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1. Derivation of human primordial germ cell-like cells in an embryonic-like culture.

Author

Esfahani, Sajedeh, Zheng, Yi, Arabpour, Auriana, Irizarry, Agnes, Kobayashi, Norio, Xue, Xufeng, Shao, Yue, Zhao, Cheng, Agranonik, Nicole, Sparrow, Megan, Hunt, Timothy, Faith, Jared, Lara, Mary, Wu, Qiu, Silber, Sherman, Petropoulos, Sophie, Yang, Ran, Chien, Kenneth, Fu, Jianping, and Clark, Amander

Subjects
Humans, Male, Semen, Germ Cells, Pluripotent Stem Cells, Cell Line, Signal Transduction, Cell Differentiation
Abstract

Primordial germ cells (PGCs) are the embryonic precursors of sperm and eggs. They transmit genetic and epigenetic information across generations. Given the prominent role of germline defects in diseases such as infertility, detailed understanding of human PGC (hPGC) development has important implications in reproductive medicine and studying human evolution. Yet, hPGC specification remains an elusive process. Here, we report the induction of hPGC-like cells (hPGCLCs) in a bioengineered human pluripotent stem cell (hPSC) culture that mimics peri-implantation human development. In this culture, amniotic ectoderm-like cells (AMLCs), derived from hPSCs, induce hPGCLC specification from hPSCs through paracrine signaling downstream of ISL1. Our data further show functional roles of NODAL, WNT, and BMP signaling in hPGCLC induction. hPGCLCs are successfully derived from eight non-obstructive azoospermia (NOA) participant-derived hPSC lines using this biomimetic platform, demonstrating its promise for screening applications.

Published
2024

2. IgM N-glycosylation correlates with COVID-19 severity and rate of complement deposition

Author

Ozonoff, Al, Ehrlich, Lauren IR, Melamed, Esther, Sesma, Ana Fernandez, Simon, Viviana, Pulendran, Bali, Nadeau, Kari C, Davis, Mark M, McCoey, Grace A, Sekaly, Rafick, Baden, Lindsey R, Levy, Ofer, Schaenman, Joanna, Reed, Elaine F, Shaw, Albert C, Hafler, David A, Montgomery, Ruth R, Kleinstein, Steven H, Becker, Patrice M, Augustine, Alison D, Calfee, Carolyn S, Erle, David J, DeBakey, Michael E, Corry, David B, Kheradmand, Farrah, Atkinson, Mark A, Brakenridge, Scott C, Higuita, Nelson I Agudelo, Metcalf, Jordan P, Hough, Catherine L, Messer, William B, Kraft, Monica, Bime, Chris, Peters, Bjoern, Milliren, Carly E, Syphurs, Caitlin, McEnaney, Kerry, Barton, Brenda, Lentucci, Claudia, Saluvan, Mehmet, Chang, Ana C, Hoch, Annmarie, Albert, Marisa, Shaheen, Tanzia, Kho, Alvin T, Liu, Shanshan, Thomas, Sanya, Chen, Jing, Murphy, Maimouna D, Cooney, Mitchell, Hayati, Arash Nemati, Bryant, Robert, Abraham, James, Jayavelu, Naresh Doni, Presnell, Scott, Jancsyk, Tomasz, Maguire, Cole, Qi, Jingjing, Lee, Brian, Fourati, Slim, Esserman, Denise A, Guan, Leying, Gygi, Jeremy, Pawar, Shrikant, Brito, Anderson, Fragiadakis, Gabriela K, Patel, Ravi, Overton, James A, Vita, Randi, Westendorf, Kerstin, Shannon, Casey P, Tebbutt, Scott J, Thyagarajan, Rama V, Rousseau, Justin F, Wylie, Dennis, Triplett, Todd A, Kojic, Erna, Chinthrajah, Sharon, Ahuja, Neera, Rogers, Angela J, Artandi, Maja, Geng, Linda, Yendewa, George, Powell, Debra L, Kim, James N, Simmons, Brent, Goonewardene, I Michael, Smith, Cecilia M, Martens, Mark, Sherman, Amy C, Walsh, Stephen R, Issa, Nicolas C, Salehi-Rad, Ramin, Dela Cruz, Charles, Farhadian, Shelli, Iwasaki, Akiko, Ko, Albert I, Anderson, Evan J, Mehta, Aneesh K, and Sevransky, Jonathan E

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Immunology, Infectious Diseases, Coronaviruses, Lung, Emerging Infectious Diseases, Inflammatory and immune system, Good Health and Well Being, Humans, COVID-19, Glycosylation, SARS-CoV-2, Glycosyltransferases, Complement System Proteins, Immunoglobulin M, IMPACC Network
Abstract

