Infrastructure to enable deployment of carbon capture, utilization, and storage in the United States
Ryan W. J. Edwards and Michael A. Celia
Carbon capture, utilization, and storage (CCUS) is a crucial technology needed to limit warming to the 2 °C target of the Paris Agreement. However, deployment is lagging far behind estimates of what is required. We demonstrate an opportunity to significantly expand CCUS in the United States in the near-term, spurred by new financial incentives enacted in February 2018, by targeting the lowest-cost capture opportunities and by deploying only commercially proven technologies. The carbon dioxide pipeline transport network would serve near-term oil industry demand for carbon dioxide while also connecting multiple prospective long-term dedicated geological storage resources. This would be a flexible long-term infrastructure asset for carbon management in the United States that would enable and accelerate future CCUS deployment. (See pp. E8815–E8824.)
Gain control explains the effect of distraction in human perceptual, cognitive, and economic decision making
Vickie Li, Elizabeth Michael, Jan Balaguer, Santiago Herce Castañón, and Christopher Summerfield
Information in the world can sometimes be irrelevant for our decisions. A good decision maker should take into account the relevant information and ignore the distracting information. However, empirical observation showed that human decisions are unduly influenced by distracting information. Diverse theories have been proposed to explain the cost that distracters incur during decision making across perceptual, cognitive, and economics domains. Here, we propose a single, unified model that is based on adaptive gain control to explain the influence of distraction across domains. (See pp. E8825–E8834.)
Infants distinguish between leaders and bullies
Francesco Margoni, Renée Baillargeon, and Luca Surian
Prior research indicates that infants can represent power asymmetries and expect them to both endure over time and extend across situations. Building on these efforts, we examined whether 21-month-old infants could distinguish between two different bases of social power. Infants first saw three protagonists interact with a powerful character who was either a leader (with respect-based power) or a bully (with fear-based power). Next, the character gave an order to the protagonists. Infants expected the protagonists to continue to obey the leader’s order after she left the scene, but they expected the protagonists to obey the bully’s order only when she remained present. Thus, by 21 months of age, infants can already distinguish between respect-based and fear-based power relations. (See pp. E8835–E8843.)
Altered ER–mitochondria contact impacts mitochondria calcium homeostasis and contributes to neurodegeneration in vivo in disease models
Kyu-Sun Lee, Sungun Huh, Seongsoo Lee, Zhihao Wu, Ae-Kyeong Kim, Ha-Young Kang, and Bingwei Lu
Ca2+ regulates cellular metabolism, proliferation, and differentiation. Ca2+ homeostasis is critical for cellular function and health. Mitochondria help buffer transient Ca2+ elevations and prevent cell death induced by Ca2+ overload. Mito-Ca2+ is also required for optimal activity of certain key mitochondrial functions, such as oxidative phosphorylation and metabolism. Thus, mito-Ca2+ homeostasis assumes central roles in cellular health. Endoplasmic reticulum (ER) and mitochondria make intimate contacts and exchange molecules such as Ca2+ and lipids. We find that ER-to-mitochondria Ca2+ transfer is important for mito-Ca2+ homeostasis and that the conserved Miro protein is critically involved. We show that mito-Ca2+ homeostasis is disrupted in neurodegenerative disease models and its restoration is beneficial. Our findings have important implications for therapeutic intervention of neurodegenerative diseases. (See pp. E8844–E8853.)
Structural elements required for coupling ion and substrate transport in the neurotransmitter transporter homolog LeuT
Yuan-Wei Zhang, Sotiria Tavoulari, Steffen Sinning, Antoniya A. Aleksandrova, Lucy R. Forrest, and Gary Rudnick
Membrane transport proteins are responsible for moving substrates, such as nutrients, vitamins, drugs, and signaling molecules across cellular membranes. A subset of these proteins, the ion-coupled transporters, use a transmembrane ion gradient to drive energetically unfavorable substrate movement from a lower concentration on one side of the membrane to a higher concentration on the other side. They do this by coupling the movement of substrate and ions in the same or the opposite direction. Coupled transport requires conformational changes that occur exclusively or predominantly when specific conditions of ion and substrate binding are met. This work identifies, for a family of Na+-coupled neurotransmitter transporters, how the rules controlling these conformational changes are encoded in the transporter structure. (See pp. E8854–E8862.)
