61 research outputs found
Using Youtube to Explain Housing
No full textIn 2021, the author ran for Borough President of Manhattan, New York. The author tried to his scholarship into his campaign by producing over twenty Youtube videos, most of which addressed land use and housing policy. The article describes the videos, and evaluates their usefulness
Using Youtube to Explain Housing
No full textIn 2021, the author ran for Borough President of Manhattan, New York. The author tried to his scholarship into his campaign by producing over twenty Youtube videos, most of which addressed land use and housing policy. The article describes the videos, and evaluates their usefulness
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Constructing, verifying, and dissecting the folding transition state of chymotrypsin inhibitor 2 with all-atom simulations
No full textExperimentally, protein engineering and Phi -value analysis is the method of choice to characterize the structure in folding transition state ensemble (TSE) of any protein. Combining experimental phi values and computer simulations has led to a deeper understanding of how proteins fold. In this report, we construct the TSE of chymotrypsin inhibitor 2 from published phi values. Importantly, we verify, by means of multiple independent simulations, that the conformations in the TSE have a probability of approximate to0.5 to reach the native state rapidly, so the TSE consists of true transition states. This finding validates the use of transition state theory underlying all phi -value analyses. Also, we present a method to dissect and study the TSE by generating conformations that have a disrupted alpha -helix (alpha -disrupted states) or disordered beta -strands 3 and 4 (beta -disrupted states). Surprisingly, the a-disrupted states have a stronger tendency to fold than the beta -disrupted states, despite the higher phi values for the a-helix in the TSE. We give a plausible explanation for this result and discuss its implications on protein folding and design. Our study shows that, by using both experiments and computer simulations, we can gain many insights into protein folding.Version of Recor
Abstract 3376: Reprogramming the estrogen signaling network is a potential mechanism for human breast tumorigenesis
No full textAbstract
Background: The estrogen receptor (ER) is expressed in approximately 70% of sporadic breast cancers and is known to activate genes driving cell proliferation. Much work in the field has characterized the mechanisms of ER signaling behind cancer progression and eventual metastasis, and therapeutic targeting of the ER signaling pathway has proven effective. However, little is known regarding the role of ER in the initial process of transformation. Since ER possesses pro-differentiation roles in normal breast development yet becomes one of the drivers of breast cancer, altered ER function is then likely a crucial early step. We seek to investigate the role of ER from the perspective of the normal breast to allow for mechanistic insights into breast tumorigenesis.
Methods: To model the normal breast epithelium, viable tissue specimens from patients undergoing reduction mammoplasty were obtained and enriched for breast epithelial cells via fluorescence-activated cell sorting (FACS). Fresh-frozen ER+ breast tumor samples were then obtained for comparison. RNA-seq, ChIP-seq for ER, and genome-wide CRISPR screening in the presence of estrogen stimulation in both normal breast and breast tumor were performed. These various modalities of genomic data were then integrated and analyzed to identify patterns in breast tumorigenesis.
Results: Gene expression profiling via RNA-seq of breast epithelial cells from seven reduction mammoplasties reveals a drastically different and muted normal response to estrogen stimulation. Genes that promote cell cycling and cell proliferation were down-regulated in normal breast but were up-regulated in breast cancer cells. Furthermore, differential ER binding alone via ER ChIP-seq is capable of segregating ten primary breast tumors from seven normal breast tissues with very few overlapping sites. Deeper motif analysis reveals the enrichment of novel transcription cofactor GRHL2 in the binding sites most closely associated to ER+ breast cancer. Further findings via genome-wide CRISPR screens reveal GRHL2 as an essential gene in luminal ER+ breast cancer with predictive ability in cancer risk and prognosis.
Conclusions: Cellular reprogramming of the ER signaling network may alter the functioning phenotype of normal mammary epithelial cells and offer insights into the series of events necessary for developing breast cancer. Notably, ER activation does not promote cellular proliferation in normal mammary epithelial cells, and the interaction with transcriptional cofactors such as GRHL2 can be a driving mechanism for breast tumorigenesis. Unraveling the differential ER signaling in normal mammary epithelium and breast cancer will enhance our understanding of breast cancer and aid the development of more effective prevention strategies and targeted therapeutics.
Citation Format: David Chi, Hari Singhal, Lewyn Li, Henry W. Long, Judy E. Garber, Myles A. Brown. Reprogramming the estrogen signaling network is a potential mechanism for human breast tumorigenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3376. doi:10.1158/1538-7445.AM2017-3376</jats:p
Lithium-cation and proton affinities of sulfoxides and sulfones: A fourier transform ion cyclotron resonance study
No full textThe kinetic method was used for the quantitative determination of lithium-cation affinities by Fourier transform ion cyclotron resonance. This method was applied to a series of XYSO and XYSO2 compounds. Proton basicities of the SO and SO2 compounds were also determined. When comparison is made between Li+ basicities and proton basicities, a linear regression encompassing XYSO and XYSO2 families suggests that Li+ may be bonded in a similar way to the SO and SO2 moieties, that is, to only one oxygen on the latter. PM3 calculations support this hypothesis
Stepwise Unfolding of Ankyrin Repeats in a Single Protein Revealed by Atomic Force Microscopy
No full textAbstractUsing single-molecule atomic force microscopy, we find that a protein consisting of six identical ankyrin repeat units flanked by N- and C-terminal modules (N6C) unfolds in a stepwise, unit-by-unit fashion under a mechanical force. Stretching a N6C molecule results in a sawtooth pattern fingerprint, with as many as six peaks separated by ∼10nm and an average unfolding force of 50±20pN. Our results demonstrate that a stretching force can unfold multiple repeat units individually in a single protein molecule, despite extensive hydrophobic interactions between adjacent units
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