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1. Continuous, quantifiable, and simple osmotic preconcentration and sensing within microfluidic devices.

Author

Andrew Jajack, Isaac Stamper, Eliot Gomez, Michael Brothers, Gavi Begtrup, and Jason Heikenfeld

Subjects
Medicine, Science
Abstract

Insurmountable detection challenges will impede the development of many of the next-generation of lab-on-a-chip devices (e.g., point-of-care and real-time health monitors). Here we present the first membrane-based, microfluidic sample preconcentration method that is continuous, quantifiable, simple, and capable of working with any analyte. Forward osmosis rapidly concentrates analytes by removing water from a stream of sample fluid. 10-100X preconcentration is possible in mere minutes. This requires careful selection of the semi-permeable membrane and draw molecule; therefore, the osmosis performance of several classes of membranes and draw molecules were systematically optimized. Proof-of-concept preconcentration devices were characterized based on their concentration ability and fouling resistance. In-silico theoretical modeling predicts the experimental findings and provides an engineering toolkit for future designs. With this toolkit, inexpensive ready-for-manufacturing prototypes were also developed. These devices provide broad-spectrum detection improvements across many analytes and sensing modalities, enabling next-generation lab-on-a-chip devices.

Published
2019
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2. Enhancing glucose flux into sweat by increasing paracellular permeability of the sweat gland.

Author

Andrew Jajack, Michael Brothers, Gerald Kasting, and Jason Heikenfeld

Subjects
Medicine, Science
Abstract

Non-invasive wearable biosensors provide real-time, continuous, and actionable health information. However, difficulties detecting diluted biomarkers in excreted biofluids limit practical applications. Most biomarkers of interest are transported paracellularly into excreted biofluids from biomarker-rich blood and interstitial fluid during normal modulation of cellular tight junctions. Calcium chelators are reversible tight junction modulators that have been shown to increase absorption across the intestinal epithelium. However, calcium chelators have not yet been shown to improve the extraction of biomarkers. Here we show that for glucose, a paracellularly transported biomarker, the flux into sweat can be increased by >10x using citrate, a calcium chelator, in combination with electroosmosis. Our results demonstrate a method of increasing glucose flux through the sweat gland epithelium, thereby increasing the concentration in sweat. Future work should examine if this method enhances flux for other paracellularly transported biomarkers to make it possible to detect more biomarkers with currently available biosensors.

Published
2018
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3. COVID Moonshot: Open Science Discovery of SARS-CoV-2 Main Protease Inhibitors by Combining Crowdsourcing, High-Throughput Experiments, Computational Simulations, and Machine Learning