Photoaffinity-engineered protein scaffold for systematically exploring native phosphotyrosine signaling complexes in tumor samples
Bizhu Chu, An He, Yeteng Tian, Wan He, Peizhong Chen, Jintao Hu, Ruilian Xu, Wenbin Zhou, Mingjie Zhang, Pengyuan Yang, Shawn S. C. Li, Ying Sun, Pengfei Li, Tony Hunter, and Ruijun Tian
Phosphotyrosine (pTyr)-dependent protein complexes are key machinery for regulating cancer signaling. We developed the Photo-pTyr-scaffold approach for unbiasedly capturing and exploring weak and dynamic pTyr protein complexes. By utilizing the Src kinase Src homology 2 superbinder with nanomolar binding affinity, Photo-pTyr-scaffold showed superior sensitivity for profiling native pTyr protein complexes in cancer cells and breast tumor samples. Importantly, we discovered PDGFRB to be a critical signaling node for mediating intercellular cancer signaling, which is highly expressed but independent of ERBB2, the well-established breast cancer therapeutic target. Our results could lead to new targeted therapies for breast cancer and generic approaches for exploring dynamic protein complexes related to other types of protein posttranslational modifications and discovering biomarkers readily from complex clinical samples. (See pp. E8863–E8872.)
14-3-3εa directs the pulsatile transport of basal factors toward the apical domain for lumen growth in tubulogenesis
Yuji Mizotani, Mayu Suzuki, Kohji Hotta, Hidenori Watanabe, Kogiku Shiba, Kazuo Inaba, Etsu Tashiro, Kotaro Oka, and Masaya Imoto
Ascidians have become a powerful model system in which to uncover basic mechanisms that govern body plan specification and elaboration. In particular, the ascidian notochord is a highly tractable model for tubulogenesis. Here, we use chemical genetics to identify roles for 14-3-3εa, and its binding partner ezrin/radixin/moesin (ERM), in tubulogenesis. Combining genetic and chemical perturbations with live cell imaging, we present evidence that 14-3-3εa–ERM interactions are required for tubulogenesis and that they act by promoting a directed cytoplasmic flow, previously uncharacterized, which carries lumen-associated components from the basal domain to the apical domain to feed lumen growth. Because many core components of this system are highly conserved, these results have broad implications for tubulogenesis in many other contexts. (See pp. E8873–E8881.)
FcαRI binding at the IgA1 CH2–CH3 interface induces long-range conformational changes that are transmitted to the hinge region
Monica T. Posgai, Sam Tonddast-Navaei, Manori Jayasinghe, George M. Ibrahim, George Stan, and Andrew B. Herr
Antibodies binding to their cognate cellular receptors can trigger important downstream immune responses. We mapped out critical amino acids on the IgA1 antibody that govern binding to its specific receptor, FcαRI. We found that two of the most important amino acids were located on a different IgA1 domain than the rest of the binding site, separated by a flexible linker. To better understand the interplay between receptor binding and dynamic motions in IgA1, we conducted dynamics simulations on the system. The results indicate that receptor binding perturbs IgA1 conformational dynamics over long distances and can link the receptor binding site to the hinge region of IgA1. We validate this finding experimentally, which has implications for the kidney disease IgA nephropathy. (See pp. E8882–E8891.)
Structure of the membrane proximal external region of HIV-1 envelope glycoprotein
Qingshan Fu, Md Munan Shaik, Yongfei Cai, Fadi Ghantous, Alessandro Piai, Hanqin Peng, Sophia Rits-Volloch, Zhijun Liu, Stephen C. Harrison, Michael S. Seaman, Bing Chen, and James J. Chou
The conserved, membrane-proximal external region (MPER) of the HIV-1 envelope glycoprotein (Env) is a potential vaccine target. To visualize its structure in the context of a lipid-bilayer membrane, we have reconstituted a polypeptide containing the HIV-1 MPER and the contiguous transmembrane domain into a bilayer-like environment and determined its atomic structure by NMR. The MPER folds into a trimeric cluster, well exposed on the bilayer surface, even in the absence of the structural constraints from the rest of the Env ectodomain. Our analyses suggest that this structure probably represents a prefusion conformation of the MPER. The findings imply that presenting a well-defined structure will be important for MPER-based immunogen design. (See pp. E8892–E8899.)
