364 research outputs found
Author's gift inscription, in The heather on fire; a tale of the Highland clearances
No full textThis edition includes an author's gift inscription, "To Mrs John Dillon with sincere esteem Mathilde Blind".Blind, Mathilde, 1841-189
Involvement of the IL-6 family of cytokines; Oncostatin M, IL-6 and IL-31 in mouse skin inflammation
No full textLe psoriasis et la dermatite atopique sont des pathologies inflammatoires cutanées chroniques, fréquentes et invalidantes. Dans la peau des patients souffrant de ces pathologies, un dérèglement de la réponse immunitaire aboutissant à une inflammation chronique est toujours observé. Le réseau cytokinique joue un rôle essentiel dans la physiopathologie cutanée en permettant la communication entre les cellules cutanées et les cellules immunitaires. Dans le psoriasis et la dermatite atopique, ce réseau est largement perturbé. En effet, un grand nombre de cytokines proinflammatoires sont surexprimées au détriment des cytokines anti-inflammatoires. Cette inflammation chronique est directement responsable de l'apparition des lésions cutanées. Parmi les cytokines surexprimées dans ces pathologies, des études antérieures du LITEC ont montré in vitro que l'Oncostatine M (OSM) est impliquée dans la production de peptides antimicrobiens et de médiateurs de l'inflammation, ainsi que dans l'inhibition de la différenciation des kératinocytes. Notre objectif était de poursuivre ces travaux en étudiant le rôle de l'OSM dans l'inflammation cutanée in vitro et in vivo chez la souris. Nous avons pour cela, comparé le rôle de l'OSM à celui d'autres cytokines de la famille de l'IL-6, l'IL-6 et l'IL-31, qui présentent également une activité sur le kératinocyte. L'activité de ces cytokines a été étudiée in vitro sur des cultures primaires de kératinocytes murins en monocouche, sur des épidermes reconstruits murins ainsi qu'in vivo dans différents modèles d'inflammation cutanée. Nous montrons que l'OSM est plus active que l'IL-6 et l'IL-31 sur les kératinocytes en culture et que la surexpression de cette cytokine in vivo dans la peau de souris à l'aide d'adénovirus recombinants induit une inflammation cutanée forte, présentant des caractéristiques communes avec le psoriasis et la dermatite atopique. Néanmoins, les souris déficientes pour le gène codant l'OSM ne présente aucune diminution du phénotype inflammatoire cutané dans le modèle de psoriasis induit par application d'Imiquimod et dans un modèle de dermatite atopique induit par application de Calcipotriol, suggérant l'existence de mécanismes de compensation par d'autres cytokines proinflammatoires. En parallèle de cette étude, nous avons mis au point un nouveau modèle d'épidermes reconstruits murins permettant l'étude de l'activité des cytokines sur les kératinocytes. Ce modèle présente l'avantage de reproduire plus finement la physiologie d'un épiderme normal par rapport aux autres modèles préalablement décrits et ouvre la perspective de développer des épidermes reconstruits à partir de kératinocytes de souris transgéniques. En conclusion, ces travaux démontrent le rôle pro-inflammatoire de l’OSM dans l'inflammation cutanée et son activité majeure sur les kératinocytes en comparaison à celles décrites pour l'IL-6 et l'IL-31. Néanmoins, la pertinence du ciblage thérapeutique de cette cytokine dans le psoriasis et la dermatite atopique reste encore à démontrer.Psoriasis and atopic dermatitis are the most prevalent cutaneous inflammatory disease in worldwide. An imbalance immune response is a characteristic feature of these diseases and through their role in the communication between cutaneous and immune cells; cytokines are key players in these diseases. Indeed, in the psoriatic and atopic lesions, an altered cytokine network is always described and mainly in favor of proinflammatory cytokines. Among them, our laboratory previously described that Oncostatin M, an IL-6 family member is up-regulated in psoriasis and atopic dermatitis lesions. In vitro, we have demonstrated that OSM induces a proinflammatory signature on human keratinocytes including the up-regulation of antimicrobials peptides and proinflammatory mediators as well as inhibiting the epidermal differentiation. The aim of this work was to confirm the role of