The glycosylation of IgG plays a critical role during human severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, activating immune cells and inducing cytokine production. However, the role of IgM N-glycosylation has not been studied during human acute viral infection. The analysis of IgM N-glycosylation from healthy controls and hospitalized coronavirus disease 2019 (COVID-19) patients reveals increased high-mannose and sialylation that correlates with COVID-19 severity. These trends are confirmed within SARS-CoV-2-specific immunoglobulin N-glycan profiles. Moreover, the degree of total IgM mannosylation and sialylation correlate significantly with markers of disease severity. We link the changes of IgM N-glycosylation with the expression of Golgi glycosyltransferases. Lastly, we observe antigen-specific IgM antibody-dependent complement deposition is elevated in severe COVID-19 patients and modulated by exoglycosidase digestion. Taken together, this work links the IgM N-glycosylation with COVID-19 severity and highlights the need to understand IgM glycosylation and downstream immune function during human disease.

Published
2024

3. Features of acute COVID-19 associated with post-acute sequelae of SARS-CoV-2 phenotypes: results from the IMPACC study

Author

McEnaney, Kerry, Barton, Brenda, Lentucci, Claudia, Saluvan, Mehmet, Chang, Ana C, Hoch, Annmarie, Albert, Marisa, Shaheen, Tanzia, Kho, Alvin T, Thomas, Sanya, Chen, Jing, Murphy, Maimouna D, Cooney, Mitchell, Hayati, Arash Nemati, Bryant, Robert, Abraham, James, Presnell, Scott, Jancsyk, Tomasz, Maguire, Cole, Lee, Brian, Fourati, Slim, Esserman, Denise A, Guan, Leying, Gygi, Jeremy, Pawar, Shrikant, Brito, Anderson, Fragiadakis, Gabriela K, Patel, Ravi, Tebbutt, Scott J, Overton, James A, Vita, Randi, Westendorf, Kerstin, Thyagarajan, Rama V, Rousseau, Justin F, Wylie, Dennis, Triplett, Todd A, Kojic, Erna, Chinthrajah, Sharon, Ahuja, Neera, Rogers, Angela J, Artandi, Maja, Yendewa, George, Powell, Debra L, Kim, James N, Simmons, Brent, Goonewardene, I Michael, Smith, Cecilia M, Martens, Mark, Sherman, Amy C, Walsh, Stephen R, Issa, Nicolas C, Salehi-Rad, Ramin, Dela Cruz, Charles, Farhadian, Shelli, Iwasaki, Akiko, Ko, Albert I, Anderson, Evan J, Mehta, Aneesh K, Sevransky, Jonathan E, Leligdowicz, Aleksandra, Matthay, Michael A, Singer, Jonathan P, Kangelaris, Kirsten N, Hendrickson, Carolyn M, Krummel, Matthew F, Woodruff, Prescott G, Anderson, Matthew L, Guirgis, Faheem W, Drevets, Douglas A, Brown, Brent R, Siegel, Sarah AR, Lu, Zhengchun, Mosier, Jarrod, Kimura, Hiroki, Khor, Bernard, Rahman, Adeeb, Stadlbauer, Daniel, Dutta, Jayeeta, Gonzalez-Reiche, Ana Silvia, van de Guchte, Adriana, Carreño, Juan Manuel, Singh, Gagandeep, Raskin, Ariel, Tcheou, Johnstone, Bielak, Dominika, Kawabata, Hisaaki, Xie, Hui, Kelly, Geoffrey, Patel, Manishkumar, Nie, Kai, Yellin, Temima, Fried, Miriam, Sullivan, Leeba, Morris, Sara, Sieg, Scott, van Zalm, Patrick, Fatou, Benoit, Mendez, Kevin, Lasky-Su, Jessica, and Hutton, Scott R

Subjects
Health Services and Systems, Biomedical and Clinical Sciences, Health Sciences, Prevention, Vaccine Related, Emerging Infectious Diseases, Biodefense, Brain Disorders, Infectious Diseases, Lung, Good Health and Well Being, Female, Humans, SARS-CoV-2, COVID-19, B-Lymphocytes, Body Fluids, Disease Progression, Phenotype, IMPACC Network
Abstract

Post-acute sequelae of SARS-CoV-2 (PASC) is a significant public health concern. We describe Patient Reported Outcomes (PROs) on 590 participants prospectively assessed from hospital admission for COVID-19 through one year after discharge. Modeling identified 4 PRO clusters based on reported deficits (minimal, physical, mental/cognitive, and multidomain), supporting heterogenous clinical presentations in PASC, with sub-phenotypes associated with female sex and distinctive comorbidities. During the acute phase of disease, a higher respiratory SARS-CoV-2 viral burden and lower Receptor Binding Domain and Spike antibody titers were associated with both the physical predominant and the multidomain deficit clusters. A lower frequency of circulating B lymphocytes by mass cytometry (CyTOF) was observed in the multidomain deficit cluster. Circulating fibroblast growth factor 21 (FGF21) was significantly elevated in the mental/cognitive predominant and the multidomain clusters. Future efforts to link PASC to acute anti-viral host responses may help to better target treatment and prevention of PASC.