A cancer-associated polymorphism in ESCRT-III disrupts the abscission checkpoint and promotes genome instability
Jessica B. A. Sadler, Dawn M. Wenzel, Lauren K. Williams, Marta Guindo-Martínez, Steven L. Alam, Josep M. Mercader, David Torrents, Katharine S. Ullman, Wesley I. Sundquist, and Juan Martin-Serrano
The final step of cell division, abscission, is temporally regulated by the Aurora B kinase and charged multivesicular body protein 4C (CHMP4C) in a conserved pathway called the “abscission checkpoint” which arrests abscission in the presence of lingering mitotic problems. Despite extensive study, the physiological importance of this pathway to human health has remained elusive. We now demonstrate that a cancer-predisposing polymorphism in CHMP4C disrupts the abscission checkpoint and results in DNA damage accumulation. Moreover, deficits in this checkpoint synergize with p53 loss and generate aneuploidy under stress conditions that increase the frequency of chromosome missegregation. Therefore, cells expressing the cancer-associated polymorphism in CHMP4C are genetically unstable, thus suggesting an oncogenic mechanism that may involve the dysregulation of abscission. (See pp. E8900–E8908.)
Evolution of metazoan morphological disparity
Bradley Deline, Jennifer M. Greenwood, James W. Clark, Mark N. Puttick, Kevin J. Peterson, and Philip C. J. Donoghue
We attempt to quantify animal “bodyplans” and their variation within Metazoa. Our results challenge the view that maximum variation was achieved early in animal evolutionary history by nonuniformitarian mechanisms. Rather, they are compatible with the view that the capacity for fundamental innovation is not limited to the early evolutionary history of clades. We perform quantitative tests of the principal hypotheses of the molecular mechanisms underpinning the establishment of animal bodyplans and corroborate the hypothesis that animal evolution has been permitted or driven by gene regulatory evolution. (See pp. E8909–E8918.)
Defective cortex glia plasma membrane structure underlies light-induced epilepsy in cpes mutants
Govind Kunduri, Daniel Turner-Evans, Yutaka Konya, Yoshihiro Izumi, Kunio Nagashima, Stephen Lockett, Joost Holthuis, Takeshi Bamba, Usha Acharya, and Jairaj K. Acharya
Approximately 1 in 100 people have epilepsy, and nearly 3% of epileptics have photosensitive epilepsy, which results in serious debilitating seizures. Despite these numbers, in 100 y of research, no clear single gene defect has been shown to be causative in photosensitive epilepsy in genetic models. Although sphingolipid defects have been shown to be causative for many lysosomal storage diseases in humans as well as animal models, our study shows an important connection to a neuronal disease, photosensitive epilepsy, using the fly system as a model. We show that in a Drosophila ceramide phosphoethanolamine synthase-null mutant cortical glial cells fail to establish plasma membrane processes required to encapsulate neuronal cell bodies, resulting in photosensitive epilepsy. (See pp. E8919–E8928.)
Chemokine receptors CCR2 and CX3CR1 regulate viral encephalitis-induced hippocampal damage but not seizures
Christopher Käufer, Chintan Chhatbar, Sonja Bröer, Inken Waltl, Luca Ghita, Ingo Gerhauser, Ulrich Kalinke, and Wolfgang Löscher
Viral encephalitis is a frequent medical emergency, often resulting in acute seizures and brain damage, which reduce quality of life, promote the development of epilepsy, and can cause death. The relative roles of activation of microglia, the brain-resident innate immune cells, versus invasion of blood-borne immune cells such as monocytes in the acute and chronic consequences of viral encephalitis are only incompletely understood. Here we show that lack of the chemokine receptors CCR2 or CX3CR1, which regulate the responses of myeloid cells such as monocytes and microglia, prevents hippocampal damage but not seizures in a mouse model of viral encephalitis. Treatment strategies aimed at inhibiting peripheral immune cells from entering the brain during encephalitis could reduce brain damage. (See pp. E8929–E8938.)
