21 Works

Systematic genetics and single-cell imaging reveal widespread morphological pleiotropy and cell-to-cell variability.

Brenda Andrews
Our ability to understand the genotype-to-phenotype relationship is hindered by the lack of detailed understanding of phenotypes at a single-cell level. To systematically assess cell-to-cell phenotypic variability, we combined automated yeast genetics, high-content screening and neural network-based image analysis of single cells, focussing on genes that influence the architecture of four subcellular compartments of the endocytic pathway as a model system. Our unbiased assessment of the morphology of these compartments — endocytic patch, actin patch,...

Characterizing and classifying neuroendocrine neoplasms through microRNA sequencing and data mining

Jina Nanayakkara, Xiaojing Yang, Kathrin Tyryshkin, Justin J.M. Wong, Kaitlin Vanderbeck, Paula S. Ginter, Theresa Scognamiglio, Yao-Tseng Chen, Nicole Panarelli, Nai-Kong Cheung, Frederike Dijk, Iddo Z. Ben-Dov, Michelle Kang Kim, Simron Singh, Pavel Morozov, Klaas E. A. Max, Thomas Tuschl & Neil Renwick
Neuroendocrine neoplasms (NENs) are clinically diverse and incompletely characterized cancers that are challenging to classify. MicroRNAs (miRNAs) are small regulatory RNAs that can be used to classify cancers. Recently, a morphology-based classification framework for evaluating NENs from different anatomic sites was proposed by experts, with the requirement of improved molecular data integration. Here, we compiled 378 miRNA expression profiles to examine NEN classification through comprehensive miRNA profiling and data mining. Following data preprocessing, our final...

Data from: Differential requirements for the RAD51 paralogs in genome repair and maintenance in human cells

Edwige B. Garcin, Stéphanie Gon, Meghan R. Sullivan, Gregory J. Brunette, Anne De Cian, Jean-Paul Concordet, Carine Giovannangeli, Wilhelm G. Dirks, Sonja Eberth, Kara A. Bernstein, Rohit Prakash, Maria Jasin & Mauro Modesti
Deficiency in several of the classical human RAD51 paralogs [RAD51B, RAD51C, RAD51D, XRCC2 and XRCC3] is associated with cancer predisposition and Fanconi anemia. To investigate their functions, isogenic disruption mutants for each were generated in non-transformed MCF10A mammary epithelial cells and in transformed U2OS and HEK293 cells. In U2OS and HEK293 cells, viable ablated clones were readily isolated for each RAD51 paralog; in contrast, with the exception of RAD51B, RAD51 paralogs are cell-essential in MCF10A...

Data from: Th2 cytokines inhibit lymphangiogenesis

Ira L. Savetsky, Swapna Ghanta, Jason C. Gardenier, Jeremy S. Torrisi, Gabriela D. Garcia Nores, Geoffrey E. Hespe, Matthew D. Nitti, Raghu P. Kataru & Babak J. Mehrara
Lymphangiogenesis is the process by which new lymphatic vessels grow in response to pathologic stimuli such as wound healing, inflammation, and tumor metastasis. It is well-recognized that growth factors and cytokines regulate lymphangiogenesis by promoting or inhibiting lymphatic endothelial cell (LEC) proliferation, migration and differentiation. Our group has shown that the expression of T-helper 2 (Th2) cytokines is markedly increased in lymphedema, and that these cytokines inhibit lymphatic function by increasing fibrosis and promoting changes...

Data from: Lymph node transplantation decreases swelling and restores immune responses in a transgenic model of lymphedema

Jung-Ju Huang, Jason C. Gardenier, Geoffrey E. Hespe, Gabriela D. García Nores, Raghu P. Kataru, Catherine L. Ly, Inés Martínez-Corral, Sagrario Ortega & Babak J. Mehrara
Introduction: Secondary lymphedema is a common complication of cancer treatment and recent studies have demonstrated that lymph node transplantation (LNT) can decrease swelling, as well as the incidence of infections. However, although these results are exciting, the mechanisms by which LNT improves these pathologic findings of lymphedema remain unknown. Using a transgenic mouse model of lymphedema, this study sought to analyze the effect of LNT on lymphatic regeneration and T cell-mediated immune responses. Methods: We...

