1
Proc Natl Acad Sci U S A
. 2020 May 29;202005077. doi: 10.1073/pnas.2005077117. Online ahead of print.
Systemic Signaling During Abiotic Stress Combination in Plants
Sara I Zandalinas 1 2, Yosef Fichman 1 2, Amith R Devireddy 1 2, Soham Sengupta 3, Rajeev K Azad 3 4, Ron Mittler 5 2 6
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PMID: 32471943 DOI: 10.1073/pnas.2005077117
Abstract
Extreme environmental conditions, such as heat, salinity, and decreased water availability, can have a devastating impact on plant growth and productivity, potentially resulting in the collapse of entire ecosystems. Stress-induced systemic signaling and systemic acquired acclimation play canonical roles in plant survival during episodes of environmental stress. Recent studies revealed that in response to a single abiotic stress, applied to a single leaf, plants mount a comprehensive stress-specific systemic response that includes the accumulation of many different stress-specific transcripts and metabolites, as well as a coordinated stress-specific whole-plant stomatal response. However, in nature plants are routinely subjected to a combination of two or more different abiotic stresses, each potentially triggering its own stress-specific systemic response, highlighting a new fundamental question in plant biology: are plants capable of integrating two different systemic signals simultaneously generated during conditions of stress combination? Here we show that plants can integrate two different systemic signals simultaneously generated during stress combination, and that the manner in which plants sense the different stresses that trigger these signals (i.e., at the same or different parts of the plant) makes a significant difference in how fast and efficient they induce systemic reactive oxygen species (ROS) signals; transcriptomic, hormonal, and stomatal responses; as well as plant acclimation. Our results shed light on how plants acclimate to their environment and survive a combination of different abiotic stresses. In addition, they highlight a key role for systemic ROS signals in coordinating the response of different leaves to stress.

Keywords: abiotic stress; reactive oxygen species; stress combination; systemic acquired acclimation; systemic signaling.

Copyright © 2020 the Author(s). Published by PNAS.

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The authors declare no competing interest.

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2
Proc Natl Acad Sci U S A
. 2020 Jun 1;201909326. doi: 10.1073/pnas.1909326117. Online ahead of print.
Leveraging Mobile Phones to Attain Sustainable Development
Valentina Rotondi 1 2 3 4, Ridhi Kashyap 5 3 4, Luca Maria Pesando 6 7, Simone Spinelli 2, Francesco C Billari 2 8
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PMID: 32482867 DOI: 10.1073/pnas.1909326117
Abstract
For billions of people across the globe, mobile phones enable relatively cheap and effective communication, as well as access to information and vital services on health, education, society, and the economy. Drawing on context-specific evidence on the effects of the digital revolution, this study provides empirical support for the idea that mobile phones are a vehicle for sustainable development at the global scale. It does so by assembling a wealth of publicly available macro- and individual-level data, exploring a wide range of demographic and social development outcomes, and leveraging a combination of methodological approaches. Macro-level analyses covering 200+ countries reveal that mobile-phone access is associated with lower gender inequality, higher contraceptive uptake, and lower maternal and child mortality. Individual-level analyses of survey data from sub-Saharan Africa, linked with detailed geospatial information, further show that women who own a mobile phone are better informed about sexual and reproductive health services and empowered to make independent decisions. Payoffs are larger among the least-developed countries and among the most disadvantaged micro-level clusters. Overall, our findings suggest that boosting mobile-phone access and coverage and closing digital divides, particularly among women, can be powerful tools to attain empowerment-related sustainable development goals, in an ultimate effort to enhance population health and well-being and reduce poverty.

Keywords: SDGs; gender equality; mobile phones.

Copyright © 2020 the Author(s). Published by PNAS.

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The authors declare no competing interest.

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3
Proc Natl Acad Sci U S A
. 2020 Jun 1;202003170. doi: 10.1073/pnas.2003170117. Online ahead of print.
MHC-II Alleles Shape the CDR3 Repertoires of Conventional and Regulatory Naïve CD4 + T Cells
Nadezhda N Logunova 1, Valeriia V Kriukova 2 3, Pavel V Shelyakin 2, Evgeny S Egorov 2 4, Alina Pereverzeva 2, Nina G Bozhanova 5 6, Mikhail Shugay 2 3 4, Dmitrii S Shcherbinin 4, Mikhail V Pogorelyy 2 4, Ekaterina M Merzlyak 2 4, Vasiliy N Zubov 2, Jens Meiler 5 6 7, Dmitriy M Chudakov 2 3 4, Alexander S Apt 8, Olga V Britanova 9
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PMID: 32482872 DOI: 10.1073/pnas.2003170117
Abstract
T cell maturation and activation depend upon T cell receptor (TCR) interactions with a wide variety of antigenic peptides displayed in a given major histocompatibility complex (MHC) context. Complementarity-determining region 3 (CDR3) is the most variable part of the TCRα and -β chains, which govern interactions with peptide-MHC complexes. However, it remains unclear how the CDR3 landscape is shaped by individual MHC context during thymic selection of naïve T cells. We established two mouse strains carrying distinct allelic variants of H2-A and analyzed thymic and peripheral production and TCR repertoires of naïve conventional CD4+ T (Tconv) and naïve regulatory CD4+ T (Treg) cells. Compared with tuberculosis-resistant C57BL/6 (H2-Ab) mice, the tuberculosis-susceptible H2-Aj mice had fewer CD4+ T cells of both subsets in the thymus. In the periphery, this deficiency was only apparent for Tconv and was compensated for by peripheral reconstitution for Treg We show that H2-Aj favors selection of a narrower and more convergent repertoire with more hydrophobic and strongly interacting amino acid residues in the middle of CDR3α and CDR3β, suggesting more stringent selection against a narrower peptide-MHC-II context. H2-Aj and H2-Ab mice have prominent reciprocal differences in CDR3α and CDR3β features, probably reflecting distinct modes of TCR fitting to MHC-II variants. These data reveal the mechanics and extent of how MHC-II shapes the naïve CD4+ T cell CDR3 landscape, which essentially defines adaptive response to infections and self-antigens.

Keywords: MHC-II; TCR repertoire landscape; naïve CD4+ T cells; regulatory T cells.

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The authors declare no competing interest.

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4
Proc Natl Acad Sci U S A
. 2020 Jun 1;202001103. doi: 10.1073/pnas.2001103117. Online ahead of print.
A Cost-Effectiveness Analysis of the Number of Samples to Collect and Test From a Sexual Assault
Zhengli Wang 1, Kevin MacMillan 2, Mark Powell 2, Lawrence M Wein 3
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PMID: 32482858 DOI: 10.1073/pnas.2001103117
Abstract
Although the backlog of untested sexual assault kits in the United States is starting to be addressed, many municipalities are opting for selective testing of samples within a kit, where only the most probative samples are tested. We use data from the San Francisco Police Department Criminalistics Laboratory, which tests all samples but also collects information on the samples flagged by sexual assault forensic examiners as most probative, to build a standard machine learning model that predicts (based on covariates gleaned from sexual assault kit questionnaires) which samples are most probative. This model is embedded within an optimization framework that selects which samples to test from each kit to maximize the Combined DNA Index System (CODIS) yield (i.e., the number of kits that generate at least one DNA profile for the criminal DNA database) subject to a budget constraint. Our analysis predicts that, relative to a policy that tests only the samples deemed probative by the sexual assault forensic examiners, the proposed policy increases the CODIS yield by 45.4% without increasing the cost. Full testing of all samples has a slightly lower cost-effectiveness than the selective policy based on forensic examiners, but more than doubles the yield. In over half of the sexual assaults, a sample was not collected during the forensic medical exam from the body location deemed most probative by the machine learning model. Our results suggest that electronic forensic records coupled with machine learning and optimization models could enhance the effectiveness of criminal investigations of sexual assaults.

Keywords: crime solving; forensic science; machine learning; optimization; sexual assaults.

Copyright © 2020 the Author(s). Published by PNAS.

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The authors declare no competing interest.

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5
Proc Natl Acad Sci U S A
. 2020 Jun 1;201922701. doi: 10.1073/pnas.1922701117. Online ahead of print.
Structural Basis for Allosteric Transitions of a Multidomain Pentameric Ligand-Gated Ion Channel
Haidai Hu 1 2, Rebecca J Howard 3, Ugo Bastolla 4, Erik Lindahl 3, Marc Delarue 5
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PMID: 32482881 DOI: 10.1073/pnas.1922701117
Abstract
Pentameric ligand-gated ion channels (pLGICs) are allosteric receptors that mediate rapid electrochemical signal transduction in the animal nervous system through the opening of an ion pore upon binding of neurotransmitters. Orthologs have been found and characterized in prokaryotes and they display highly similar structure-function relationships to eukaryotic pLGICs; however, they often encode greater architectural diversity involving additional amino-terminal domains (NTDs). Here we report structural, functional, and normal-mode analysis of two conformational states of a multidomain pLGIC, called DeCLIC, from a Desulfofustis deltaproteobacterium, including a periplasmic NTD fused to the conventional ligand-binding domain (LBD). X-ray structure determination revealed an NTD consisting of two jelly-roll domains interacting across each subunit interface. Binding of Ca2+ at the LBD subunit interface was associated with a closed transmembrane pore, with resolved monovalent cations intracellular to the hydrophobic gate. Accordingly, DeCLIC-injected oocytes conducted currents only upon depletion of extracellular Ca2+; these were insensitive to quaternary ammonium block. Furthermore, DeCLIC crystallized in the absence of Ca2+ with a wide-open pore and remodeled periplasmic domains, including increased contacts between the NTD and classic LBD agonist-binding sites. Functional, structural, and dynamical properties of DeCLIC paralleled those of sTeLIC, a pLGIC from another symbiotic prokaryote. Based on these DeCLIC structures, we would reclassify the previous structure of bacterial ELIC (the first high-resolution structure of a pLGIC) as a "locally closed" conformation. Taken together, structures of DeCLIC in multiple conformations illustrate dramatic conformational state transitions and diverse regulatory mechanisms available to ion channels in pLGICs, particularly involving Ca2+ modulation and periplasmic NTDs.

Keywords: crystallography; electrophysiology; ligand-gated ion channels; structural biology.

Conflict of interest statement
The authors declare no competing interest.

