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1. Massively parallel kinetic profiling of natural and engineered CRISPR nucleases

Author

Jones, Stephen K, Hawkins, John A, Johnson, Nicole V, Jung, Cheulhee, Hu, Kuang, Rybarski, James R, Chen, Janice S, Doudna, Jennifer A, Press, William H, and Finkelstein, Ilya J

Subjects
Biological Sciences, Bioinformatics and Computational Biology, Human Genome, Genetics, Biotechnology, Bacterial Proteins, CRISPR-Associated Protein 9, CRISPR-Associated Proteins, CRISPR-Cas Systems, Endodeoxyribonucleases, Gene Editing, High-Throughput Nucleotide Sequencing, Kinetics, Protein Binding, Protein Engineering, RNA, Guide, Kinetoplastida, Substrate Specificity
Abstract

Engineered SpCas9s and AsCas12a cleave fewer off-target genomic sites than wild-type (wt) Cas9. However, understanding their fidelity, mechanisms and cleavage outcomes requires systematic profiling across mispaired target DNAs. Here we describe NucleaSeq-nuclease digestion and deep sequencing-a massively parallel platform that measures the cleavage kinetics and time-resolved cleavage products for over 10,000 targets containing mismatches, insertions and deletions relative to the guide RNA. Combining cleavage rates and binding specificities on the same target libraries, we benchmarked five SpCas9 variants and AsCas12a. A biophysical model built from these data sets revealed mechanistic insights into off-target cleavage. Engineered Cas9s, especially Cas9-HF1, dramatically increased cleavage specificity but not binding specificity compared to wtCas9. Surprisingly, AsCas12a cleavage specificity differed little from that of wtCas9. Initial DNA cleavage sites and end trimming varied by nuclease, guide RNA and the positions of mispaired nucleotides. More broadly, NucleaSeq enables rapid, quantitative and systematic comparisons of specificity and cleavage outcomes across engineered and natural nucleases.

Published
2021

2. Noncoding RNA-nucleated heterochromatin spreading is intrinsically labile and requires accessory elements for epigenetic stability.

Author

Greenstein, RA, Jones, Stephen K, Spivey, Eric C, Rybarski, James R, Finkelstein, Ilya J, and Al-Sady, Bassem

Subjects
Heterochromatin, Schizosaccharomyces, Hydroxamic Acids, Hydroxyurea, Histones, RNA, Untranslated, Stochastic Processes, Reproducibility of Results, Temperature, Epigenesis, Genetic, Inheritance Patterns, Mutation, Genes, Mating Type, Fungal, Stress, Physiological, Single-Cell Analysis, Cell Cycle Checkpoints, S. pombe, cellular identity, chromosomes, epigenetic inheritance, epigenetics and environment, gene expression, heterochromatin spreading, histone turnover, multigenerational single cell tracking, RNA, Untranslated, Epigenesis, Genetic, Genes, Mating Type, Fungal, Stress, Physiological, Biochemistry and Cell Biology
Abstract

The heterochromatin spreading reaction is a central contributor to the formation of gene-repressive structures, which are re-established with high positional precision, or fidelity, following replication. How the spreading reaction contributes to this fidelity is not clear. To resolve the origins of stable inheritance of repression, we probed the intrinsic character of spreading events in fission yeast using a system that quantitatively describes the spreading reaction in live single cells. We show that spreading triggered by noncoding RNA-nucleated elements is stochastic, multimodal, and fluctuates dynamically across time. This lack of stability correlates with high histone turnover. At the mating type locus, this unstable behavior is restrained by an accessory cis-acting element REIII, which represses histone turnover. Further, REIII safeguards epigenetic memory against environmental perturbations. Our results suggest that the most prevalent type of spreading, driven by noncoding RNA-nucleators, is epigenetically unstable and requires collaboration with accessory elements to achieve high fidelity.