OSM in cutaneous inflammatory diseases and compare it to others IL-6 family members such as IL-6 and IL-31 also described for their potent activities on keratinocytes. The activity of theses cytokines was study in vitro on normal murine epidermal keratinocytes or in reconstituted murine epidermis and in vivo in inflammatory murine models. Compared to IL-6 and IL-31, OSM is a strong inducer of proinflammatory signature in vitro on keratinocyte and in vivo using recombinant adenovirus overexpressing theses cytokines. The inflammatory phenotype induces by overexpression of OSM in mouse ears mimics key features of psoriatic and atopic skins. However, deficiency mice for the gene encoding OSM dot not demonstrated reduced phenotype in a mouse model of psoriasiform dermatitis induce by imiquimod or in a mouse model of atopic dermatitis induced by calcipotriol suggesting that compensatory cytokines are sufficient to maintain phenotype in the absence of OSM. Concurrent to this study, we also developed a model of reconstituted murine epidermis in order to test the activity of cytokines in a model reproducing more closely the epidermal physiology. The in vitro model could be used to study the function of numerous epidermal proteins of cytokine using transgenic mice and will provide a useful tool in the dermatological research field. Finally this work demonstrated the proinflammatory role of OSM in cutaneous inflammation through its major activities on keratinocytes in comparison to IL-6 and IL-31. However, the relevance of therapeutic strategies to block the activity of this cytokine in inflammatory skin diseases remains to be demonstrated
Defining fibroblast niches in colorectal cancer
No full textColorectal cancer (CRC) is a heterogenous disease and high stromal content and specifically fibroblasts have been associated with advanced stage and poor prognosis. Fibroblasts are versatile cells that can alter from quiescent cells to myofibroblasts, that secrete extracellular matrix components and become contractile in situations such as wound healing, or alter to inflammatory fibroblasts, that secrete cytokines and chemokines to recruit immune cells. These phenotypes have been identified across multiple types of cancer through scRNAseq, and the key cytokines driving these clusters are hypothesised as TGFβ for myofibroblastic cancer associated fibroblasts (myCAFs) and IL-1 for inflammatory CAFs (iCAFs). However, few studies have identified them in situ in CRC and no fibroblast subsets have been conclusively associated with prognosis in this disease. It is also unknown whether the fibroblast clusters seen on scRNAseq represent permanent differentiation states or temporary responses to stimulation.
Here we use multiplex imaging of 60 rectal cancer sections to identify myCAF-like and iCAF-like stromal cells in situ. We have shown differences in their abundance with the Consensus Molecular subtypes (CMS), with iCAFs being found in CMS3 and myCAF-like stromal cells in CMS4. We have also stained adjacent slides with a panel to look for immune subsets and found greater numbers of both T-cells and neutrophils in CMS1 disease. We have found that the iCAF-like stromal cells are found in close association with immune cells, particularly neutrophils, consistent with the hypothesis of IL-1 driving this phenotype. We have also confirmed that treating primary stromal cells in vitro with IL-1β gives them an inflammatory phenotype that allows them to map more closely to iCAF clusters seen in scRNAseq. The myCAF-like stromal cells were identified deep within stromal tracts. We have also identified a CD56+ stromal subset, found surrounding the tumour nests and associated with CMS2 CRC.
We also hypothesised that fibroblasts from CRC tumours may be hyper-responsive to these key cytokines, TGFβ and IL-1β, compared to the matched normal adjacent fibroblasts, consolidating pathological phenotypes. However, we found no evidence that once in vitro there were any differences in the stromal cells from tumour and normal adjacent, either at baseline or in terms of response to cytokine stimulation. This suggests that the CAF clusters seen are temporary activation states depending on the micro-environment the cells were exposed to immediately prior to sequencing.
