Proc Natl Acad Sci U S A
. 2020 Jul 6;201922664. doi: 10.1073/pnas.1922664117. Online ahead of print.
Universal Inference
Larry Wasserman 1 2, Aaditya Ramdas 3, Sivaraman Balakrishnan 3
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PMID: 32631986 DOI: 10.1073/pnas.1922664117
Abstract
We propose a general method for constructing confidence sets and hypothesis tests that have finite-sample guarantees without regularity conditions. We refer to such procedures as "universal." The method is very simple and is based on a modified version of the usual likelihood-ratio statistic that we call "the split likelihood-ratio test" (split LRT) statistic. The (limiting) null distribution of the classical likelihood-ratio statistic is often intractable when used to test composite null hypotheses in irregular statistical models. Our method is especially appealing for statistical inference in these complex setups. The method we suggest works for any parametric model and also for some nonparametric models, as long as computing a maximum-likelihood estimator (MLE) is feasible under the null. Canonical examples arise in mixture modeling and shape-constrained inference, for which constructing tests and confidence sets has been notoriously difficult. We also develop various extensions of our basic methods. We show that in settings when computing the MLE is hard, for the purpose of constructing valid tests and intervals, it is sufficient to upper bound the maximum likelihood. We investigate some conditions under which our methods yield valid inferences under model misspecification. Further, the split LRT can be used with profile likelihoods to deal with nuisance parameters, and it can also be run sequentially to yield anytime-valid P values and confidence sequences. Finally, when combined with the method of sieves, it can be used to perform model selection with nested model classes.

Keywords: confidence sequence; irregular models; likelihood; testing.

Conflict of interest statement
Competing interest statement: L.W. and R.T. are coauthors on a manuscript written in 2015 and published in 2018.

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2
Proc Natl Acad Sci U S A
. 2020 Jul 6;201922097. doi: 10.1073/pnas.1922097117. Online ahead of print.
The Ecology of Human-Carnivore Coexistence
Clayton T Lamb 1 2, Adam T Ford 2, Bruce N McLellan 3, Michael F Proctor 4, Garth Mowat 5 6, Lana Ciarniello 7, Scott E Nielsen 8, Stan Boutin 8
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PMID: 32632004 DOI: 10.1073/pnas.1922097117
Abstract
With a shrinking supply of wilderness and growing recognition that top predators can have a profound influence on ecosystems, the persistence of large carnivores in human-dominated landscapes has emerged as one of the greatest conservation challenges of our time. Carnivores fascinate society, yet these animals pose threats to people living near them, resulting in high rates of carnivore death near human settlements. We used 41 y of demographic data for more than 2,500 brown bears-one of the world's most widely distributed and conflict-prone carnivores-to understand the behavioral and demographic mechanisms promoting carnivore coexistence in human-dominated landscapes. Bear mortality was high and unsustainable near people, but a human-induced shift to nocturnality facilitated lower risks of bear mortality and rates of conflict with people. Despite these behavioral shifts, projected population growth rates for bears in human-dominated areas revealed a source-sink dynamic. Despite some female bears successfully reproducing in the sink areas, bear persistence was reliant on a supply of immigrants from areas with minimal human influence (i.e., wilderness). Such mechanisms of coexistence reveal a striking paradox: Connectivity to wilderness areas supplies bears that likely will die from people, but these bears are essential to avert local extirpation. These insights suggest carnivores contribute to human-carnivore coexistence through behavioral and demographic mechanisms, and that connected wilderness is critical to sustain coexistence landscapes.

Keywords: coadaptation; demography; grizzly bear; source-sink; wilderness.

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

Conflict of interest statement
The authors declare no competing interest.

