurement by the short observation time compared to the auto-correlation time scale of DM

Search for eccentric black hole coalescences during the third observing run of LIGO and Virgo

Despite the growing number of confident binary black hole coalescences observed through gravitational waves so far, the astrophysical origin of these binaries remains uncertain. Orbital eccentricity is one of the clearest tracers of binary formation channels. Identifying binary eccentricity, however, remains challenging due to the limited availability of gravitational waveforms that include effects of eccentricity. Here, we present observational results for a waveform-independent search sensitive to eccentric black hole coalescences, covering the third observing run (O3) of the LIGO and Virgo detectors. We identified no new high-significance candidates beyond those that were already identified with searches focusing on quasi-circular binaries. We determine the sensitivity of our search to high-mass (total mass M&gt;70 M⊙) binaries covering eccentricities up to 0.3 at 15 Hz orbital frequency, and use this to compare model predictions to search results. Assuming all detections are indeed quasi-circular, for our fiducial population model, we place an upper limit for the merger rate density of high-mass binaries with eccentricities 0&lt;e≤0.3 at 0.33 Gpc−3 yr−1 at 90\% confidence level

Exploration de combinaisons exceptionnelles : le féminisme de Night and Day

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‘Walled-in’: The Psychology of the English Garden in Virginia Woolf’s Mrs Dalloway

International audienceModernist writers are often considered to have moved away from ambivalent or even negative representations of the city – which Victorian writers had depicted as the antithesis to the Eden-like countryside – and shifted towards a celebration of city life. While Mrs Dalloway is celebrated for its city scenes, casual allusions to conversations ‘among the vegetables’ reveal an often overlooked subtext. For Woolf and for Cusk, the garden functions as a contained space through which to work through problematic emotions and achieve at least temporary reconciliation between the past and present. Rather than working within polarised conceptions of a paradise lost or regained, both authors experiment with the idea of a fragmented paradise that can be pieced together in sudden moments of self-realisation. The cultivated space of a domestic garden brings into focus the perception of being ‘walled-in’ (MD, 64) by emotional perceptions of past experiences. Self-consciousness that struggles to be articulated is realised with sudden clarity in heightened ‘moments of being’. Virginia Woolf and Rachel Cusk thus experiment with the trope of the garden in order to explore the depths of the self, beyond the urban spaces that have been so central in their writings.Alors que les Victoriens avaient présenté la campagne comme une version de l’Eden, les Modernistes ont pu sembler s’éloigner des représentations ambivalentes, voire négatives, de la ville pour parfois en venir à la célébrer. Si on loue souvent Mrs Dalloway pour les scènes de cette modernité, les bribes d’une « rêverie parmi les légumes ? » pointent vers une autre interprétation qui peut souvent passer inaperçue. Pour Woolf comme pour Cusk, le jardin fonctionne comme un espace clos à travers lequel les personnages construisent des émotions complexes qui aboutissent à une réconciliation du passé et du présent, bien que temporaire. Au lieu d’hésiter entre des conceptions polarisées entre le paradis perdu ou retrouvé, les deux auteurs mettent en jeu l’idée d’un paradis fragmenté qui peut être recomposé lors de moments soudains de compréhension de soi. L’espace cultivé d’un jardin domestique met au cœur du texte la perception d’être « enclos(e) » (MD, 64) dans des perceptions et des émotions passées. La conscience de soi, qui trouve difficilement à s’exprimer, en vient à se réaliser dans des moments de clarté soudaine, des « moments d’être ». Virginia Woolf et Rachel Cusk mettent donc en jeu le trope du jardin afin d’explorer les profondeurs du moi, au-delà des espaces urbains qui ont été si centraux dans leur écriture

Le Symptôme de la maladie mentale dans la littérature du long 20ème siècle : du déchiffrement à l’invention, depuis le Modernisme

International audienceLe Symptôme de la maladie mentale dans la littérature du long 20 ème siècle : du déchiffrement à l'invention, depuis le Modernisme Je voudrais commencer par remercier le département de Psychanalyse de Paris 8 de m'accueillir ce matin pour vous présenter mes travaux de recherche et préciser d'emblée que si la psychanalyse ne m'est pas totalement étrangère (j'ai fait ma thèse avec Sophie Marret-Maleval en 2008, je suis en analyse depuis 12 ans et je fais partie de l'ACF MAP), je ne suis pas clinicien et ma pratique théorique de la psychanalyse se penche donc sur les textes littéraires pour en saisir la logique subjective à l'oeuvre. Je vais ici vous présenter la problématique de recherche qui est la mienne et qui constitue le noyau dur d'un bouquin que j'écris actuellement, à paraître l'an prochain

