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    Residence of the Schermerhorn family

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    Residence of the Schermerhorn family, foot of 64th Street and East River Reproduced from the original print owned by Cris Kenzel and given to RU Archives by Joshua Lederberg on January 26th, 1981. Almost 120 years ago the search for a permanent site for the new Rockefeller Institute for Medical Research ended with the purchase of the Schermerhorn estate, an almost perfectly preserved 18th-centuryDutch farm, complete with grazing cows and chickens and a house described as “a Swiss chalet with Dutch trimmings.” The house, built in 1747, served for a number of years as the “country” retreat of George Clinton, who later became the first governor of New York and who served twice as vice president.https://digitalcommons.rockefeller.edu/the-evolving-campus/1001/thumbnail.jp

    Remark by David Rockefeller during the launching of the River Campus ceremony

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    Remark by David Rockefeller during the launching of the River Campus ceremony, 2014 Marc Tessier-Lavigne, former president of The Rockefeller University, on November 24th, 2014, announced two leadership pledges of $75 million each from the Stavros Niarchos Foundation and David Rockefeller to launch a major extension of the University’s campus on the East River. “Stavros Niarchos and David Rockefeller were close friends and legendary business partners for over half a century,” said Andreas C. Dracopoulos, great-nephew of the late Stavros Niarchos, co-president of the Stavros Niarchos Foundation and a member of the University’s Board of Trustees. “They did well together in the twentieth century, and now they’re joining forces again to do good in the twenty-first.https://digitalcommons.rockefeller.edu/the-evolving-campus/1095/thumbnail.jp

    Conformational Dynamics of the Nuclear Pore Complex Studied With Coarse-Grained Modelling and Polarized Light Microscopy

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    In my thesis work, I explored the organization and dynamics of the nuclear pore complex (NPC) through coarse-grained modelling and polarized-total internal reflection fluorescence (pol-TIRF) microscopy. The NPC is a large (~120 MDa in humans) macromolecular assembly that controls the flow of molecules into and out of the nucleus. The NPC is a key regulator of intracellular trafficking, nuclear organization, and gene expression. The study of this cellular gatekeeper is hampered by its size and complexity, as well as the difficulty of measuring protein dynamics in vivo. Although various models for how cargo translocates the NPC have been proposed, the mechanism remains unclear. However, most models for transport propose a crucial role for the phenylalanine-glycine nucleoporins (FG-Nups). I constructed a coarse-grained model to investigate the dynamics of these proteins. My coarse-grained model was able to recapitulate in vivo experimental results previously measured in our lab. My results also suggest that, at the time-scale of cargo translocation, some of the FG-Nups are highly mobile and capable of translocating back and forth across the NPC in milliseconds. This coarse-grained computational model and its results will be discussed in Chapter 2. The entire NPC and its constituent nucleoporins (Nups) have been subject to a great many structural studies; however, monitoring the dynamics of the NPC in vivo has proven to be highly difficult. In order to overcome this challenge, I have built and validated a series of fluorescent orientational sensors. These sensors can be used in conjunction with a pol-TIRF imaging scheme to resolve the orientations and dynamics of specific Nups inside individual NPCs within living cells. By rigidly conjugating mEGFP to various Nups in the scaffold rings of the NPC, I have been able monitor Nups within the Y-shaped complex, the adaptor ring, and the inner channel ring of the NPC. In Chapter 3, I will describe the tools I have built to test NPC dynamics. I proceeded to measure the orientations and dynamics of the Nups under different transport conditions with these tools. In Chapter 4, I show that Nup54, a member of the inner channel ring, undergoes a shift in conformation under a variety of transport conditions. An orientational shift was not observed in Nup133, a member of the Y-shaped complex. These results suggest that the inner channel ring may reorganize with respect to the NPC in response to cargo translocation. In the final chapter of this thesis, I explore the implications of our findings and outline the immediate future directions of this work. I will close by describing how polarization microscopy can be applied to other biological systems and proposing some basic technological improvements to this technique

    Molecular Mechanisms Underlying Stress-Induced Glia Remodeling in the Nematode C. Elegans