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6
Proc Natl Acad Sci U S A
. 2020 May 29;201922498. doi: 10.1073/pnas.1922498117. Online ahead of print.
Longitudinal Analysis Reveals Transition Barriers Between Dominant Ecological States in the Gut Microbiome
Roie Levy 1, Andrew T Magis 1, John C Earls 1, Ohad Manor 2, Tomasz Wilmanski 1, Jennifer Lovejoy 1, Sean M Gibbons 1 3, Gilbert S Omenn 1 4, Leroy Hood 5, Nathan D Price 5
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PMID: 32471946 DOI: 10.1073/pnas.1922498117
Abstract
The Pioneer 100 Wellness Project involved quantitatively profiling 108 participants' molecular physiology over time, including genomes, gut microbiomes, blood metabolomes, blood proteomes, clinical chemistries, and data from wearable devices. Here, we present a longitudinal analysis focused specifically around the Pioneer 100 gut microbiomes. We distinguished a subpopulation of individuals with reduced gut diversity, elevated relative abundance of the genus Prevotella, and reduced levels of the genus Bacteroides We found that the relative abundances of Bacteroides and Prevotella were significantly correlated with certain serum metabolites, including omega-6 fatty acids. Primary dimensions in distance-based redundancy analysis of clinical chemistries explained 18.5% of the variance in bacterial community composition, and revealed a Bacteroides/Prevotella dichotomy aligned with inflammation and dietary markers. Finally, longitudinal analysis of gut microbiome dynamics within individuals showed that direct transitions between Bacteroides-dominated and Prevotella-dominated communities were rare, suggesting the presence of a barrier between these states. One implication is that interventions seeking to transition between Bacteroides- and Prevotella-dominated communities will need to identify permissible paths through ecological state-space that circumvent this apparent barrier.

Keywords: Bacteroides; Prevotella; microbiome; multiomic; state transition.

Copyright © 2020 the Author(s). Published by PNAS.

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The authors declare no competing interest.

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7
Proc Natl Acad Sci U S A
. 2020 Jun 1;201918162. doi: 10.1073/pnas.1918162117. Online ahead of print.
Global Variation in the Thermal Tolerances of Plants
Lesley T Lancaster 1, Aelys M Humphreys 2 3
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PMID: 32482870 DOI: 10.1073/pnas.1918162117
Abstract
Thermal macrophysiology is an established research field that has led to well-described patterns in the global structuring of climate adaptation and risk. However, since it was developed primarily in animals, we lack information on how general these patterns are across organisms. This is alarming if we are to understand how thermal tolerances are distributed globally, improve predictions of climate change, and mitigate effects. We approached this knowledge gap by compiling a geographically and taxonomically extensive database on plant heat and cold tolerances and used this dataset to test for thermal macrophysiological patterns and processes in plants. We found support for several expected patterns: Cold tolerances are more variable and exhibit steeper latitudinal clines and stronger relationships with local environmental temperatures than heat tolerances overall. Next, we disentangled the importance of local environments and evolutionary and biogeographic histories in generating these patterns. We found that all three processes have significantly contributed to variation in both heat and cold tolerances but that their relative importance differs. We also show that failure to simultaneously account for all three effects overestimates the importance of the included variable, challenging previous conclusions drawn from less comprehensive models. Our results are consistent with rare evolutionary innovations in cold acclimation ability structuring plant distributions across biomes. In contrast, plant heat tolerances vary mainly as a result of biogeographical processes and drift. Our results further highlight that all plants, particularly at mid-to-high latitudes and in their nonhardened state, will become increasingly vulnerable to ongoing climate change.

Keywords: cold and heat; hardening; latitude; macrophysiology; temperature.

Conflict of interest statement
The authors declare no competing interest.

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8
Proc Natl Acad Sci U S A
. 2020 Jun 1;201916646. doi: 10.1073/pnas.1916646117. Online ahead of print.
Activity-dependent Myelination: A Glial Mechanism of Oscillatory Self-Organization in Large-Scale Brain Networks
Rabiya Noori 1 2, Daniel Park 1 3, John D Griffiths 4 5, Sonya Bells 6, Paul W Frankland 6, Donald Mabbott 6 7, Jeremie Lefebvre 8 2 3 9
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PMID: 32482855 DOI: 10.1073/pnas.1916646117
Abstract
Communication and oscillatory synchrony between distributed neural populations are believed to play a key role in multiple cognitive and neural functions. These interactions are mediated by long-range myelinated axonal fiber bundles, collectively termed as white matter. While traditionally considered to be static after development, white matter properties have been shown to change in an activity-dependent way through learning and behavior-a phenomenon known as white matter plasticity. In the central nervous system, this plasticity stems from oligodendroglia, which form myelin sheaths to regulate the conduction of nerve impulses across the brain, hence critically impacting neural communication. We here shift the focus from neural to glial contribution to brain synchronization and examine the impact of adaptive, activity-dependent changes in conduction velocity on the large-scale phase synchronization of neural oscillators. Using a network model based on primate large-scale white matter neuroanatomy, our computational and mathematical results show that such plasticity endows white matter with self-organizing properties, where conduction delay statistics are autonomously adjusted to ensure efficient neural communication. Our analysis shows that this mechanism stabilizes oscillatory neural activity across a wide range of connectivity gain and frequency bands, making phase-locked states more resilient to damage as reflected by diffuse decreases in connectivity. Critically, our work suggests that adaptive myelination may be a mechanism that enables brain networks with a means of temporal self-organization, resilience, and homeostasis.

Keywords: adaptive myelination; glia; modeling; synchronization; white matter plasticity.

Conflict of interest statement
The authors declare no competing interest.

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9
Proc Natl Acad Sci U S A
. 2020 May 29;202000344. doi: 10.1073/pnas.2000344117. Online ahead of print.
Developmental Plasticity Shapes Social Traits and Selection in a Facultatively Eusocial Bee
Karen M Kapheim 1 2, Beryl M Jones 3, Hailin Pan 4 5 6, Cai Li 7, Brock A Harpur 8, Clement F Kent 9, Amro Zayed 9, Panagiotis Ioannidis 10, Robert M Waterhouse 11 12, Callum Kingwell 2 13, Eckart Stolle 14, Arián Avalos 15, Guojie Zhang 4 5 6, W Owen McMillan 2, William T Wcislo 2
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PMID: 32471944 DOI: 10.1073/pnas.2000344117
Abstract
Developmental plasticity generates phenotypic variation, but how it contributes to evolutionary change is unclear. Phenotypes of individuals in caste-based (eusocial) societies are particularly sensitive to developmental processes, and the evolutionary origins of eusociality may be rooted in developmental plasticity of ancestral forms. We used an integrative genomics approach to evaluate the relationships among developmental plasticity, molecular evolution, and social behavior in a bee species (Megalopta genalis) that expresses flexible sociality, and thus provides a window into the factors that may have been important at the evolutionary origins of eusociality. We find that differences in social behavior are derived from genes that also regulate sex differentiation and metamorphosis. Positive selection on social traits is influenced by the function of these genes in development. We further identify evidence that social polyphenisms may become encoded in the genome via genetic changes in regulatory regions, specifically in transcription factor binding sites. Taken together, our results provide evidence that developmental plasticity provides the substrate for evolutionary novelty and shapes the selective landscape for molecular evolution in a major evolutionary innovation: Eusociality.

Keywords: Megalopta genalis; gene regulation; genetic accommodation; social evolution; transcription factor binding.

Copyright © 2020 the Author(s). Published by PNAS.

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The authors declare no competing interest.

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10
Proc Natl Acad Sci U S A
. 2020 Jun 1;202003090. doi: 10.1073/pnas.2003090117. Online ahead of print.
The Great Oxidation Event Preceded a Paleoproterozoic "Snowball Earth"
Matthew R Warke 1, Tommaso Di Rocco 2 3, Aubrey L Zerkle 2 4, Aivo Lepland 5 6, Anthony R Prave 2, Adam P Martin 7 8, Yuichiro Ueno 9 10, Daniel J Condon 7, Mark W Claire 2 4 11
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PMID: 32482849 DOI: 10.1073/pnas.2003090117
Abstract
The inability to resolve the exact temporal relationship between two pivotal events in Earth history, the Paleoproterozoic Great Oxidation Event (GOE) and the first "snowball Earth" global glaciation, has precluded assessing causality between changing atmospheric composition and ancient climate change. Here we present temporally resolved quadruple sulfur isotope measurements (δ34S, ∆33S, and ∆36S) from the Paleoproterozoic Seidorechka and Polisarka Sedimentary Formations on the Fennoscandian Shield, northwest Russia, that address this issue. Sulfides in the former preserve evidence of mass-independent fractionation of sulfur isotopes (S-MIF) falling within uncertainty of the Archean reference array with a ∆36S/∆33S slope of -1.8 and have small negative ∆33S values, whereas in the latter mass-dependent fractionation of sulfur isotopes (S-MDF) is evident, with a ∆36S/∆33S slope of -8.8. These trends, combined with geochronological constraints, place the S-MIF/S-MDF transition, the key indicator of the GOE, between 2,501.5 ± 1.7 Ma and 2,434 ± 6.6 Ma. These are the tightest temporal and stratigraphic constraints yet for the S-MIF/S-MDF transition and show that its timing in Fennoscandia is consistent with the S-MIF/S-MDF transition in North America and South Africa. Further, the glacigenic part of the Polisarka Formation occurs 60 m above the sedimentary succession containing S-MDF signals. Hence, our findings confirm unambiguously that the S-MIF/S-MDF transition preceded the Paleoproterozoic snowball Earth. Resolution of this temporal relationship constrains cause-and-effect drivers of Earth's oxygenation, specifically ruling out conceptual models in which global glaciation precedes or causes the evolution of oxygenic photosynthesis.

Keywords: Great Oxidation Event; mass independent fractionation; quadruple sulfur isotopes; snowball Earth.

Copyright © 2020 the Author(s). Published by PNAS.

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The authors declare no competing interest.

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11
Proc Natl Acad Sci U S A
. 2020 Jun 1;201919032. doi: 10.1073/pnas.1919032117. Online ahead of print.
Estimating US Fossil Fuel CO 2 Emissions From Measurements of 14 C in Atmospheric CO 2
Sourish Basu 1 2, Scott J Lehman 3, John B Miller 4, Arlyn E Andrews 4, Colm Sweeney 4, Kevin R Gurney 5, Xiaomei Xu 6, John Southon 6, Pieter P Tans 4
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PMID: 32482875 DOI: 10.1073/pnas.1919032117
Abstract
We report national scale estimates of CO2 emissions from fossil-fuel combustion and cement production in the United States based directly on atmospheric observations, using a dual-tracer inverse modeling framework and CO2 and [Formula: see text] measurements obtained primarily from the North American portion of the National Oceanic and Atmospheric Administration's Global Greenhouse Gas Reference Network. The derived US national total for 2010 is 1,653 ± 30 TgC yr-1 with an uncertainty ([Formula: see text]) that takes into account random errors associated with atmospheric transport, atmospheric measurements, and specified prior CO2 and 14C fluxes. The atmosphere-derived estimate is significantly larger ([Formula: see text]) than US national emissions for 2010 from three global inventories widely used for CO2 accounting, even after adjustments for emissions that might be sensed by the atmospheric network, but which are not included in inventory totals. It is also larger ([Formula: see text]) than a similarly adjusted total from the US Environmental Protection Agency (EPA), but overlaps EPA's reported upper 95% confidence limit. In contrast, the atmosphere-derived estimate is within [Formula: see text] of the adjusted 2010 annual total and nine of 12 adjusted monthly totals aggregated from the latest version of the high-resolution, US-specific "Vulcan" emission data product. Derived emissions appear to be robust to a range of assumed prior emissions and other parameters of the inversion framework. While we cannot rule out a possible bias from assumed prior Net Ecosystem Exchange over North America, we show that this can be overcome with additional [Formula: see text] measurements. These results indicate the strong potential for quantification of US emissions and their multiyear trends from atmospheric observations.

