A5085393914- Genomics and Chromatin Dynamics
- Cancer Genomics and Diagnostics
- Chromosomal and Genetic Variations
- Microtubule and mitosis dynamics
- Genomic variations and chromosomal abnormalities
- Protein Structure and Dynamics
- Genomics and Phylogenetic Studies
- Gene Regulatory Network Analysis
- CRISPR and Genetic Engineering
- DNA Repair Mechanisms
- Cell Adhesion Molecules Research
- BRCA gene mutations in cancer
- RNA modifications and cancer
- Viral Infectious Diseases and Gene Expression in Insects
- Computational Drug Discovery Methods
- RNA Research and Splicing
- Photosynthetic Processes and Mechanisms
- Monoclonal and Polyclonal Antibodies Research
- Cellular Mechanics and Interactions
- T-cell and Retrovirus Studies
- Chronic Myeloid Leukemia Treatments
- Melanoma and MAPK Pathways
- Satellite Communication Systems
- Machine Learning in Materials Science
- Gene expression and cancer classification
Weill Cornell Medicine
2019-2023
Cornell University
2016-2023
New York Genome Center
2019-2023
Tri-Institutional PhD Program in Chemical Biology
2016-2021
Memorial Sloan Kettering Cancer Center
2015-2018
New York Structural Biology Center
2016
Pennsylvania State University
2015
University of Cologne
2014
Objectives: To assess the influence of an infusion clonidine 1 μg/kg/hr on fentanyl and midazolam requirement in ventilated newborns infants. Design: Prospective, double-blind, randomized controlled multicenter trial. Controlled trials.com/ISRCTN77772144. Setting: Twenty-eight level 3 German PICUs/neonatal ICUs. Patients: Ventilated infants: stratum I (1–28 d), II, (29–120 III (121 d to 2 yr). Interventions: Patients received or placebo day 4 after intubation. Fentanyl were adjusted achieve...
Many eukaryotic protein kinases are activated by phosphorylation on a specific conserved residue in the regulatory activation loop, post-translational modification thought to stabilize active DFG-In state of catalytic domain. Here we use battery spectroscopic methods that track different elements kinase domain show ~100 fold mitotic Aurora A (AurA) occurs without population shift from DFG-Out state, and loop remains highly dynamic. Instead, molecular dynamics simulations electron...
Abstract Short-read sequencing is the workhorse of cancer genomics yet thought to miss many structural variants (SVs), particularly large chromosomal alterations. To characterize missing SVs in short-read whole genomes, we analyzed ‘loose ends’—local violations mass balance between adjacent DNA segments. In landscape loose ends across 1,330 high-purity most (>10-kb) clonal were fully resolved by short reads 87% human genome where copy number could be reliably measured. Some represent...
Homologous recombination (HR) deficiency is associated with DNA rearrangements and cytogenetic aberrations1. Paradoxically, the types of that are specifically HR-deficient cancers only minimally affect chromosomal structure2. Here, to address this apparent contradiction, we combined genome-graph analysis short-read whole-genome sequencing (WGS) profiles across thousands tumours deep linked-read WGS 46 BRCA1- or BRCA2-mutant breast cancers. These data revealed a distinct class...
Abstract Higher-order chromatin structure arises from the combinatorial physical interactions of many genomic loci. To investigate this aspect genome architecture we developed Pore-C, which couples conformation capture with Oxford Nanopore Technologies (ONT) long reads to directly sequence multi-way contacts without amplification. In GM12878, demonstrate that pairwise interaction patterns implicit in Pore-C are consistent gold standard Hi-C contact maps at compartment, TAD, and loop scales....
Kinases play a critical role in cellular signaling and are dysregulated number of diseases, such as cancer, diabetes, neurodegeneration. Therapeutics targeting kinases currently account for roughly 50% cancer drug discovery efforts. The ability to explore human kinase biochemistry biophysics the laboratory is essential designing selective inhibitors studying resistance. Bacterial expression systems superior insect or mammalian cells terms simplicity cost effectiveness but have historically...
