2,889 research outputs found
T Helper Cells: The Modulators of Inflammation in Multiple Sclerosis
No full textMultiple sclerosis (MS) is a chronic neurodegenerative disease characterized by the progressive loss of axonal myelin in several areas of the central nervous system (CNS) that is responsible for clinical symptoms such as muscle spasms, optic neuritis, and paralysis. The progress made in more than one decade of research in animal models of MS for clarifying the pathophysiology of MS disease validated the concept that MS is an autoimmune inflammatory disorder caused by the recruitment in the CNS of self-reactive lymphocytes, mainly CD4+ T cells. Indeed, high levels of T helper (Th) cells and related cytokines and chemokines have been found in CNS lesions and in cerebrospinal fluid (CSF) of MS patients, thus contributing to the breakdown of the blood-brain barrier (BBB), the activation of resident astrocytes and microglia, and finally the outcome of neuroinflammation. To date, several types of Th cells have been discovered and designated according to the secreted lineage-defining cytokines. Interestingly, Th1, Th17, Th1-like Th17, Th9, and Th22 have been associated with MS. In this review, we discuss the role and interplay of different Th cell subpopulations and their lineage-defining cytokines in modulating the inflammatory responses in MS and the approved as well as the novel therapeutic approaches targeting T lymphocytes in the treatment of the disease
Rozpor ako východisko, láska ako smer u Simone Weilovej (Contradiction as base, Love as direction in writings of Simone Weil)
No full textArticle is explaining contradiction and love, Simone Weil‘s essential terms of hermeneutics of human Being. It introduces close relation of these terms with her understanding of God as well as with her overall concept of religion. Author also mentions Simone Weil‘s inspirations with philosophical and spiritual concepts of the East
CELLULAR AND MOLECULAR MECHANISMS OF CHEMORESISTANCE IN ACUTE MYELOID LEUKEMIA
No full textAcute Myeloid Leukemia (AML) remains an incurable disease, with a 5-year survival rate below 30%. While the introduction of new therapeutic approaches, such as targeted therapies and immunotherapy, has had a modest impact on AML prognosis, the standard treatment of AML is still based on chemotherapy regimens (like "7+3") that have been in use for over 50 years. Approximately 20% of patients do not respond to standard chemotherapy, and even among those who initially respond, around 50% eventually relapse due to the development of chemotherapy resistance. Chemoresistance is the cause of death for over 90% of AML patients.
The mechanisms underlying chemoresistance in AML are not yet fully understood, and targeted therapies aimed at preventing chemoresistance are not currently available. Chemoresistance in AML is primarily driven by non-genetic mechanisms. While leukemic stem cells (LSCs) have been implicated, recent studies suggest that AML blasts that survive chemotherapy, known as Chemotherapy Persistent Blasts, enter a senescence-like and diapause state. Though they can contribute to disease recurrence, these Persistent Blasts are not inherently therapy-resistant as they revert to a drug-sensitive state upon drug withdrawal. However, a lack of robust in vivo models of clinical chemoresistance in human AML hinders our understanding of these mechanisms. To address this, I aimed to generate in vivo models of truly chemoresistant AML to investigate non-genetic mechanisms of chemotherapy resistance.
I utilized mouse models of human AML, specifically Patient-Derived Xenografts (PDXs), to establish treatment protocols mimicking the standard "7+3" chemotherapy regimen used clinically. One model (AML9) mirrored the behavior of most patients treated with standard chemotherapy, exhibiting clinical remission followed by relapse. In contrast, the other model (AML20) showed a modest response to chemotherapy with rapid leukemia re-expansion. Notably, relapsed leukemias in both models were completely resistant to retreatment with the same chemotherapy regimen, and this resistant phenotype persisted even after re-transplantation. Extensive genomic profiling revealed that chemoresistance in relapsed leukemias was not associated with the emergence of de novo DNA mutations. AML9 and AML20 represent the first two available AML models of true clinical chemoresistance, mirroring primary and secondary resistance, respectively.
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To investigate mechanisms of chemoresistance in these models, I characterized the cellular and molecular properties of Chemotherapy Persistent Blasts isolated at the end of the chemotherapy regimen. To monitor and isolate quiescent blasts during leukemia growth and after chemotherapy treatment, I incorporated a label-retaining (LR) assay into the PDX models, enabling cell division tracking through inducible expression of H2B-GFP. I found that: i) in vitro, Persistent Blasts from both models exhibited significantly higher IC50 values compared to non-treated blasts, suggesting the induction or selection of a stable and cell- autonomous chemoresistant phenotype; ii) Quiescent blasts were slightly enriched among Persistent Blasts, but a portion of leukemia cells continued to proliferate during treatment, generating a population of Persistent Blasts of both proliferating and quiescent cells; iii) Persistent Blasts retained regenerative potential in vivo, primarily attributed to persistent quiescent blasts, suggesting that quiescence, while not a specific trait of chemoresistance, is integral to the relapsing properties of these cells; iv) the AML clonal structure remained unchanged after chemotherapy treatment, as determined by lineage tracing of Persistent Blasts and relapsed leukemias, suggesting that chemotherapy does not select specific cellular lineages; v) Persistent Blasts exhibited distinct transcriptional features compared to untreated leukemias, characterized by stem-cell signatures and activation of the Interferon (IFN) signaling pathway. Notably, IFN signaling activation was a distinguishing feature of both quiescent and proliferating blasts and was predictive of clinical response to standard chemotherapy in AML patients.