Additionally, we hypothesised that TGFβ1, TGFβ2 and TGFβ3, may be having differential effects on fibroblasts. However, on bulk RNAseq we found no evidence that the transcriptional response to TGFβ stimulation is of a different character or magnitude between the three isoforms
Gender and pedagogics - Mathilde Vaerting, professor of educational science (Jena, 1923-1933)
No full textDer Aufsatz skizziert Leben und Karriere von Mathilde Vaerting (1884-1977), der ersten Professorin für Erziehungswissenschaft in Deutschland, Jena 1923-1933. Ihr Hauptwerk „Neubegründung der Psychologie von Mann und Weib", 1921ff., wird unter Aspekten der Forschungslogik analysiert und auf Konsequenzen für die Erziehungswissenschaft befragt. Ihre Forderung nach Gleichberechtigung und Abwehr jeglicher Herrschaft werden vor dem Hintergrund heutiger feministischer Forderungen diskutiert. Im Anschluß an die Betrachtung der zeitgenössischen Rezeption Mathilde Vaertings wird die Frage aufgeworfen, inwieweit ihr Leben und ihre Karriere die Stellung der Frau in der Wissenschaft während der zwanziger Jahre (und auch später?) spiegeln. (DIPF/Orig.)The author outlines the biography and career of Mathilde Vaerting (1884-1977), the first woman to hold a chair in educational science in Germany. Her major work - Neubegründung der Psychologie von Mannund Weib (1921 fol.) - is analyzed from a methodological point of view and with respect to its implications for educational research. Vaerting\u27s demands for equal rights for women and her rejection of any kind of domination are discussed within the framework of present feminist positions. After having studied how contemporaries reacted to Mathilde Vaerting\u27s writings, the author raises the question of whether Vaerting\u27s life and career reflect the Status of women in science during the 1920s (and later on?). (DIPF/Orig.
The role of the tissue microenvironment in inflammatory bowel disease
No full textExtensive remodelling of the extracellular matrix (ECM) occurs in the pathogenesis of inflammatory bowel disease (IBD). The ECM is an active determinant of cellular behaviour – both influencing immune cell migration and activating cells by binding immune receptors directly. Characterizing these changes in IBD holds potential to uncover novel mechanisms of ECM-mediated pathology of disease.
Publicly available bulk and single cell RNA sequencing datasets of IBD patients were interrogated to identify transcriptional matrisome changes in IBD. A matrisome-enriched (43.6%) co-expression module was identified to be associated with IBD incidence, inflammation severity and ulceration. Expression of the module was predictive of non-response to anti-TNF and corticosteroid therapies. Single cell RNA sequencing datasets identified high expression of the module in inflammatory fibroblasts, a disease-specific fibroblast subset found in colon ulcer beds. The module was upregulated in damage-driven murine colitis models of IBD.
Using this module as a longlist, further in-depth analysis was carried out on Fam20C and its binding partner and allosteric activator Fam20A. Fam20C and Fam20A form the only known secretory serine kinase system. Fam20A expression was upregulated in IBD and both genes were expressed specifically by ulcer-specific inflammatory fibroblasts. Recapitulating the cytokine environment of the ulcer induced Fam20C and Fam20A expression in a human fibroblast model. A small molecule inhibitor was used to investigate the role of Fam20C activity in murine colitis models. These studies identified that Fam20C expression is increased following epithelial damage, and its activity was associated with neutrophil activation and delayed wound healing.