Published
2018

4. A memory element imposes epigenetic behavior on intrinsically labile RNAi-induced heterochromatin spread

Author

Greenstein, RA, Jones, Stephen K, Spivey, Eric C, Rybarski, James R, Finkelstein, Ilya J, and Al-Sady, Bassem

Subjects
Biochemistry and Cell Biology, Physical Sciences, Biological Sciences, Genetics, Biotechnology
Abstract

ABTRACT The heterochromatin spreading reaction is a central contributor to the formation of gene-repressive structures, which are re-established with high fidelity following replication. The high fidelity of this process is not obviously encoded in the primary spreading reaction. To resolve origins of stable inheritance of repression, we probed the intrinsic fidelity of spreading events in fission yeast using a system that quantitatively describes the spreading reaction in live single cells. We show that spreading from RNAi-nucleated elements is stochastic, multimodal, and fluctuates dynamically across time. In contrast, a second form of spreading, nucleated by the cis -acting element REIII , is deterministic, has high memory capacity and acts as the source of locus fidelity. REIII enables fidelity in part by endowing the locus with resistance to perturbations. Together, our results suggest that epigenetic capacity may not be intrinsically encoded in the spreading reaction, but rather requires collaboration with specialized memory elements.

Published
2017

5. Evolutionary Selection on Barrier Activity: Bar1 Is an Aspartyl Protease with Novel Substrate Specificity

Author

Jones, Stephen K, Clarke, Starlynn C, Craik, Charles S, and Bennett, Richard J

Subjects
Biochemistry and Cell Biology, Biological Sciences, Infectious Diseases, Aspartic Acid Proteases, Candida albicans, Hydrogen-Ion Concentration, Pepstatins, Pheromones, Protease Inhibitors, Proteolysis, Signal Transduction, Substrate Specificity, Microbiology, Biochemistry and cell biology, Medical microbiology
Abstract

UnlabelledPeptide-based pheromones are used throughout the fungal kingdom for coordinating sexual responses between mating partners. Here, we address the properties and function of Bar1, an aspartyl protease that acts as a "barrier" and antagonist to pheromone signaling in multiple species. Candida albicans Bar1 was purified and shown to exhibit preferential cleavage of native α pheromone over pheromones from related fungal species. This result establishes that protease substrate specificity coevolved along with changes in its pheromone target. Pheromone cleavage by Bar1 occurred between residues Thr-5 and Asn-6 in the middle of the tridecapeptide sequence. Surprisingly, proteolytic activity was independent of the amino acid residues present at the scissile bond and instead relied on residues at the C terminus of α pheromone. Unlike most aspartyl proteases, Bar1 also exhibited a near-neutral pH optimum and was resistant to the class-wide inhibitor pepstatin A. In addition, genetic analysis was performed on C. albicans BAR1 and demonstrated that the protease not only regulates endogenous pheromone signaling but also can limit interspecies pheromone signaling. We discuss these findings and propose that the unusual substrate specificity of Bar1 is a consequence of its coevolution with the α pheromone receptor Ste2 for their shared peptide target.ImportancePheromones are important for intraspecies communication across the tree of life. In the fungal kingdom, extracellular proteases play a key role in antagonizing pheromone signaling in multiple species. This study examines the properties and function of Candida albicans Bar1, an aspartyl protease that cleaves and thereby inactivates α pheromone. We demonstrate that Bar1 plays important roles in regulating both intra- and interspecies pheromone signaling. The fungal protease shows preferential activity on the endogenous pheromone, but, surprisingly, cleavage activity is dependent on amino acid residues distal to the scissile bond. We propose that the unusual substrate specificity of Bar1 is a direct result of coevolution with Ste2, the receptor for α pheromone, for recognition of the same peptide target. The novel specificity of Bar1 reveals the complex forces shaping the evolution of mating pathways in fungi and uncovers a protease with potentially important applications in the biotechnology industry.