Woolf’s Exploration of —Combinations: Feminism in Night and Day

Le roman Night and Day (1919) a été négligé par les lecteurs tout comme les critiques, surtout si on compare la réception de ce texte à celle d’autres œuvres woolfiennes. Malgré un intérêt renouvelé pour certains écrits moins canoniques de l’auteure ces dernières années, le roman n’a cessé d’être lu comme une œuvre de second rang. Le mariage y est l’objet des préoccupations des deux héroïnes, et constitue le principe structurant du roman. On est peut-être encore plus surpris de constater que le roman ne soit que très peu étudié par la critique féministe, comme en témoigne par exemple le fait que l’ouvrage de référence de Rachel Bowlby n’y fasse référence que de manière anecdotique (Bowlby). Night and Day est pourtant le seul roman dans lequel l’un des personnages principaux est engagé dans le mouvement des Suffragettes, alors pourtant qu’on connait bien l’implication de Woolf elle-même sur la question féministe et qu’on aurait pu s’attendre à ce que cet engagement politique forme un ensemble plus significatif dans son œuvre de fiction. Si certaines réserves exprimées par les critiques ont pu être rediscutées récemment, telles que la place de la Grande Guerre (Briggs ; Pelan), tous les critiques semblent convenir que la structure du roman, si ce n’est son matériau, est traditionnelle, décevante et, in fine, n’est pas assez féministe. Alors, qu’est-ce qui résiste dans ce roman woolfien et pourquoi l’exception de cette œuvre est-elle construite comme une faiblesse plutôt que comme une force ? Cet article propose de voir que les contradictions du roman de Woolf ne sont pas jugées comme féministes si on s’attend à ce qu’un engagement sans faille pour la cause politique soit exprimé par des héroïnes qui seraient alors des porte-paroles. Toutefois, ces contradictions sont bel et bien féministes si on pense que le féminisme est une question, plutôt qu’une solution, posée à l’endroit de la possibilité pour les femmes de s’engager dans une action collective, et si le féminisme s’entend comme une manière de trouver à définir les femmes en dehors de la norme patriarcale. Cette proposition a des répercussions sur la question de l’inclusion de Woolf dans le réalisme et dans l’écriture féminine.Night and Day (1919) has been neglected by both readers and critics, especially if the reception of the novel is compared to that of other Woolfian writings. Despite recent revaluations of Woolf’s less canonical works, it has continuously been read as a second-rate novel. Marriage is the object of the heroines’ concern and the demanding principle of the novel’s structure. One is even more surprised perhaps that the novel features very infrequently in Woolf’s feminist criticism, the seminal work by Rachel Bowlby for example referring to Night and Day only in passing (Bowlby). And yet, Night and Day is the only novel in which the main character is involved in the Suffragette movement, despite the fact that Woolf’s own contribution to the movement is well-known and could have been expected to represent a more significant bulk in her fiction. If some of the critics’ reservations have been re-discussed recently, such as the place of the Great War (Briggs; Pelan), all critics seem to agree that the structure of the novel, if not its material, is traditional, disappointing, and ultimately not feminist enough. So what is it that resists feminism in Woolf’s novel and why is exception construed as negative rather than positive? This paper argues that Woolf’s novel exposes contradictions that are not judged feminist because they do not reflect a solid political engagement in which the heroines would be regarded as spokeswomen for the cause. However, these contradictions are very much feminist if feminism is understood as a question, instead of being a solution, posed to the possibility for women to be involved in some collective action, and if feminism lies in finding a way of defining woman outside the patriarchal norms. This reverberates back to the question of the inclusion of Woolf in the tradition of realist writers, and women’s writing

A Life of Fiction, The Lagoon and Other Stories: Naissance d'une Oeuvre

recensionanet Frame’s fiction has always remained on the margins of the establishment: the author was shortlisted for the Nobel Prize several times, unsuccessfully, and after critical studies flourished in the 1980s and 1990s, her works seem to have gradually sunk into oblivion, were it not for the passion of a few isolated scholar

Neo-Modernist Writings: Rachel Cusk

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