ASU Regents' Professors Open Access Works
The title “Regents’ Professor” is the highest faculty honor awarded at Arizona State University. It is conferred on ASU faculty who have made pioneering contributions in their areas of expertise, who have achieved a sustained level of distinction, and who enjoy national and international recognition for these accomplishments. This collection contains primarily open access works by ASU Regents' Professors.
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- Creators: Kumar, Sudhir
- Creators: Conrad, Chelsie
Description
Background:
Many pharmaceutical drugs are known to be ineffective or have negative side effects in a substantial proportion of patients. Genomic advances are revealing that some non-synonymous single nucleotide variants (nsSNVs) may cause differences in drug efficacy and side effects. Therefore, it is desirable to evaluate nsSNVs of interest in their ability to modulate the drug response.
Results:
We found that the available data on the link between drug response and nsSNV is rather modest. There were only 31 distinct drug response-altering (DR-altering) and 43 distinct drug response-neutral (DR-neutral) nsSNVs in the whole Pharmacogenomics Knowledge Base (PharmGKB). However, even with this modest dataset, it was clear that existing bioinformatics tools have difficulties in correctly predicting the known DR-altering and DR-neutral nsSNVs. They exhibited an overall accuracy of less than 50%, which was not better than random diagnosis. We found that the underlying problem is the markedly different evolutionary properties between positions harboring nsSNVs linked to drug responses and those observed for inherited diseases. To solve this problem, we developed a new diagnosis method, Drug-EvoD, which was trained on the evolutionary properties of nsSNVs associated with drug responses in a sparse learning framework. Drug-EvoD achieves a TPR of 84% and a TNR of 53%, with a balanced accuracy of 69%, which improves upon other methods significantly.
Conclusions:
The new tool will enable researchers to computationally identify nsSNVs that may affect drug responses. However, much larger training and testing datasets are needed to develop more reliable and accurate tools.
ContributorsGerek, Nevin Z. (Author) / Liu, Li (Author) / Gerold, Kristyn (Author) / Biparva, Pegah (Author) / Thomas, Eric D. (Author) / Kumar, Sudhir (Author) / Biodesign Institute (Contributor) / Center for Evolution and Medicine (Contributor)
Created2015-01-15
Description
The advent and application of the X-ray free-electron laser (XFEL) has uncovered the structures of proteins that could not previously be solved using traditional crystallography. While this new technology is powerful, optimization of the process is still needed to improve data quality and analysis efficiency. One area is sample heterogeneity, where variations in crystal size (among other factors) lead to the requirement of large data sets (and thus 10–100 mg of protein) for determining accurate structure factors. To decrease sample dispersity, we developed a high-throughput microfluidic sorter operating on the principle of dielectrophoresis, whereby polydisperse particles can be transported into various fluid streams for size fractionation. Using this microsorter, we isolated several milliliters of photosystem I nanocrystal fractions ranging from 200 to 600 nm in size as characterized by dynamic light scattering, nanoparticle tracking, and electron microscopy. Sorted nanocrystals were delivered in a liquid jet via the gas dynamic virtual nozzle into the path of the XFEL at the Linac Coherent Light Source. We obtained diffraction to ∼4 Å resolution, indicating that the small crystals were not damaged by the sorting process. We also observed the shape transforms of photosystem I nanocrystals, demonstrating that our device can optimize data collection for the shape transform-based phasing method. Using simulations, we show that narrow crystal size distributions can significantly improve merged data quality in serial crystallography. From this proof-of-concept work, we expect that the automated size-sorting of protein crystals will become an important step for sample production by reducing the amount of protein needed for a high quality final structure and the development of novel phasing methods that exploit inter-Bragg reflection intensities or use variations in beam intensity for radiation damage-induced phasing. This method will also permit an analysis of the dependence of crystal quality on crystal size.