Author

Anna Carbery, Annette von Delft, Boris Kovar, Vishwanath Swamy, Ronen Gabizon, Nathan Wright, Charlie Weatherall, Susana Tomasio, Hannah E. Bruce Macdonald, Daniel Zaidmann, Ailsa Powell, P. Gehrtz, Noam Erez, Walter Ward, Vladimir Psenak, Finny S. Varghese, Edward J Griffen, Halina Mikolajek, Sharon Melamed, Emma Cattermole, A. Aimon, Elad Bar-David, Louise Dunnett, Maneesh Pingle, Warren Thompson, Efrat Resnick, William G. Glass, Mark Daniel Calmiano, J. L. Kiappes, Lizbe Koekemoer, Mariana Vaschetto, Andrew Jajack, Nir London, Martin Walsh, Beth MacLean, Charline Giroud, Haim Levy, Anastassia L. Kantsadi, Vladas Oleinikovas, Andrew Thompson, Vincent A. Voelz, Assa Sittner, Tomer Israely, John Spencer, Itai Glinert, Matthew F. D. Hurley, Richard Foster, T.J. Gorrie-Stone, Aarif Shaikh, Gijs J. Overheul, Conor Francis Wild, Michael Fairhead, Benjamin Ian Perry, David Owen, Michelle L. Hill, Peter W. Kenny, Sarma Bvnbs, Galit Cohen, Ralph P. Robinson, Jakir Pinjari, Carina Gileadi, Amir Ben-Shmuel, Shay Weiss, Victor L. Rangel, Matthew C. Robinson, Anthony Tumber, D. Fearon, Jag Paul Heer, Boaz Politi, Nicole Zitzmann, Claire Strain-Damerell, Tika R. Malla, Oleg M. Michurin, Peter K. Eastman, Christopher J. Schofield, Matthew Wittmann, Jin Pan, Eric Jnoff, Shirly Duberstein, Mihaela D. Smilova, Haim Barr, Ronald P. van Rij, Joseph E. Coffland, Garrett M. Morris, Austin Clyde, Khriesto A. Shurrush, Einat B. Vitner, Ruby Pai, Alessandro Contini, St Patrick Reid, Jose Brandao Neto, Lisa Cox, Tatiana Matviiuk, Jiye Shi, Sam Horrell, Ioannis Vakonakis, Aaron Morris, Hadeer Zidane, Juliane Brun, Yfat Yahalom-Ronen, Hadas Tamir, R. Skyner, Tobias John, John D. Chodera, Nir Paran, Alex Dias, Dominic Rufa, Willam McCorkindale, Reut Puni, Hagit Achdout, Rachael Tennant, Holly Foster, Tim Dudgeon, Bruce A. Lefker, Rambabu N. Reddi, Marian V. Gorichko, Frank von Delft, Alpha A. Lee, Milan Cvitkovic, T. Krojer, Demetri Moustakas, Oleg Fedorov, Robert C. Glen, Jason C. Cole, Petra Lukacik, Matteo P. Ferla, Melissa L Bobby, Adam Smalley, Jim Bennett, Melody Jane Morwitzer, and Alice Douangamath

Subjects
Open science, Protease, Computer science, business.industry, Drug discovery, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), medicine.medical_treatment, Crowdsourcing, Machine learning, computer.software_genre, Enzymatic Assays, medicine, Ic50 values, Artificial intelligence, business, Throughput (business), computer
Abstract

Herein we provide a living summary of the data generated during the COVID Moonshot project focused on the development of SARS-CoV-2 main protease (Mpro) inhibitors. Our approach uniquely combines crowdsourced medicinal chemistry insights with high throughput crystallography, exascale computational chemistry infrastructure for simulations, and machine learning in triaging designs and predicting synthetic routes. This manuscript describes our methodologies leading to both covalent and non-covalent inhibitors displaying protease IC50 values under 150 nM and viral inhibition under 5 uM in multiple different viral replication assays. Furthermore, we provide over 200 crystal structures of fragment-like and lead-like molecules in complex with the main protease. Over 1000 synthesized and ordered compounds are also reported with the corresponding activity in Mpro enzymatic assays using two different experimental setups. The data referenced in this document will be continually updated to reflect the current experimental progress of the COVID Moonshot project, and serves as a citable reference for ensuing publications. All of the generated data is open to other researchers who may find it of use.

Published
2020
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4. SARS-CoV-2 infects the human kidney and drives fibrosis in kidney organoids