These data indicate that inflammatory fibroblasts in the ulcer niche of the inflamed colon exhibit an inflamed ECM signature with upregulated activity of the secretory kinase Fam20C. The broad substrate base of Fam20C includes structural ECM proteins and pleiotropic extracellular signalling molecules, suggesting pathological activity of Fam20C in the ulcer niche may regulate diverse functions. Understanding how Fam20C activity affects subsequent changes to the extracellular microenvironment and inflammatory signalling could uncover novel mechanisms at play in inflammation and aid the identification of therapeutic targets in treatment-refractory IBD
The role of GGT5+ fibroblasts in leukocyte compartmentalisation in the gut and synovium
No full textThe spatial organisation of leukocytes within tissues is essential for coordinated immune responses. While stromal cells such as fibroblasts are well known to structure leukocyte niches in secondary lymphoid organs (SLOs), their role in organising immune cells within inflamed non‑lymphoid tissues remains unclear. Building on mechanisms described in germinal centres (GCs), where follicular dendritic cells (FDCs) restrict B cell movement through the GGT5–GGG–P2RY8 axis, this thesis tests the hypothesis that stromal programs, particularly the induction of GGT5 by fibroblasts, establish perivascular confinement zones that spatially position P2RY8⁺ leukocytes within inflamed synovial and intestinal tissues.Analysis of publicly available single-cell RNA-sequencing datasets revealed that GGT5, an enzyme shaping local gradients of the inhibitory ligand GGG, is broadly expressed by stromal cells across multiple inflamed tissues. In most tissues, GGT5 expression is restricted to endothelial cells and pericytes, but in RA synovium it expands beyond vascular rings into neighbouring fibroblasts, whereas in gut it is broadly distributed, forming a perivascular gradient associated with vascular activation. TNFα and NOTCH3 ligands induce GGT5 in synovial fibroblasts, while endothelial‑cell–derived factors stimulate GGT5 in both synovial and intestinal fibroblasts, suggesting that vascular–stromal communication provides an endothelium‑linked cue during inflammation.Functionally, GGG inhibited CXCL12‑ and CXCL13‑directed migration of human tonsil T follicular helper (Tfh) and GC B cells, and Tfh from inflamed gut, consistent with P2RY8‑dependent immobilisation. Pilot live‑imaging provides an analysis framework for quantifying chemotactic index and speed under GGG. As inflammation unfolds, leukocytes infiltrate via blood vessels, triggering neighbouring fibroblasts to upregulate GGT5 expression. This facilitates the establishment of a perivascular confinement zone, wherein GGT5⁺ fibroblasts, through the GGT5–GGG–P2RY8 axis, regulate the motility and positioning of P2RY8⁺ leukocytes, contributing to leukocyte compartmentalisation.Complementary murine colitis and arthritis models probe Ggt5 biology in vivo. However, mice lack P2RY8, limiting direct inference about GGG–P2RY8 signalling. Given that Ggt5 also participates in the leukotriene pathway, in vivo experiments have explored alternative roles for Ggt5 beyond P2RY8 signalling. Together, the data in this thesis supports a model in which endothelial activation and fibroblast GGT5 induction establish perivascular confinement zones that tune leukocyte positioning in IMIDs. These findings motivate the development of tools to map GGG in situ and suggest therapeutic strategies to modulate GGT5 activity to either stabilise protective niches or disperse pathogenic aggregates in RA and IBD
Effi Briest, Mathilde Möhring. The Development of Theodor Fontane's Female Characters on the Background of Women Emancipation.
No full textTheodore Fontane is best known as the author of numerous women's novels, which he wrote in the last ten years of his life. This diploma thesis deals with the topic of women's emancipation on the basis of textual analysis of two latter novels by Theodore Fontane - Effi Briest and Mathilde Möhring. In the first part, it characterizes the topic of the period women's emancipation and puts the author's biography into context. In the second part, it creates the picture of position of the main women characters. The last part describes the personal development of the women characters, on the basis of which I determine how much the women's emancipation reflects in the author's work and what is his attitude towards it. This thesis deals with the interpretation of the author's intent to illustrate the creation of an advanced character like Mathilde Möhring. Key words: Theodore Fontane, women's emancipation, Effi Briest, Mathilde Möhring, development of women's characters, women's novels, interpretation, author's intent, counterpoin
Effi Briest, Mathilde Möhring. Vývoj postavy žen na pozadí dobové emancipace ve stejnojmenných románech Theodora Fontana.