Keywords: atmospheric inverse modeling; fossil fuel CO2; radiocarbon.

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The authors declare no competing interest.

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12
Proc Natl Acad Sci U S A
. 2020 Jun 1;202000134. doi: 10.1073/pnas.2000134117. Online ahead of print.
Airborne Bacteria Confirm the Pristine Nature of the Southern Ocean Boundary Layer
Jun Uetake 1, Thomas C J Hill 1, Kathryn A Moore 1, Paul J DeMott 1, Alain Protat 2, Sonia M Kreidenweis 3
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PMID: 32482865 DOI: 10.1073/pnas.2000134117
Abstract
Microorganisms are ubiquitous and highly diverse in the atmosphere. Despite the potential impacts of airborne bacteria found in the lower atmosphere over the Southern Ocean (SO) on the ecology of Antarctica and on marine cloud phase, no previous region-wide assessment of bioaerosols over the SO has been reported. We conducted bacterial profiling of boundary layer shipboard aerosol samples obtained during an Austral summer research voyage, spanning 42.8 to 66.5°S. Contrary to findings over global subtropical regions and the Northern Hemisphere, where transport of microorganisms from continents often controls airborne communities, the great majority of the bacteria detected in our samples were marine, based on taxonomy, back trajectories, and source tracking analysis. Further, the beta diversity of airborne bacterial communities varied with latitude and temperature, but not with other meteorological variables. Limited meridional airborne transport restricts southward community dispersal, isolating Antarctica and inhibiting microorganism and nutrient deposition from lower latitudes to these same regions. A consequence and implication for this region's marine boundary layer and the clouds that overtop it is that it is truly pristine, free from continental and anthropogenic influences, with the ocean as the dominant source controlling low-level concentrations of cloud condensation nuclei and ice nucleating particles.

Keywords: Southern Ocean; bioaerosol; marine aerosol.

Copyright © 2020 the Author(s). Published by PNAS.

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The authors declare no competing interest.

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13
Proc Natl Acad Sci U S A
. 2020 Jun 1;201916869. doi: 10.1073/pnas.1916869117. Online ahead of print.
The Onset of the Frictional Motion of Dissimilar Materials
Hadar Shlomai 1, David S Kammer 2, Mokhtar Adda-Bedia 3, Jay Fineberg 4
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PMID: 32482877 DOI: 10.1073/pnas.1916869117
Abstract
Frictional motion between contacting bodies is governed by propagating rupture fronts that are essentially earthquakes. These fronts break the contacts composing the interface separating the bodies to enable their relative motion. The most general type of frictional motion takes place when the two bodies are not identical. Within these so-called bimaterial interfaces, the onset of frictional motion is often mediated by highly localized rupture fronts, called slip pulses. Here, we show how this unique rupture mode develops, evolves, and changes the character of the interface's behavior. Bimaterial slip pulses initiate as "subshear" cracks (slower than shear waves) that transition to developed slip pulses where normal stresses almost vanish at their leading edge. The observed slip pulses propagate solely within a narrow range of "transonic" velocities, bounded between the shear wave velocity of the softer material and a limiting velocity. We derive analytic solutions for both subshear cracks and the leading edge of slip pulses. These solutions both provide an excellent description of our experimental measurements and quantitatively explain slip pulses' limiting velocities. We furthermore find that frictional coupling between local normal stress variations and frictional resistance actually promotes the interface separation that is critical for slip-pulse localization. These results provide a full picture of slip-pulse formation and structure that is important for our fundamental understanding of both earthquake motion and the most general types of frictional processes.

Keywords: earthquake dynamics; fracture; friction; rupture fronts; seismic radiation.

Conflict of interest statement
The authors declare no competing interest.

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14
Proc Natl Acad Sci U S A
. 2020 Jun 1;201917969. doi: 10.1073/pnas.1917969117. Online ahead of print.
MAML1/2 Promote YAP/TAZ Nuclear Localization and Tumorigenesis
Jiyoung Kim 1, Hyeryun Kwon 1, You Keun Shin 2, Gahyeon Song 1, Taebok Lee 3, Youngeun Kim 1, Wonyoung Jeong 1, Ukjin Lee 1, Xianglan Zhang 4, Gilyeong Nam 2, Hei-Cheul Jeung 2, Wantae Kim 5, Eek-Hoon Jho 6
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PMID: 32482852 DOI: 10.1073/pnas.1917969117
Abstract
The Hippo pathway plays a pivotal role in tissue homeostasis and tumor suppression. YAP and TAZ are downstream effectors of the Hippo pathway, and their activities are tightly suppressed by phosphorylation-dependent cytoplasmic retention. However, the molecular mechanisms governing YAP/TAZ nuclear localization have not been fully elucidated. Here, we report that Mastermind-like 1 and 2 (MAML1/2) are indispensable for YAP/TAZ nuclear localization and transcriptional activities. Ectopic expression or depletion of MAML1/2 induces nuclear translocation or cytoplasmic retention of YAP/TAZ, respectively. Additionally, mutation of the MAML nuclear localization signal, as well as its YAP/TAZ interacting region, both abolish nuclear localization and transcriptional activity of YAP/TAZ. Importantly, we demonstrate that the level of MAML1 messenger RNA (mRNA) is regulated by microRNA-30c (miR-30c) in a cell-density-dependent manner. In vivo and clinical results suggest that MAML potentiates YAP/TAZ oncogenic function and positively correlates with YAP/TAZ activation in human cancer patients, suggesting pathological relevance in the context of cancer development. Overall, our study not only provides mechanistic insight into the regulation of YAP/TAZ subcellular localization, but it also strongly suggests that the miR30c-MAML-YAP/TAZ axis is a potential therapeutic target for developing novel cancer treatments.

Keywords: Hippo signaling; MAML1/2; TEAD; YAP/TAZ; nuclear localization.

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The authors declare no competing interest.

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15
Proc Natl Acad Sci U S A
. 2020 May 29;201922884. doi: 10.1073/pnas.1922884117. Online ahead of print.
HTLV-1 Induces T Cell Malignancy and Inflammation by Viral Antisense Factor-Mediated Modulation of the Cytokine Signaling
Yusuke Higuchi 1 2, Jun-Ichirou Yasunaga 3 2, Yu Mitagami 1, Hirotake Tsukamoto 4, Kazutaka Nakashima 5, Koichi Ohshima 5, Masao Matsuoka 1 2
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PMID: 32471947 DOI: 10.1073/pnas.1922884117
Abstract
Human T cell leukemia virus type 1 (HTLV-1) is the etiologic agent of a T cell neoplasm and several inflammatory diseases. A viral gene, HTLV-1 bZIP factor (HBZ), induces pathogenic Foxp3-expressing T cells and triggers systemic inflammation and T cell lymphoma in transgenic mice, indicating its significance in HTLV-1-associated diseases. Here we show that, unexpectedly, a proinflammatory cytokine, IL-6, counteracts HBZ-mediated pathogenesis. Loss of IL-6 accelerates inflammation and lymphomagenesis in HBZ transgenic mice. IL-6 innately inhibits regulatory T cell differentiation, suggesting that IL-6 functions as a suppressor against HBZ-associated complications. HBZ up-regulates expression of the immunosuppressive cytokine IL-10. IL-10 promotes T cell proliferation only in the presence of HBZ. As a mechanism of growth promotion by IL-10, HBZ interacts with STAT1 and STAT3 and modulates the IL-10/JAK/STAT signaling pathway. These findings suggest that HTLV-1 promotes the proliferation of infected T cells by hijacking the machinery of regulatory T cell differentiation. IL-10 induced by HBZ likely suppresses the host immune response and concurrently promotes the proliferation of HTLV-1 infected T cells.

Keywords: HBZ; HTLV-1; IL-10; IL-6; JAK/STAT signaling pathway.

Copyright © 2020 the Author(s). Published by PNAS.

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The authors declare no competing interest.

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16
Proc Natl Acad Sci U S A
. 2020 Jun 1;202002825. doi: 10.1073/pnas.2002825117. Online ahead of print.
Regional Brain Responses Associated With Using Imagination to Evoke and Satiate Thirst
Pascal Saker 1, Steve Carey 2, Marcus Grohmann 3, Michael J Farrell 4 5 6, Philip J Ryan 1, Gary F Egan 7 6, Michael J McKinley 1 8, Derek A Denton 9 10 11
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PMID: 32482871 DOI: 10.1073/pnas.2002825117
Abstract
In response to dehydration, humans experience thirst. This subjective state is fundamental to survival as it motivates drinking, which subsequently corrects the fluid deficit. To elicit thirst, previous studies have manipulated blood chemistry to produce a physiological thirst stimulus. In the present study, we investigated whether a physiological stimulus is indeed required for thirst to be experienced. Functional MRI (fMRI) was used to scan fully hydrated participants while they imagined a state of intense thirst and while they imagined drinking to satiate thirst. Subjective ratings of thirst were significantly higher for imagining thirst compared with imagining drinking or baseline, revealing a successful dissociation of thirst from underlying physiology. The imagine thirst condition activated brain regions similar to those reported in previous studies of physiologically evoked thirst, including the anterior midcingulate cortex (aMCC), anterior insula, precentral gyrus, inferior frontal gyrus, middle frontal gyrus, and operculum, indicating a similar neural network underlies both imagined thirst and physiologically evoked thirst. Analogous brain regions were also activated during imagined drinking, suggesting the neural representation of thirst contains a drinking-related component. Finally, the aMCC showed an increase in functional connectivity with the insula during imagined thirst relative to imagined drinking, implying functional connectivity between these two regions is needed before thirst can be experienced. As a result of these findings, this study provides important insight into how the neural representation of subjective thirst is generated and how it subsequently motivates drinking behavior.

Keywords: cingulate; dehydration; fMRI; insula; thirst.

Conflict of interest statement
The authors declare no competing interest.