Author

Jitske Jansen, Katharina C. Reimer, James S. Nagai, Finny S. Varghese, Gijs J. Overheul, Marit de Beer, Rona Roverts, Deniz Daviran, Liline A.S. Fermin, Brigith Willemsen, Marcel Beukenboom, Sonja Djudjaj, Saskia von Stillfried, Larissa E. van Eijk, Mirjam Mastik, Marian Bulthuis, Wilfred den Dunnen, Harry van Goor, Jan-Luuk Hillebrands, Sergio H. Triana, Theodore Alexandrov, Marie-Cherelle Timm, Bartholomeus T. van den Berge, Martijn van den Broek, Quincy Nlandu, Joelle Heijnert, Eric M.J. Bindels, Remco M. Hoogenboezem, Fieke Mooren, Christoph Kuppe, Pascal Miesen, Katrien Grünberg, Ties Ijzermans, Eric J. Steenbergen, Jan Czogalla, Michiel F. Schreuder, Nico Sommerdijk, Anat Akiva, Peter Boor, Victor G. Puelles, Jürgen Floege, Tobias B. Huber, Ronald P. van Rij, Ivan G. Costa, Rebekka K. Schneider, Bart Smeets, Rafael Kramann, Hagit Achdout, Anthony Aimon, Elad Bar-David, Haim Barr, Amir Ben-Shmuel, James Bennett, Melissa L. Boby, Bruce Borden, Gregory R. Bowman, Juliane Brun, Sarma BVNBS, Mark Calmiano, Anna Carbery, Emma Cattermole, Eugene Chernychenko, John D. Choder, Austin Clyde, Joseph E. Coffland, Galit Cohen, Jason Cole, Alessandro Contini, Lisa Cox, Milan Cvitkovic, Alex Dias, Kim Donckers, David L. Dotson, Alica Douangamath, Shirly Duberstein, Tim Dudgeon, Louise Dunnett, Peter K. Eastman, Noam Erez, Charles J. Eyermann, Mike Fairhead, Gwen Fate, Daren Fearon, Oleg Federov, Matteo Ferla, Rafaela S. Fernandes, Lori Ferrins, Richard Foster, Holly Foster, Ronen Gabizon, Adolfo Garcia-Sastre, Victor O. Gawriljuk, Paul Gehrtz, Carina Gileadi, Charline Giroud, William G. Glass, Robert Glen, null Itai glinert, Andre S. Godoy, Marian Gorichko, Tyler Gorrie-Stone, Ed J. Griffen, Storm Hassell Hart, Jag Heer, Micheal Henry, Michelle Hill, Sam Horrell, Matthew F.D. Hurley, Tomer Israely, Andrew Jajack, Eric Jnoff, Dirk Jochmans, Tobias John, Steven De Jonghe, Anastassia L. Kantsadi, Peter W. Kenny, J.L. Kiappes, Lizbe Koekemoer, Boris Kovar, Tobias Krojer, Alpha A. Lee, Bruce A. Lefker, Haim Levy, Nir London, Petra Lukacik, Hannah Bruce Macdonald, Beth Maclean, Tika R. Malla, Tatiana Matviiuk, Willam McCorkindale, Briana L. McGovern, Sharon Melamed, Oleg Michurin, Halina Mikolajek, Bruce F. Milne, Aaron Morris, Garret M. Morris, Melody Jane Morwitzer, Demetri Moustakas, Aline M. Nakamura, Jose Brandao Neto, Johan Neyts, Luong Nguyen, Gabriela D. Noske, Vladas Oleinikovas, Glaucius Oliva, David Owen, Vladimir Psenak, Ruby Pai, Jin Pan, Nir Paran, Benjamin Perry, Maneesh Pingle, Jakir Pinjari, Boaz Politi, Ailsa Powell, Reut Puni, Victor L. Rangel, Ranbabu N. Reddi, St Patrick Reid, Efrat Resnick, Emily Grace Ripka, Matthew C. Robinson, Ralph P. Robinson, Jaime Rodriguez-Guerra, Romel Rosales, Dominic Rufa, Chris Schofield, Mikhail Shafeev, Aarif Shaikh, Jiye Shi, Khriesto Shurrush, Sukrit Sing, Assa Sittner, Rachael Skyner, Adam Smalley, Mihaela D. Smilova, Leonardo J. Solmesky, John Spencer, Claire Strain-Damarell, Vishwanath Swamy, Hadas Tamir, Rachael Tennant, Warren Thompson, Andrew Thompson, Susana Tomasia, Anthony Tumber, Ioannis Vakonakis, Laura van Geel, Mariana Vaschetto, Einat B. Vitner, Vincent Voelz, Andra Volkamer, Frank von Delft, Annette von Delft, Martin Walsh, Walter Ward, Charlie Weatherall, Shay Weiss, Kris M. White, Conor Francis Wild, Matthew Wittmann, Nathan Wright, Yfat Yahalom-Ronen, Daniel Zaidmann, Hadeer Zidane, Nicole Zitzmann, Hematology, Developmental Biology, Internal Medicine, Molecular Neuroscience and Ageing Research (MOLAR), Groningen Institute for Organ Transplantation (GIOT), and Groningen Kidney Center (GKC)