Published
2015

15. List of Contributors

Author

Abdullah, Anthony, primary, Abrouk, Michael, additional, Ahad, Tashmeeta, additional, Ahmed, Imtiaz, additional, Al Hammadi, Anwar, additional, Allen, Caroline, additional, Almohssen, Amer Ali, additional, Alwan, Wisam, additional, Ameen, Mahreen, additional, Amini, Sadegh, additional, Anderson, Bryan E., additional, Anhalt, Grant J., additional, Baker, Donald J., additional, Bala, Harini Rajgopal, additional, Baltz, Julia, additional, Banach, David, additional, Banfield, Cedric C., additional, Baran, Robert, additional, Bardhan, Ajoy, additional, Barkham, Melissa C., additional, Bello, Ysabel M., additional, Benton, Emma, additional, Bergfeld, Wilma F., additional, Berkowitz, Eric, additional, Berman, Brian, additional, Bernhard, Jeffrey D., additional, Bernstein, Daniel, additional, Berth-Jones, John, additional, Bhate, Chinmoy, additional, Bhatia, Bhavnit K., additional, Blume, Jonathan E., additional, Bordet, Nevianna, additional, Borysiewicz, Catherine, additional, Brauner, Gary J., additional, Brodell, Robert T., additional, Brown, Marc D., additional, Burd, Robert M., additional, Burdick, Anne E., additional, Butala, Niraj, additional, Callen, Jeffrey P., additional, Camacho, Ivan D., additional, Camasmie, Helena, additional, Caplivski, Daniel, additional, Cappell, Mitchell S., additional, Casey, Genevieve A., additional, Chan, Lawrence S., additional, Chan, Loi-Yuen, additional, Chen, Jennifer K., additional, Chen, Chen “Mary”, additional, Chiang, Nicole Yi Zhen, additional, Chiaravalloti, Anthony J., additional, Child, Fiona J., additional, Chu, Anthony C., additional, Clayton, Timothy H., additional, Cohen, Steven R., additional, Cooper, Elizabeth A., additional, Cooper, Susan M., additional, Collier, Nick, additional, Correnti, Christina M., additional, Coulson, Ian H., additional, Council, M. Laurin, additional, Cowper, Shawn E., additional, Craven, Nicholas M., additional, Creamer, Daniel, additional, Cruz, Ponciano D., additional, Cusack, Carrie Ann R., additional, Daunton, Adam, additional, Davis, Mark D.P., additional, Dawe, Robert S., additional, D’Cruz, David P., additional, de Berker, David, additional, DeHoratius, Danielle M., additional, Deng, Min, additional, Desai, Seemal R., additional, Devlin, Georgina, additional, DiGiovanna, John J., additional, Doctoroff, Alexander, additional, Dodiuk-Gad, Roni P., additional, Eichenfield, Dawn Z., additional, Eichenfield, Lawrence F., additional, Eisen, Drore, additional, Eke, Ure, additional, Elston, Dirk M., additional, Emanuel, Patrick O.M., additional, Enos, Clinton W., additional, Ensanyat, Shaheen H., additional, Falabella, Anna F., additional, Farberg, Aaron S., additional, Feigenbaum, Lawrence S., additional, Fernandez, Kristen Heins, additional, Fett, Nicole, additional, Finlay, Andrew Y., additional, Firoz, Bahar F., additional, Firoz, Elnaz F., additional, Fitzpatrick, James E., additional, Flischel, Amy E., additional, Foley, Kelly A., additional, Freedman, Derek, additional, Fremlin, Georgina A., additional, Fried, Richard, additional, Friedlander, Philip, additional, Friedman, Adam, additional, Forrestel, Amy K., additional, Fuchs, Brian S., additional, Gach, Joanna E., additional, Galan, Anjela, additional, Ganesh, Jaya, additional, Garg, Amit, additional, Geller, Lauren, additional, Gelmetti, Carlo M., additional, Ghazi, Elizabeth, additional, Ghunawat, Sneha, additional, Goldberg, Leonard H., additional, Goodfield, Mark J.D., additional, Gordon, Marsha L., additional, Gowda, Asha, additional, Grabell, Daniel A., additional, Grant, Matthew, additional, Grattan, Clive E.H., additional, Greaves, Malcolm W., additional, Green, Justin J., additional, Griffiths, Christopher E.M., additional, Gropper, Charles A., additional, Grossberg, Anna L., additional, Gupta, Aditya K., additional, Hadi, Ali S., additional, Hadi, Suhail M., additional, Hagans, Iris A., additional, Hairston, Bethany R., additional, Halpern, Analisa