Data from: Splicing factor SF3B1K700E mutant dysregulates erythroid differentiation via aberrant alternative splicing of transcription factor TAL1

Shuiling Jin, Hairui Su, Ngoc-Tung Tran, Jing Song, Sydney S. Lu, Ying Li, Suming Huang, Omar Abdel-Wahab, Yanyan Liu & Xinyang Zhao
More than 60% of myeloid dysplasia syndrome (MDS) contains mutations in genes encoding for splicing factors such as SF3B1, U2AF, SRSF2 and ZRSR2. Mutations in SF3B1 are associated with 80% cases of refractory anemia with ring sideroblast (RARS), a subtype of MDS. SF3B1K700E is the most frequently mutated site among mutations on SF3B1. Yet the molecular mechanisms on how mutations of splicing factors lead to defective erythropoiesis are not clear. SF3B1K700E mutant binds to an...

Systematic genetics and single-cell imaging reveal widespread morphological pleiotropy and cell-to-cell variability.

Brenda Andrews
Our ability to understand the genotype-to-phenotype relationship is hindered by the lack of detailed understanding of phenotypes at a single-cell level. To systematically assess cell-to-cell phenotypic variability, we combined automated yeast genetics, high-content screening and neural network-based image analysis of single cells, focussing on genes that influence the architecture of four subcellular compartments of the endocytic pathway as a model system. Our unbiased assessment of the morphology of these compartments — endocytic patch, actin patch,...

Binding Modes of Ligands Using Enhanced Sampling (BLUES): Rapid Decorrelation of Ligand Binding Modes via Nonequilibrium Candidate Monte Carlo

Samuel Gill, Nathan Lim, Patrick Grinaway, Ariën Rustenburg, Josh Fass, Gregory Ross, John Chodera & David Mobley
Accurately predicting protein-ligand binding affinities and binding modes is a major goal in computational chemistry, but even the prediction of ligand binding modes in proteins poses major challenges. Here, we focus on solving the binding mode prediction problem for rigid fragments. That is, we focus on computing the dominant placement, conformation, and orientations of a relatively rigid, fragment-like ligand in a receptor, and the populations of the multiple binding modes which may be relevant. This...

Data from: Genomic DNA transposition induced by human PGBD5

Anton G. Henssen, Elizabeth Henaff, Eileen Jiang, Amy R. Eisenberg, Julianne R. Carson, Camila M. Villasante, Mondira Ray, Eric Still, Melissa Burns, Jorge Gandara, Cedric Feschotte, Christopher E. Mason & Alex Kentsis
Transposons are mobile genetic elements that are found in nearly all organisms, including humans. Mobilization of DNA transposons by transposase enzymes can cause genomic rearrangements, but our knowledge of human genes derived from transposases is limited. In this study, we find that the protein encoded by human PGBD5, the most evolutionarily conserved transposable element-derived gene in vertebrates, can induce stereotypical cut-and-paste DNA transposition in human cells. Genomic integration activity of PGBD5 requires distinct aspartic acid...

Data from: Cutting through the complexity of cell collectives

Carey D. Nadell, Vanni Bucci, Knut Drescher, Simon A. Levin, Bonnie L. Bassler & Joao B. Xavier
Via strength in numbers, groups of cells can influence their environments in ways that individual cells cannot. Large-scale structural patterns and collective functions underpinning virulence, tumour growth and bacterial biofilm formation are emergent properties of coupled physical and biological processes within cell groups. Owing to the abundance of factors influencing cell group behaviour, deriving general principles about them is a daunting challenge. We argue that combining mechanistic theory with theoretical ecology and evolution provides a...