No full textTheodore Fontane is best known as the author of numerous women's novels, which he wrote in the last ten years of his life. This diploma thesis deals with the topic of women's emancipation on the basis of textual analysis of two latter novels by Theodore Fontane - Effi Briest and Mathilde Möhring. In the first part, it characterizes the topic of the period women's emancipation and puts the author's biography into context. In the second part, it creates the picture of position of the main women characters. The last part describes the personal development of the women characters, on the basis of which I determine how much the women's emancipation reflects in the author's work and what is his attitude towards it. This thesis deals with the interpretation of the author's intent to illustrate the creation of an advanced character like Mathilde Möhring. Key words: Theodore Fontane, women's emancipation, Effi Briest, Mathilde Möhring, development of women's characters, women's novels, interpretation, author's intent, counterpointTheodor Fontane je známý především jako autor četných ženských románů, které psal ve svém pokročilém věku. Tato práce zpracovává na základě analýzy textu téma ženské emancipace v jeho dvou pozdějších románech - Manželství Effi Briestové a Mathilda Möhringová. V první části charakterizuje téma dobové ženské emancipace a zasazuje autorovu biografii do kontextu. V druhé části utváří obraz pozice hlavních románových hrdinek. V poslední části je shrnut osobní vývoj ženských postav, na jejímž základě má být zodpovězena otázka, nakolik se ženská emancipace odráží v autorově díle a jaký je jeho postoj k ní. Práce se zároveň zabývá intepretací autorova záměru, který vytvořil postavu pokročilé Mathildy Möhringové, čímž dosáhl kontrapunktu k tomu, co doposud psal. Klíčová slova: Theodor Fontane, ženská emancipace, Effi Briest, Mathilde Möhring, vývoj ženských postav, interpretace, ženské romány, záměr autora, kontrapunktInstitute of Germanic StudiesÚstav germánských studiíFilozofická fakultaFaculty of Art
Tunisian Politics in France: Long-Distance Activism since the 1980s
No full textInternational audienceWhat does it mean to oppose or support an authoritarian regime from afar? During the years of Ben Ali's dictatorship in Tunisia between 1987 and 2011, diaspora activism played a key role in the developments of post-independence Tunisian politics. Centring this study on long-distance activism in France, where the majority of leftist and Islamist exile groups took refuge, Mathilde Zederman explores how this activism helps to shed new light on Tunisia's political history. Tunisian Politics in France closely explores the interactions and conflicts between different constellations of pro-regime and oppositional actors in France, examining the dynamics of what the author persuasively describes as a 'trans-state space of mobilisation'. In doing so, Zederman draws attention to the constraints and possibilities of long-distance activism. Utilising material gathered from extensive fieldwork in France and Tunisia, this study considers how the evolution of diaspora activism both challenges and reinforces the boundaries of Tunisian politics
Book review: Photography of protest and community: the radical collectives of the 1970s by Noni Stacey
No full textIn Photography of Protest and Community: The Radical Collectives of the 1970s, Noni Stacey shows how a 1970s network of London-based photography collectives raised fundamental questions about the politics of photography, the role and responsibilities of photographers in relation to local communities and the uses of photography in the context of social activism. This book is a welcome addition to the expanding field of research on the photography of protest, writes Mathilde Bertrand, contributing to the ongoing documentation of this strong current in British photographic history. If you are interested in this book review, you can read an LSE RB interview with author Dr Noni Stacey. The archive of the Exit Photography Group is held at LSE Library; readers can find out more about the archive and the catalogue. Photography of Protest and Community: The Radical Collectives of the 1970s. Noni Stacey. Lund Humphries. 2020
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