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    Animals can adapt to long-term environmental changes by modifying their behavior, which can be accompanied by structural alterations of the nervous system. Such alterations are common in sensory organs, composed of sensory neurons and glia, which initially detect environmental stress. The molecular mechanisms driving cell shape remodeling following environmental stress and the effects of such remodeling on animal survival are not well understood. C. elegans is an excellent model in which to study neuronal and glial cell remodeling. Under normal growth conditions, the sensory receptive endings of the bilateral AWC sensory neurons, which respond to volatile odorants, are individually ensheathed by processes of adjacent amphid sheath (AMsh) glial cells. Upon exposure to high temperature, starvation, or crowding, animals enter an alternative developmental state, called dauer, in which bilateral AMsh glia membranes surrounding the AWC neuron fuse, connecting the two glial cells, and allowing the AWC neuronal receptive endings to expand. Previous studies from our lab identified several AMsh glia proteins required for remodeling. These include (1) the cell fusion protein AFF-1, (2) a VEGFR-related protein VER-1, (3) the Otd/Otx transcription factor TTX-1, and (4) the zinc-finger transcription factor ZTF-16. ver-1 expression in AMsh glia is induced by dauer entry or by cultivation at high temperature, and requires direct binding of TTX-1 to ver-1 regulatory sequences. To identify additional genes involved in stress-induced sensory organ remodeling, we performed a forward genetic screen, seeking mutants in which ver-1 expression at high temperature is not induced. One mutant recovered from this screen harbors a causal lesion in F47D2.11 gene, which encodes a 7- transmembrane G-protein coupled receptor (GPCR). Mutations in F47D2.11 not only block ver-1 induction, but also prevent dauer-induced AMsh glia remodeling and result in a delay in exit from the dauer state following exposure to a favorable environment. F47D2.11 mutants can be rescued by expression of the wild-type cDNA in AMsh glia but not in AWC neurons. These results implicate F47D2.11 in the sensation of dauer conditions in AMsh glia, required for dauer-induced glial remodeling and timely dauer exit

    Modeling Alzheimer\u27s Disease Using CRISPR/CAS9 Gene Editing and Induced Pluripotent Stem Cells Reveals Conserved Cellular Mechanisms

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    Alzheimer\u27s disease (AD) is the most common cause of dementia worldwide and a leading cause of death in the United States. Rare cases of autosomal dominant familial AD (fAD) result from genetic mutations in three key genes: amyloid precursor protein (APP), and two APP processing-related genes (presenilin-1 (PSEN1), and presenilin-2 (PSEN2)), supporting the theory that altered APP metabolism is a central cause of AD. However, which product of APP metabolism is causal remains a matter of investigation. A probable source of this lack of understanding stems from the poor disease model systems that have been utilized in the field for many years. Recently, advances in human induced pluripotent stem cell (iPSC) technology has enabled the study of uniquely human diseases, such as AD, in human tissue. However, the inability to precisely and efficiently genetically engineer human iPSCs has limited their use in effectively studying monogenic human diseases like fAD

    Scale weights

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    Scale weights, circa 1950s Scale weights used in a mechanical torsion scale to weight chemicals Courtesy of Vincent Fischetti Photo by Lubosh Stepanekhttps://digitalcommons.rockefeller.edu/the-evolving-campus/1048/thumbnail.jp

    Sarah J. Schlesinger Oral History. Part 11: Advice to young scientists

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    Interview recorded in spring 2019. Part of The Rita and Frits Markus Library Oral History project.https://digitalcommons.rockefeller.edu/sarah-schlesinger/1010/thumbnail.jp

    Sarah J. Schlesinger Oral History. Part 8: Experimental treatment for Dr. Steinman

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    Interview recorded in spring 2019. Part of The Rita and Frits Markus Library Oral History project.https://digitalcommons.rockefeller.edu/sarah-schlesinger/1007/thumbnail.jp

    Foreword to the booklet The Rockefeller University by Detlev W. Bronk

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    Foreword to the booklet The Rockefeller University by Detlev W. Bronk, June 1968https://digitalcommons.rockefeller.edu/the-evolving-campus/1068/thumbnail.jp

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