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"Wendland, Kristin"
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Interferon-driven brain phenotype in a mouse model of RNaseT2 deficient leukoencephalopathy
Infantile-onset RNaseT2 deficient leukoencephalopathy is characterised by cystic brain lesions, multifocal white matter alterations, cerebral atrophy, and severe psychomotor impairment. The phenotype is similar to congenital cytomegalovirus brain infection and overlaps with type I interferonopathies, suggesting a role for innate immunity in its pathophysiology. To date, pathophysiological studies have been hindered by the lack of mouse models recapitulating the neuroinflammatory encephalopathy found in patients. In this study, we generated
Rnaset2
−/−
mice using CRISPR/Cas9-mediated genome editing.
Rnaset2
−/−
mice demonstrate upregulation of interferon-stimulated genes and concurrent IFNAR1-dependent neuroinflammation, with infiltration of CD8
+
effector memory T cells and inflammatory monocytes into the grey and white matter. Single nuclei RNA sequencing reveals homeostatic dysfunctions in glial cells and neurons and provide important insights into the mechanisms of hippocampal-accentuated brain atrophy and cognitive impairment. The
Rnaset2
−/−
mice may allow the study of CNS damage associated with RNaseT2 deficiency and may be used for the investigation of potential therapies.
Studies on interferon-driven brain pathology have so far been hampered by the lack of appropriate animal models. Here the authors characterize RNASET2-deficient mice and show that neuroinflammation and brain atrophy are IFNAR1-dependent.
Journal Article
The Cambridge companion to tango
\"An innovative resource which shatters tango stereotypes to account for the genre's impact on arts, culture, and society around the world. Twenty chapters by North and South American, European, and Asian contributors, some publishing in English for the first time, collectively cover tango's history, culture, and performance practice\"-- Provided by publisher.
Book
Investigating Gene Function for Neuronal Survival After Metabolic Stress Using Semi-Automated Fluorescence Microscopy and Automated Image Analysis
Overexpression approaches and fluorescence microscopy techniques allow investigating important spatiotemporal aspects of gene regulation as well as quantifying gene function. Consequently, fluorescence microscopy techniques help answer important questions on gene regulation such as addressing the role of a specific gene product for neuronal survival under different treatments. Here, we describe a versatile tool to measure effects of a transfected gene of interest on neuronal survival upon metabolic stress. We focus on nutrient starvation of cultured rodent primary neurons as a model of metabolic stress but our approach can easily be generalized and adapted to other cell types or to investigate single gene function in regulating neuronal survival under various conditions.
Journal Article
Unlocking microglia pyroptosis in a model of type I interferon-driven neuroinflammation: lessons from Rnaset2−/− mice
RNaseT2-deficient cystic leukoencephalopathy (CLE) presents with severe psychomotor retardation, cystic brain lesions, white matter alterations, and cerebral atrophy. The Rnaset2 −/− mouse mirrors key features of this disease and represents the first murine model with a distinct neurological phenotype for type I interferonopathies. Rnaset2 −/− mice exhibit activated microglia, perivascular monocyte and CD8 + T cell infiltration, and hippocampal accentuated atrophy. However, the mechanisms linking interferon-driven neuroinflammation to neurodegeneration remain unclear, underscoring the need to clarify which molecular processes contribute to tissue injury in a time-dependent manner. We found a sustained upregulation of interferon-stimulated genes (IRF9, RIG-I) over three to 28 weeks of age in the brains of Rnaset2 −/− mice compared to controls. Expression of the chemokines Ccl2, Ccl5 , and Cxcl10 peaked early but declined thereafter. Pyroptosis-related markers (ASC, CASP1, GSDMD) were significantly increased already at three to 6 weeks of age and decreased thereafter, whereas apoptotic markers such as Bax, Bad, Bid, CASP3, CASP8, and PARP were not differentially expressed compared to controls. Finally, Cd3e as well as Tnf peaked later (at 17 weeks of age) and declined at 28 weeks. Interestingly, double IHC confirmed the co-localization of the pyroptosis-related marker ASC with the microglia marker IBA-1. Taken together, these findings support the notion that pyroptosis is an early, disease-associated event restricted to microglia that likely contributes to establishing a proinflammatory milieu prior to T cell infiltration and brain atrophy. Targeting pyroptosis could therefore represent a potential strategy to attenuate neurodegeneration in type I interferon–driven neuroinflammatory disorders.