Atomistic molecular simulations are a powerful way to make quantitative predictions, but the accuracy of these predictions depends entirely on quality force field employed. Although experimental measurements fundamental physical properties offer straightforward approach for evaluating quality, bulk this information has been tied up in formats that not machine-readable. Compiling benchmark data sets from non-machine-readable sources requires substantial human effort and is prone accumulation...
Abstract Telomere crisis contributes to cancer genome evolution, yet only a subset of cancers display breakage-fusion-bridge (BFB) cycles and chromothripsis, hallmarks experimental telomere identified in previous studies. We examine the spectrum structural variants (SVs) instigated by natural crisis. Eight spontaneous post-crisis clones did not show prominent patterns BFB or chromothripsis. Their crisis-induced rearrangements varied from infrequent simple SVs more frequent complex SVs. In...
Abstract Somatic mobilization of LINE-1 (L1) has been implicated in cancer etiology. We analyzed a recent TCGA data release comprised nearly 5000 pan-cancer paired tumor-normal whole-genome sequencing (WGS) samples and ~9000 tumor RNA samples. developed TotalReCall an improved algorithm pipeline for detection L1 retrotransposition (RT), finding high correlation between expression “RT burden” per sample. Furthermore, we mathematically model the dual regulatory roles p53, where mutations TP53...
Abstract Somatic activity of LINE-1 (L1) mobile elements has been implicated in cancer etiology, which may be related to the loss p53-mediated regulation as a result TP53 mutations. Quantifying mechanisms L1 challenging. Here, we build statistical model by simultaneously quantifying retrotransposition, expression, and fitness costs mutated with precision. We first developed Total ReCall, an algorithm specifically tailored reintegration, detect insertions from short-read whole-genome...
Summary Cancer genomes often harbor hundreds of somatic DNA rearrangement junctions, many which cannot be easily classified into simple (e.g. deletion, translocation) or complex chromothripsis, chromoplexy) structural variant classes. Applying a novel genome graph computational paradigm to analyze the topology junction copy number (JCN) across 2,833 tumor whole sequences (WGS), we introduce three phenomena: pyrgo, rigma , and tyfonas . Pyrgo are “towers” low-JCN duplications associated with...
This work focuses on one component of a larger research effort to develop simulation tool model populations flowing cells. Specifically, in this study local the biochemical interactions between circulating melanoma tumor cells (TC) and substrate adherent polymorphonuclear neutrophils (PMN) is developed. provides realistic three-dimensional distributions bond formation attendant attraction repulsion forces that are consistent with time dependent Computational Fluid Dynamics (CFD) framework...
Abstract Kinases play a critical role in many cellular signaling pathways and are dysregulated number of diseases, such as cancer, diabetes, neurodegeneration. Since the FDA approval imatinib 2001, therapeutics targeting kinases now account for roughly 50% current cancer drug discovery efforts. The ability to explore human kinase biochemistry, biophysics, structural biology laboratory is essential making rapid progress understanding regulation, designing selective inhibitors, studying...
Abstract Many eukaryotic protein kinases are activated by phosphorylation on a specific conserved residue in the regulatory activation loop, post-translational modification thought to stabilize active DFG-In state of catalytic domain. Here we use battery spectroscopic methods that track different elements kinase domain show ~100-fold mitotic Aurora A (AurA) occurs without population shift state, and loop remains highly dynamic. Instead, molecular dynamics simulations electron paramagnetic...
Abstract Telomere crisis contributes to cancer genome evolution, yet only a subset of cancers display breakage-fusion-bridge (BFB) cycles and chromothripsis, hallmarks previous experimental telomere studies. We examine the spectrum SVs instigated by natural crisis. Spontaneous post-crisis clones from prior studies had both complex simple without BFB or chromothripsis. In contrast, chromothripsis occurred in that escaped after CRISPR-controlled telomerase activation MRC5 fibroblasts. This...
Summary Recent pan-cancer studies have delineated patterns of structural genomic variation across thousands tumor whole genome sequences. It is not known to what extent the shortcomings short read (≤ 150 bp) sequencing (WGS) used for variant analysis has limited our understanding cancer structure. To formally address this, we introduce concept “loose ends” - copy number alterations that cannot be mapped a rearrangement by WGS but can indirectly detected through junction-balanced graphs....