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17
Proc Natl Acad Sci U S A
. 2020 Jun 1;202000175. doi: 10.1073/pnas.2000175117. Online ahead of print.
Organ of Corti Size Is Governed by Yap/Tead-mediated Progenitor Self-Renewal
Ksenia Gnedeva 1 2, Xizi Wang 3 2, Melissa M McGovern 4, Matthew Barton 5, Litao Tao 3 2, Talon Trecek 3 2, Tanner O Monroe 6 7, Juan Llamas 3 2, Welly Makmura 3 2, James F Martin 7 8 9, Andrew K Groves 4 8 10, Mark Warchol 5, Neil Segil 1 2
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PMID: 32482884 DOI: 10.1073/pnas.2000175117
Abstract
Precise control of organ growth and patterning is executed through a balanced regulation of progenitor self-renewal and differentiation. In the auditory sensory epithelium-the organ of Corti-progenitor cells exit the cell cycle in a coordinated wave between E12.5 and E14.5 before the initiation of sensory receptor cell differentiation, making it a unique system for studying the molecular mechanisms controlling the switch between proliferation and differentiation. Here we identify the Yap/Tead complex as a key regulator of the self-renewal gene network in organ of Corti progenitor cells. We show that Tead transcription factors bind directly to the putative regulatory elements of many stemness- and cell cycle-related genes. We also show that the Tead coactivator protein, Yap, is degraded specifically in the Sox2-positive domain of the cochlear duct, resulting in down-regulation of Tead gene targets. Further, conditional loss of the Yap gene in the inner ear results in the formation of significantly smaller auditory and vestibular sensory epithelia, while conditional overexpression of a constitutively active version of Yap, Yap5SA, is sufficient to prevent cell cycle exit and to prolong sensory tissue growth. We also show that viral gene delivery of Yap5SA in the postnatal inner ear sensory epithelia in vivo drives cell cycle reentry after hair cell loss. Taken together, these data highlight the key role of the Yap/Tead transcription factor complex in maintaining inner ear progenitors during development, and suggest new strategies to induce sensory cell regeneration.

Keywords: Hippo signaling pathway; Taz; Yap; inner ear; organ of Corti.

Conflict of interest statement
J.F.M. is a founder and owns shares in Yap therapeutics.

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18
Proc Natl Acad Sci U S A
. 2020 Jun 1;201915455. doi: 10.1073/pnas.1915455117. Online ahead of print.
A Multiomic Analysis of in Situ Coral-Turf Algal Interactions
Ty N F Roach 1 2 3 4, Mark Little 3 4, Milou G I Arts 5 6 7, Joel Huckeba 5, Andreas F Haas 6, Emma E George 7, Robert A Quinn 8, Ana G Cobián-Güemes 3, Douglas S Naliboff 3, Cynthia B Silveira 3 4, Mark J A Vermeij 6 9, Linda Wegley Kelly 3, Pieter C Dorrestein 10, Forest Rohwer 11 4
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PMID: 32482859 DOI: 10.1073/pnas.1915455117
Abstract
Viruses, microbes, and host macroorganisms form ecological units called holobionts. Here, a combination of metagenomic sequencing, metabolomic profiling, and epifluorescence microscopy was used to investigate how the different components of the holobiont including bacteria, viruses, and their associated metabolites mediate ecological interactions between corals and turf algae. The data demonstrate that there was a microbial assemblage unique to the coral-turf algae interface displaying higher microbial abundances and larger microbial cells. This was consistent with previous studies showing that turf algae exudates feed interface and coral-associated microbial communities, often at the detriment of the coral. Further supporting this hypothesis, when the metabolites were assigned a nominal oxidation state of carbon (NOSC), we found that the turf algal metabolites were significantly more reduced (i.e., have higher potential energy) compared to the corals and interfaces. The algae feeding hypothesis was further supported when the ecological outcomes of interactions (e.g., whether coral was winning or losing) were considered. For example, coral holobionts losing the competition with turf algae had higher Bacteroidetes-to-Firmicutes ratios and an elevated abundance of genes involved in bacterial growth and division. These changes were similar to trends observed in the obese human gut microbiome, where overfeeding of the microbiome creates a dysbiosis detrimental to the long-term health of the metazoan host. Together these results show that there are specific biogeochemical changes at coral-turf algal interfaces that predict the competitive outcomes between holobionts and are consistent with algal exudates feeding coral-associated microbes.

Keywords: coral reefs; holobiont; metabolomics; metagenomics; microbial ecology.

Copyright © 2020 the Author(s). Published by PNAS.

Conflict of interest statement
The authors declare no competing interest.

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19
Proc Natl Acad Sci U S A
. 2020 Jun 1;202001338. doi: 10.1073/pnas.2001338117. Online ahead of print.
Spiking Activity in the Human Hippocampus Prior to Encoding Predicts Subsequent Memory
Zhisen J Urgolites 1, John T Wixted 1, Stephen D Goldinger 2, Megan H Papesh 3, David M Treiman 4, Larry R Squire 5 6 7 8, Peter N Steinmetz 9
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PMID: 32482860 DOI: 10.1073/pnas.2001338117
Abstract
Encoding activity in the medial temporal lobe, presumably evoked by the presentation of stimuli (postonset activity), is known to predict subsequent memory. However, several independent lines of research suggest that preonset activity also affects subsequent memory. We investigated the role of preonset and postonset single-unit and multiunit activity recorded from epilepsy patients as they completed a continuous recognition task. In this task, words were presented in a continuous series and eventually began to repeat. For each word, the patient's task was to decide whether it was novel or repeated. We found that preonset spiking activity in the hippocampus (when the word was novel) predicted subsequent memory (when the word was later repeated). Postonset activity during encoding also predicted subsequent memory, but was simply a continuation of preonset activity. The predictive effect of preonset spiking activity was much stronger in the hippocampus than in three other brain regions (amygdala, anterior cingulate, and prefrontal cortex). In addition, preonset and postonset activity around the encoding of novel words did not predict memory performance for novel words (i.e., correctly classifying the word as novel), and preonset and postonset activity around the time of retrieval did not predict memory performance for repeated words (i.e., correctly classifying the word as repeated). Thus, the only predictive effect was between preonset activity (along with its postonset continuation) at the time of encoding and subsequent memory. Taken together, these findings indicate that preonset hippocampal activity does not reflect general arousal/attention but instead reflects what we term "attention to encoding."

Keywords: encoding; human hippocampus; multiunit activity; single-unit activity; subsequent memory.

Conflict of interest statement
The authors declare no competing interest.

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20
Proc Natl Acad Sci U S A
. 2020 May 29;201919531. doi: 10.1073/pnas.1919531117. Online ahead of print.
Redox Controls Metabolic Robustness in the Gas-Fermenting Acetogen Clostridium autoethanogenum
Vishnuvardhan Mahamkali 1, Kaspar Valgepea 1 2, Renato de Souza Pinto Lemgruber 1, Manuel Plan 1 3, Ryan Tappel 4, Michael Köpke 4, Séan Dennis Simpson 4, Lars Keld Nielsen 1 3 5, Esteban Marcellin 6 3
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PMID: 32471945 DOI: 10.1073/pnas.1919531117
Abstract
Living biological systems display a fascinating ability to self-organize their metabolism. This ability ultimately determines the metabolic robustness that is fundamental to controlling cellular behavior. However, fluctuations in metabolism can affect cellular homeostasis through transient oscillations. For example, yeast cultures exhibit rhythmic oscillatory behavior in high cell-density continuous cultures. Oscillatory behavior provides a unique opportunity for quantitating the robustness of metabolism, as cells respond to changes by inherently compromising metabolic efficiency. Here, we quantify the limits of metabolic robustness in self-oscillating autotrophic continuous cultures of the gas-fermenting acetogen Clostridium autoethanogenum Online gas analysis and high-resolution temporal metabolomics showed oscillations in gas uptake rates and extracellular byproducts synchronized with biomass levels. The data show initial growth on CO, followed by growth on CO and H2 Growth on CO and H2 results in an accelerated growth phase, after which a downcycle is observed in synchrony with a loss in H2 uptake. Intriguingly, oscillations are not linked to translational control, as no differences were observed in protein expression during oscillations. Intracellular metabolomics analysis revealed decreasing levels of redox ratios in synchrony with the cycles. We then developed a thermodynamic metabolic flux analysis model to investigate whether regulation in acetogens is controlled at the thermodynamic level. We used endo- and exo-metabolomics data to show that the thermodynamic driving force of critical reactions collapsed as H2 uptake is lost. The oscillations are coordinated with redox. The data indicate that metabolic oscillations in acetogen gas fermentation are controlled at the thermodynamic level.

Keywords: Wood-Ljungdahl pathway; acetogen; gas fermentation; metabolic robustness; oscillations.

Copyright © 2020 the Author(s). Published by PNAS.

Conflict of interest statement
Competing interest statement: LanzaTech has interest in commercial gas fermentation with Clostridium autoethanogenum. R.T., M.K., and S.D.S. are employees of LanzaTech.

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21
Proc Natl Acad Sci U S A
. 2020 Jun 1;201922067. doi: 10.1073/pnas.1922067117. Online ahead of print.
Incrementality and Efficiency Shape Pragmatics Across Languages
Paula Rubio-Fernandez 1 2, Julian Jara-Ettinger 3
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PMID: 32482876 DOI: 10.1073/pnas.1922067117
Abstract
To correctly interpret a message, people must attend to the context in which it was produced. Here we investigate how this process, known as pragmatic reasoning, is guided by two universal forces in human communication: incrementality and efficiency, with speakers of all languages interpreting language incrementally and making the most efficient use of the incoming information. Crucially, however, the interplay between these two forces results in speakers of different languages having different pragmatic information available at each point in processing, including inferences about speaker intentions. In particular, the position of adjectives relative to nouns (e.g., "black lamp" vs. "lamp black") makes visual context information available in reverse orders. In an eye-tracking study comparing four unrelated languages that have been understudied with regard to language processing (Catalan, Hindi, Hungarian, and Wolof), we show that speakers of languages with an adjective-noun order integrate context by first identifying properties (e.g., color, material, or size), whereas speakers of languages with a noun-adjective order integrate context by first identifying kinds (e.g., lamps or chairs). Most notably, this difference allows listeners of adjective-noun descriptions to infer the speaker's intention when using an adjective (e.g., "the black…" as implying "not the blue one") and anticipate the target referent, whereas listeners of noun-adjective descriptions are subject to temporary ambiguity when deriving the same interpretation. We conclude that incrementality and efficiency guide pragmatic reasoning across languages, with different word orders having different pragmatic affordances.

Keywords: adjective position; cross-linguistic variation; interpretation processes; pragmatics; visual search.

Conflict of interest statement
The authors declare no competing interest.