Published
2024

8. Rational design of a JAK1-selective siRNA inhibitor for the modulation of autoimmunity in the skin

Author

Tang, Qi, Fakih, Hassan H., Zain UI Abideen, Mohammad, Hildebrand, Samuel R., Afshari, Khashayar, Gross, Katherine Y., Sousa, Jacquelyn, Maebius, Allison S., Bartholdy, Christina, Søgaard, Pia Pernille, Jackerott, Malene, Hariharan, Vignesh, Summers, Ashley, Fan, Xueli, Okamura, Ken, Monopoli, Kathryn R., Cooper, David A., Echeverria, Dimas, Bramato, Brianna, McHugh, Nicholas, Furgal, Raymond C., Dresser, Karen, Winter, Sarah J., Biscans, Annabelle, Chuprin, Jane, Haddadi, Nazgol-Sadat, Sherman, Shany, Yıldız-Altay, Ümmügülsüm, Rashighi, Mehdi, Richmond, Jillian M., Bouix-Peter, Claire, Blanchard, Carine, Clauss, Adam, Alterman, Julia F., Khvorova, Anastasia, and Harris, John E.

Published
2023
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11. Author Correction: Single-cell RNA sequencing reveals the effects of chemotherapy on human pancreatic adenocarcinoma and its tumor microenvironment

Author

Werba, Gregor, Weissinger, Daniel, Kawaler, Emily A., Zhao, Ende, Kalfakakou, Despoina, Dhara, Surajit, Wang, Lidong, Lim, Heather B., Oh, Grace, Jing, Xiaohong, Beri, Nina, Khanna, Lauren, Gonda, Tamas, Oberstein, Paul, Hajdu, Cristina, Loomis, Cynthia, Heguy, Adriana, Sherman, Mara H., Lund, Amanda W., Welling, Theodore H., Dolgalev, Igor, Tsirigos, Aristotelis, and Simeone, Diane M.

Published
2023
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13. Half a century of rising extinction risk of coral reef sharks and rays

Author

Sherman, C. Samantha, Simpfendorfer, Colin A., Pacoureau, Nathan, Matsushiba, Jay H., Yan, Helen F., Walls, Rachel H. L., Rigby, Cassandra L., VanderWright, Wade J., Jabado, Rima W., Pollom, Riley A., Carlson, John K., Charvet, Patricia, Bin Ali, Ahmad, Fahmi, Cheok, Jessica, Derrick, Danielle H., Herman, Katelyn B., Finucci, Brittany, Eddy, Tyler D., Palomares, Maria Lourdes D., Avalos-Castillo, Christopher G., Kinattumkara, Bineesh, Blanco-Parra, María-del-Pilar, Dharmadi, Espinoza, Mario, Fernando, Daniel, Haque, Alifa B., Mejía-Falla, Paola A., Navia, Andrés F., Pérez-Jiménez, Juan Carlos, Utzurrum, Jean, Yuneni, Ranny R., and Dulvy, Nicholas K.

Published
2023
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14. Single-cell RNA sequencing reveals the effects of chemotherapy on human pancreatic adenocarcinoma and its tumor microenvironment

Author

Werba, Gregor, Weissinger, Daniel, Kawaler, Emily A., Zhao, Ende, Kalfakakou, Despoina, Dhara, Surajit, Wang, Lidong, Lim, Heather B., Oh, Grace, Jing, Xiaohong, Beri, Nina, Khanna, Lauren, Gonda, Tamas, Oberstein, Paul, Hajdu, Cristina, Loomis, Cynthia, Heguy, Adriana, Sherman, Mara H., Lund, Amanda W., Welling, Theodore H., Dolgalev, Igor, Tsirigos, Aristotelis, and Simeone, Diane M.