Evolution and regulation of microbial secondary metabolism

Joao Xavier, Francisc Pinto, Zhe Wang, Kyu Rhee, Chen Liao, Guillem Santamaria & Jinyuan Yan
Microbes have disproportionate impacts on the macroscopic world. This is in part due to their ability to grow to large groups and cooperatively secrete massive amounts of secondary metabolites that impact their environment. Yet, the conditions enabling secondary metabolism without compromising primary needs remain unclear. Here we investigated the biosynthesis of thamnolipids, a secondary metabolite that Pseudomonas aeruginosa makes to decrease the surface tension of surrounding liquid. Using a combination of genomics, metabolomics, transcriptomics, and...

SUVfdg: a standard-uptake-value (SUV) body habitus normalizer specific to fluorodeoxyglucose (FDG) in humans

Bradley Beattie, Tim Akhurst, Finn Augensen & John Humm
In PET, several different Standard Uptake Value (SUV) metrics have been proposed utilizing different normalizers in an attempt to take into consideration the patient to patient differences in radionuclide uptake due to differences in body habitus (body weight, surface area, lean body mass). These normalizers are to some extent aribitrary in that they are selected from the list of proposed body habitus metrics, none of which necessarily describes well the distribution volume into which a...

Data from: Alternative splicing substantially diversifies the transcriptome during early photomorphogenesis and correlates with the energy availability in Arabidopsis

Lisa Hartmann, Philipp Drewe-Boß, Theresa Wießner, Gabriele Wagner, Sascha Geue, Hsin-Chieh Lee, Dominik M. Obermüller, André Kahles, Jonas Behr, Fabian H. Sinz, Gunnar Rätsch & Andreas Wachter
Plants use light as source of energy and information to detect diurnal rhythms and seasonal changes. Sensing changing light conditions is critical to adjust plant metabolism and to initiate developmental transitions. Here we analyzed transcriptome-wide alterations in gene expression and alternative splicing (AS) of etiolated seedlings undergoing photomorphogenesis upon exposure to blue, red, or white light. Our analysis revealed massive transcriptome reprograming as reflected by differential expression of ~20% of all genes and changes in...

Data from: Sequence co-evolution gives 3D contacts and structures of protein complexes

Thomas A. Hopf, Charlotta P. I. Schärfe, João P. G. L. M. Rodrigues, Anna G. Green, Chris Sander, Alexandre M. J. J. Bonvin, Debora S. Marks & Oliver Kohlbacher
Protein-protein interactions are fundamental to many biological processes. Experimental screens have identified tens of thousands of interactions and structural biology has provided detailed functional insight for select 3D protein complexes. An alternative rich source of information about protein interactions is the evolutionary sequence record. Building on earlier work, we show that analysis of correlated evolutionary sequence changes across proteins identifies residues that are close in space with sufficient accuracy to determine the three-dimensional structure of...

Data from: Reflectance confocal microscopy features of BRAF V600E mutated thin melanomas detected by immunohistochemistry

Ana Claudia Urvanegia, Juliana Casagrande Tavoloni Braga, Danielle Shitara, Jose Humberto Fregnani, Jose Ivanildo Neves, Clovis Antonio Pinto, Ashfaq A. Marghoob, Joao Pedreira Duprat & Gisele Gargantini Rezze
The classification of melanoma into four histological subtypes has been questioned regarding its clinical validity in providing relevant information for treatment for metastatic tumors. Specific genetic alterations are associated with particular clinical and histopathological features, suggesting that these could be helpful in refining existing melanoma classification schemes. We analyzed BRAF V600E mutated melanomas to explore the Reflectance confocal microscopy (RCM) utility as a screening aid in the evaluation of the most appropriate patients for genetic...

USP8 and TP53 drivers are associated with CNV in a corticotroph adenoma cohort enriched for aggressive tumors

Andrew Uzilov & Eliza Geer
Context: Pituitary corticotroph adenomas are rare tumors that can be associated with excess adrenocorticotropic hormone (ACTH) and adrenal cortisol production, resulting in the clinically debilitating endocrine condition Cushing disease. A subset of corticotroph tumors behave aggressively, and genomic drivers behind the development of these tumors are largely unknown. Objective: To investigate genomic drivers of corticotroph tumors at risk for aggressive behavior. Design: Whole-exome sequencing of patient-matched corticotroph tumor and normal DNA from a patient cohort...