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22
Proc Natl Acad Sci U S A
. 2020 May 29;201907969. doi: 10.1073/pnas.1907969117. Online ahead of print.
COP1 Destabilizes DELLA Proteins in Arabidopsis
Noel Blanco-Touriñán 1, Martina Legris 2, Eugenio G Minguet 1, Cecilia Costigliolo-Rojas 2, Marίa A Nohales 3, Elisa Iniesto 4, Marta Garcίa-Leόn 4, Manuel Pacίn 5, Nicole Heucken 6, Tim Blomeier 6, Antonella Locascio 1, Martin Černý 7, David Esteve-Bruna 1, Mόnica Dίez-Dίaz 8, Břetislav Brzobohatý 7, Henning Frerigmann 9, Matίas D Zurbriggen 6, Steve A Kay 3, Vicente Rubio 4, Miguel A Blázquez 1, Jorge J Casal 10 5, David Alabadί 11
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PMID: 32471952 DOI: 10.1073/pnas.1907969117
Abstract
DELLA transcriptional regulators are central components in the control of plant growth responses to the environment. This control is considered to be mediated by changes in the metabolism of the hormones gibberellins (GAs), which promote the degradation of DELLAs. However, here we show that warm temperature or shade reduced the stability of a GA-insensitive DELLA allele in Arabidopsis thaliana Furthermore, the degradation of DELLA induced by the warmth preceded changes in GA levels and depended on the E3 ubiquitin ligase CONSTITUTIVELY PHOTOMORPHOGENIC1 (COP1). COP1 enhanced the degradation of normal and GA-insensitive DELLA alleles when coexpressed in Nicotiana benthamiana. DELLA proteins physically interacted with COP1 in yeast, mammalian, and plant cells. This interaction was enhanced by the COP1 complex partner SUPRESSOR OF phyA-105 1 (SPA1). The level of ubiquitination of DELLA was enhanced by COP1 and COP1 ubiquitinated DELLA proteins in vitro. We propose that DELLAs are destabilized not only by the canonical GA-dependent pathway but also by COP1 and that this control is relevant for growth responses to shade and warm temperature.

Keywords: environment; gibberellin; growth; shade avoidance; thermomorphogenesis.

Conflict of interest statement
The authors declare no competing interest.

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23
Proc Natl Acad Sci U S A
. 2020 Jun 1;201919921. doi: 10.1073/pnas.1919921117. Online ahead of print.
Remote Nongenetic Optical Modulation of Neuronal Activity Using Fuzzy Graphene
Sahil K Rastogi 1, Raghav Garg 2, Matteo Giuseppe Scopelliti 3, Bernardo I Pinto 4, Jane E Hartung 5, Seokhyoung Kim 6, Corban G E Murphey 6, Nicholas Johnson 2, Daniel San Roman 2, Francisco Bezanilla 4, James F Cahoon 6, Michael S Gold 5, Maysam Chamanzar 3, Tzahi Cohen-Karni 7 2
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PMID: 32482882 DOI: 10.1073/pnas.1919921117
Abstract
The ability to modulate cellular electrophysiology is fundamental to the investigation of development, function, and disease. Currently, there is a need for remote, nongenetic, light-induced control of cellular activity in two-dimensional (2D) and three-dimensional (3D) platforms. Here, we report a breakthrough hybrid nanomaterial for remote, nongenetic, photothermal stimulation of 2D and 3D neural cellular systems. We combine one-dimensional (1D) nanowires (NWs) and 2D graphene flakes grown out-of-plane for highly controlled photothermal stimulation at subcellular precision without the need for genetic modification, with laser energies lower than a hundred nanojoules, one to two orders of magnitude lower than Au-, C-, and Si-based nanomaterials. Photothermal stimulation using NW-templated 3D fuzzy graphene (NT-3DFG) is flexible due to its broadband absorption and does not generate cellular stress. Therefore, it serves as a powerful toolset for studies of cell signaling within and between tissues and can enable therapeutic interventions.

Keywords: dorsal root ganglia neurons; graphene; nanowire; optical modulation; spheroids.

Copyright © 2020 the Author(s). Published by PNAS.

Conflict of interest statement
The authors declare no competing interest.

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24
Proc Natl Acad Sci U S A
. 2020 Jun 1;202002619. doi: 10.1073/pnas.2002619117. Online ahead of print.
Abiotic Hydrogen (H 2) Sources and Sinks Near the Mid-Ocean Ridge (MOR) With Implications for the Subseafloor Biosphere
Stacey L Worman 1, Lincoln F Pratson 2, Jeffrey A Karson 3, William H Schlesinger 1 4
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PMID: 32482880 DOI: 10.1073/pnas.2002619117
Abstract
Free hydrogen (H2) is a basal energy source underlying chemosynthetic activity within igneous ocean crust. In an attempt to systematically account for all H2 within young oceanic lithosphere (<10 Ma) near the Mid-Ocean Ridge (MOR), we construct a box model of this environment. Within this control volume, we assess abiotic H2 sources (∼6 × 1012 mol H2/y) and sinks (∼4 × 1012 mol H2/y) and then attribute the net difference (∼2 × 1012 mol H2/y) to microbial consumption in order to balance the H2 budget. Despite poorly constrained details and large uncertainties, our analytical framework allows us to synthesize a vast body of pertinent but currently disparate information in order to propose an initial global estimate for microbial H2 consumption within young ocean crust that is tractable and can be iteratively improved upon as new data and studies become available. Our preliminary investigation suggests that microbes beneath the MOR may be consuming a sizeable portion (at least ∼30%) of all produced H2, supporting the widely held notion that subseafloor microbes voraciously consume H2 and play a fundamental role in the geochemistry of Earth's ocean-atmosphere system.

Keywords: Mid-Ocean Ridge; biogeochemistry; hydrogen; microbes; origins of life.

Conflict of interest statement
The authors declare no competing interest.

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25
Proc Natl Acad Sci U S A
. 2020 Jun 1;201921815. doi: 10.1073/pnas.1921815117. Online ahead of print.
TiPARP Forms Nuclear Condensates to Degrade HIF-1α and Suppress Tumorigenesis
Lu Zhang 1, Ji Cao 1, Longying Dong 2, Hening Lin 3 1 4
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PMID: 32482854 DOI: 10.1073/pnas.1921815117
Abstract
Precisely controlling the activation of transcription factors is crucial for physiology. After a transcription factor is activated and carries out its transcriptional activity, it also needs to be properly deactivated. Here, we report a deactivation mechanism of HIF-1 and several other oncogenic transcription factors. HIF-1 promotes the transcription of an ADP ribosyltransferase, TiPARP, which serves to deactivate HIF-1. Mechanistically, TiPARP forms distinct nuclear condensates or nuclear bodies in an ADP ribosylation-dependent manner. The TiPARP nuclear bodies recruit both HIF-1α and an E3 ubiquitin ligase HUWE1, which promotes the ubiquitination and degradation of HIF-1α. Similarly, TiPARP promotes the degradation of c-Myc and estrogen receptor. By suppressing HIF-1α and other oncogenic transcription factors, TiPARP exerts strong antitumor effects both in cell culture and in mouse xenograft models. Our work reveals TiPARP as a negative-feedback regulator for multiple oncogenic transcription factors, provides insights into the functions of protein ADP-ribosylation, and suggests activating TiPARP as an anticancer strategy.

Keywords: ADP-ribosylation; HIF-1; TiPARP; nuclear condensates; ubiquitination.

Copyright © 2020 the Author(s). Published by PNAS.

Conflict of interest statement
The authors declare no competing interest.

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26
Proc Natl Acad Sci U S A
. 2020 Jun 1;201916637. doi: 10.1073/pnas.1916637117. Online ahead of print.
Solar Geoengineering May Lead to Excessive Cooling and High Strategic Uncertainty
Anna Lou Abatayo 1 2, Valentina Bosetti 1 2 3, Marco Casari 4 5, Riccardo Ghidoni 6 7, Massimo Tavoni 3 8 9
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PMID: 32482856 DOI: 10.1073/pnas.1916637117
Abstract
Climate engineering-the deliberate large-scale manipulation of the Earth's climate system-is a set of technologies for reducing climate-change impacts and risks. It is controversial and raises novel governance challenges [T. C. Schelling, Climatic Change, 33, 303-307 (1996); J. Virgoe, Climatic Change, 95, 103-119 (2008)]. We focus on the strategic implications of solar geoengineering. When countries engineer the climate, conflict can arise because different countries might prefer different temperatures. This would result in too much geoengineering: the country with the highest preference for geoengineering cools the planet beyond what is socially optimal at the expense of the others-a theoretical possibility termed "free-driving" [M. L. Weitzman, Scand. J. Econ., 117, 1049-1068 (2015)]. This study is an empirical test of this hypothesis. We carry out an economic laboratory experiment based on a public "good or bad" game. We find compelling evidence of free-driving: global geoengineering exceeds the socially efficient level and leads to welfare losses. We also evaluate the possibility of counteracting the geoengineering efforts of others. Results show that countergeoengineering generates high payoff inequality as well as heavy welfare losses, resulting from both strategic and behavioral factors. Finally, we compare strategic behavior in bilateral and multilateral settings. We find that welfare deteriorates even more under multilateralism when countergeoengineering is a possibility. These results have general implications for governing global good or bad commons.

Keywords: climate governance; geoengineering; inequality; multilateralism.

Conflict of interest statement
The authors declare no competing interest.

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27
Proc Natl Acad Sci U S A
. 2020 Jun 1;202002630. doi: 10.1073/pnas.2002630117. Online ahead of print.
Pivotal Role of the Transcriptional Co-Activator YAP in Trophoblast Stemness of the Developing Human Placenta
Gudrun Meinhardt 1, Sandra Haider 1, Victoria Kunihs 1, Leila Saleh 1, Jürgen Pollheimer 1, Christian Fiala 2, Szabolcs Hetey 3, Zsofia Feher 3, Andras Szilagyi 3, Nandor Gabor Than 3 4 5, Martin Knöfler 6
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PMID: 32482863 DOI: 10.1073/pnas.2002630117
Abstract
Various pregnancy complications, such as severe forms of preeclampsia or intrauterine growth restriction, are thought to arise from failures in the differentiation of human placental trophoblasts. Progenitors of the latter either develop into invasive extravillous trophoblasts, remodeling the uterine vasculature, or fuse into multinuclear syncytiotrophoblasts transporting oxygen and nutrients to the growing fetus. However, key regulatory factors controlling trophoblast self-renewal and differentiation have been poorly elucidated. Using primary cells, three-dimensional organoids, and CRISPR-Cas9 genome-edited JEG-3 clones, we herein show that YAP, the transcriptional coactivator of the Hippo signaling pathway, promotes maintenance of cytotrophoblast progenitors by different genomic mechanisms. Genetic or chemical manipulation of YAP in these cellular models revealed that it stimulates proliferation and expression of cell cycle regulators and stemness-associated genes, but inhibits cell fusion and production of syncytiotrophoblast (STB)-specific proteins, such as hCG and GDF15. Genome-wide comparisons of primary villous cytotrophoblasts overexpressing constitutively active YAP-5SA with YAP KO cells and syncytializing trophoblasts revealed common target genes involved in trophoblast stemness and differentiation. ChIP-qPCR unraveled that YAP-5SA overexpression increased binding of YAP-TEAD4 complexes to promoters of proliferation-associated genes such as CCNA and CDK6 Moreover, repressive YAP-TEAD4 complexes containing the histone methyltransferase EZH2 were detected in the genomic regions of the STB-specific CGB5 and CGB7 genes. In summary, YAP plays a pivotal role in the maintenance of the human placental trophoblast epithelium. Besides activating stemness factors, it also directly represses genes promoting trophoblast cell fusion.