Published
2023
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16. Author Correction: The evolution of RET inhibitor resistance in RET-driven lung and thyroid cancers

Author

Rosen, Ezra Y., Won, Helen H., Zheng, Youyun, Cocco, Emiliano, Selcuklu, Duygu, Gong, Yixiao, Friedman, Noah D., de Bruijn, Ino, Sumer, Onur, Bielski, Craig M., Savin, Casey, Bourque, Caitlin, Falcon, Christina, Clarke, Nikeysha, Jing, Xiaohong, Meng, Fanli, Zimel, Catherine, Shifman, Sophie, Kittane, Srushti, Wu, Fan, Ladanyi, Marc, Ebata, Kevin, Kherani, Jennifer, Brandhuber, Barbara J., Fagin, James, Sherman, Eric J., Rekhtman, Natasha, Berger, Michael F., Scaltriti, Maurizio, Hyman, David M., Taylor, Barry S., and Drilon, Alexander

Published
2022
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19. Predicting the structural basis of targeted protein degradation by integrating molecular dynamics simulations with structural mass spectrometry

Author

Dixon, Tom, MacPherson, Derek, Mostofian, Barmak, Dauzhenka, Taras, Lotz, Samuel, McGee, Dwight, Shechter, Sharon, Shrestha, Utsab R., Wiewiora, Rafal, McDargh, Zachary A., Pei, Fen, Pal, Rajat, Ribeiro, João V., Wilkerson, Tanner, Sachdeva, Vipin, Gao, Ning, Jain, Shourya, Sparks, Samuel, Li, Yunxing, Vinitsky, Alexander, Zhang, Xin, Razavi, Asghar M., Kolossváry, István, Imbriglio, Jason, Evdokimov, Artem, Bergeron, Louise, Zhou, Wenchang, Adhikari, Jagat, Ruprecht, Benjamin, Dickson, Alex, Xu, Huafeng, Sherman, Woody, and Izaguirre, Jesus A.

Published
2022
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21. The evolution of RET inhibitor resistance in RET-driven lung and thyroid cancers

Author

Rosen, Ezra Y., Won, Helen H., Zheng, Youyun, Cocco, Emiliano, Selcuklu, Duygu, Gong, Yixiao, Friedman, Noah D., de Bruijn, Ino, Sumer, Onur, Bielski, Craig M., Savin, Casey, Bourque, Caitlin, Falcon, Christina, Clarke, Nikeysha, Jing, Xiaohong, Meng, Fanli, Zimel, Catherine, Shifman, Sophie, Kittane, Srushti, Wu, Fan, Ladanyi, Marc, Ebata, Kevin, Kherani, Jennifer, Brandhuber, Barbara J., Fagin, James, Sherman, Eric J., Rekhtman, Natasha, Berger, Michael F., Scaltriti, Maurizio, Hyman, David M., Taylor, Barry S., and Drilon, Alexander

Published
2022
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27. On the tear resistance of skin.

Author

Yang, Wen, Sherman, Vincent R, Gludovatz, Bernd, Schaible, Eric, Stewart, Polite, Ritchie, Robert O, and Meyers, Marc A

Subjects
Skin, Dermis, Animals, Rabbits, Fibrillar Collagens, Microscopy, Electron, Scanning, Elasticity, Stress, Mechanical, Tensile Strength, Biomechanical Phenomena
Abstract

Tear resistance is of vital importance in the various functions of skin, especially protection from predatorial attack. Here, we mechanistically quantify the extreme tear resistance of skin and identify the underlying structural features, which lead to its sophisticated failure mechanisms. We explain why it is virtually impossible to propagate a tear in rabbit skin, chosen as a model material for the dermis of vertebrates. We express the deformation in terms of four mechanisms of collagen fibril activity in skin under tensile loading that virtually eliminate the possibility of tearing in pre-notched samples: fibril straightening, fibril reorientation towards the tensile direction, elastic stretching and interfibrillar sliding, all of which contribute to the redistribution of the stresses at the notch tip.

Published
2015

28. Remote ischemic conditioning counteracts the intestinal damage of necrotizing enterocolitis by improving intestinal microcirculation

Author

Koike, Yuhki, Li, Bo, Ganji, Niloofar, Zhu, Haitao, Miyake, Hiromu, Chen, Yong, Lee, Carol, Janssen Lok, Maarten, Zozaya, Carlos, Lau, Ethan, Lee, Dorothy, Chusilp, Sinobol, Zhang, Zhen, Yamoto, Masaya, Wu, Richard Y., Inoue, Mikihiro, Uchida, Keiichi, Kusunoki, Masato, Delgado-Olguin, Paul, Mertens, Luc, Daneman, Alan, Eaton, Simon, Sherman, Philip M., and Pierro, Agostino

Published
2020
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34. A novel rapamycin analog is highly selective for mTORC1 in vivo

Author

Schreiber, Katherine H., Arriola Apelo, Sebastian I., Yu, Deyang, Brinkman, Jacqueline A., Velarde, Michael C., Syed, Faizan A., Liao, Chen-Yu, Baar, Emma L., Carbajal, Kathryn A., Sherman, Dawn S., Ortiz, Denise, Brunauer, Regina, Yang, Shany E., Tzannis, Stelios T., Kennedy, Brian K., and Lamming, Dudley W.