ContributorsAbdallah, Bahige (Author) / Zatsepin, Nadia (Author) / Roy Chowdhury, Shatabdi (Author) / Coe, Jesse (Author) / Conrad, Chelsie (Author) / Dorner, Katerina (Author) / Sierra, Raymond G. (Author) / Stevenson, Hilary P. (Author) / Camacho Alanis, Fernanda (Author) / Grant, Thomas D. (Author) / Nelson, Garrett (Author) / James, Daniel (Author) / Calero, Guillermo (Author) / Wachter, Rebekka (Author) / Spence, John (Author) / Weierstall, Uwe (Author) / Fromme, Petra (Author) / Ros, Alexandra (Author) / Department of Chemistry and Biochemistry (Contributor) / College of Liberal Arts and Sciences (Contributor) / School of Molecular Sciences (Contributor) / Biodesign Institute (Contributor) / Applied Structural Discovery (Contributor) / Department of Physics (Contributor)
Created2015-08-19
Description
Crystal structure determination of biological macromolecules using the novel technique of serial femtosecond crystallography (SFX) is severely limited by the scarcity of X-ray free-electron laser (XFEL) sources. However, recent and future upgrades render microfocus beamlines at synchrotron-radiation sources suitable for room-temperature serial crystallography data collection also. Owing to the longer exposure times that are needed at synchrotrons, serial data collection is termed serial millisecond crystallography (SMX). As a result, the number of SMX experiments is growing rapidly, with a dozen experiments reported so far. Here, the first high-viscosity injector-based SMX experiments carried out at a US synchrotron source, the Advanced Photon Source (APS), are reported. Microcrystals (5–20 µm) of a wide variety of proteins, including lysozyme, thaumatin, phycocyanin, the human A[subscript 2A] adenosine receptor (A[subscript 2A]AR), the soluble fragment of the membrane lipoprotein Flpp3 and proteinase K, were screened. Crystals suspended in lipidic cubic phase (LCP) or a high-molecular-weight poly(ethylene oxide) (PEO; molecular weight 8 000 000) were delivered to the beam using a high-viscosity injector. In-house data-reduction (hit-finding) software developed at APS as well as the SFX data-reduction and analysis software suites Cheetah and CrystFEL enabled efficient on-site SMX data monitoring, reduction and processing. Complete data sets were collected for A[subscript 2A]AR, phycocyanin, Flpp3, proteinase K and lysozyme, and the structures of A[subscript 2A]AR, phycocyanin, proteinase K and lysozyme were determined at 3.2, 3.1, 2.65 and 2.05 Å resolution, respectively. The data demonstrate the feasibility of serial millisecond crystallography from 5–20 µm crystals using a high-viscosity injector at APS. The resolution of the crystal structures obtained in this study was dictated by the current flux density and crystal size, but upcoming developments in beamline optics and the planned APS-U upgrade will increase the intensity by two orders of magnitude. These developments will enable structure determination from smaller and/or weakly diffracting microcrystals.
ContributorsMartin Garcia, Jose Manuel (Author) / Conrad, Chelsie (Author) / Nelson, Garrett (Author) / Stander, Natasha (Author) / Zatsepin, Nadia (Author) / Zook, James (Author) / Zhu, Lan (Author) / Geiger, James (Author) / Chun, Eugene (Author) / Kissick, David (Author) / Hilgart, Mark C. (Author) / Ogata, Craig (Author) / Ishchenko, Andrii (Author) / Nagaratnam, Nirupa (Author) / Roy Chowdhury, Shatabdi (Author) / Coe, Jesse (Author) / Subramanian, Ganesh (Author) / Schaffer, Alexander (Author) / James, Daniel (Author) / Ketwala, Gihan (Author) / Venugopalan, Nagarajan (Author) / Xu, Shenglan (Author) / Corcoran, Stephen (Author) / Ferguson, Dale (Author) / Weierstall, Uwe (Author) / Spence, John (Author) / Cherezov, Vadim (Author) / Fromme, Petra (Author) / Fischetti, Robert F. (Author) / Liu, Wei (Author) / College of Liberal Arts and Sciences (Contributor) / School of Molecular Sciences (Contributor) / Biodesign Institute (Contributor) / Applied Structural Discovery (Contributor) / Department of Physics (Contributor)
Created2017-05-24
Description
Gene expression patterns assayed across development can offer key clues about a gene’s function and regulatory role. Drosophila melanogaster is ideal for such investigations as multiple individual and high-throughput efforts have captured the spatiotemporal patterns of thousands of embryonic expressed genes in the form of in situ images. FlyExpress (www.flyexpress.net), a knowledgebase based on a massive and unique digital library of standardized images and a simple search engine to find coexpressed genes, was created to facilitate the analytical and visual mining of these patterns. Here, we introduce the next generation of FlyExpress resources to facilitate the integrative analysis of sequence data and spatiotemporal patterns of expression from images. FlyExpress 7 now includes over 100,000 standardized in situ images and implements a more efficient, user-defined search algorithm to identify coexpressed genes via Genomewide Expression Maps (GEMs). Shared motifs found in the upstream 5′ regions of any pair of coexpressed genes can be visualized in an interactive dotplot. Additional webtools and link-outs to assist in the downstream validation of candidate motifs are also provided. Together, FlyExpress 7 represents our largest effort yet to accelerate discovery via the development and dispersal of new webtools that allow researchers to perform data-driven analyses of coexpression (image) and genomic (sequence) data.