Vincent, additional, Halverstam, Caroline, additional, Harper, Natasha, additional, Harries, Matthew J., additional, Harris, John, additional, Harrison, Shannon, additional, Hatch, Michael M., additional, Heagerty, Adrian H.M., additional, Hebert, Adelaide A., additional, Helms, Stephen E., additional, Hexsel, Camile L., additional, Hexsel, Doris M., additional, Heymann, Warren R., additional, Higgins, Elisabeth M., additional, Higgins, Claire L., additional, High, Whitney A., additional, Hönigsmann, Herbert, additional, Horenstein, Marcelo G., additional, Hruza, George J., additional, Hui, Andrea, additional, Huo, Ran, additional, Ibbotson, Sally H., additional, Ibrahim, Sherrif F., additional, Ilchyshyn, Andrew, additional, Ismail, Dina, additional, Jablonska, Stefania, additional, Jacobe, Heidi T., additional, James, William D., additional, Javed, Aysha, additional, Jemec, Gregor B.E., additional, Johnston, Graham A., additional, Jones, Stephen K., additional, Junkins-Hopkins, Jacqueline M., additional, Kaffenberger, Jessica, additional, Kane, Kelly R., additional, Kanelleas, Antonios, additional, Karadağ, Ayşe Serap, additional, Karas, Laura, additional, Katugampola, Ruwani P., additional, Katz, Bruce E., additional, Kellen, Roselyn, additional, Khan, Murtaza, additional, Khorasani, Hooman, additional, Kim, Ellen J., additional, Kim, Hee J., additional, Kirby, Brian, additional, Kirby, Joslyn S., additional, Klein, Rachel S., additional, Kleydman, Kate, additional, Koch, Dimitra, additional, Kohorst, John J., additional, Koo, John Y.M., additional, Kopp, Sandra A., additional, Korman, Neil J., additional, Kovarik, Carrie, additional, Kraemer, Kenneth H., additional, Krafchik, Bernice R., additional, Krishnamurthy, Karthik, additional, Kvernebo, Knut, additional, Lam, Charlene, additional, Lambert, Peter C., additional, Langtry, James A.A., additional, Larian, Amir A., additional, Larocca, Cecilia A., additional, Lawlor, E. Frances, additional, Lawrence, Clifford M., additional, Lebwohl, Mark G., additional, Lebwohl, Oscar, additional, Lehman, Julia S., additional, Leslie, Tabi A., additional, Lessin, Stuart R., additional, Levitt, Jacob O., additional, Lewis, Fiona M., additional, Liaqat, Maryam, additional, Liu, Kristina J., additional, Loosemore, Michael P., additional, Luger, Thomas A., additional, Lupi, Omar, additional, Lushniak, Boris D., additional, Lyon, Calum C., additional, Maderal, Andrea D., additional, Mahmoud, Bassel H., additional, Majewski, Slawomir, additional, Mallett, Richard B., additional, Manders, Steven M., additional, Mann, Ranon, additional, Mansouri, Yasaman, additional, Margolis, David J., additional, Markowitz, Orit, additional, Marsland, Alexander, additional, Martin-Clavijo, Agustin, additional, Martinez, Daniela, additional, Matiz, Catalina, additional, Maurer, Marcus, additional, McKerrow, Kevin, additional, Meah, Nekma, additional, Micali, Giuseppe, additional, Micheletti, Robert G., additional, Millard, Leslie G., additional, Miller, James E., additional, Wong Millsop, Jillian W., additional, Mimouni, Daniel, additional, Mirowski, Ginat W., additional, Mirza, Sultan A., additional, Molin, Sonja, additional, Morales-Burgos, Adisbeth, additional, Morison, Warwick L., additional, Mørk, Cato, additional, Morton, Colin A., additional, Motley, Richard J., additional, Mowbray, Megan, additional, Muldoon, Eavan G., additional, Muncaster, Anna E., additional, Murakawa, George J., additional, Murase, Jenny E., additional, Murdoch, Michele E., additional, Nabatian, Adam S., additional, Nakamura, Mio, additional, Nalluri, Rajani, additional, Nawas, Zeena Y., additional, Needham, Glen R., additional, Newell, Glenn C., additional, Newton-Bishop, Julia, additional, Nguyen, Adam V., additional, Nixon, Rosemary L., additional, O’Brien, Jack C., additional, Ogden, Stephanie, additional, Olbricht, Suzanne M., additional, O’Shea, Sally Jane, additional, Owen, Cindy E., additional, Pan, Michael, additional, Pappas-Taffer, Lisa, additional, Parish, Jennifer