Keywords: placenta; stemness; trophoblast.

Copyright © 2020 the Author(s). Published by PNAS.

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The authors declare no competing interest.

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28
Proc Natl Acad Sci U S A
. 2020 Jun 1;201921628. doi: 10.1073/pnas.1921628117. Online ahead of print.
Human Influence Has Intensified Extreme Precipitation in North America
Megan C Kirchmeier-Young 1, Xuebin Zhang 2
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PMID: 32482861 DOI: 10.1073/pnas.1921628117
Abstract
Precipitation extremes have implications for many facets of both the human and natural systems, predominantly through flooding events. Observations have demonstrated increasing trends in extreme precipitation in North America, and models and theory consistently suggest continued increases with future warming. Here, we address the question of whether observed changes in annual maximum 1- and 5-d precipitation can be attributed to human influence on the climate. Although attribution has been demonstrated for global and hemispheric scales, there are few results for continental and subcontinental scales. We utilize three large ensembles, including simulations from both a fully coupled Earth system model and a regional climate model. We use two different attribution approaches and find many qualitatively consistent results across different methods, different models, and different regional scales. We conclude that external forcing, dominated by human influence, has contributed to the increase in frequency and intensity of regional precipitation extremes in North America. If human emissions continue to increase, North America will see further increases in these extremes.

Keywords: attribution; extreme precipitation; regional climate change.

Copyright © 2020 the Author(s). Published by PNAS.

Conflict of interest statement
The authors declare no competing interest.

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29
Proc Natl Acad Sci U S A
. 2020 Jun 1;201919501. doi: 10.1073/pnas.1919501117. Online ahead of print.
Plastid Biogenesis in Malaria Parasites Requires the Interactions and Catalytic Activity of the Clp Proteolytic System
Anat Florentin 1 2, Dylon R Stephens 2 3, Carrie F Brooks 1 2, Rodrigo P Baptista 2 4, Vasant Muralidharan 5 2
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PMID: 32482878 DOI: 10.1073/pnas.1919501117
Abstract
The human malaria parasite, Plasmodium falciparum, contains an essential plastid called the apicoplast. Most apicoplast proteins are encoded by the nuclear genome and it is unclear how the plastid proteome is regulated. Here, we study an apicoplast-localized caseinolytic-protease (Clp) system and how it regulates organelle proteostasis. Using null and conditional mutants, we demonstrate that the P. falciparum Clp protease (PfClpP) has robust enzymatic activity that is essential for apicoplast biogenesis. We developed a CRISPR/Cas9-based system to express catalytically dead PfClpP, which showed that PfClpP oligomerizes as a zymogen and is matured via transautocatalysis. The expression of both wild-type and mutant Clp chaperone (PfClpC) variants revealed a functional chaperone-protease interaction. Conditional mutants of the substrate-adaptor (PfClpS) demonstrated its essential function in plastid biogenesis. A combination of multiple affinity purification screens identified the Clp complex composition as well as putative Clp substrates. This comprehensive study reveals the molecular composition and interactions influencing the proteolytic function of the apicoplast Clp system and demonstrates its central role in the biogenesis of the plastid in malaria parasites.

Keywords: Clp protease; Clp proteins; Plasmodium; malaria; plastid.

Conflict of interest statement
The authors declare no competing interest.

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30
Proc Natl Acad Sci U S A
. 2020 Jun 1;201917151. doi: 10.1073/pnas.1917151117. Online ahead of print.
Gaussian Determinantal Processes: A New Model for Directionality in Data
Subhroshekhar Ghosh 1, Philippe Rigollet 2
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PMID: 32482857 DOI: 10.1073/pnas.1917151117
Abstract
Determinantal point processes (DPPs) have recently become popular tools for modeling the phenomenon of negative dependence, or repulsion, in data. However, our understanding of an analogue of a classical parametric statistical theory is rather limited for this class of models. In this work, we investigate a parametric family of Gaussian DPPs with a clearly interpretable effect of parametric modulation on the observed points. We show that parameter modulation impacts the observed points by introducing directionality in their repulsion structure, and the principal directions correspond to the directions of maximal (i.e., the most long-ranged) dependency. This model readily yields a viable alternative to principal component analysis (PCA) as a dimension reduction tool that favors directions along which the data are most spread out. This methodological contribution is complemented by a statistical analysis of a spiked model similar to that employed for covariance matrices as a framework to study PCA. These theoretical investigations unveil intriguing questions for further examination in random matrix theory, stochastic geometry, and related topics.

Keywords: determinantal point processes; dimension reduction; spiked model.

Conflict of interest statement
The authors declare no competing interest.

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31
Proc Natl Acad Sci U S A
. 2020 Jun 1;201919690. doi: 10.1073/pnas.1919690117. Online ahead of print.
Selective Reactivation of STING Signaling to Target Merkel Cell Carcinoma
Wei Liu 1, Gloria B Kim 1 2, Nathan A Krump 1, Yuqi Zhou 1 2, James L Riley 1 2, Jianxin You 3
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PMID: 32482869 DOI: 10.1073/pnas.1919690117
Abstract
Merkel cell carcinoma (MCC) is a lethal skin cancer that metastasizes rapidly. Few effective treatments are available for patients with metastatic MCC. Poor intratumoral T cell infiltration and activation are major barriers that prevent MCC eradication by the immune system. However, the mechanisms that drive the immunologically restrictive tumor microenvironment remain poorly understood. In this study, we discovered that the innate immune regulator stimulator of IFN genes (STING) is completely silenced in MCCs. To reactivate STING in MCC, we developed an application of a human STING mutant, STINGS162A/G230I/Q266I, which we found to be readily stimulated by a mouse STING agonist, DMXAA. This STING molecule was efficiently delivered to MCC cells via an AAV vector. Introducing STINGS162A/G230I/Q266I expression and stimulating its activity by DMXAA in MCC cells reactivates their antitumor inflammatory cytokine/chemokine production. In response to MCC cells with restored STING, cocultured T cells expressing MCPyV-specific T cell receptors (TCRs) show increased cytokine production, migration toward tumor cells, and tumor cell killing. Our study therefore suggests that STING deficiency contributes to the immune suppressive nature of MCCs. More importantly, DMXAA stimulation of STINGS162A/G230I/Q266I causes robust cell death in MCCs as well as several other STING-silenced cancers. Because tumor antigens and DNA released by dying cancer cells have the potential to amplify innate immune response and activate antitumor adaptive responses, our finding indicates that targeted delivery and activation of STINGS162A/G230I/Q266I in tumor cells holds great therapeutic promise for the treatment of MCC and many other STING-deficient cancers.

Keywords: DMXAA; Merkel cell carcinoma; STING; antitumor immune response; gene therapy.

Conflict of interest statement
The authors declare no competing interest.

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32
Proc Natl Acad Sci U S A
. 2020 Jun 1;202001128. doi: 10.1073/pnas.2001128117. Online ahead of print.
Counterintuitive Effects of Isotopic Doping on the Phase Diagram of H 2-HD-D 2 Molecular Alloy
Xiao-Di Liu 1, Philip Dalladay-Simpson 2, Ross T Howie 2, Hui-Chao Zhang 3 4, Wan Xu 3 4, Jack Binns 2, Graeme J Ackland 5 6, Ho-Kwang Mao 7, Eugene Gregoryanz 1 2 5 6
Affiliations expand
PMID: 32482874 DOI: 10.1073/pnas.2001128117
Abstract
Molecular hydrogen forms the archetypical quantum solid. Its quantum nature is revealed by behavior which is classically impossible and by very strong isotope effects. Isotope effects between [Formula: see text], [Formula: see text], and HD molecules come from mass difference and the different quantum exchange effects: fermionic [Formula: see text] molecules have antisymmetric wavefunctions, while bosonic [Formula: see text] molecules have symmetric wavefunctions, and HD molecules have no exchange symmetry. To investigate how the phase diagram depends on quantum-nuclear effects, we use high-pressure and low-temperature in situ Raman spectroscopy to map out the phase diagrams of [Formula: see text]-HD-[Formula: see text] with various isotope concentrations over a wide pressure-temperature (P-T) range. We find that mixtures of [Formula: see text], HD, and [Formula: see text] behave as an isotopic molecular alloy (ideal solution) and exhibit symmetry-breaking phase transitions between phases I and II and phase III. Surprisingly, all transitions occur at higher pressures for the alloys than either pure [Formula: see text] or [Formula: see text] This runs counter to any quantum effects based on isotope mass but can be explained by quantum trapping of high-kinetic energy states by the exchange interaction.

Keywords: deuterium; high pressure; hydrogen.

Conflict of interest statement
The authors declare no competing interest.

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33
Proc Natl Acad Sci U S A
. 2020 May 29;201918307. doi: 10.1073/pnas.1918307117. Online ahead of print.
Combined Inhibition of JAK/STAT Pathway and Lysine-Specific Demethylase 1 as a Therapeutic Strategy in CSF3R/CEBPA Mutant Acute Myeloid Leukemia
Theodore P Braun 1 2, Cody Coblentz 1, Brittany M Smith 1, Daniel J Coleman 1, Zachary Schonrock 1, Sarah A Carratt 1, Rowan L Callahan 1, Breanna Maniaci 1, Brian J Druker 3 2, Julia E Maxson 3 2
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PMID: 32471953 DOI: 10.1073/pnas.1918307117
Abstract
Acute myeloid leukemia (AML) is a deadly hematologic malignancy with poor prognosis, particularly in the elderly. Even among individuals with favorable-risk disease, approximately half will relapse with conventional therapy. In this clinical circumstance, the determinants of relapse are unclear, and there are no therapeutic interventions that can prevent recurrent disease. Mutations in the transcription factor CEBPA are associated with favorable risk in AML. However, mutations in the growth factor receptor CSF3R are commonly co-occurrent in CEBPA mutant AML and are associated with an increased risk of relapse. To develop therapeutic strategies for this disease subset, we performed medium-throughput drug screening on CEBPA/CSF3R mutant leukemia cells and identified sensitivity to inhibitors of lysine-specific demethylase 1 (LSD1). Treatment of CSF3R/CEBPA mutant leukemia cells with LSD1 inhibitors reactivates differentiation-associated enhancers driving immunophenotypic and morphologic differentiation. LSD1 inhibition is ineffective as monotherapy but demonstrates synergy with inhibitors of JAK/STAT signaling, doubling median survival in vivo. These results demonstrate that combined inhibition of JAK/STAT signaling and LSD1 is a promising therapeutic strategy for CEBPA/CSF3R mutant AML.

Keywords: CSF3R; LSD1; acute myeloid leukemia; epigenetics; targeted.