Lack of Sprouty 1 and 2 enhances survival of effector CD8+ T cells and yields more protective memory cells
Hesham M. Shehata, Shahzada Khan, Elise Chen, Patrick E. Fields, Richard A. Flavell, and Shomyseh Sanjabi
Sprouty (Spry) molecules are known regulators of the Erk signaling pathway. We determined how the absence of Spry 1 and Spry 2 affects the formation and function of effector and memory CD8+ T cells. We found that absence of Spry1/2 enhances the survival of effector CD8+ T cells and results in the formation of more polyfunctional memory cells. As increased numbers of memory CD8+ T cells strongly correlate with enhanced protection against tumors and pathogenic infections, our findings identify the Spry1 and Spry2 loci as attractive targets for increasing the number, survival, and function of antigen-specific memory CD8+ T cells. This may provide an opportunity for better future engineering of T cells against tumors and chronic viral infections. (See pp. E8939–E8947.)
Expansion of cancer stem cell pool initiates lung cancer recurrence before angiogenesis
Lei Li, Jiang-Chao Li, Hong Yang, Xu Zhang, Lu-Lu Liu, Yan Li, Ting-Ting Zeng, Ying-Hui Zhu, Xiao-Dong Li, Yan Li, Dan Xie, Li Fu, and Xin-Yuan Guan
Latent tumor cells are the crucial reason of tumor recurrence and the death of cancer patients. Preventing latent tumor relapse can prolong patients’ survival and have a long time surviving with latent tumor cells. Here, we describe a lung cancer suspensive tumor model in mouse and find that a high level of cancer stem cells undergoing asymmetric cell division in latent tumor is the key issue to reactivate a suspensive tumor. The results clearly delineate the state of latent tumor in vivo. A high level of serum IGF-1 can induce the suspensive-to-progressive tumor transition though promoting CSCs symmetric division, which illuminate a key checkpoint of cancer relapse before angiogenesis, highlighting a potential therapeutic target for preventing tumor recurrence. (See pp. E8948–E8957.)
Phylogenetic approach to recover integration dates of latent HIV sequences within-host
Bradley R. Jones, Natalie N. Kinloch, Joshua Horacsek, Bruce Ganase, Marianne Harris, P. Richard Harrigan, R. Brad Jones, Mark A. Brockman, Jeffrey B. Joy, Art F. Y. Poon, and Zabrina L. Brumme
Studies characterizing within-host latent HIV sequence diversity have yielded insight into reservoir dynamics and persistence. Our understanding of these processes, however, can be further enhanced if reservoir diversity is interpreted in context of HIV’s within-host evolutionary history. Approaches to infer the original establishment (i.e., integration) dates of individual within-host latent HIV lineages would be particularly useful in this regard. We describe a phylogenetic framework to infer latent HIV ages from viral sequence information and apply it to latent HIV sequences sampled up to 10 y on suppressive therapy to yield insights into HIV reservoir dynamics. The ability to infer within-host latent HIV ages from sequence information has broad potential applications that may advance us toward an HIV cure. (See pp. E8958–E8967.)
Enterotoxigenic E. coli virulence gene regulation in human infections
Alexander A. Crofts, Simone M. Giovanetti, Erica J. Rubin, Frédéric M. Poly, Ramiro L. Gutiérrez, Kawsar R. Talaat, Chad K. Porter, Mark S. Riddle, Barbara DeNearing, Jessica Brubaker, Milton Maciel Jr., Ashley N. Alcala, Subhra Chakraborty, Michael G. Prouty, Stephen J. Savarino, Bryan W. Davies, and M. Stephen Trent
Bacterial pathogens must sense cues in the host environment and adapt with appropriate transcriptional responses to cause infections. Although identifying global transcriptional changes in a pathogen during infections would reveal these mechanisms of success, such work in human infections is difficult and rare. Here we use samples from a controlled human model of enterotoxigenic Escherichia coli (ETEC) infection to identify ETEC’s global transcriptional response to the human host. We found ETEC senses environmental oxygen to coordinate virulence gene expression during human infections via the transcriptional regulator FNR, and that FNR regulates biofilm formation in ETEC. This work identified a global regulator of virulence genes in ETEC where toxin and adhesin expression is coordinated with pathogen proximity to the epithelium. (See pp. E8968–E8976.)