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3
Proc Natl Acad Sci U S A
. 2020 Jul 6;202002898. doi: 10.1073/pnas.2002898117. Online ahead of print.
A Negative Reciprocal Regulatory Axis Between Cyclin D1 and HNF4α Modulates Cell Cycle Progression and Metabolism in the Liver
Heng Wu 1 2, Tzachi Reizel 3, Yue J Wang 3, Jessica L Lapiro 1 2, Betsy T Kren 4, Jonathan Schug 3, Shilpa Rao 3, Ashleigh Morgan 3, Adam Herman 5, Laurie L Shekels 1 4, Matthew S Rassette 4, Andrew N Lane 6, Teresa Cassel 6, Teresa W M Fan 6, Juan C Manivel 7, Sumedha Gunewardena 8, Udayan Apte 9, Piotr Sicinski 10 11, Klaus H Kaestner 3, Jeffrey H Albrecht 12 2
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PMID: 32631996 DOI: 10.1073/pnas.2002898117
Abstract
Hepatocyte nuclear factor 4α (HNF4α) is a master regulator of liver function and a tumor suppressor in hepatocellular carcinoma (HCC). In this study, we explore the reciprocal negative regulation of HNF4α and cyclin D1, a key cell cycle protein in the liver. Transcriptomic analysis of cultured hepatocyte and HCC cells found that cyclin D1 knockdown induced the expression of a large network of HNF4α-regulated genes. Chromatin immunoprecipitation-sequencing (ChIP-seq) demonstrated that cyclin D1 inhibits the binding of HNF4α to thousands of targets in the liver, thereby diminishing the expression of associated genes that regulate diverse metabolic activities. Conversely, acute HNF4α deletion in the liver induces cyclin D1 and hepatocyte cell cycle progression; concurrent cyclin D1 ablation blocked this proliferation, suggesting that HNF4α maintains proliferative quiescence in the liver, at least, in part, via repression of cyclin D1. Acute cyclin D1 deletion in the regenerating liver markedly inhibited hepatocyte proliferation after partial hepatectomy, confirming its pivotal role in cell cycle progression in this in vivo model, and enhanced the expression of HNF4α target proteins. Hepatocyte cyclin D1 gene ablation caused markedly increased postprandial liver glycogen levels (in a HNF4α-dependent fashion), indicating that the cyclin D1-HNF4α axis regulates glucose metabolism in response to feeding. In AML12 hepatocytes, cyclin D1 depletion led to increased glucose uptake, which was negated if HNF4α was depleted simultaneously, and markedly elevated glycogen synthesis. To summarize, mutual repression by cyclin D1 and HNF4α coordinately controls the cell cycle machinery and metabolism in the liver.

Keywords: cell cycle; glycogen; liver regeneration; partial hepatectomy; pyruvate carboxylase.

Conflict of interest statement
Competing interest statement: P.S. has been a consultant at Novartis, Genovis, Guidepoint, The Planning Shop, ORIC Pharmaceuticals, and Exo Therapeutics; his laboratory receives research funding from Novartis.

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4
Proc Natl Acad Sci U S A
. 2020 Jul 6;201916631. doi: 10.1073/pnas.1916631117. Online ahead of print.
A Tiny Ornithodiran Archosaur From the Triassic of Madagascar and the Role of Miniaturization in Dinosaur and Pterosaur Ancestry
Christian F Kammerer 1, Sterling J Nesbitt 2, John J Flynn 3 4, Lovasoa Ranivoharimanana 5, André R Wyss 6
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PMID: 32631980 DOI: 10.1073/pnas.1916631117
Abstract
Early members of the dinosaur-pterosaur clade Ornithodira are very rare in the fossil record, obscuring our understanding of the origins of this important group. Here, we describe an early ornithodiran (Kongonaphon kely gen. et sp. nov.) from the Mid-to-Upper Triassic of Madagascar that represents one of the smallest nonavian ornithodirans. Although dinosaurs and gigantism are practically synonymous, an analysis of body size evolution in dinosaurs and other archosaurs in the context of this taxon and related forms demonstrates that the earliest-diverging members of the group may have been smaller than previously thought, and that a profound miniaturization event occurred near the base of the avian stem lineage. In phylogenetic analysis, Kongonaphon is recovered as a member of the Triassic ornithodiran clade Lagerpetidae, expanding the range of this group into Africa and providing data on the craniodental morphology of lagerpetids. The conical teeth of Kongonaphon exhibit pitted microwear consistent with a diet of hard-shelled insects, indicating a shift in trophic ecology to insectivory associated with diminutive body size. Small ancestral body size suggests that the extreme rarity of early ornithodirans in the fossil record owes more to taphonomic artifact than true reflection of the group's evolutionary history.

Keywords: Dinosauria; Triassic; body size; evolution; phylogeny.

Conflict of interest statement
The authors declare no competing interest.