Published
2019
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37. The DNA-binding network of Mycobacterium tuberculosis

Author

Minch, Kyle J., Rustad, Tige R., Peterson, Eliza J. R., Winkler, Jessica, Reiss, David J., Ma, Shuyi, Hickey, Mark, Brabant, William, Morrison, Bob, Turkarslan, Serdar, Mawhinney, Chris, Galagan, James E., Price, Nathan D., Baliga, Nitin S., and Sherman, David R.

Published
2015
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38. A transthalamic pathway crucial for perception

Author

Christina Mo, Claire McKinnon, and S. Murray Sherman

Subjects
Science
Abstract

Abstract Perception is largely supported by cortical processing that involves communication among multiple areas, typically starting with primary sensory cortex and then involving higher order cortices. This communication is served in part by transthalamic (cortico-thalamo-cortical) pathways, which ubiquitously parallel direct corticocortical pathways, but their role in sensory processing has largely remained unexplored. Here, we suggest that transthalamic processing propagates task-relevant information required for correct sensory decisions. Using optogenetics, we specifically inhibited the pathway at its synapse in higher order somatosensory thalamus of mice performing a texture-based discrimination task. We concurrently monitored the cellular effects of inhibition in primary or secondary cortex using two-photon calcium imaging. Inhibition severely impaired performance despite intact direct corticocortical projections, thus challenging the purely corticocentric map of perception. Interestingly, the inhibition did not reduce overall cell responsiveness to texture stimulation in somatosensory cortex, but rather disrupted the texture selectivity of cells, a discriminability that develops over task learning. This discriminability was more disrupted in the secondary than primary somatosensory cortex, emphasizing the feedforward influence of the transthalamic route. Transthalamic pathways may therefore act to deliver performance-relevant information to higher order cortex and are underappreciated hierarchical pathways in perceptual decision-making.

Published
2024
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39. Discovering type I cis-AT polyketides through computational mass spectrometry and genome mining with Seq2PKS

Author

Donghui Yan, Muqing Zhou, Abhinav Adduri, Yihao Zhuang, Mustafa Guler, Sitong Liu, Hyonyoung Shin, Torin Kovach, Gloria Oh, Xiao Liu, Yuting Deng, Xiaofeng Wang, Liu Cao, David H. Sherman, Pamela J. Schultz, Roland D. Kersten, Jason A. Clement, Ashootosh Tripathi, Bahar Behsaz, and Hosein Mohimani

Subjects
Science
Abstract

Abstract Type 1 polyketides are a major class of natural products used as antiviral, antibiotic, antifungal, antiparasitic, immunosuppressive, and antitumor drugs. Analysis of public microbial genomes leads to the discovery of over sixty thousand type 1 polyketide gene clusters. However, the molecular products of only about a hundred of these clusters are characterized, leaving most metabolites unknown. Characterizing polyketides relies on bioactivity-guided purification, which is expensive and time-consuming. To address this, we present Seq2PKS, a machine learning algorithm that predicts chemical structures derived from Type 1 polyketide synthases. Seq2PKS predicts numerous putative structures for each gene cluster to enhance accuracy. The correct structure is identified using a variable mass spectral database search. Benchmarks show that Seq2PKS outperforms existing methods. Applying Seq2PKS to Actinobacteria datasets, we discover biosynthetic gene clusters for monazomycin, oasomycin A, and 2-aminobenzamide-actiphenol.

Published
2024
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40. Derivation of human primordial germ cell-like cells in an embryonic-like culture

Author

Sajedeh Nasr Esfahani, Yi Zheng, Auriana Arabpour, Agnes M. Resto Irizarry, Norio Kobayashi, Xufeng Xue, Yue Shao, Cheng Zhao, Nicole L. Agranonik, Megan Sparrow, Timothy J. Hunt, Jared Faith, Mary Jasmine Lara, Qiu Ya Wu, Sherman Silber, Sophie Petropoulos, Ran Yang, Kenneth R. Chien, Amander T. Clark, and Jianping Fu

Subjects
Science
Abstract

Abstract Primordial germ cells (PGCs) are the embryonic precursors of sperm and eggs. They transmit genetic and epigenetic information across generations. Given the prominent role of germline defects in diseases such as infertility, detailed understanding of human PGC (hPGC) development has important implications in reproductive medicine and studying human evolution. Yet, hPGC specification remains an elusive process. Here, we report the induction of hPGC-like cells (hPGCLCs) in a bioengineered human pluripotent stem cell (hPSC) culture that mimics peri-implantation human development. In this culture, amniotic ectoderm-like cells (AMLCs), derived from hPSCs, induce hPGCLC specification from hPSCs through paracrine signaling downstream of ISL1. Our data further show functional roles of NODAL, WNT, and BMP signaling in hPGCLC induction. hPGCLCs are successfully derived from eight non-obstructive azoospermia (NOA) participant-derived hPSC lines using this biomimetic platform, demonstrating its promise for screening applications.