Conflict of interest statement
Competing interest statement: B.J.D. declares the following potential competing interests: Monojul, Patient True Talk; SAB: Aileron Therapeutics, ALLCRON, Cepheid, Gilead Sciences, Vivid Biosciences, Celgene & Baxalta (inactive); SAB and stock: Aptose Biosciences, Blueprint Medicines, Beta Cat, GRAIL, Third Coast Therapeutics, CTI BioPharma (inactive); scientific founder and stock: MolecularMD; board of directors and stock: Amgen; board of directors: Burroughs Wellcome Fund, CureOne; joint steering committee: Beat AML LLS; clinical trial funding: Novartis, Bristol-Myers Squibb, Pfizer; royalties: OHSU #606-Novartis exclusive license, OHSU #2573; Dana-Farber Cancer Institute #2063 - Merck exclusive license. J.E.M. receives grant funding from the Gilead Research Scholars Program. The remaining authors declare no competing interests.

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34
Proc Natl Acad Sci U S A
. 2020 Jun 1;201920343. doi: 10.1073/pnas.1920343117. Online ahead of print.
Natural Cryptic Variation in Epigenetic Modulation of an Embryonic Gene Regulatory Network
Chee Kiang Ewe 1 2, Yamila N Torres Cleuren 3 2 4, Sagen E Flowers 1 2, Geneva Alok 1 2, Russell G Snell 2 4, Joel H Rothman 3 2 4
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PMID: 32482879 DOI: 10.1073/pnas.1920343117
Abstract
Gene regulatory networks (GRNs) that direct animal embryogenesis must respond to varying environmental and physiological conditions to ensure robust construction of organ systems. While GRNs are evolutionarily modified by natural genomic variation, the roles of epigenetic processes in shaping plasticity of GRN architecture are not well understood. The endoderm GRN in Caenorhabditis elegans is initiated by the maternally supplied SKN-1/Nrf2 bZIP transcription factor; however, the requirement for SKN-1 in endoderm specification varies widely among distinct C. elegans wild isotypes, owing to rapid developmental system drift driven by accumulation of cryptic genetic variants. We report here that heritable epigenetic factors that are stimulated by transient developmental diapause also underlie cryptic variation in the requirement for SKN-1 in endoderm development. This epigenetic memory is inherited from the maternal germline, apparently through a nuclear, rather than cytoplasmic, signal, resulting in a parent-of-origin effect (POE), in which the phenotype of the progeny resembles that of the maternal founder. The occurrence and persistence of POE varies between different parental pairs, perduring for at least 10 generations in one pair. This long-perduring POE requires piwi-interacting RNA (piRNA) function and the germline nuclear RNA interference (RNAi) pathway, as well as MET-2 and SET-32, which direct histone H3K9 trimethylation and drive heritable epigenetic modification. Such nongenetic cryptic variation may provide a resource of additional phenotypic diversity through which adaptation may facilitate evolutionary changes and shape developmental regulatory systems.

Keywords: SKN-1; endoderm; epigenetic inheritance; imprinting; parent-of-origin effect.

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The authors declare no competing interest.

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35
Proc Natl Acad Sci U S A
. 2020 Jun 1;202001753. doi: 10.1073/pnas.2001753117. Online ahead of print.
A Molecular Tandem Cell for Efficient Solar Water Splitting
Degao Wang 1 2 3, Jun Hu 3, Benjamin D Sherman 4, Matthew V Sheridan 3, Liang Yan 3, Christopher J Dares 5, Yong Zhu 6, Fei Li 6, Qing Huang 7 2, Wei You 8, Thomas J Meyer 8
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PMID: 32482883 DOI: 10.1073/pnas.2001753117
Abstract
Artificial photosynthesis provides a way to store solar energy in chemical bonds. Achieving water splitting without an applied external potential bias provides the key to artificial photosynthetic devices. We describe here a tandem photoelectrochemical cell design that combines a dye-sensitized photoelectrosynthesis cell (DSPEC) and an organic solar cell (OSC) in a photoanode for water oxidation. When combined with a Pt electrode for H2 evolution, the electrode becomes part of a combined electrochemical cell for water splitting, 2H2O → O2 + 2H2, by increasing the voltage of the photoanode sufficiently to drive bias-free reduction of H+ to H2 The combined electrode gave a 1.5% solar conversion efficiency for water splitting with no external applied bias, providing a mimic for the tandem cell configuration of PSII in natural photosynthesis. The electrode provided sustained water splitting in the molecular photoelectrode with sustained photocurrent densities of 1.24 mA/cm2 for 1 h under 1-sun illumination with no applied bias.

Keywords: bias-free; molecular tandem cell; organic cell; solar fuels; water splitting.

Conflict of interest statement
The authors declare no competing interest.

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36
Proc Natl Acad Sci U S A
. 2020 May 29;202007739. doi: 10.1073/pnas.2007739117. Online ahead of print.
Scribble and Dlg Organize a Protection Racket to Ensure Apical-Basal Polarity
Anja Schmidt 1 2, Mark Peifer 3 2
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PMID: 32471949 DOI: 10.1073/pnas.2007739117
Conflict of interest statement
The authors declare no competing interest.

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37
Proc Natl Acad Sci U S A
. 2020 Jun 1;201907335. doi: 10.1073/pnas.1907335117. Online ahead of print.
CAMSAP3 Facilitates Basal Body Polarity and the Formation of the Central Pair of Microtubules in Motile Cilia
Alan M Robinson 1, Satoe Takahashi 1, Eva J Brotslaw 2, Aisha Ahmad 3, Emma Ferrer 1, Daniele Procissi 4, Claus-Peter Richter 1 3 5, Mary Ann Cheatham 3 5, Brian J Mitchell 2, Jing Zheng 6 3 5
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PMID: 32482850 DOI: 10.1073/pnas.1907335117
Abstract
Synchronized beating of cilia on multiciliated cells (MCCs) generates a directional flow of mucus across epithelia. This motility requires a "9 + 2" microtubule (MT) configuration in axonemes and the unidirectional array of basal bodies of cilia on the MCCs. However, it is not fully understood what components are needed for central MT-pair assembly as they are not continuous with basal bodies in contrast to the nine outer MT doublets. In this study, we discovered that a homozygous knockdown mouse model for MT minus-end regulator calmodulin-regulated spectrin-associated protein 3 (CAMSAP3), Camsap3 tm1a/tm1a , exhibited multiple phenotypes, some of which are typical of primary ciliary dyskinesia (PCD), a condition caused by motile cilia defects. Anatomical examination of Camsap3 tm1a/tm1a mice revealed severe nasal airway blockage and abnormal ciliary morphologies in nasal MCCs. MCCs from different tissues exhibited defective synchronized beating and ineffective generation of directional flow likely underlying the PCD-like phenotypes. In normal mice, CAMSAP3 localized to the base of axonemes and at the basal bodies in MCCs. However, in Camsap3 tm1a/tm1a , MCCs lacked CAMSAP3 at the ciliary base. Importantly, the central MT pairs were missing in the majority of cilia, and the polarity of the basal bodies was disorganized. These phenotypes were further confirmed in MCCs of Xenopus embryos when CAMSAP3 expression was knocked down by morpholino injection. Taken together, we identified CAMSAP3 as being important for the formation of central MT pairs, proper orientation of basal bodies, and synchronized beating of motile cilia.

Keywords: CAMSAP3; basal body orientation; central MT pair; motile cilia; primary ciliary dyskinesia.

Copyright © 2020 the Author(s). Published by PNAS.

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The authors declare no competing interest.

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38
Proc Natl Acad Sci U S A
. 2020 Jun 1;201922686. doi: 10.1073/pnas.1922686117. Online ahead of print.
Vertebrates on the Brink as Indicators of Biological Annihilation and the Sixth Mass Extinction
Gerardo Ceballos 1, Paul R Ehrlich 2, Peter H Raven 3
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PMID: 32482862 DOI: 10.1073/pnas.1922686117
Abstract
The ongoing sixth mass species extinction is the result of the destruction of component populations leading to eventual extirpation of entire species. Populations and species extinctions have severe implications for society through the degradation of ecosystem services. Here we assess the extinction crisis from a different perspective. We examine 29,400 species of terrestrial vertebrates, and determine which are on the brink of extinction because they have fewer than 1,000 individuals. There are 515 species on the brink (1.7% of the evaluated vertebrates). Around 94% of the populations of 77 mammal and bird species on the brink have been lost in the last century. Assuming all species on the brink have similar trends, more than 237,000 populations of those species have vanished since 1900. We conclude the human-caused sixth mass extinction is likely accelerating for several reasons. First, many of the species that have been driven to the brink will likely become extinct soon. Second, the distribution of those species highly coincides with hundreds of other endangered species, surviving in regions with high human impacts, suggesting ongoing regional biodiversity collapses. Third, close ecological interactions of species on the brink tend to move other species toward annihilation when they disappear-extinction breeds extinctions. Finally, human pressures on the biosphere are growing rapidly, and a recent example is the current coronavirus disease 2019 (Covid-19) pandemic, linked to wildlife trade. Our results reemphasize the extreme urgency of taking much-expanded worldwide actions to save wild species and humanity's crucial life-support systems from this existential threat.

Keywords: conservation; ecosystem services; endangered species; population extinctions; sixth mass extinction.

Copyright © 2020 the Author(s). Published by PNAS.

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The authors declare no competing interest.

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39
Proc Natl Acad Sci U S A
. 2020 Jun 1;201917569. doi: 10.1073/pnas.1917569117. Online ahead of print.
Liquid Network Connectivity Regulates the Stability and Composition of Biomolecular Condensates With Many Components
Jorge R Espinosa 1 2 3, Jerelle A Joseph 1 2 3, Ignacio Sanchez-Burgos 1 2 3, Adiran Garaizar 1 2 3, Daan Frenkel 2, Rosana Collepardo-Guevara 4 2 3
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PMID: 32482873 DOI: 10.1073/pnas.1917569117
Abstract
One of the key mechanisms used by cells to control the spatiotemporal organization of their many components is the formation and dissolution of biomolecular condensates through liquid-liquid phase separation (LLPS). Using a minimal coarse-grained model that allows us to simulate thousands of interacting multivalent proteins, we investigate the physical parameters dictating the stability and composition of multicomponent biomolecular condensates. We demonstrate that the molecular connectivity of the condensed-liquid network-i.e., the number of weak attractive protein-protein interactions per unit of volume-determines the stability (e.g., in temperature, pH, salt concentration) of multicomponent condensates, where stability is positively correlated with connectivity. While the connectivity of scaffolds (biomolecules essential for LLPS) dominates the phase landscape, introduction of clients (species recruited via scaffold-client interactions) fine-tunes it by transforming the scaffold-scaffold bond network. Whereas low-valency clients that compete for scaffold-scaffold binding sites decrease connectivity and stability, those that bind to alternate scaffold sites not required for LLPS or that have higher-than-scaffold valencies form additional scaffold-client-scaffold bridges increasing stability. Proteins that establish more connections (via increased valencies, promiscuous binding, and topologies that enable multivalent interactions) support the stability of and are enriched within multicomponent condensates. Importantly, proteins that increase the connectivity of multicomponent condensates have higher critical points as pure systems or, if pure LLPS is unfeasible, as binary scaffold-client mixtures. Hence, critical points of accessible systems (i.e., with just a few components) might serve as a unified thermodynamic parameter to predict the composition of multicomponent condensates.