To investigate the contribution of the activated IFN signaling pathway to chemoresistance, I examined the effect of silencing IFI6, the top upregulated gene in the IFN signature. IFI6 silencing prolonged latency and reduced engraftment frequency in AMLs, due to its detrimental effect on leukemia-initiating cells (LICs). However, IFI6 silencing did not impact leukemia outgrowth kinetics. Strikingly, IFI6 silencing completely reversed the chemoresistant phenotype in both AML models in vivo and increased the chemosensitivity of established AML cell lines in vitro.
To further explore mechanism of IFI6-mediated chemo-sensitization, I investigated the interaction between IFI6 and STING. I found that IFI6 is upregulated upon chemotherapy treatment and relocates to the ERGIC compartment in proximity to STING, where STING activation by chemotherapy-induced DNA damage initiates a cascade leading to IFN signaling and cell death. Based on these findings, I initiated experiments to determine
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whether IFI6-mediated chemoresistance is due to its ability to downregulate STING activation, thereby preventing the execution of IFN-induced cell death
“I beg you to tell me what has become of Djamila”: The Political Mobilization of Simone de Beauvoir’s Readers During the Boupacha Affair
No full textBy Sophia Millman This is a condensed version of a Masters thesis dedicated to the political mobilization of Simone de Beauvoir’s readers. The citations from the letters were translated from French by the author. *** On June 2, 1960, the French government ordered all copies of the daily Algiers edition of Le Monde seized and destroyed to suppress the publication of Simone de Beauvoir’s article “Pour Djamila Boupacha.” Beauvoir, a self-professed “woman of letters”, not “of action[1]”, and one ..
A comparative study of form and theology in the works of Flannery O'Connor and Simone Weil
No full textIn this comparative study of the form and theology of Flannery O'Connor and Simone Weil I interrogate how Weil's philosophical writings and her theology illuminate O'Connor's use of both narrative and non-fictional forms, and her Catholicism. The Introduction analyses how Weil's concept of superposed reading provides a new method of approaching both O'Connor, her writings, and O'Connor
studies, and focuses on how such apparently different women interconnect. Chapter One explores how both Weil and O'Connor attempt to write their theologies on the
souls of their readers yet are each subject to constraints imposed by form. Weil's concept of locating equilibrium between incommensurates is discussed, and her
distinctively philosophical approach to fictions and fictionality is used to investigate O'Connor's notion of prophetic fictions and the writer's role. Chapter Two assesses how both writers revivify Christian paradoxes. Weil's monstrous concept of affiiction, and O'Connor's use of the grotesque genre to jolt secular man into an
awareness of the sacred are scrutinised. Chapter Three studies how both writers consider an encounter between God and man is possible through the action of grace. My Conclusion interrogates how Weil's work can deepen our understanding of O'Connor's writings, and examines how successful O'Connor is at realising a truly
Christian literature. I conclude that despite being a writer of powerful fictions, O'Connor can not be totally successful in her mission as writer-prophet because
ultimately fiction escapes orthodoxy
Microlinices benthovus Simone 2014
No full textbenthovus, Microlinices Simone, 2014 Microlinices benthovus Simone, 2014: 575–578 (figs 6A–J, 7A–H, 11A–C). Gastropoda, Naticidae Paratypes (22 spc): MZSP 105269. Paratypes 1 (15 spc): MZSP 105270. Paratypes 2 (16 spc): MZSP 105271. Paratypes 3 (7 spc): MZSP 105272. Localities: Brazil, Espírito Santo, off Itaúnas, Abrolhos Slope, 18°59' S, 37°50' W, MD55 sta. DC 73, 637 m depth, 27 May 1987; 1) 19°00' S, 37°48' W, MD55 sta. DC72, 950– 1050 m, 27 May 1987; 2) off Regência, 19°40' S, 37°48' W, MD55 sta. CB77, 790– 940 m depth, 27 May 1987; 3) off Itaúnas, Abrolhos Slope, 19°01' S, 37°47' W, MD55 sta. CB79, 1500–1575 m depth, 28 May 1987. Collectors: P. Bouchet, J.H. Leal and B. Métivier. Preservation: Dry. Remarks: Former MNHN, Paris. The catalogue number MZSP 105250 is mentioned twice in Simone’s (2014) paper, among the paratypes of M. ibitingus Simone, 2014 and M. benthovus. This duplicity was a mistake by the author: the latter is an erroneous designation and should be disregarded. The only valid paratype lots for M. benthovus are the ones shown above.Published as part of Cavallari, Daniel C., Dornellas, Ana Paula S. & Simone, Luiz Ricardo L., 2016, Second annotated list of type specimens of molluscs deposited in the Museu de Zoologia da Universidade de São Paulo, Brazil, pp. 1-59 in European Journal of Taxonomy 213 on page 10, DOI: 10.5852/ejt.2016.213, http://zenodo.org/record/384012
