Biology subjects

Yang, S.

Publications and source records attributed to Yang, S..

27 records · Page 2Linked to original sources

bioRxiv2017

Imaging-Genomics Study Of Head-Neck Squamous Cell Carcinoma: Associations Between Radiomic Phenotypes And Genomic Mechanisms Via Integration Of TCGA And TCIA

PurposeRecent data suggest that imaging radiomics features for a tumor could predict important genomic biomarkers. Understanding the relationship between radiomic and genomic features is important for basic cancer research and future patient care. For Head and Neck Squamous Cell Carcinoma (HNSCC), we perform a comprehensive study to discover the imaging-genomics associations and explore the potential of predicting tumor genomic alternations using radiomic features.\n\nMethodsOur retrospective study integrates whole-genome multi-omics data from The Cancer Genome Atlas (TCGA) with matched computed tomography imaging data from The Cancer Imaging Archive (TCIA) for the same set of 126 HNSCC patients. Linear regression analysis and gene set enrichment analysis are used to identify statistically significant associations between radiomic imaging features and genomic features. Random forest classifier is used to predict two key HNSCC molecular biomarkers, the status of human papilloma virus (HPV) and disruptive TP53 mutation, based on radiomic features.\n\nResultsWide-spread and statistically significant associations are discovered between genomic features (including miRNA expressions, protein expressions, somatic mutations, and transcriptional activities, copy number variations, and promoter region DNA methylation changes of pathways) and radiomic features characterizing the size, shape, and texture of tumor. Prediction of HPV and TP53 mutation status using radiomic features achieves an area under the receiver operating characteristics curve (AUC) of 0.71 and 0.641, respectively.\n\nConclusionOur analysis suggests that radiomic features are associated with genomic characteristics in HNSCC and provides justification for continued development of radiomics as biomarkers for relevant genomic alterations in HNSCC.

cancer biology↗

bioRxiv2017

TCGA-Assembler 2: Software Pipeline for Retrieval and Processing of TCGA/CPTAC Data

MotivationThe Cancer Genome Atlas (TCGA) program has produced huge amounts of cancer genomics data providing unprecedented opportunities for research. In 2014, we developed TCGA-Assembler (Zhu et al, 2014), a software pipeline for retrieval and processing of public TCGA data. In 2016, TCGA data were transferred from the TCGA data portal to the Genomic Data Commons (GDC), which is supported by a different set of data storage and retrieval mechanisms. In addition, new proteomics data of TCGA samples have been generated by the Clinical Proteomic Tumor Analysis Consortium (CPTAC) program, which were not available for downloading through TCGA-Assembler. It is desirable to acquire and integrate data from both GDC and CPTAC.\n\nResultsWe develop TCGA-Assembler 2 (TA2) to automatically download and integrate data from GDC and CPTAC. We make substantial improvement on the functionality of TA2 to enhance user experience and software performance. TA2 together with its previous version have helped more than 2,000 researchers from 64 countries to access and utilize TCGA and CPTAC data in their research. Availability of TA2 will continue to allow existing and new users to conduct reproducible research based on TCGA and CPTAC data.\n\nAvailabilityhttp://www.compgenome.org/TCGA-Assembler/\n\nContactkoaeraser@gmail.com or zhuyitan@gmail.com

bioinformatics↗

bioRxiv2017

Identification of Cancer-associated Metabolic Vulnerabilities by Modeling Multi-objective Optimality in Metabolism

Computational modeling of the genome-wide metabolic network is essential for designing new therapeutics targeting cancer-associated metabolic disorder, which is a hallmark of human malignancies. However, previous studies generally assumed that metabolic fluxes of cancer cells are subjected to the maximization of biomass production, despite the wide existence of trade-offs among multiple metabolic objectives. To address this issue, we developed a multi-objective model of cancer metabolism with algorithms depicting approximate Pareto surfaces and incorporating multiple omics datasets. To validate this approach, we built individualized models for NCI-60 cancer cell lines, and accurately predicted cell growth rates and other biological consequences of metabolic perturbations in these cells. By analyzing the landscape of approximate Pareto surface, we identified a list of metabolic targets essential for cancer cell proliferation and the Warburg effect, and further demonstrated their close association with cancer patient survival. Finally, metabolic targets predicted to be essential for tumor progression were validated by cell-based experiments, confirming this multi-objective modelling method as a novel and effective strategy to identify cancer-associated metabolic vulnerabilities.

systems biology↗

bioRxiv2017

Inhibition of mitochondrial fission preserves photoreceptors after retinal detachment