Journal Article
City, Servant, Wisdom/Folly: Personified Figures and the Jerusalem Temple
Utilizing the spatial theory of Henri Lefebvre, I discuss ways that aspects of the conceived space of the Jerusalem Temple are alternatively developed within the Old Testament through personification. In this dissertation I discuss three personified figures who each take up an aspect or element of this conceived space. Each of the figures studied does this in a different way and takes up different aspects associated with the Temple. Personified Jerusalem appears in Lamentations 1 in the aftermath of the destruction of the Jerusalem Temple at the hands of the Babylonians in 587 BCE. An emphasis on Jerusalem’s personified body receiving violence and responding to that violence depicts this personified figure as a substantial representation of the fallen buildings and Temple within Jerusalem. The personified Servant in Isaiah 52:13-53:12 appears somewhat later than personified Jerusalem in Lamentations 1, still at a time when the Temple does not stand. Identified as YHWH’s Servant, this figure personifies Israel’s exilic community as it returns to Jerusalem with a divinely-given task for the people of Jerusalem. Through metaphors of one who bears the pain and sins of others and of cultic reparation, the Servant functions within the poem as the means of reparation between Jerusalem and YHWH and between the residents of Jerusalem and the returning exiles. In Proverbs 1-9 the two personified figures of Woman Wisdom and Woman Folly together offer two alternative ways for the son, or student, of the instructions to follow: to live a good life in accord with Wisdom or to lead a diminished life in accord with Folly. Attention to such boundaries and an ordered creation are also characteristics of Temple ideology, particularly in terms of the Priestly worldview. In this case the personified figures do not replace the Temple so much as function as alternative to the Second Jerusalem Temple.
Dissertation
The Allure of Tango: Grafting Traditional Performance Practice and Style onto Art-Tangos
Rhythm and meter are crucial to the definition of the tango; earlier versions of the dance form are in 2/4 meter, while later tangos were often in a slower 4/4 meter. Most tangos lyrically describe tragic and dramatic life situations with a simple melody and accompaniment and are in minor keys. The late pianist and professor Yvar Mikhashoff initiated the International Tango Collection in 1983 at the University of Buffalo, which gathered over 126 short art-music tangos for solo piano that range in easily recognizable tango rhythms to no recognizable tango elements. The two analytical steps necessary to perform a convincing interpretation of any stylized popular form of music are a familiarity with the form's original nature and an understanding of how these elements are superimposed onto the stylized composition. Tangos from the Mikhashoff Collection by William Schimmel, Jackson Hill, William Duckworth, Erik Satie and John Cage are discussed in the context of these steps.
Journal Article
The major choral works of Robert Starer and their place in American music
This essay balances an historical and analytical approach to ten choral works by Robert Starer with emphasis on his three large pieces Ariel (Visions of Isaiah) (1959), Images of Man (1973) and The People, Yes (1976). An examination of his commissioning groups both places Starer in an historical context and reflects on how those commissions had an impact on his compositions. The analysis focuses on Starer's accessible musical language, which synthesizes traditional and modern elements into an expanded tonality, and on his dramatic style and treatment of texts. A record of performances and reviews follows the analysis of the major pieces. The text includes fifty-four examples of score excerpts and analytical sketches. Two appendices follow. The first is a catalogue of Starer's complete choral works, and the second supplements sketched analyses with scores. An annotated bibliography encompasses selected writings by Starer, criticism and reviews of his choral works, general sources, and a list of interviews.
Dissertation