7,366 research outputs found

    Complicated objects: artifacts from the Yuanming Yuan in Victorian Britain

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    The 1860 spoliation of the Summer Palace at the close of the Second Opium War by British and French troops was a watershed event within the development of Britain as an imperialist nation, which guaranteed a market for opium produced in its colony India and demonstrated the power of its armed forces. The distribution of the spoils to officers and diplomatic corps by campaign leaders in Beijing was also a sign of the British Army’s rising power as an instrument of the imperialist state. These conditions would suggest that objects looted from the site would be integrated into an imperialist aesthetic that reflected and promoted the material benefits of military engagement overseas and foregrounded the circumstances of their removal to Britain for campaign members and the British public. This study mines sources dating to the two decades following the war – including British newspapers, auction house records, exhibition catalogs and works of art – to test this hypothesis. Findings show that initial movements of looted objects through the military and diplomatic corps did reinforce notions of imperialist power by enabling campaign members to profit from the spoliation through sales of looted objects and trophy displays. However, material from the Summer Palace arrived at a moment when British manufacturers and cultural leaders were engaged in a national effort to improve the quality of British goods to compete in the international marketplace and looted art was quickly interpolated in this national conversation. Ironically, the same “free trade” imperatives that motivated the invasion energized a new design movement that embraced Chinese ornament. As a consequence, political interpretations of the material outside of military collections were quickly joined by a strong response to Chinese ornament from cultural institutions and design leaders. Art from the Summer Palace held a prominent place at industrial art exhibitions of the postwar period and inspired new designs in a number of mediums. While the availability of Chinese imperial art was the consequence of a military invasion and therefore a product of imperialist expansion, evidence presented here shows that the design response to looted objects was not circumscribed by this political reality. Chinese ornament on imperial wares was ultimately celebrated for its formal qualities and acknowledged links to the Summer Palace were an indicator of good design, not a celebration of victory over a failed Chinese state. Therefore, the looting of the Summer Palace was ultimately an essential factor in the development of modern design, the essence of which is a break with Classical ornament

    Photochemical Generation of Alkyl and Acyl Radicals and their Application in Synthetic Organic Chemistry

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    Recent developments in photoredox catalysis provided many new concepts, methodologies, and applications to synthesize organic compounds. One mutual goal for synthetic chemists across different disciplines is to provide facial and straightforward access to the molecule of interest. One concept to do so in an enantioselective manner is asymmetric ion-pairing catalysis. Despite being part of the chemist’s toolbox for quite some time now, its application in the field of photoredox catalysis is relatively scarce. The introductory Chapter I provides an overview of current transformations and strategies in counter-ion directed and ion-binding catalysis in the light of photoredox catalysis. The other part of the thesis is dedicated to developing new photo-chemical methodologies. Chapter II explores a highly efficient photochemical synthesis of benzophenones. The developed methodology exploits the photophysical properties of the aromatic aldehyde starting material and the diaryl ketone products. Both carbonyl compounds can be photoexcited to their triplet state by UV light and thereby could act as a hydrogen-atom-transfer catalyst to activate the formyl C−H bond. A nickel diimine complex then catalyzes the coupling of the generated acyl radical with various aryl bromides. Through this reactant-focused reaction design, the need for expensive iridium or ruthenium photocatalysts, as well as the additional use of HAT-catalysts, can elegantly be avoided. Like carbonyl compounds, the decatungstate anion can act as a hydrogen-atom-transfer catalyst upon its excitation with UV light and activate alkanes, which exhibit rather strong C(sp3)−H bonds. In Chapter III, we applied this exceptional property to synthesize trifluoromethylthiolated compounds. This structural motive is vital in medicinal chemistry, as it adds both lipophilicity and polarity to a compound, properties that generally contradict each other. By identifying the decatungstate anion as a suitable catalyst for the direct transformation of C−H bonds into the C−SCF3 group, we gained facial access to trifluoromethylthioethers, -acetals, and esters. The applicability of our methodology was demonstrated by the synthesis of SCF3 derivatives of two drug molecules and the functionalization of several natural products. Chapter IV revisits photo-nickel dual catalysis and again addresses the quest to replace iridium or ruthenium photocatalysts and run these kinds of cross-coupling reactions more sustainably. Therefore, the heterogeneous semiconductor material mpg-CN is introduced as an alternative photocatalyst for the cross-coupling of alkyl silicates with aryl and alkenyl bromides. Recycling experiments showed the reusability of the catalyst in this transformation