Photoreceptor degeneration is a leading cause of visual impairment worldwide. Separation of neurosensory retina from the underlying retinal pigment epithelium is a prominent feature preceding photoreceptor degeneration in a variety of retinal diseases. Although ophthalmic surgeries have been well developed to restore retinal structures, post-op patients usually experience progressive photoreceptor degeneration and irreversible vision loss that is incurable at present. Previous studies point to a critical role of mitochondria-mediated apoptotic pathway in photoreceptor degeneration, but the upstream triggers remain largely unexplored. In this study, we show that after experimental RD induction, photoreceptors activate dynamin-related protein 1 (Drp1)-dependent mitochondrial fission pathway and subsequent apoptotic cascades. Mechanistically, endogenous ROS is necessary for Drp1 activation in vivo and exogenous ROS insult is sufficient to activate Drp1-dependent mitochondrial fission in cultured photoreceptors. Accordingly, inhibition of Drp1 activity effectively preserves mitochondrial integrity and rescues photoreceptors. Collectively, our data delineates a ROS-Drp1-mitochondria axis that promotes photoreceptor degeneration in retinal diseased models.

neuroscience↗

bioRxiv2017

Cryo-EM structure of the bacterial actin AlfA reveals unique assembly and ATP-binding interactions and the absence of a conserved subdomain

Bacterial actins are an evolutionarily diverse family of ATP-dependent filaments built from protomers with a conserved structural fold. Actin-based segregation systems are encoded on many bacterial plasmids and function to partition plasmids into daughter cells. The bacterial actin AlfA segregates plasmids by a mechanism distinct from other partition systems, dependent on its unique dynamic properties. Here, we report the near-atomic resolution cryo-EM structure of the AlfA filament, which reveals a strikingly divergent filament architecture resulting from the loss of a subdomain conserved in all other actins and a novel mode of ATP binding. Its unusual assembly interfaces and nucleotide interactions provide insight into AlfA dynamics, and expand the range of evolutionary variation accessible to actin quaternary structure.\n\nSignificance StatementActin filaments are dynamic cytoskeletal elements that assemble upon ATP binding. Actin homologs are present in all domains of life, and all share a similar three-dimensional structure of the assembling subunit, but evolutionary changes to subunit have generated many different actin filament structures. The filament structure of the bacterial actin AlfA, which positions plasmids - small, circular DNA molecules that encode important genes - to ensure that each daughter cell receives a copy at cell division. AlfA is different from all other actins in two critical ways: it binds to ATP in a unique way, and it is missing a quarter of the conserved structural core. These differences explain unusual AlfA assembly dynamics that underlie its ability to move plasmids.

biophysics↗

bioRxiv2017

Structural basis of the Cope rearrangement and C-C bond-forming cascade in hapalindole/fischerindole biogenesis

STRUCTURESThe atomic coordinates and structure factors for:\n\nHpiC1 W73M/K132M SeMet (P212121) -1.7 [A]\n\nHpiC1 native (C2) -1.5 [A]\n\nHpiC1 native (P42) -2.1 [A]\n\nHpiC1 Y101F (C2) -1.4 [A]\n\nHpiC1 Y101S (C2) -1.4 [A]\n\nHpiC1 F138S (P21) -1.7 [A]\n\nHpiC1 Y101F/F138S (P21 -1.65 [A] have been deposited with the Research Collaboratory for Structural Bioinformatics as Protein Data Bank entries 5WPP, 5WPR, 6AL6, 5WPR, 5WPU, 6AL7, and 6AL8 (www.rcsb.org).\n\nGRANTSThis work was supported by: The authors thank the National Science Foundation under the CCI Center for Selective C-H Functionalization (CHE-1205646), the National Institutes of Health (CA70375 to RMW and DHS), R35 GM118101, R01 GM076477 and the Hans W. Vahlteich Professorship (to DHS) for financial support. M.G-B. thanks the Ramon Areces Foundation for a postdoctoral fellowship. J.N.S. acknowledges the support of the National Institute of General Medical Sciences of the National Institutes of Health under Award Number F32GM122218. Computational resources were provided by the UCLA Institute for Digital Research and Education (IDRE) and the Extreme Science and Engineering Discovery Environment (XSEDE), which is supported by the NSF (OCI-1053575). The content does not necessarily represent the official views of the National Institutes of Health.\n\nABSTRACTHapalindole alkaloids are a structurally diverse class of cyanobacterial natural products defined by their varied polycyclic ring systems and diverse biological activities. These polycyclic scaffolds are generated from a common biosynthetic intermediate by the Stig cyclases in three mechanistic steps, including a rare Cope-rearrangement, 6-exo-trig cyclization, and electrophilic aromatic substitution. Here we report the structure of HpiC1, a Stig cyclase that catalyzes the formation of 12-epi-hapalindole U in vitro. The 1.5 [A] structure reveals a dimeric assembly with two calcium ions per monomer and the active sites located at the distal ends of the protein dimer. Mutational analysis and computational methods uncovered key residues for an acid catalyzed [3,3]-sigmatropic rearrangement and specific determinants that control the position of terminal electrophilic aromatic substitution leading to a switch from hapalindole to fischerindole alkaloids.