ContributorsKumar, Sudhir (Author) / Konikoff, Charlotte (Author) / Sanderford, Maxwell (Author) / Liu, Li (Author) / Newfeld, Stuart (Author) / Ye, Jieping (Author) / Kulathinal, Rob J. (Author) / College of Health Solutions (Contributor) / Department of Biomedical Informatics (Contributor) / College of Liberal Arts and Sciences (Contributor) / School of Life Sciences (Contributor)
Created2017-06-30
Description
The evolution of resistance in Staphylococcus aureus occurs rapidly, and in response to all known antimicrobial treatments. Numerous studies of model species describe compensatory roles of mutations in mediating competitive fitness, and there is growing evidence that these mutation types also drive adaptation of S. aureus strains. However, few studies have tracked amino acid changes during the complete evolutionary trajectory of antibiotic adaptation or been able to predict their functional relevance. Here, we have assessed the efficacy of computational methods to predict biological resistance of a collection of clinically known Resistance Associated Mutations (RAMs). We have found that >90% of known RAMs are incorrectly predicted to be functionally neutral by at least one of the prediction methods used. By tracing the evolutionary histories of all of the false negative RAMs, we have discovered that a significant number are reversion mutations to ancestral alleles also carried in the MSSA476 methicillin-sensitive isolate. These genetic reversions are most prevalent in strains following daptomycin treatment and show a tendency to accumulate in biological pathway reactions that are distinct from those accumulating non-reversion mutations. Our studies therefore show that in addition to non-reversion mutations, reversion mutations arise in isolates exposed to new antibiotic treatments. It is possible that acquisition of reversion mutations in the genome may prevent substantial fitness costs during the progression of resistance. Our findings pose an interesting question to be addressed by further clinical studies regarding whether or not these reversion mutations lead to a renewed vulnerability of a vancomycin or daptomycin resistant strain to antibiotics administered at an earlier stage of infection.
ContributorsChampion, Mia (Author) / Gray, Vanessa (Author) / Eberhard, Carl (Author) / Kumar, Sudhir (Author) / Biodesign Institute (Contributor) / Center for Evolution and Medicine (Contributor)
Created2013-02-12
Description
Serial femtosecond crystallography (SFX) using X-ray free-electron laser sources is an emerging method with considerable potential for time-resolved pump-probe experiments. Here we present a lipidic cubic phase SFX structure of the light-driven proton pump bacteriorhodopsin (bR) to 2.3 Å resolution and a method to investigate protein dynamics with modest sample requirement. Time-resolved SFX (TR-SFX) with a pump-probe delay of 1 ms yields difference Fourier maps compatible with the dark to M state transition of bR. Importantly, the method is very sample efficient and reduces sample consumption to about 1 mg per collected time point. Accumulation of M intermediate within the crystal lattice is confirmed by time-resolved visible absorption spectroscopy. This study provides an important step towards characterizing the complete photocycle dynamics of retinal proteins and demonstrates the feasibility of a sample efficient viscous medium jet for TR-SFX.
