42 research outputs found
Schematic of the NVU.
No full text<p>The NVU comprises the cerebral microvascular endothelium (shown in red), its basement membrane, and associated pericytes (yellow) and astrocytes (orange). The perivascular space exists between the endothelium and astrocytic endfeet. The endothelium provides the structural and functional basis for the blood–brain barrier (BBB), while astrocytes and pericytes control barrier induction and maintenance [<a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.1002300#pbio.1002300.ref007" target="_blank">7</a>]. Junctional proteins exist between endothelial cells and astrocytes (glia limitans) to help regulate entrance into the CNS parenchyma. <i>Image credit</i>: <i>Gareth R</i>. <i>John & Benjamin M</i>. <i>Laitman</i>.</p
The impacts of exercise on age-related cognitive decline.
No full text<p>Three major factors have been implicated in promoting age-related cognitive decline: inflammation, neurovascular changes, and changes in CNS structure and function. Exercise has been shown to be beneficial in impacting these three categories. It has been shown to promote neurogenesis [<a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.1002300#pbio.1002300.ref016" target="_blank">16</a>], increase CBF and angiogenesis [<a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.1002300#pbio.1002300.ref014" target="_blank">14</a>], and reduce inflammation [<a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.1002300#pbio.1002300.ref004" target="_blank">4</a>,<a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.1002300#pbio.1002300.ref017" target="_blank">17</a>], correlating with improved cognitive performance. Soto et al. adds to this data (red text) by demonstrating that exercise reduces the age-related loss of pericytes, basement membrane components, and astrocyte reactivity at the NVU, and reduces the amount of complement induction in myeloid cells. <i>Image credit</i>: <i>Gareth R</i>. <i>John & Benjamin M</i>. <i>Laitman</i>.</p
High-Throughput Functional Analysis Distinguishes Pathogenic, Nonpathogenic, and Compensatory Transcriptional Changes in Neurodegeneration
No full textDiscriminating transcriptional changes that drive disease pathogenesis from nonpathogenic and compensatory responses is a daunting challenge. This is particularly true for neurodegenerative diseases, which affect the expression of thousands of genes in different brain regions at different disease stages. Here we integrate functional testing and network approaches to analyze previously reported transcriptional alterations in the brains of Huntington disease (HD) patients. We selected 312 genes whose expression is dysregulated both in HD patients and in HD mice and then replicated and/or antagonized each alteration in a Drosophila HD model. High-throughput behavioral testing in this model and controls revealed that transcriptional changes in synaptic biology and calcium signaling are compensatory, whereas alterations involving the actin cytoskeleton and inflammation drive disease. Knockdown of disease-driving genes in HD patient-derived cells lowered mutant Huntingtin levels and activated macroautophagy, suggesting a mechanism for mitigating pathogenesis. Our multilayered approach can thus untangle the wealth of information generated by transcriptomics and identify early therapeutic intervention points
<i>Kpna4</i> is an important regulator of CNTF-induced oligodendrocyte differentiation.
No full text(A-C) Confocal imaging of Kpna4 expression in vivo in P1 (A) and P14 (C) thoracolumbar mouse spinal cord sections. Kpna4 is expressed in multiple cells within the CNS including APC+Olig2+ OLs (representative cells indicated with white arrows), but not by immature Olig2+APC- cells (yellow arrowhead). The region outlined in (A) is magnified in panels to the right. Panel (B) shows a high power image of Olig2+ cells in thoracolumbar spinal cord at P1. Cells show both nuclear (B, red arrowheads) and cytoplasmic Kpna4 immunoreactivity (B, white arrowheads). (D) qPCR data from OLP nucleofected with siKpna4 or siNT control for 24h. Silencing is efficient and is selective for Kpna4. (E,F) Representative confocal image and associated quantification from primary mouse OLP silenced for Kpna4 versus nontargeting control, then allowed to proliferate in the presence of the mitogens PDGFAA and bFGF for 24h. Active proliferation was assessed by immunocytochemistry for Ki67, confocal imaging, and quantitation of %Ki67/DAPI cells. (G-I) To directly compare responses of Kpna4-deficient cells and controls to CNTF vs. T3 in parallel, primary cultures were