Ehrlichia type IV secretion system effector Etf-2 binds to active RAB5 and delays endosome maturation
Qi Yan, Mingqun Lin, Weiyan Huang, Omid Teymournejad, Jennifer M. Johnson, Franklin A. Hays, Zhimin Liang, Guangpu Li, and Yasuko Rikihisa
Phagocytosis and subsequent destruction of pathogens when the phagosomes in which they reside are fused with lysosomes are pillars of the eukaryotic innate immune defense. Consequently, evading trafficking to phagolysosomes is a fundamental survival strategy of most intracellular pathogens that replicate inside eukaryotic host cells. The obligatory intracellular bacterium Ehrlichia chaffeensis also avoids routing to host-cell phagolysosomes, but in a unique way: Ehrlichia secretes a protein, Ehrlichia translocated factor-2 (Etf-2), that has a Tre2-Bub2-Cdc16 (TBC)-like motif lacking RAB-GTPase–activating protein (GAP) activity. Etf-2 binds RAB5 on Ehrlichia inclusions and interferes with the engagement of RAB5-specific GAP with RAB5, thereby maintaining RAB5 in a GTP-bound active form on bacterial inclusions. Etf-2 is a unique example of a RAB-associated regulatory protein with a TBC-like motif lacking RABGAP activity. (See pp. E8977–E8986.)
Elimination of the error signal in the superior colliculus impairs saccade motor learning
Yoshiko Kojima and Robijanto Soetedjo
Theories of cerebellar-dependent motor learning use the error between the desired and actual movement to correct the erroneous movement. To support this idea, several studies have tried to eliminate the error signal to the cerebellum and demonstrate an impairment of learning. However, such former approaches have not been successful because blocking the error signal also affected the movement to be learned. In this study, we selectively block an error signal for saccade adaptation, a type of cerebellar motor learning, by inactivating the source of the error signal in the superior colliculus without affecting the movement to be learned. Saccade adaptation was impaired. Thus, our study provides the first experimental evidence that an error signal is required for cerebellar motor learning. (See pp. E8987–E8995.)
PKCε contributes to lipid-induced insulin resistance through cross talk with p70S6K and through previously unknown regulators of insulin signaling
Brandon M. Gassaway, Max C. Petersen, Yulia V. Surovtseva, Karl W. Barber, Joshua B. Sheetz, Hans R. Aerni, Jane S. Merkel, Varman T. Samuel, Gerald I. Shulman, and Jesse Rinehart
We investigated the role of PKCε in driving lipid-induced hepatic insulin resistance beyond direct insulin receptor phosphorylation/inhibition using an in vivo model of acute hepatic insulin resistance and phosphoproteomic analysis. Many of the phosphoproteins we uncovered have not been previously associated with insulin signaling; to validate these connections, we developed a functional siRNA-based screen, which confirmed a direct role in regulating insulin signaling. We validated direct PKCε–substrate interactions using a recently developed peptide substrate library, which confirmed the cross talk between PKCε and p70S6K that our proteomic analysis suggested and which may result in aberrant negative feedback upon lipid-induced PKCε activation. Taken together, we expand the potential landscape of therapeutic targets for the treatment of insulin resistance and diabetes. (See pp. E8996–E9005.)
Glutamate-activated BK channel complexes formed with NMDA receptors
Jiyuan Zhang, Xin Guan, Qin Li, Andrea L. Meredith, Hui-Lin Pan, and Jiusheng Yan
Large-conductance BK channels are dually activated by voltage and Ca2+ and play a powerful integrative role in regulating cellular excitability and Ca2+ signaling in neurons. However, BK channels have a requirement of high intracellular free Ca2+ concentrations for activation under physiological conditions, and the Ca2+ sources for their activation are not well understood. In this work, we establish that BK channels physically form protein complexes with Ca2+-permeable NMDA receptors via their obligatory BKα and GluN1 subunits. The activation mechanism and function of postsynaptic BK channels at synapses remain largely unknown. We found that postsynaptic BK channels in medial perforant path-dentate gyrus granule cell synapses are activated by NMDA receptor-mediated Ca2+ influx and modulate excitatory synaptic transmission. (See pp. E9006–E9014.)
Mid-level visual features underlie the high-level categorical organization of the ventral stream
Bria Long, Chen-Ping Yu, and Talia Konkle
While neural responses to object categories are remarkably systematic across human visual cortex, the nature of these responses has been hotly debated for the past 20 y. In this paper, a class of stimuli (texforms) is used to examine how mid-level features contribute to the large-scale organization of the ventral visual stream. Despite their relatively primitive visual appearance, these unrecognizable texforms elicited the entire large-scale organizations of the ventral stream by animacy and object size. This work demonstrates that much of ventral stream organization can be explained by relatively primitive mid-level features without requiring explicit recognition of the objects themselves. (See pp. E9015–E9024.)