    Proteomic analysis and characterization of newly identified interacting partners of the delta-opioid receptor involved in the regulation of its trafficking

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    Au cours des derniĂšres annĂ©es, de nombreuses Ă©tudes ont mis en Ă©vidence le rĂ©cepteur aux opioĂŻdes de type delta (DOPr) comme une cible thĂ©rapeutique prometteuse pour le traitement de la douleur chronique, une condition qui atteint plus de 20% des Canadiens. En plus d’ĂȘtre associĂ©s Ă  des profils d’effets indĂ©sirables moins dĂ©lĂ©tĂšres que les opioĂŻdes actuellement prescrits, les agonistes sĂ©lectifs du DOPr peuvent induire des rĂ©ponses antinociceptives efficaces dans divers modĂšles animaux de douleur chronique, incluant les modĂšles de douleur neuropathique, inflammatoire, diabĂ©tique et liĂ©e au cancer. Alors que la majoritĂ© des rĂ©cepteurs couplĂ©s aux protĂ©ines G (RCPGs) sont exprimĂ©s Ă  la membrane plasmique, le DOPr est principalement localisĂ© au niveau intracellulaire, rendant ainsi son ciblage par des composĂ©s pharmacologiques plutĂŽt difficile. De façon intĂ©ressante, la densitĂ© de DOPr Ă  la membrane neuronale peut ĂȘtre augmentĂ©e sous certaines conditions, telles que des traitements chroniques Ă  la morphine ou dans un contexte de douleur inflammatoire. Cette translocation vers la surface cellulaire est Ă©galement corrĂ©lĂ©e avec une augmentation des effets analgĂ©siques mĂ©diĂ©s par les agonistes du DOPr. Cependant, les mĂ©canismes cellulaires et les protĂ©ines rĂ©gulatrices impliquĂ©s dans ce routage atypique restent inconnus. MalgrĂ© leur importance thĂ©rapeutique inestimable, l’étude in vivo des RCPGs demeure encore Ă  ce jour un dĂ©fi de taille, principalement en raison de leurs propriĂ©tĂ©s structurelles, leur faible abondance et le manque d’anticorps spĂ©cifiques. Dans un premier article, nous avons dĂ©crit une approche permettant l’identification de protĂ©ines endogĂšnes interagissant avec le DOPr Ă  partir de lysats de cerveaux murins, une approche inĂ©dite pour le domaine des RCPGs. En combinant des modĂšles de souris transgĂ©niques uniques et des analyses protĂ©omiques, nous avons rĂ©vĂ©lĂ© plusieurs nouveaux interacteurs endogĂšnes du DOPr potentiellement impliquĂ©s dans la modulation du repliement des protĂ©ines, du trafic et de la transduction de signal. Parmi les protĂ©ines candidates nouvellement identifiĂ©es, nous avons caractĂ©risĂ© les rĂŽles de Rab10 dans la modulation de l’expression de surface du DOPr. Dans une Ă©tude subsĂ©quente, nous avons investiguĂ© l’implication de diverses isoformes de Homer1 dans la rĂ©gulation de l’export du DOPr vers la membrane plasmique. Ensemble, les recherches prĂ©sentĂ©es dans le cadre de cette thĂšse rĂ©vĂšlent de nouvelles pistes pour la dĂ©couverte de mĂ©canismes molĂ©culaires et cellulaires sous-tendant le routage du DOPr in vivo.Over the past several years, numerous studies have highlighted the delta-opioid receptor (DOPr) as a promising therapeutic target for chronic pain, a condition affecting more than 20% of Canadians. In addition to displaying a milder side-effect profile, its specific agonists can elicit effective antinociceptive responses in various animal models of chronic pain, including inflammatory, neuropathic, diabetic and cancer-related pain. As opposed to most other G protein-coupled receptors (GPCRs), the DOPr exhibits a predominant intracellular localization, rendering its effective targeting by pharmacological compounds challenging. Interestingly, we and others have observed that neuronal plasma membrane density of DOPr could be increased under specific conditions such as chronic morphine treatments or inflammatory pain. This translocation from the intracellular compartments to the plasma membrane was also correlated with an increase of DOPr agonist-mediated analgesic effects. However, the molecular mechanisms and regulatory proteins underlying such recruitment to the cell surface remain unknown. Despite their invaluable pharmacological and therapeutic relevance, GPCRs are still arduous to study in vivo, principally due to their structural properties, low abundance, and the lack of highly specific and potent antibodies. In a first article, we thus describe an approach allowing the identification of endogenous DOPr-interacting proteins from brain homogenates, a first-of-kind approach for the GPCR field. Using proteomics and unique transgenic mouse models, we reveal several novel DOPr interactors potentially involved in a wide range of functions, including the modulation of protein folding, trafficking and signal transduction. Among the newly identified candidate proteins, we further characterize the roles of Rab10 in the regulation of DOPr cell surface expression. In a follow-up study, we investigate the involvement of various Homer1 isoforms in the regulation of DOPr plasma membrane targeting. Altogether, the research presented here provides new leads for the discovery of molecular and cellular mechanisms regulating DOPr signaling and trafficking in vivo. Also, since the developed approach can be transposed to the study of any other receptor, our work could also be pivotal in elucidating the endogenous interactome of several GPCRs