ContributorsNogly, Przemyslaw (Author) / Panneels, Valerie (Author) / Nelson, Garrett (Author) / Gati, Cornelius (Author) / Kimura, Tetsunari (Author) / Milne, Christopher (Author) / Milathianaki, Despina (Author) / Kubo, Minoru (Author) / Wu, Wenting (Author) / Conrad, Chelsie (Author) / Coe, Jesse (Author) / Bean, Richard (Author) / Zhao, Yun (Author) / Bath, Petra (Author) / Dods, Robert (Author) / Harimoorthy, Rajiv (Author) / Beyerlein, Kenneth R. (Author) / Rheinberger, Jan (Author) / James, Daniel (Author) / Deponte, Daniel (Author) / Li, Chufeng (Author) / Sala, Leonardo (Author) / Williams, Garth J. (Author) / Hunter, Mark S. (Author) / Koglin, Jason E. (Author) / Berntsen, Peter (Author) / Nango, Eriko (Author) / Iwata, So (Author) / Chapman, Henry N. (Author) / Fromme, Petra (Author) / Frank, Matthias (Author) / Abela, Rafael (Author) / Boutet, Sebastien (Author) / Barty, Anton (Author) / White, Thomas A. (Author) / Weierstall, Uwe (Author) / Spence, John (Author) / Neutze, Richard (Author) / Schertler, Gebhard (Author) / Standfuss, Jorg (Author) / College of Liberal Arts and Sciences (Contributor) / Department of Physics (Contributor) / Department of Chemistry and Biochemistry (Contributor) / Biodesign Institute (Contributor) / Applied Structural Discovery (Contributor) / School of Molecular Sciences (Contributor)
Created2016-08-22
Description
Serial femtosecond crystallography (SFX) has opened a new era in crystallography by permitting nearly damage-free, room-temperature structure determination of challenging proteins such as membrane proteins. In SFX, femtosecond X-ray free-electron laser pulses produce diffraction snapshots from nanocrystals and microcrystals delivered in a liquid jet, which leads to high protein consumption. A slow-moving stream of agarose has been developed as a new crystal delivery medium for SFX. It has low background scattering, is compatible with both soluble and membrane proteins, and can deliver the protein crystals at a wide range of temperatures down to 4°C. Using this crystal-laden agarose stream, the structure of a multi-subunit complex, phycocyanin, was solved to 2.5 Å resolution using 300 µg of microcrystals embedded into the agarose medium post-crystallization. The agarose delivery method reduces protein consumption by at least 100-fold and has the potential to be used for a diverse population of proteins, including membrane protein complexes.
ContributorsConrad, Chelsie (Author) / Basu, Shibom (Author) / James, Daniel (Author) / Wang, Dingjie (Author) / Schaffer, Alexander (Author) / Roy Chowdhury, Shatabdi (Author) / Zatsepin, Nadia (Author) / Aquila, Andrew (Author) / Coe, Jesse (Author) / Gati, Cornelius (Author) / Hunter, Mark S. (Author) / Koglin, Jason E. (Author) / Kupitz, Christopher (Author) / Nelson, Garrett (Author) / Subramanian, Ganesh (Author) / White, Thomas A. (Author) / Zhao, Yun (Author) / Zook, James (Author) / Boutet, Sebastien (Author) / Cherezov, Vadim (Author) / Spence, John (Author) / Fromme, Raimund (Author) / Weierstall, Uwe (Author) / Fromme, Petra (Author) / Department of Chemistry and Biochemistry (Contributor) / Biodesign Institute (Contributor) / Applied Structural Discovery (Contributor) / College of Liberal Arts and Sciences (Contributor) / Department of Physics (Contributor) / School of Molecular Sciences (Contributor)
Created2015-06-30
Description
Serial femtosecond crystallography (SFX) using X-ray free-electron lasers has produced high-resolution, room temperature, time-resolved protein structures. We report preliminary SFX of Sindbis virus, an enveloped icosahedral RNA virus with ∼700 Å diameter. Microcrystals delivered in viscous agarose medium diffracted to ∼40 Å resolution. Small-angle diffuse X-ray scattering overlaid Bragg peaks and analysis suggests this results from molecular transforms of individual particles. Viral proteins undergo structural changes during entry and infection, which could, in principle, be studied with SFX. This is an important step toward determining room temperature structures from virus microcrystals that may enable time-resolved studies of enveloped viruses.
ContributorsLawrence, Robert (Author) / Conrad, Chelsie (Author) / Zatsepin, Nadia (Author) / Grant, Thomas D. (Author) / Liu, Haiguang (Author) / James, Daniel (Author) / Nelson, Garrett (Author) / Subramanian, Ganesh (Author) / Aquila, Andrew (Author) / Hunter, Mark S. (Author) / Liang, Mengning (Author) / Boutet, Sebastien (Author) / Coe, Jesse (Author) / Spence, John (Author) / Weierstall, Uwe (Author) / Liu, Wei (Author) / Fromme, Petra (Author) / Cherezov, Vadim (Author) / Hogue, Brenda (Author) / Biodesign Institute (Contributor) / Infectious Diseases and Vaccinology (Contributor) / Applied Structural Discovery (Contributor) / Department of Chemistry and Biochemistry (Contributor) / College of Liberal Arts and Sciences (Contributor) / Department of Physics (Contributor) / School of Life Sciences (Contributor)
Created2015-08-20
Description
Although conflict is a normative part of parent–adolescent relationships, conflicts that are long or highly negative are likely to be detrimental to these relationships and to youths’ development. In the present article, sequential analyses of data from 138 parent–adolescent dyads (adolescents’ mean age was 13.44, SD = 1.16; 52 % girls, 79 % non-Hispanic White) were used to define conflicts as reciprocal exchanges of negative emotion observed while parents and adolescents were discussing “hot,” conflictual issues. Dynamic components of these exchanges, including who started the conflicts, who ended them, and how long they lasted, were identified. Mediation analyses revealed that a high proportion of conflicts ended by adolescents was associated with longer conflicts, which in turn predicted perceptions of the “hot” issue as unresolved and adolescent behavior problems. The findings illustrate advantages of using sequential analysis to identify patterns of interactions and, with some certainty, obtain an estimate of the contingent relationship between a pattern of behavior and child and parental outcomes. These interaction patterns are discussed in terms of the roles that parents and children play when in conflict with each other, and the processes through which these roles affect conflict resolution and adolescents’ behavior problems.