Was bringt die Föderalismusreform? Wahrscheinliche Effekte der geänderten Zustimmungspflicht
No full textThe recently enacted reform of German federalism is supposed to make legislation faster, more efficient and better. To what extent are these expectations justified? In order to assess the likely effects of the reform, this study uses a research design that was recently applied by the Research and Reference Services of the German Bundestag (parliament): we estimate the future effects of the reform by analyzing the impact it would have had on the legislation in the 14th and 15th term of the Bundestag if it had already been been in force at that time. In particular we ask: To what extent would the number of laws requiring the consent of the states' chamber, the Bundesrat, have been reduced? Which type of laws would have been affected by this reduction - the more controversial ones, or the less controversial ones? Which policy sectors would have seen the greatest reduction? How much would the reduction have increased the government's capacity to act effectively? Would the legislative process have been accelerated? -- Die verabschiedete Föderalismusreform soll die Gesetzgebung in Deutschland schneller, effizienter und besser machen. Inwiefern sind diese Erwartungen berechtigt? Zur Abschätzung der Reformfolgen auf die Bundesgesetzgebung folgen wir in dem vorliegenden Working Paper einer Vorgehensweise, die der Wissenschaftliche Dienst des Bundestages kürzlich in einer Studie angewandt hat: Die Auswirkungen der Föderalismusreform insbesondere auf die Zustimmungspflicht werden anhand der Gesetzgebung der 14. und 15. Legislaturperiode untersucht. Wir fragen insbesondere: Wie stark hätte sich der Anteil der Zustimmungsgesetze verringert, wenn die neuen Zustimmungsregeln schon in diesen beiden Legislaturperioden gegolten hätten? Wären eher zwischen Regierung strittige oder unstrittige Gesetze von der Zustimmungspflicht befreit worden? Welche Politikbereiche wären betroffen? Wie sehr hätte sich die politische Handlungsfreiheit der Bundesregierung erhöht? Wäre die Gesetzgebung durch die veränderten Zustimmungsregeln beschleunigt worden?
Idea ofiary u Simone Weil
No full textAutorka omawia ofiarę, jaką z samej siebie złożyła Simone Weil. Głównym celem autorki artykułu jest wykazanie, iż idea ofiary była najważniejszą myślą w życiu francuskiej filozof. W artykule ukazano myśl o ofierze w życiu i pismach intelektualistki, jak również analogie, które rzucają nowe światło na ofiarę Weil. Jako klucz do interpretacji i zrozumienia ofiary Weil, autorka analizuje myśl Emmanuela Levinasa oraz Józefa Tischnera.The author interprets the sacrifice that Simone Weil filed with itself. The main point of the present article is the assumption that the sacrifice Simone Weil was the most important idea of her life. A thought about the victim is portraying the article in the life and letters of the intellectual, as well as is portraying analogies which are shedding new light on the Weil victim. As the key to interpretation and understanding the her victim, the author is analysing the thought of Emmanuel Levinas and Jozef Tischner.Udostępnienie publikacji Wydawnictwa Uniwersytetu Łódzkiego finansowane w ramach projektu „Doskonałość naukowa kluczem do doskonałości kształcenia”. Projekt realizowany jest ze środków Europejskiego Funduszu Społecznego w ramach Programu Operacyjnego Wiedza Edukacja Rozwój; nr umowy: POWER.03.05.00-00-Z092/17-00
My life on the road: the exhilarating experience of travel
No full textVERSION FRANÇAISE ICI By Tiphaine Martin Researcher at Babel, University of Toulon, Member of the editorial board of Simone de Beauvoir Studies and author of a doctoral dissertation about Simone de Beauvoir's travels Translated from French by Marine Rouch (under the kind supervision of her dear friend Daniel Sawyer) I will begin with a brief criticism of the French edition. While the translation is very pleasant and captures Gloria Steinem's fluidity, humor and appetite for life, there is no..
Problematiche dell’indotto Fiat di Cassino: proposte per la valorizzazione delle PMI e il rilancio del territorio. Un modello di intervento per rilanciare il sistema
No full textGATTI M., GATTI C., PROIETTI L., SIMONE C., Problematiche dell’indotto Fiat di Cassino: proposte per la valorizzazione delle PMI e il rilancio del territorio. Un modello di intervento per rilanciare il sistema produttivo di Cassino, Bic Notes – Quaderni di Bic Lazio, Numero Speciale, 2006, 9-152
Volume senza attribuzioni ai singoli AutoriM. CATS, CATS C., L. Proietti, SIMONE C. Issues industries Fiat Cassino: proposals for the development of SMEs and the revitalization of the area. A model of intervention to revive the productive system of Cassino, Bic Notes - Papers Bic Lazio, Special Issue, 2006 9-152 Volume without attribution to individual author
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