Keywords: biomolecular condensates; cell compartmentalization; liquid–liquid phase separation; membraneless organelles.

Conflict of interest statement
The authors declare no competing interest.

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40
Proc Natl Acad Sci U S A
. 2020 Jun 1;201919507. doi: 10.1073/pnas.1919507117. Online ahead of print.
MYC Protein Stability Is Negatively Regulated by BRD4
Ballachanda N Devaiah 1, Jie Mu 1, Ben Akman 1, Sheetal Uppal 1, Jocelyn D Weissman 1, Dan Cheng 1, Laura Baranello 2, Zuqin Nie 2, David Levens 2, Dinah S Singer 3
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PMID: 32482868 DOI: 10.1073/pnas.1919507117
Abstract
The protooncogene MYC regulates a variety of cellular processes, including proliferation and metabolism. Maintaining MYC at homeostatic levels is critical to normal cell function; overexpression drives many cancers. MYC stability is regulated through phosphorylation: phosphorylation at Thr58 signals degradation while Ser62 phosphorylation leads to its stabilization and functional activation. The bromodomain protein 4 (BRD4) is a transcriptional and epigenetic regulator with intrinsic kinase and histone acetyltransferase (HAT) activities that activates transcription of key protooncogenes, including MYC We report that BRD4 phosphorylates MYC at Thr58, leading to MYC ubiquitination and degradation, thereby regulating MYC target genes. Importantly, BRD4 degradation, but not inhibition, results in increased levels of MYC protein. Conversely, MYC inhibits BRD4's HAT activity, suggesting that MYC regulates its own transcription by limiting BRD4-mediated chromatin remodeling of its locus. The MYC stabilizing kinase, ERK1, regulates MYC levels directly and indirectly by inhibiting BRD4 kinase activity. These findings demonstrate that BRD4 negatively regulates MYC levels, which is counteracted by ERK1 activation.

Keywords: BRD4 histone acetyltransferase; BRD4 kinase; ERK1; MYC phosphorylation; MYC stability.

Copyright © 2020 the Author(s). Published by PNAS.

Conflict of interest statement
The authors declare no competing interest.

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41
Proc Natl Acad Sci U S A
. 2020 Jun 1;202003895. doi: 10.1073/pnas.2003895117. Online ahead of print.
Midgap Radiative Centers in Carbon-Enriched Hexagonal Boron Nitride
Maciej Koperski 1, Diana Vaclavkova 2, Kenji Watanabe 3, Takashi Taniguchi 4, Kostya S Novoselov 1, Marek Potemski 5 6
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PMID: 32482864 DOI: 10.1073/pnas.2003895117
Abstract
When serving as a protection tissue and/or inducing a periodic lateral modulation for/in atomically thin crystals, hexagonal boron nitride (hBN) has revolutionized the research on van der Waals heterostructures. By itself, hBN appears as an emergent wide-bandgap material, which, importantly, can be optically bright in the far-ultraviolet range and which frequently displays midgap defect-related centers of yet-unclear origin, but, interestingly, acting as single-photon emitters. Controlling the hBN doping is of particular interest in view of the possible practical use of this material. Here, we demonstrate that enriching hBN with carbon (C) activates an optical response of this material in the form of a series of well-defined resonances in visible and near-infrared regions, which appear in the luminescence spectra measured under below-bandgap excitation. Two, qualitatively different, C-related radiative centers are identified: One follows the Franck-Condon principle that describes transitions between two defect states with emission/annihilation of optical phonons, and the other shows atomic-like resonances characteristic of intradefect transitions. With a detailed characterization of the energy structure and emission dynamics of these radiative centers, we contribute to the development of controlled doping of hBN with midgap centers.

Keywords: defects; hexagonal boron nitride; midgap centers; single-photon emitters.

Copyright © 2020 the Author(s). Published by PNAS.

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The authors declare no competing interest.

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42
Proc Natl Acad Sci U S A
. 2020 Jun 1;201914892. doi: 10.1073/pnas.1914892117. Online ahead of print.
Modulation of Innate Immune Signaling by a Coxiella burnetii Eukaryotic-Like Effector Protein
Melanie Burette 1, Julie Allombert 1, Karine Lambou 1, Ghizlane Maarifi 1, Sébastien Nisole 1, Elizabeth Di Russo Case 2, Fabien P Blanchet 1, Cedric Hassen-Khodja 3, Stéphanie Cabantous 4, James Samuel 2, Eric Martinez 1, Matteo Bonazzi 5
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PMID: 32482853 DOI: 10.1073/pnas.1914892117
Abstract
The Q fever agent Coxiella burnetii uses a defect in organelle trafficking/intracellular multiplication (Dot/Icm) type 4b secretion system (T4SS) to silence the host innate immune response during infection. By investigating C. burnetii effector proteins containing eukaryotic-like domains, here we identify NopA (nucleolar protein A), which displays four regulator of chromosome condensation (RCC) repeats, homologous to those found in the eukaryotic Ras-related nuclear protein (Ran) guanine nucleotide exchange factor (GEF) RCC1. Accordingly, NopA is found associated with the chromatin nuclear fraction of cells and uses the RCC-like domain to interact with Ran. Interestingly, NopA triggers an accumulation of Ran-GTP, which accumulates at nucleoli of transfected or infected cells, thus perturbing the nuclear import of transcription factors of the innate immune signaling pathway. Accordingly, qRT-PCR analysis on a panel of cytokines shows that cells exposed to the C. burnetii nopA::Tn or a Dot/Icm-defective dotA::Tn mutant strain present a functional innate immune response, as opposed to cells exposed to wild-type C. burnetii or the corresponding nopA complemented strain. Thus, NopA is an important regulator of the innate immune response allowing Coxiella to behave as a stealth pathogen.

Keywords: Coxiella burnetii; effector proteins; host/pathogen interactions; innate immune sensing; nucleocytoplasmic transport.

Conflict of interest statement
The authors declare no competing interest.

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43
Proc Natl Acad Sci U S A
. 2020 May 29;202007742. doi: 10.1073/pnas.2007742117. Online ahead of print.
Evidence That Hurricanes Are Getting Stronger
Kerry Emanuel 1
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PMID: 32471950 DOI: 10.1073/pnas.2007742117
Conflict of interest statement
The author declares no competing interest.

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44
Proc Natl Acad Sci U S A
. 2020 May 29;202007441. doi: 10.1073/pnas.2007441117. Online ahead of print.
Nitrogen-responsive Transcription Factor Kinetics Meter Plant Growth
Garo Z Akmakjian 1, Julia Bailey-Serres 2
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PMID: 32471951 DOI: 10.1073/pnas.2007441117
Conflict of interest statement
The authors declare no competing interest.

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45
Proc Natl Acad Sci U S A
. 2020 Jun 1;202003347. doi: 10.1073/pnas.2003347117. Online ahead of print.
High-throughput Photocapture Approach for Reaction Discovery
Alison A Bayly 1, Benjamin R McDonald 1, Milan Mrksich 2, Karl A Scheidt 2
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PMID: 32482866 DOI: 10.1073/pnas.2003347117
Abstract
Modern organic reaction discovery and development relies on the rapid assessment of large arrays of hypothesis-driven experiments. The time-intensive nature of reaction analysis presents the greatest practical barrier for the execution of this iterative process that underpins the development of new bioactive agents. Toward addressing this critical bottleneck, we report herein a high-throughput analysis (HTA) method of reaction mixtures by photocapture on a 384-spot diazirine-terminated self-assembled monolayer, and self-assembled monolayers for matrix-assisted laser desorption/ionization mass spectrometry (SAMDI-MS) analysis. This analytical platform has been applied to the identification of a single-electron-promoted reductive coupling of acyl azolium species.

Keywords: azoliums; high-throughput analysis; photocapture; self-assembled monolayers.

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The authors declare no competing interest.

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46
Proc Natl Acad Sci U S A
. 2020 May 29;201912789. doi: 10.1073/pnas.1912789117. Online ahead of print.
The Frontier of Simulation-Based Inference
Kyle Cranmer 1 2, Johann Brehmer 3 2, Gilles Louppe 4
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PMID: 32471948 DOI: 10.1073/pnas.1912789117
Abstract
Many domains of science have developed complex simulations to describe phenomena of interest. While these simulations provide high-fidelity models, they are poorly suited for inference and lead to challenging inverse problems. We review the rapidly developing field of simulation-based inference and identify the forces giving additional momentum to the field. Finally, we describe how the frontier is expanding so that a broad audience can appreciate the profound influence these developments may have on science.

Keywords: approximate Bayesian computation; implicit models; likelihood-free inference; neural density estimation; statistical inference.

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The authors declare no competing interest.

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47
Proc Natl Acad Sci U S A
. 2020 Jun 1;202008909. doi: 10.1073/pnas.2008909117. Online ahead of print.
Freeman J. Dyson 1923-2020: Legendary Physicist, Writer, and Fearless Intellectual Explorer
Robbert Dijkgraaf 1
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PMID: 32482851 DOI: 10.1073/pnas.2008909117
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The author declares no competing interest.

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48
Published Erratum Proc Natl Acad Sci U S A
. 2020 Jun 1;202009211. doi: 10.1073/pnas.2009211117. Online ahead of print.
Correction for Gomez Et Al., Influence of Spatially Segregated IP 3-producing Pathways on Spike Generation and Transmitter Release in Purkinje Cell Axons
No authors listed
PMID: 32482848 DOI: 10.1073/pnas.2009211117
Erratum for
Influence of spatially segregated IP3-producing pathways on spike generation and transmitter release in Purkinje cell axons.
Gomez LC, Kawaguchi SY, Collin T, Jalil A, Gomez MDP, Nasi E, Marty A, Llano I.
Proc Natl Acad Sci U S A. 2020 May 19;117(20):11097-11108. doi: 10.1073/pnas.2000148117. Epub 2020 May 1.
PMID: 32358199
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 Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology

The impact of Oral Medicine’s global efforts on advancing oral health care, discovery, and dissemination of best practices

Publication date: Available online 3 June 2020Source: Oral Surgery, Oral Medicine, Oral Pathology and Oral RadiologyAuthor(s): David Mason

Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology

Wed Jun 03, 2020 15:23

Deep learning systems for detecting and classifying the presence of impacted supernumerary teeth in the maxillary incisor region on panoramic radiographs

Publication date: Available online 2 June 2020Source: Oral Surgery, Oral Medicine, Oral Pathology and Oral RadiologyAuthor(s): Chiaki Kuwada, Yoshiko Ariji, Motoki Fukuda, Yoshitaka Kise, Hiroshi Fujita, Akitoshi Katsumata, Eiichiro Ariji

Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology

Wed Jun 03, 2020 15:23

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