Published
2024
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41. Single-sided magnetic resonance-based sensor for point-of-care evaluation of muscle

Author

Sydney E. Sherman, Alexa S. Zammit, Won-Seok Heo, Matthew S. Rosen, and Michael J. Cima

Subjects
Science
Abstract

Abstract Magnetic resonance imaging is a widespread clinical tool for the detection of soft tissue morphology and pathology. However, the clinical deployment of magnetic resonance imaging scanners is ultimately limited by size, cost, and space constraints. Here, we discuss the design and performance of a low-field single-sided magnetic resonance sensor intended for point-of-care evaluation of skeletal muscle in vivo. The 11 kg sensor has a penetration depth of >8 mm, which allows for an accurate analysis of muscle tissue and can avoid signal from more proximal layers, including subcutaneous adipose tissue. Low operational power and shielding requirements are achieved through the design of a permanent magnet array and surface transceiver coil. The sensor can acquire high signal-to-noise measurements in minutes, making it practical as a point-of-care tool for many quantitative diagnostic measurements, including T2 relaxometry. In this work, we present the in vitro and human in vivo performance of the device for muscle tissue evaluation.

Published
2024
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42. Rational design of a JAK1-selective siRNA inhibitor for the modulation of autoimmunity in the skin

Author

Qi Tang, Hassan H. Fakih, Mohammad Zain UI Abideen, Samuel R. Hildebrand, Khashayar Afshari, Katherine Y. Gross, Jacquelyn Sousa, Allison S. Maebius, Christina Bartholdy, Pia Pernille Søgaard, Malene Jackerott, Vignesh Hariharan, Ashley Summers, Xueli Fan, Ken Okamura, Kathryn R. Monopoli, David A. Cooper, Dimas Echeverria, Brianna Bramato, Nicholas McHugh, Raymond C. Furgal, Karen Dresser, Sarah J. Winter, Annabelle Biscans, Jane Chuprin, Nazgol-Sadat Haddadi, Shany Sherman, Ümmügülsüm Yıldız-Altay, Mehdi Rashighi, Jillian M. Richmond, Claire Bouix-Peter, Carine Blanchard, Adam Clauss, Julia F. Alterman, Anastasia Khvorova, and John E. Harris

Subjects
Science
Abstract

Abstract Inhibition of Janus kinase (JAK) family enzymes is a popular strategy for treating inflammatory and autoimmune skin diseases. In the clinic, small molecule JAK inhibitors show distinct efficacy and safety profiles, likely reflecting variable selectivity for JAK subtypes. Absolute JAK subtype selectivity has not yet been achieved. Here, we rationally design small interfering RNAs (siRNAs) that offer sequence-specific gene silencing of JAK1, narrowing the spectrum of action on JAK-dependent cytokine signaling to maintain efficacy and improve safety. Our fully chemically modified siRNA supports efficient silencing of JAK1 expression in human skin explant and modulation of JAK1-dependent inflammatory signaling. A single injection into mouse skin enables five weeks of duration of effect. In a mouse model of vitiligo, local administration of the JAK1 siRNA significantly reduces skin infiltration of autoreactive CD8+ T cells and prevents epidermal depigmentation. This work establishes a path toward siRNA treatments as a new class of therapeutic modality for inflammatory and autoimmune skin diseases.

Published
2023
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43. Hippocampal firing fields anchored to a moving object predict homing direction during path-integration-based behavior

Author

Maryam Najafian Jazi, Adrian Tymorek, Ting-Yun Yen, Felix Jose Kavarayil, Moritz Stingl, Sherman Richard Chau, Benay Baskurt, Celia García Vilela, and Kevin Allen

Subjects
Science
Abstract

Abstract Homing based on path integration (H-PI) is a form of navigation in which an animal uses self-motion cues to keep track of its position and return to a starting point. Despite evidence for a role of the hippocampus in homing behavior, the hippocampal spatial representations associated with H-PI are largely unknown. Here we developed a homing task (AutoPI task) that required a mouse to find a randomly placed lever on an arena before returning to its home base. Recordings from the CA1 area in male mice showed that hippocampal neurons remap between random foraging and AutoPI task, between trials in light and dark conditions, and between search and homing behavior. During the AutoPI task, approximately 25% of the firing fields were anchored to the lever position. The activity of 24% of the cells with a lever-anchored field predicted the homing direction of the animal on each trial. Our results demonstrate that the activity of hippocampal neurons with object-anchored firing fields predicts homing behavior.