L., additional, Parish, Lawrence Charles, additional, Payette, Michael, additional, Peck, Gary L., additional, Pena, Sandra, additional, Peranteau, Jarad, additional, Pereira, Frederick A., additional, Perkins, William, additional, Perlis, Clifford S., additional, Phelps, Robert G., additional, Phillips, Tania J., additional, Poh-Fitzpatrick, Maureen B., additional, Pomeranz, Miriam Keltz, additional, Pop, Samantha R., additional, Porcu, Pierluigi, additional, Powell, James B., additional, Prok, Lori D., additional, Pyle, Tia M., additional, Qazaz, Surod, additional, Rajkomar, Vikram, additional, Rashid, Rabia S., additional, Rashighi, Mehdi, additional, Ratnavel, Ravi, additional, Regula, Christie G., additional, Renzi, Michael, additional, Revuz, Jean, additional, Reynolds, Rachel V., additional, Richard, Elisabeth, additional, Richard, Gabriele, additional, Rigel, Darrell S., additional, Robles, Wanda Sonia, additional, Rogge, Megan, additional, Rook, Alain H., additional, Manning, Jamie R., additional, Rosen, Ted, additional, Rosenbach, Misha, additional, Rosenfeld, David, additional, Rowland Payne, Christopher, additional, Rubin, Adam I., additional, Rubin, Courtney, additional, Rustin, Malcolm H.A., additional, Ruzicka, Thomas, additional, Samimi, Sara, additional, Schachner, Lawrence A., additional, Scheinfeld, Noah, additional, Schlosser, Bethanee J., additional, Schnur, Rhonda E., additional, Schwartz, Robert A., additional, Scorer, Matthew J., additional, Selkin, Bryan A., additional, Seymour, Jamie, additional, Shaver, Christine M., additional, Shea, Christopher R., additional, Shear, Neil H., additional, Shim, Tang Ngee, additional, Shimizu, Hiroshi, additional, Siegel, Julia, additional, Singer, Elisha, additional, Skelsey, Maral Kibarian, additional, Sladden, Chris, additional, Sladden, Michael, additional, Smith, Janellen, additional, Smucker, Joanne E., additional, Somani, Najwa, additional, Sommer, Lacy L., additional, Sommerlad, Mary, additional, Soon, Christine, additional, Sopkovich, Jennifer A., additional, Soter, Nicholas A., additional, Spencer, James M., additional, Staughton, Richard C.D., additional, Sterling, Jane C., additional, Sunderkötter, Cord, additional, Taibjee, Saleem M., additional, Tamura, Deborah, additional, Tan, Eunice, additional, Tang, William Y-M., additional, Taylor, Lynsey, additional, Thiers, Bruce H., additional, Thomas, Lucy J., additional, Thornton, Cody R., additional, Tobin, Anne-Marie, additional, Torgerson, Rochelle R., additional, Tosti, Antonella, additional, Tsatsou, Fragkiski, additional, Tsuji-Abe, Yukiko, additional, Tucker, William F.G., additional, Tyring, Stephen K., additional, Udkoff, Jeremy, additional, Unger, Robin H., additional, Unger, Walter P., additional, Utz, Sarah, additional, Valbuena, Martha C., additional, van de Kerkhof, Peter, additional, Van Voorhees, Abby S., additional, Vangipuram, Ramya, additional, Veitch, David, additional, Venning, Vanessa, additional, Versteeg, Sarah G., additional, Viera, Martha, additional, Vittorio, Carmela C., additional, Vleugels, Ruth Ann, additional, Wali, Gorav N., additional, Wallengren, Joanna, additional, Wan, Joy, additional, Wanat, Karolyn A., additional, Weichert, Gabriele, additional, Weidmann, Anja K., additional, Weinberg, Jeffrey M., additional, Werth, Victoria P., additional, White, Lucile E., additional, Wiener, Adam H., additional, Wilkin, Jonathan K., additional, Wilkin, Nathaniel K., additional, Williams, Jason, additional, Wilson, Niall, additional, Wiss, Karen, additional, Witkowski, Joseph A., additional, Wiznia, Lauren E., additional, Wong, Henry K., additional, Wong, Junie Li Chun, additional, Wright, Andrew L., additional, Wriston, Cooper C., additional, Wu, Benedict C., additional, Wulkan, Adam, additional, Zaenglein, Andrea L., additional, Zaki, Irshad, additional, Zeichner, Joshua A., additional, Zhu, Tian Hao, additional, Zone, John J., additional, Zouboulis, Christos C., additional, and Zuberbeir, Torstein, additional