ContributorsMoed, Anat (Author) / Gershoff, Elizabeth T. (Author) / Eisenberg, Nancy (Author) / Hofer, Claire (Author) / Losoya, Sandra (Author) / Spinrad, Tracy (Author) / Liew, Jeffrey (Author) / College of Liberal Arts and Sciences (Contributor) / Department of Psychology (Contributor) / Sanford School of Social and Family Dynamics (Contributor)
Created2015-08-01
Description
Premise of the study: Land-plant plastid genomes have only rarely undergone significant changes in gene content and order. Thus, discovery of additional examples adds power to tests for causes of such genome-scale structural changes.
Methods: Using next-generation sequence data, we assembled the plastid genome of saguaro cactus and probed the nuclear genome for transferred plastid genes and functionally related nuclear genes. We combined these results with available data across Cactaceae and seed plants more broadly to infer the history of gene loss and to assess the strength of phylogenetic association between gene loss and loss of the inverted repeat (IR).
Key results: The saguaro plastid genome is the smallest known for an obligately photosynthetic angiosperm (∼113 kb), having lost the IR and plastid ndh genes. This loss supports a statistically strong association across seed plants between the loss of ndh genes and the loss of the IR. Many nonplastid copies of plastid ndh genes were found in the nuclear genome, but none had intact reading frames; nor did three related nuclear-encoded subunits. However, nuclear pgr5, which functions in a partially redundant pathway, was intact.
Conclusions: The existence of an alternative pathway redundant with the function of the plastid NADH dehydrogenase-like complex (NDH) complex may permit loss of the plastid ndh gene suite in photoautotrophs like saguaro. Loss of these genes may be a recurring mechanism for overall plastid genome size reduction, especially in combination with loss of the IR.
Methods: Using next-generation sequence data, we assembled the plastid genome of saguaro cactus and probed the nuclear genome for transferred plastid genes and functionally related nuclear genes. We combined these results with available data across Cactaceae and seed plants more broadly to infer the history of gene loss and to assess the strength of phylogenetic association between gene loss and loss of the inverted repeat (IR).
Key results: The saguaro plastid genome is the smallest known for an obligately photosynthetic angiosperm (∼113 kb), having lost the IR and plastid ndh genes. This loss supports a statistically strong association across seed plants between the loss of ndh genes and the loss of the IR. Many nonplastid copies of plastid ndh genes were found in the nuclear genome, but none had intact reading frames; nor did three related nuclear-encoded subunits. However, nuclear pgr5, which functions in a partially redundant pathway, was intact.
Conclusions: The existence of an alternative pathway redundant with the function of the plastid NADH dehydrogenase-like complex (NDH) complex may permit loss of the plastid ndh gene suite in photoautotrophs like saguaro. Loss of these genes may be a recurring mechanism for overall plastid genome size reduction, especially in combination with loss of the IR.
ContributorsSanderson, Michael J. (Author) / Copetti, Dario (Author) / Burquez, Alberto (Author) / Bustamante, Enriquena (Author) / Charboneau, Joseph L. M. (Author) / Eguiarte, Luis E. (Author) / Kumar, Sudhir (Author) / Lee, Hyun Oh (Author) / Lee, Junki (Author) / McMahon, Michelle (Author) / Steele, Kelly (Author) / Wing, Rod (Author) / Yang, Tae-Jin (Author) / Zwickl, Derrick (Author) / Wojciechowski, Martin (Author) / College of Integrative Sciences and Arts (Contributor) / College of Liberal Arts and Sciences (Contributor) / School of Life Sciences (Contributor)
Created2015-07-01