Published
2023
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44. Creating resistance to avian influenza infection through genome editing of the ANP32 gene family

Author

Alewo Idoko-Akoh, Daniel H. Goldhill, Carol M. Sheppard, Dagmara Bialy, Jessica L. Quantrill, Ksenia Sukhova, Jonathan C. Brown, Samuel Richardson, Ciara Campbell, Lorna Taylor, Adrian Sherman, Salik Nazki, Jason S. Long, Michael A. Skinner, Holly Shelton, Helen M. Sang, Wendy S. Barclay, and Mike J. McGrew

Subjects
Science
Abstract

Abstract Chickens genetically resistant to avian influenza could prevent future outbreaks. In chickens, influenza A virus (IAV) relies on host protein ANP32A. Here we use CRISPR/Cas9 to generate homozygous gene edited (GE) chickens containing two ANP32A amino acid substitutions that prevent viral polymerase interaction. After IAV challenge, 9/10 edited chickens remain uninfected. Challenge with a higher dose, however, led to breakthrough infections. Breakthrough IAV virus contained IAV polymerase gene mutations that conferred adaptation to the edited chicken ANP32A. Unexpectedly, this virus also replicated in chicken embryos edited to remove the entire ANP32A gene and instead co-opted alternative ANP32 protein family members, chicken ANP32B and ANP32E. Additional genome editing for removal of ANP32B and ANP32E eliminated all viral growth in chicken cells. Our data illustrate a first proof of concept step to generate IAV-resistant chickens and show that multiple genetic modifications will be required to curtail viral escape.

Published
2023
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45. Retina-derived signals control pace of neurogenesis in visual brain areas but not circuit assembly

Author

Shachar Sherman, Irene Arnold-Ammer, Martin W. Schneider, Koichi Kawakami, and Herwig Baier

Subjects
Science
Abstract

Abstract Brain development is orchestrated by both innate and experience-dependent mechanisms, but their relative contributions are difficult to disentangle. Here we asked if and how central visual areas are altered in a vertebrate brain depleted of any and all signals from retinal ganglion cells throughout development. We transcriptionally profiled neurons in pretectum, thalamus and other retinorecipient areas of larval zebrafish and searched for changes in lakritz mutants that lack all retinal connections. Although individual genes are dysregulated, the complete set of 77 neuronal types develops in apparently normal proportions, at normal locations, and along normal differentiation trajectories. Strikingly, the cell-cycle exits of proliferating progenitors in these areas are delayed, and a greater fraction of early postmitotic precursors remain uncommitted or are diverted to a pre-glial fate. Optogenetic stimulation targeting groups of neurons normally involved in processing visual information evokes behaviors indistinguishable from wildtype. In conclusion, we show that signals emitted by retinal axons influence the pace of neurogenesis in visual brain areas, but do not detectably affect the specification or wiring of downstream neurons.

Published
2023
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46. Grid integration feasibility and investment planning of offshore wind power under carbon-neutral transition in China

Author

Xinyang Guo, Xinyu Chen, Xia Chen, Peter Sherman, Jinyu Wen, and Michael McElroy

Subjects
Science
Abstract

Abstract Offshore wind power, with accelerated declining levelized costs, is emerging as a critical building-block to fully decarbonize the world’s largest CO2 emitter, China. However, system integration barriers as well as system balancing costs have not been quantified yet. Here we develop a bottom-up model to test the grid accommodation capabilities and design the optimal investment plans for offshore wind power considering resource distributions, hourly power system simulations, and transmission/storage/hydrogen investments. Results indicate that grid integration barriers exist currently at the provincial level. For 2030, optimized offshore wind investment levels should be doubled compared with current government plans, and provincial allocations should be significantly improved considering both resource quality and grid conditions. For 2050, offshore wind capacity in China could reach as high as 1500 GW, prompting a paradigm shift in national transmission structure, favoring long-term storage in the energy portfolio, enabling green hydrogen production in coastal demand centers, resulting in the world’s largest wind power market.