Published
2018
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16. A kinetic model predicts SpCas9 activity, improves off-target classification, and reveals the physical basis of targeting fidelity

Author

Eslami Mossallam, B. (author), Klein, M. (author), Smagt, Constantijn V.D. (author), Sanden, Koen V.D. (author), Jones, Stephen K. (author), Hawkins, John A. (author), Finkelstein, Ilya J. (author), Depken, S.M. (author), Eslami Mossallam, B. (author), Klein, M. (author), Smagt, Constantijn V.D. (author), Sanden, Koen V.D. (author), Jones, Stephen K. (author), Hawkins, John A. (author), Finkelstein, Ilya J. (author), and Depken, S.M. (author)

Abstract

The S. pyogenes (Sp) Cas9 endonuclease is an important gene-editing tool. SpCas9 is directed to target sites based on complementarity to a complexed single-guide RNA (sgRNA). However, SpCas9-sgRNA also binds and cleaves genomic off-targets with only partial complementarity. To date, we lack the ability to predict cleavage and binding activity quantitatively, and rely on binary classification schemes to identify strong off-targets. We report a quantitative kinetic model that captures the SpCas9-mediated strand-replacement reaction in free-energy terms. The model predicts binding and cleavage activity as a function of time, target, and experimental conditions. Trained and validated on high-throughput bulk-biochemical data, our model predicts the intermediate R-loop state recently observed in single-molecule experiments, as well as the associated conversion rates. Finally, we show that our quantitative activity predictor can be reduced to a binary off-target classifier that outperforms the established state-of-the-art. Our approach is extensible, and can characterize any CRISPR-Cas nuclease – benchmarking natural and future high-fidelity variants against SpCas9; elucidating determinants of CRISPR fidelity; and revealing pathways to increased specificity and efficiency in engineered systems., BN/Martin Depken Lab, BN/Bionanoscience

Published
2022
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18. 99mTc-radiolabeled composites enabling in vivo imaging of arterial dispersal and retention of microspheres in the vascular network of rabbit lungs, liver, and liver tumors

Author

Stephens, Ross W, Tredwell, Gregory D, Knox, Karen J, Philip, Lee A, King, David W, Debono, Kelly M, Bell, Jessica L, Senden, Tim J, Tanudji, Marcel R, Winter, Jillean G, Bickley, Stephanie A, Tapner, Michael J, and Jones, Stephen K

Subjects
liver cancer, radiolabeled microspheres, medical imaging, SIRT, Original Research
Abstract