    Legal Strategies to Minimize Subway Air Pollution in the United States

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    Air pollution in U.S. subway systems poses a major threat to public health. People in subway stations breathe in dangerously high levels of dusts, called particulate matter. Current legislation does not effectively address this problem; in fact, the United States does not have a comprehensive indoor air quality law at all. Left unregulated, people regularly exposed to subway air pollution could suffer respiratory and cardiovascular issues and even premature death. To mitigate these health effects, some countries have imposed PM standards in subway systems and underground spaces. Others have standards covering all indoor spaces. In the United States, many subway systems have begun exploring technologies to filter subway air in the wake of the coronavirus pandemic. To support their efforts and innovation, the United States should enact legislation establishing a grant and loan program for subway systems’ air-purifying initiatives. Modeled after the successful Diesel Emissions Reduction Act, this law would adopt a carrot-based approach to effectively reduce subway air pollution, allowing each system to tailor initiatives to their unique characteristics. While the United States should explore a mandatory standards-based approach long term, it should prioritize this legislation to protect the public more quickly from this ongoing threat

    Open Problems and Fundamental Limitations of Reinforcement Learning from Human Feedback

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    Reinforcement learning from human feedback (RLHF) is a technique for training AI systems to align with human goals. RLHF has emerged as the central method used to finetune state-of-the-art large language models (LLMs). Despite this popularity, there has been relatively little public work systematizing its flaws. In this paper, we (1) survey open problems and fundamental limitations of RLHF and related methods; (2) overview techniques to understand, improve, and complement RLHF in practice; and (3) propose auditing and disclosure standards to improve societal oversight of RLHF systems. Our work emphasizes the limitations of RLHF and highlights the importance of a multi-faceted approach to the development of safer AI systems

    The oncogenic role of the lysine-specific demethylase KDM1A in chronic lymphocytic leukemia