Published
2023
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47. Affinity maturation generates pathogenic antibodies with dual reactivity to DNase1L3 and dsDNA in systemic lupus erythematosus

Author

Eduardo Gomez-Bañuelos, Yikai Yu, Jessica Li, Kevin S. Cashman, Merlin Paz, Maria Isabel Trejo-Zambrano, Regina Bugrovsky, Youliang Wang, Asiya Seema Chida, Cheryl A. Sherman-Baust, Dylan P. Ferris, Daniel W. Goldman, Erika Darrah, Michelle Petri, Iñaki Sanz, and Felipe Andrade

Subjects
Science
Abstract

Antibodies directed against DNA in systemic lupus erythematosus are functionally diverse. This study demonstrates that DNAse1L3 is the primary target of a subset of autoantibodies previously considered specific for double-stranded DNA.

Published
2023
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48. Single-cell RNA sequencing reveals the effects of chemotherapy on human pancreatic adenocarcinoma and its tumor microenvironment

Author

Gregor Werba, Daniel Weissinger, Emily A. Kawaler, Ende Zhao, Despoina Kalfakakou, Surajit Dhara, Lidong Wang, Heather B. Lim, Grace Oh, Xiaohong Jing, Nina Beri, Lauren Khanna, Tamas Gonda, Paul Oberstein, Cristina Hajdu, Cynthia Loomis, Adriana Heguy, Mara H. Sherman, Amanda W. Lund, Theodore H. Welling, Igor Dolgalev, Aristotelis Tsirigos, and Diane M. Simeone

Subjects
Science
Abstract

Abstract The tumor microenvironment (TME) in pancreatic ductal adenocarcinoma (PDAC) is a complex ecosystem that drives tumor progression; however, in-depth single cell characterization of the PDAC TME and its role in response to therapy is lacking. Here, we perform single-cell RNA sequencing on freshly collected human PDAC samples either before or after chemotherapy. Overall, we find a heterogeneous mixture of basal and classical cancer cell subtypes, along with distinct cancer-associated fibroblast and macrophage subpopulations. Strikingly, classical and basal-like cancer cells exhibit similar transcriptional responses to chemotherapy and do not demonstrate a shift towards a basal-like transcriptional program among treated samples. We observe decreased ligand-receptor interactions in treated samples, particularly between TIGIT on CD8 + T cells and its receptor on cancer cells, and identify TIGIT as the major inhibitory checkpoint molecule of CD8 + T cells. Our results suggest that chemotherapy profoundly impacts the PDAC TME and may promote resistance to immunotherapy.

Published
2023
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49. Half a century of rising extinction risk of coral reef sharks and rays

Author

C. Samantha Sherman, Colin A. Simpfendorfer, Nathan Pacoureau, Jay H. Matsushiba, Helen F. Yan, Rachel H. L. Walls, Cassandra L. Rigby, Wade J. VanderWright, Rima W. Jabado, Riley A. Pollom, John K. Carlson, Patricia Charvet, Ahmad Bin Ali, Fahmi, Jessica Cheok, Danielle H. Derrick, Katelyn B. Herman, Brittany Finucci, Tyler D. Eddy, Maria Lourdes D. Palomares, Christopher G. Avalos-Castillo, Bineesh Kinattumkara, María-del-Pilar Blanco-Parra, Dharmadi, Mario Espinoza, Daniel Fernando, Alifa B. Haque, Paola A. Mejía-Falla, Andrés F. Navia, Juan Carlos Pérez-Jiménez, Jean Utzurrum, Ranny R. Yuneni, and Nicholas K. Dulvy

Subjects
Science
Abstract

Sharks and rays are vital coral reef species. This study shows that nearly two thirds (59%) of the 134 coral-reef associated species are threatened with extinction. The main cause of their decline is found to be overfishing, both targeted and unintentional, and extinction risk is greater for larger species found in nations with higher fishing pressure and weaker governance.

Published
2023
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50. Predicting the structural basis of targeted protein degradation by integrating molecular dynamics simulations with structural mass spectrometry

Author

Tom Dixon, Derek MacPherson, Barmak Mostofian, Taras Dauzhenka, Samuel Lotz, Dwight McGee, Sharon Shechter, Utsab R. Shrestha, Rafal Wiewiora, Zachary A. McDargh, Fen Pei, Rajat Pal, João V. Ribeiro, Tanner Wilkerson, Vipin Sachdeva, Ning Gao, Shourya Jain, Samuel Sparks, Yunxing Li, Alexander Vinitsky, Xin Zhang, Asghar M. Razavi, István Kolossváry, Jason Imbriglio, Artem Evdokimov, Louise Bergeron, Wenchang Zhou, Jagat Adhikari, Benjamin Ruprecht, Alex Dickson, Huafeng Xu, Woody Sherman, and Jesus A. Izaguirre

Subjects
Science
Abstract

The formation of ternary degrader-protein complexes is a key step in the targeted degradation of proteins of interest. Here, the authors explore the structure and dynamics of such complexes applying high-performance computer simulations augmented with experimental data.

Published
2022
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