Supporting Information: Toward learned chemical perception of force field typing rules

Camila Zanette, Caitlin C. Bannan, Christopher I. Bayly, Josh Fass, Michael K. Gilson, Michael R. Shirts, John D. Chodera & David L. Mobley
The Open Force Field Initiative seeks to to automate force field development in order to advance force fields and improve accuracy (openforcefield.org). An important part of this effort includes automating the determination of chemical perception --- that is, the way force field parameters are assigned to a molecule based on chemical environment. We developed a novel technology for this purpose, termed SMARTY. It generalizes atom typing by using direct chemical perception with SMARTS strings adopting...

Data from: Cell signaling-based classifier predicts response to induction therapy in elderly patients with acute myeloid leukemia

Alessandra Cesano, Cheryl L. Willman, Kenneth J. Kopecky, Urte Gayko, Santosh Putta, Brent Louie, Matt Westfall, Norman Purvis, David C. Spellmeyer, Carol Marimpietri, Aileen C. Cohen, James Hackett, Jing Shi, Michael G. Walker, Zhuoxin Sun, Elisabeth Paietta, Martin S. Tallman, Larry D. Cripe, Susan Atwater, Frederick R. Appelbaum & Jerald P. Radich
Single-cell network profiling (SCNP) data generated from multi-parametric flow cytometry analysis of bone marrow (BM) and peripheral blood (PB) samples collected from patients >55 years old with non-M3 AML were used to train and validate a diagnostic classifier (DXSCNP) for predicting response to standard induction chemotherapy (complete response [CR] or CR with incomplete hematologic recovery [CRi] versus resistant disease [RD]). SCNP-evaluable patients from four SWOG AML trials were randomized between Training (N = 74 patients...

Data from: Ensembler: enabling high-throughput molecular simulations at the superfamily scale

Daniel L. Parton, Patrick B. Grinaway, Sonya M. Hanson, Kyle A. Beauchamp & John D. Chodera
The rapidly expanding body of available genomic and protein structural data provides a rich resource for understanding protein dynamics with biomolecular simulation. While computational infrastructure has grown rapidly, simulations on an omics scale are not yet widespread, primarily because software infrastructure to enable simulations at this scale has not kept pace. It should now be possible to study protein dynamics across entire (super)families, exploiting both available structural biology data and conformational similarities across homologous proteins....

Data from: Forward genetic screen of human transposase genomic rearrangements

Anton G. Henssen, Eileen Jiang, Jiali Zhuang, Luca Pinello, Nicholas D. Socci, Richard Koche, Mithat Gonen, Camila M. Villasante, Scott A. Armstrong, Daniel E. Bauer, Zhiping Weng & Alex Kentsis
Background: Numerous human genes encode potentially active DNA transposases or recombinases, but our understanding of their functions remains limited due to shortage of methods to profile their activities on endogenous genomic substrates. Results: To enable functional analysis of human transposase-derived genes, we combined forward chemical genetic hypoxanthine-guanine phosphoribosyltransferase 1 (HPRT1) screening with massively parallel paired-end DNA sequencing and structural variant genome assembly and analysis. Here, we report the HPRT1 mutational spectrum induced by the human...

Data from: Clonal relatedness between lobular carcinoma in situ and synchronous malignant lesions

Victor P. Andrade, Irina Ostrovnaya, Venkatraman E. Seshan, Mary Morrogh, Dilip Giri, Narciso Olvera, Marina De Brot, Monica Morrow, Colin B. Begg & Tari A. King
INTRODUCTION: Lobular carcinoma in situ (LCIS) has been accepted as a marker of risk for the development of invasive breast cancer, yet modern models of breast carcinogenesis include LCIS as a precursor of low-grade carcinomas. We provide evidence favoring a clonal origin for LCIS and synchronous estrogen receptor-positive malignant lesions of the ductal and lobular phenotype. METHODS: Patients with prior LCIS undergoing mastectomy were identified preoperatively from 2003-2008. Specimens were widely sampled, and frozen blocks...

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