biochemistry↗

bioRxiv2017

Expanding the Atlas of Functional Missense Variation for Human Genes

Although we now routinely sequence human genomes, we can confidently identify only a fraction of the sequence variants that have a functional impact. Here we developed a deep mutational scanning framework that produces exhaustive maps for human missense variants by combining random codon-mutagenesis and multiplexed functional variation assays with computational imputation and refinement. We applied this framework to four proteins corresponding to six human genes: UBE2I (encoding SUMO E2 conjugase), SUMO1 (small ubiquitin-like modifier), TPK1 (thiamin pyrophosphokinase), and CALM1/2/3 (three genes encoding the protein calmodulin). The resulting maps recapitulate known protein features, and confidently identify pathogenic variation. Assays potentially amenable to deep mutational scanning are already available for 57% of human disease genes, suggesting that DMS could ultimately map functional variation for all human disease genes.

molecular biology↗

bioRxiv2017

Identification Of Cellular-Activity Dynamics Across Large Tissue Volumes In The Mammalian Brain

Tracking the coordinated activity of cellular events through volumes of intact tissue is a major challenge in biology that has inspired significant technological innovation. Yet scanless measurement of the high-speed activity of individual neurons across three dimensions in scattering mammalian tissue remains an open problem. Here we develop and validate a computational imaging approach (SWIFT) that integrates high-dimensional, structured statistics with light field microscopy to allow the synchronous acquisition of single-neuron resolution activity throughout intact tissue volumes as fast as a camera can capture images (currently up to 100 Hz at full camera resolution), attaining rates needed to keep pace with emerging fast calcium and voltage sensors. We demonstrate that this large field-of-view, single-snapshot volume acquisition method--which requires only a simple and inexpensive modification to a standard fluorescence microscope--enables scanless capture of coordinated activity patterns throughout mammalian neural volumes. Further, the volumetric nature of SWIFT also allows fast in vivo imaging, motion correction, and cell identification throughout curved subcortical structures like the dorsal hippocampus, where cellular-resolution dynamics spanning hippocampal subfields can be simultaneously observed during a virtual context learning task in a behaving animal. SWIFTs ability to rapidly and easily record from volumes of many cells across layers opens the door to widespread identification of dynamical motifs and timing dependencies among coordinated cell assemblies during adaptive, modulated, or maladaptive physiological processes in neural systems.

neuroscience↗

bioRxiv2017

PGC-1α coordinates with Bcl-2 to control cell cycle in U251 cells through reducing ROS

B-cell lymphoma 2 (Bcl-2) has a dual function, acting both as an oncogene and an anti-tumor gene. It is well known that Bcl-2 exerts its tumor promoting function through the mitochondrial pathway. However, the mechanism by which Bcl-2 suppresses tumor formation is not well understood. We have previously shown that Bcl-2 inhibits cell cycle progression from the G0/G1 to the S phase after serum starvation, and that quiescent Bcl-2 expressing cells maintained a significant lower level of mitochondrial reactive oxygen species (ROS) than the control cells. Based on the fact that ROS mediate cell cycle progression, and are controlled by peroxisome proliferator-activated receptor-{gamma} co-activator 1 (PGC-1), a key molecule induced by prolonged starvation and involved in mitochondrial metabolism, we hypothesized that PGC-1 might be related with the cell cycle function of Bcl-2. Here, we showed that PGC-1 was upregulated upon Bcl-2 overexpression and downregulated following Bcl-2 knockdown during serum starvation. Knockdown of PGC-1 activated Bcl-2 expression. Taken together, our results suggest that after serum depletion, PGC-la might coordinate with Bcl-2 to reduce ROS, which in turn delay cell cycle progression.\n\nSummary statementPGC-1 coordinate with Bcl-2 delay cell cycle progression to reduce ROS after serum depletion in human glioma U251 cells.

biochemistry↗