nucleofected with siRNA for Kpna4 or nontargeting (NT) control, then treated with either CNTF or T3. (G) Representative confocal image and associated quantification from primary mouse OLP nucleofected with siKpna4 or siNT control and then differentiated with T3 (60 ng/ml) or CNTF (100 ng/ml) for 72h. This image shows maturation markers for OLP (NG2), immature/mature OL (O4), and mature OL (MBP) in the Olig2+ OL lineage in Kpna4-deficient cultures and controls treated with T3 or CNTF. Maturation was assessed by quantifying %O4/DAPI (H) and %MBP/DAPI (I) expressing cells. Maturation was reduced in CNTF-treated cultures. In T3-treated cultures, only a slight reduction was observed in the proportion of MBP expressing cells, which did not reach significance, illustrating a differential impact of silencing Kpna4 depending on the growth factor added to induce differentiation. (J,K) The reduction in maturation markers coincided with a loss in complexity of branching morphology, a marker of OL maturity, as assessed by fractal analysis. Fractal results are represented by the box-counting fractal dimension (Db). (L,M) Cell death was unchanged in these cultures regardless of treatment with CNTF (L) or T3 (M), measured by both assessments of apoptosis (%Cleaved-caspase 3 (CC3)/DAPI) and total cell number (DAPI counts per field). Data are mean ± S.E.M. and representative of 3 (D,F,L,M) or 5 (H-K) independent cultures. Statistics, (D,F,L,M,J,K) Student’s t-test, (H,I) Two-way ANOVA plus Bonferroni test, *ppp(A) 50μm, 25μm inset, (B) 10μM, (C) 25μm, (E) 20μm, (G) 20μm. Individual data values are in S1 data.</p
Parade of Passions: Notes on Three Performances
No full textTwo recitals and an opera role were performed in lieu of a written dissertation.
The following notes on three dissertation performances, “Ways of Seeing,” “Parade of Passions,” and “Familiar and Well Belovèd,” represent paths through vocal craftsmanship, scholarship and pedagogy as a doctoral student at the University of Michigan. The opera role of Alcina, flanked by two vocal recitals, together built experience in a range of languages, styles, cultural contexts and technical developments. Though the works discussed have diverse origins and narratives, there is a distinctive theme of intimacy in each of these projects. In the first recital, “Ways of Seeing,” perception as a dictate of meaning was explored by proposing a new lens through which to “see” or internalize poetry around a common theme of the female body. The idea of a subjective or shifting interior life was explored in the character of Alcina, particularly as it manifested as a diverse array of musical textures offered by Georg Friderich Handel. Finally, intimate space—whether objective, performative or personal—was explored as a conduit for universal connection and belonging in the recital entitled, “Familiar and Well Belovèd,” featuring the music of Johannes Brahms, Samuel Barber and Benjamin C.S Boyle.
Recital 1: “Ways of Seeing.” November 17, 2018, 5:30 pm, Stamps Auditorium, Ann Arbor, MI. Michael McElvain, piano.
Program: “Galathea,” Arnold Schoenberg; “Take, O take those lips away,” Amy Beach; “Pur dicesti o bocca bocca bella,” Antonio Lotti; “Dein blaues Auge,” Johannes Brahms; “Lady when I behold the roses,” William Walton; “Troubled Woman,” Ricky Ian Gordon; “Chanson de mer,” Pauline Viardot; “Ich stand in dunkeln Träumen,” Clara Schumann; “Storia breve,” Ottorino Respighi; “Tus ojillos negros,” Manuel de Falla; “Song to the dark virgin,” Florence Price; “Jane,” Claude Debussy; “El mirar de la maja,” Enrique Granados; “Seit ich ihn gesehen,” Robert Schumann; “The mystery,” Lori Laitman; “Lyric for Truelove,” Undine Smith Moore; “My love in her attire,” William Walton; “Homme au sourire tendre,” Francis Poulenc; “Réversibilité,” Louis Vierne.
Recital 2: In lieu of a recital, the title role in the opera, Alcina, by Georg Friedrich Handel was performed on March 28 and 30, 2019, at the Lydia Mendelssohn Theater, Ann Arbor, MI.
Grant Preisser, director; Stephanie Rhodes Russell, conductor.
Recital 3: “Familiar and Well Belovèd.” April 16, 2019, 7:00 pm, Kerrytown Concert House, Ann Arbor, MI. Michael McElvain, Chao Gao and Joshua Marzan, piano; Jessica Dold, soprano, Samuel Kidd, baritone, Brandon Motz, tenor, and Nicholas Music, tenor.
Program: Neue Liebeslieder Walzer, Johannes Brahms; Knoxville: Summer of 1915, Samuel Barber; Song of Solomon, Benjamin C.S. Boyle (world premiere).Doctor of Musical Arts (DMA)Music: PerformanceUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttps://deepblue.lib.umich.edu/bitstream/2027.42/151698/1/kellybix_1.pd