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    Chronic lymphocytic leukemia (CLL) is the most prevalent leukemia in adults in the Western world. Despite the advances in the identification of various genomic and molecular alterations and the management of treatment for CLL, it remains an incurable disease. Epigenetic alterations are considered to centrally shape the transcriptional signatures that drive disease evolution and underlie the biological and clinical subsets in CLL. However, characterizations of epigenetic regulators, particularly histone-modifying enzymes, are very rudimentary in CLL. Aberrant expression of the T-cell leukemia/lymphoma 1A (TCL1A) proto-oncogene is a hallmark of CLL and high TCL1A levels are associated with aggressive disease features. As a well-accepted disease model, EÎŒ-TCL1A transgenic (tg) mice produce B-cell proliferations that closely resemble human CLL. In the context of the yet-evolving molecular concept of the 14kDa TCL1A protein, it was shown that TCL1A interacts with the DNA methyltransferase 3A (DNMT3A), thereby reducing its enzymatic activity and contributing to epigenetic reprogramming in CLL. Fittingly, induced mono- or bi-allelic losses of Dnmt3a result in murine CLL. Nevertheless, the functional network around TCL1A, particularly with epigenetics, is incomplete and as a causal oncogene in CLL, a better molecular understanding would help in improving disease concepts and treatment rationales in this still incurable neoplasm. Here, we identify the epigenetic modifier, lysine-specific demethylase KDM1A as a novel interaction partner of the TCL1A protein in B cells. This demethylase has been implicated in many cancer entities and its overexpression has been linked to poor prognoses. Currently, KDM1A inhibitors are being investigated for cancer therapy in clinal trials. In this context, we proposed that KDM1A is involved in CLL pathogenesis by altering its epigenetic landscape. Therefore, we set out to address: (1) how does TCL1A affect KDM1A’s function/activity? (2) what are the biological outcomes of increased KDM1A levels in CLL? (3) which KDM1A-mediated pathways contribute to the biology of CLL? To address these central questions, we have analyzed the subcellular localization of TCL1A and KDM1A as well as their interacting complex. TCL1A interacted with KDM1A in the nucleus. Interestingly, their protein interaction increased the histone demethylase activity of KDM1A in B cells. TCL1A also affected histone posttranslational modifications (PTMs). Furthermore, we could show that KDM1A is overexpressed in CLL B cells as compared to healthy B cells. By analyzing the gene expression profiling (GEP) data of patients included in the CLL8 trial, we demonstrated that higher KDM1A expression levels and the associated gene signatures correlate with adverse clinical characteristics and unfavorable clinical outcomes, e.g., higher white blood cell (WBC) counts, higher serum thymidine kinase levels, a higher rate of TP53 mutations/deletions, and shorter progression-free survival (PFS). In addition, enrichment of different pathways involved in tumor progression was also associated with KDM1A expression levels. Next, we took advantage of the doxycycline (Dox)-inducible Kdm1a knockdown mouse model and the TCL1A-tg EÎŒ-TCL1A mice to achieve a whole-organismal Kdm1a knockdown in murine CLL. The genetic Kdm1a depletion in E”-TCL1A mice reduced the leukemic burden in peripheral blood, spleen, and bone marrow. This was accompanied by upregulation of p53 and pro-apoptotic pathways identified by RNA-sequencing analysis. The analysis of differentially expressed genes (DEGs) upon Kdm1a knockdown suggested that Kdm1a acts as a transcriptional repressor in murine CLL. This might be due to enrichment of regulatory elements of upregulated genes with H3K4 methylation upon the Kdm1a knockdown, which leads to activation these genes. Thus, we performed chromatin immunoprecipitation sequencing (ChIP-seq) experiments, which demonstrated an increase in H3K4me3 marks in Kdm1a knockdown leukemic cells. Moreover, KDM1A expression in the components of the microenvironment had an impact on their support for CLL progression. The loss of KDM1A in monocytic cells and stromal cells led to impaired support of CLL cell proliferation and survival in vitro. Notably, Kdm1a knockdown in E”-TCL1A prolonged the overall survival (OS) of leukemic animals. In vitro, KDM1A inhibition by the pharmacologic compound C12 induced apoptosis and increased H3K4/9 target methylation levels in leukemic B cells. Overall, in completion of all aims, we established a relevant pathogenic role for KDM1A in CLL, as a pro-oncogenic molecule in CLL cells and in components of their microenvironment. Our data further provide a rationale for therapeutic KDM1A inhibition in CLL