Purpose Selective internal radiation therapy (SIRT) is an effective treatment option for liver tumors, using Y-90-loaded polymer microspheres that are delivered via catheterization of the hepatic artery. Since Y-90 is a beta emitter and not conveniently imaged by standard clinical instrumentation, dosimetry is currently evaluated in each patient using a surrogate particle, 99mTechnetium-labeled macroaggregated albumin (99mTc-MAA). We report a new composite consisting of 99mTc-labeled nanoparticles attached to the same polymer microspheres as used for SIRT, which can be imaged with standard SPECT. Methods Carbon nanoparticles with an encapsulated core of 99mTc were coated with the polycation protamine sulfate to provide electrostatic attachment to anionic polystyrene sulfonate microspheres of different sizes (30, 12, and 8 µm). The in vivo stability of these composites was determined via intravenous injection and entrapment in the capillary network of normal rabbit lungs for up to 3 hours. Furthermore, we evaluated their biodistribution in normal rabbit livers, and livers implanted with VX2 tumors, following intrahepatic artery instillation. Results We report distribution tests for three different sizes of radiolabeled microspheres and compare the results with those obtained using 99mTc-MAA. Lung retention of the radiolabeled microspheres ranged from 72.8% to 92.9%, with the smaller diameter microspheres showing the lowest retention. Liver retention of the microspheres was higher, with retention in normal livers ranging from 99.2% to 99.8%, and in livers with VX2 tumors from 98.2% to 99.2%. The radiolabeled microspheres clearly demonstrated preferential uptake at tumor sites due to the increased arterial perfusion produced by angiogenesis. Conclusion We describe a novel use of radiolabeled carbon nanoparticles to generate an imageable microsphere that is stable in vivo under the shear stress conditions of arterial networks. Following intra-arterial instillation in the normal rabbit liver, they distribute in a distinct segmented pattern, with the smaller microspheres extending throughout the organ in finer detail, while still being well retained within the liver. Furthermore, in livers hosting an implanted VX2 tumor, they reveal the increased arterial perfusion of tumor tissue resulting from angiogenesis. These novel composites may have potential as a more representative mimic of the vascular distribution of therapeutic microspheres in patients undergoing SIRT.

Published
2019

30. An ergonomic evaluation of the Kinesis Ergonomic Computer Keyboard

Author

Gerard, Michael J., Jones, Stephen K., Smith, Leo A., Thomas, Robert E., and Wang, Tai

Subjects
Typewriting -- Analysis, Electromyography -- Analysis, Motor learning -- Analysis, Architecture and design industries, Business
Abstract

A study of the electromyographic activity and initial learning rates of six professional typists while they learnt to use the Kinesis Ergonomic Computer Keyboard revealed that the typists achieved on the Kinesis Ergonomic Computer Keyboard 72% of their speed and 97% of their accuracy on a standard 101 key IBM PS/2 keyboard in 115 minutes in 65 minutes, respectively. There is less strain on the flexor carpi ulnaris and flexor digitorum sublimis in sustaining the resting posture on the Kinesis Ergonomic Computer Keyboard than on the standard keyboard. The subjects rapidly relearned to use the Kinesis Ergonomic Computer Keyboard even after several weeks of not using it subsequent to the initial learning period.

Published
1994

33. Steam on the Sirhowy Tramroad and its Neighbours: By Michael Lewis. Pp 176, illustrated. London: Railway & Canal Historical Society, 2020. £25. [Hardback]. ISBN 978 0 901461 69 8.

Author

Jones, Stephen K.

Subjects
HISTORY associations, RAILROADS, STEAM locomotives, DIGITAL technology, TECHNOLOGICAL innovations, PHOTOCOPYING
Abstract

Often considered to be the Achilles heel of the tramroad as far as locomotives were concerned were cast iron tramplate breakages due to the weight of the locomotives. I Part 2 (The locomotives) i is a comprehensive survey which follows the various tramroad locomotives, many of which were built at the Neath Abbey ironworks. Finally, I Part 3 (The tramroads at work) i examines the working of the tramroad including the social and economic impact on local communities and is based on many primary and secondary sources including contemporary newspaper accounts. [Extracted from the article]

Published
2022
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40. Massively Parallel Biophysical Analysis of CRISPR-Cas Complexes on Next Generation Sequencing Chips

Author

Jung, Cheulhee, primary, Hawkins, John A., additional, Jones, Stephen K., additional, Xiao, Yibei, additional, Rybarski, James R., additional, Dillard, Kaylee E., additional, Hussmann, Jeffrey, additional, Saifuddin, Fatema A., additional, Savran, Cagri A., additional, Ellington, Andrew D., additional, Ke, Ailong, additional, Press, William H., additional, and Finkelstein, Ilya J., additional

Published
2017
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43. Stress measurements in silicon devices through Raman spectroscopy: Bridging the gap between theory and experiment.

Author

De Wolf, Ingrid, Maes, H. E., and Jones, Stephen K.

Subjects
STRAINS & stresses (Mechanics), RAMAN spectroscopy
Abstract

Presents information on a study that discussed the different steps that have to be taken in order to derive information about local mechanical stress in silicon using micro-Raman spectroscopy. Methodology of the study; Results and discussion on the study; Conclusions.