Subjects
FÍGADO, viruses, lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4], Rare cancers Radboud Institute for Molecular Life Sciences [Radboudumc 9], Kidney, All institutes and research themes of the Radboud University Medical Center, Post-Acute COVID-19 Syndrome, SDG 3 - Good Health and Well-being, Urological cancers Radboud Institute for Molecular Life Sciences [Radboudumc 15], Genetics, Humans, SARS-CoV-2, human iPSC kidney organoids, fibrosis, fungi, COVID-19, Cell Biology, Clinical and Translational Report, Fibrosis, Organoids, Reconstructive and regenerative medicine Radboud Institute for Molecular Life Sciences [Radboudumc 10], Renal disorders Radboud Institute for Molecular Life Sciences [Radboudumc 11], kidney injury, Molecular Medicine, protease blocker, Nanomedicine Radboud Institute for Molecular Life Sciences [Radboudumc 19], chronic kidney disease
Abstract

Kidney failure is frequently observed during and after COVID-19, but it remains elusive whether this is a direct effect of the virus. Here, we report that SARS-CoV-2 directly infects kidney cells and is associated with increased tubule-interstitial kidney fibrosis in patient autopsy samples. To study direct effects of the virus on the kidney independent of systemic effects of COVID-19, we infected human induced pluripotent stem cell-derived kidney organoids with SARS-CoV-2. Single cell RNA-sequencing indicated injury and dedifferentiation of infected cells with activation of pro-fibrotic signaling pathways. Importantly, SARS-CoV-2 infection also led to increased collagen 1 protein expression in organoids. A SARS-CoV-2 protease inhibitor was able to ameliorate the infection of kidney cells by SARS-CoV-2. Our results suggest that SARS-CoV-2 can directly infect kidney cells and induce cell injury with subsequent fibrosis. These data could explain both acute kidney injury in COVID-19 patients and the development of chronic kidney disease in Long-COVID., Graphical Abstract, Jansen, Reimer, Nagai et al report that SARS-CoV-2 infects kidney cells and is associated with kidney fibrosis in patients. Using single cell transcriptomics of infected kidney organoids, they show that SARS-CoV-2 causes kidney injury and stimulates pro-fibrotic signaling. Viral infection in organoids was inhibited by a recently developed protease blocker.

Published
2022

5. Accessing analytes in biofluids for peripheral biochemical monitoring

Author

Jason, Heikenfeld, Andrew, Jajack, Benjamin, Feldman, Steve W, Granger, Supriya, Gaitonde, Gavi, Begtrup, and Benjamin A, Katchman

Subjects
Adult, Blood Glucose, Male, Extracellular Fluid, Biosensing Techniques, Body Fluids, Wearable Electronic Devices, Young Adult, Glucose, Humans, Female, Saliva, Sweat, Biotechnology, Monitoring, Physiologic
Abstract

Peripheral biochemical monitoring involves the use of wearable devices for minimally invasive or noninvasive measurement of analytes in biofluids such as interstitial fluid, saliva, tears and sweat. The goal in most cases is to obtain measurements that serve as surrogates for circulating analyte concentrations in blood. Key technological developments to date include continuous glucose monitors, which use an indwelling sensor needle to measure glucose in interstitial fluid, and device-integrated sweat stimulation for continuous access to analytes in sweat. Further development of continuous sensing technologies through new electrochemical sensing modalities will be a major focus of future research. While there has been much investment in wearable technologies to sense analytes, less effort has been directed to understanding the physiology of biofluid secretion. Elucidating the underlying biology is crucial for accelerating technological progress, as the biofluid itself often presents the greatest challenge in terms of sample volumes, secretion rates, filtration, active analyte channels, variable pH and salinity, analyte breakdown and other confounding factors.

Published
2018

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