    Adopting a multi-systems approach: examining the academic belongingness of first-generation college students with multiple stigmatized identities in STEM

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    First-generation college students often experience greater social alienation and marginalization due to a mismatch of their cultural values compared to those of their university and often report lower academic satisfaction and sense of belonging. The effects on sense of belonging and satisfaction are intensified when first-generation college students have identities that intersect with other stigmatized social and cultural identities, like low socioeconomic status, Black or Latinx racial identities or religious identities, specifically for STEM majors. Students’ holistic health and well-being, including their sense of belonging, is highly correlated to their academic achievement, persistence, and overall student success, especially for underrepresented minority groups. However, there has been limited consideration for the nuanced experiences of first-generation college students with multiple stigmatized identities, and for how the academic STEM environment shapes student’s perceptions of inclusivity considering their social identities. To address these concerns, we used the Bioecological Systems theory to contextualize drivers of sense of belonging for students with stigmatized social and cultural identities by allowing space to explicitly consider institutional, departmental, classroom and societal-level phenomena that may operate to erode or fortify belonging for some individuals over others. Findings were organized contextually first, revealing how broader societal and familial values shaped their perceptions of their first-generation identity. Next, we reported how various forms of engagement and interactions with institutional agents impacted their perceptions of support at the institutional level. We then documented behavioral patterns within STEM departments that culminated to reveal how first-generation college students’ sense of belonging was impacted by perceived departmental culture. Last, we revealed interactions within STEM classrooms that signaled inclusivity through humanizing and intentional pedagogical practices. Infused throughout all findings are instances where student experiences were mediated through their multiple identities and were shaped by dual global pandemics of 2020, that being COVID-19 and the racial unrest resurfaced by the murder of George Floyd. Implications for this work have the potential to restructure how institutions provide support for first-generation college students given the salience of their intersecting stigmatized identities in shaping their institutional, disciplinary, and classroom belonging

    Civility, Epistemic Injustice, and Criticality: Toward a Praxis of Affective Democratic Friction

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    Socially-privileged students’ discomfort in the social justice classroom as injustice is dramatically increasing in public discourse, especially as the Anti-Critical Race Theory (CRT) movement thrives. It is in the current climate of Anti-CRT that social justice educators must be vigilant of how classrooms could reproduce the very injustices they seek to problematize. Coupled alongside social justice educators’ fears of job security and violence—physical, emotional, and epistemic—calls for civility that function to mute discomfort about systemic injustices could easily creep into classrooms. I claim civility can function speciously—when appeals to civility falsely claim, even if well-intentioned, to create just, open dialogue. Specious civility acts to conceal reiterations of socially-unjust power relations and, in turn, reify epistemologies of whiteness under the guise of “safe” or “comforting” spaces. I assert that such functions of civility conceal/maintain white students’ resistance to engage with counter testimony, especially testimony that might reveal their complicity in systemic oppressions. Social justice educators, then, must be hyper-cognizant of possible epistemic injustices perpetrated toward socially-marginalized students/testifiers. Building on the work of Miranda Fricker and JosĂ© Medina, I propose that our evaluations of testimony may be better served by practices of criticality that acknowledge the social, communal aspects of inquiry/critique/reflection. I, then, develop and illustrate a praxis of affective democratic friction, expanding on AnaLouise Keating’s “pedagogies of invitation,” Medina’s “epistemic friction and activism,” and Gloria AnzaldĂșa’s “spiritual activism,” to propose teaching practices that could incite students to recognize their discomfort, postpone assessment/judgments of testimony, and create opportunities for recognizing the affective happenings causing distress and, in turn, cultivate a relational criticality
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