Published
1996
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49. The interaction of sterically stabilized magnetic nanoparticles with fresh human red blood cells

Author

Pham,Binh TT, Jain,Nirmesh, Kuchel,Philip W, Chapman,Bogdan E, Bickley,Stephanie A, Jones,Stephen K, Hawkett,Brian S, Pham,Binh TT, Jain,Nirmesh, Kuchel,Philip W, Chapman,Bogdan E, Bickley,Stephanie A, Jones,Stephen K, and Hawkett,Brian S

Abstract

Binh TT Pham,1 Nirmesh Jain,1 Philip W Kuchel,2 Bogdan E Chapman,2,† Stephanie A Bickley,3 Stephen K Jones,3 Brian S Hawkett11School of Chemistry, University of Sydney, 2School of Molecular Bioscience, University of Sydney, 3Sirtex Medical Limited, Sydney, NSW, Australia†Bogdan E Chapman passed away on August 16, 2014Abstract: Sterically stabilized superparamagnetic iron oxide nanoparticles (SPIONs) were incubated with fresh human erythrocytes (red blood cells [RBCs]) to explore their potential application as magnetic resonance imaging contrast agents. The chemical shift and linewidth of 133Cs+ resonances from inside and outside the RBCs in 133Cs nuclear magnetic resonance spectra were monitored as a function of time. Thus, we investigated whether SPIONs of two different core sizes and with three different types of polymeric stabilizers entered metabolically active RBCs, consuming glucose at 37°C. The SPIONs broadened the extracellular 133Cs+ nuclear magnetic resonance, and brought about a small change in its chemical shift to a higher frequency; while the intracellular resonance remained unchanged in both amplitude and chemical shift. This situation pertained over incubation times of up to 90 minutes. If the SPIONs had entered the RBCs, the intracellular resonance would have become broader and possibly even shifted. Therefore, we concluded that our SPIONs did not enter the RBCs. In addition, the T2 relaxivity of the small and large particles was 368 and 953 mM-1 s-1, respectively (three and nine times that of the most effective commercially available samples). This suggests that these new SPIONs will provide a superior performance to any others reported thus far as magnetic resonance imaging contrast agents.Keywords: 133Cs NMR spectroscopy, bulk magnetic susceptibility, fresh human erythrocyte, particle stability, paramagnetic shift, superparamagnetic iron oxide nanoparticles, SPIONs

Published
2015

50. The uptake of soluble and nanoparticulate imaging isotope in model liver tumours after intra-venous and intra-arterial administration

Author

Stephens, Ross W, Knox, Karen J, Philip, Lee A, Debono, Kelly M, Bell, Jessica L, King, David W, Parish, Christopher, Senden, Tim J, Tanudji, Marcel R, Winter, Jillean G, Bickley, Stephanie A, Tapner, Michael J., Pang, Jian H, Jones, Stephen K, Stephens, Ross W, Knox, Karen J, Philip, Lee A, Debono, Kelly M, Bell, Jessica L, King, David W, Parish, Christopher, Senden, Tim J, Tanudji, Marcel R, Winter, Jillean G, Bickley, Stephanie A, Tapner, Michael J., Pang, Jian H, and Jones, Stephen K

Abstract

Delivery of chemotherapeutic drugs to tumours by reformulation as nanoparticles has often been proposed as a means of facilitating increased selective uptake, exploiting the increased permeability of the tumour vasculature. However realisation of this improvement in drug delivery in cancer patients has met with limited success. We have compared tumour uptake of soluble Tc99m-pertechnetate and a colloid of nanoparticles with a Tc99m core, using both intra-venous and intra-arterial routes of administration in a rabbit liver VX2 tumour model. The radiolabelled nanoparticles were tested both in untreated and cationised form. The results from this tumour model in an internal organ show a marked advantage in intra-arterial administration over the intra-venous route, even for the soluble isotope. Tumour accumulation of nanoparticles from arterial administration was augmented by cationisation of the nanoparticle surface with histone proteins, which consistently facilitated selective accumulation within microvessels at the periphery of tumours.

Published
2015

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