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5
Proc Natl Acad Sci U S A
. 2020 Jul 6;201914866. doi: 10.1073/pnas.1914866117. Online ahead of print.
A Partially Disordered Region Connects Gene Repression and Activation Functions of EZH2
Lianying Jiao 1 2, Murtada Shubbar 1 2, Xin Yang 1 2, Qi Zhang 1 2, Siming Chen 1 2, Qiong Wu 2, Zhe Chen 2, Josep Rizo 2 3 4, Xin Liu 5 2
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PMID: 32631994 DOI: 10.1073/pnas.1914866117
Abstract
Enhancer of Zeste Homolog 2 (EZH2) is the catalytic subunit of Polycomb Repressive Complex 2 (PRC2), which minimally requires two other subunits, EED and SUZ12, for enzymatic activity. EZH2 has been traditionally known to mediate histone H3K27 trimethylation, a hallmark of silent chromatin. Emerging evidence indicates that EZH2 also activates gene expression in cancer cells in a context distinct from canonical PRC2. The molecular mechanism underlying the functional conversion of EZH2 from a gene repressor to an activator is unclear. Here, we show that EZH2 harbors a hidden, partially disordered transactivation domain (TAD) capable of interacting with components of active transcription machinery, mimicking archetypal acidic activators. The EZH2 TAD comprises the SRM (Stimulation-Responsive Motif) and SANT1 (SWI3, ADA2, N-CoR, and TFIIIB 1) regions that are normally involved in H3K27 methylation. The crystal structure of an EZH2-EED binary complex indicates that the EZH2 TAD mediates protein oligomerization in a noncanonical PRC2 context and is entirely sequestered. The EZH2 TAD can be unlocked by cancer-specific EZH2 phosphorylation events to undergo structural transitions that may enable subsequent transcriptional coactivator binding. The EZH2 TAD directly interacts with the transcriptional coactivator and histone acetyltransferase p300 and activates gene expression in a p300-dependent manner in cells. The corresponding TAD may also account for the gene activation function of EZH1, the paralog of EZH2. Distinct kinase signaling pathways that are known to abnormally convert EZH2 into a gene activator in cancer cells can now be understood in a common structural context of the EZH2 TAD.

Keywords: EZH2; gene activation; p300; phosphorylation; transcriptional activation domain.

Conflict of interest statement
The authors declare no competing interest.

supplementary info
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6
Proc Natl Acad Sci U S A
. 2020 Jul 6;202003857. doi: 10.1073/pnas.2003857117. Online ahead of print.
A TAL Effector-Like Protein of an Endofungal Bacterium Increases the Stress Tolerance and Alters the Transcriptome of the Host
Morgan E Carter 1, Sara C D Carpenter 1, Zoë E Dubrow 1, Mark R Sabol 1, Fabio C Rinaldi 1, Olga A Lastovetsky 2, Stephen J Mondo 1, Teresa E Pawlowska 1, Adam J Bogdanove 3
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PMID: 32632014 DOI: 10.1073/pnas.2003857117
Abstract
Symbioses of bacteria with fungi have only recently been described and are poorly understood. In the symbiosis of Mycetohabitans (formerly Burkholderia) rhizoxinica with the fungus Rhizopus microsporus, bacterial type III (T3) secretion is known to be essential. Proteins resembling T3-secreted transcription activator-like (TAL) effectors of plant pathogenic bacteria are encoded in the three sequenced Mycetohabitans spp. genomes. TAL effectors nuclear-localize in plants, where they bind and activate genes important in disease. The Burkholderia TAL-like (Btl) proteins bind DNA but lack the N- and C-terminal regions, in which TAL effectors harbor their T3 and nuclear localization signals, and activation domain. We characterized a Btl protein, Btl19-13, and found that, despite the structural differences, it can be T3-secreted and can nuclear-localize. A btl19 -13 gene knockout did not prevent the bacterium from infecting the fungus, but the fungus became less tolerant to cell membrane stress. Btl19-13 did not alter transcription in a plant-based reporter assay, but 15 R. microsporus genes were differentially expressed in comparisons both of the fungus infected with the wild-type bacterium vs. the mutant and with the mutant vs. a complemented strain. Southern blotting revealed btl genes in 14 diverse Mycetohabitans isolates. However, banding patterns and available sequences suggest variation, and the btl19-13 phenotype could not be rescued by a btl gene from a different strain. Our findings support the conclusion that Btl proteins are effectors that act on host DNA and play important but varied or possibly host genotype-specific roles in the M. rhizoxinica-R. microsporus symbiosis.

Keywords: Btl proteins; Rhizopus microsporus; TAL effector; symbiosis; type III secretion.

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

Conflict of interest statement
The authors declare no competing interest.

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7
Proc Natl Acad Sci U S A
. 2020 Jul 6;202000238. doi: 10.1073/pnas.2000238117. Online ahead of print.
Lineage Reconstruction From Clonal Correlations
Caleb Weinreb 1, Allon M Klein 2
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PMID: 32632001 DOI: 10.1073/pnas.2000238117
Abstract
A central task in developmental biology is to learn the sequence of fate decisions that leads to each mature cell type in a tissue or organism. Recently, clonal labeling of cells using DNA barcodes has emerged as a powerful approach for identifying cells that share a common ancestry of fate decisions. Here we explore the idea that stochasticity of cell fate choice during tissue development could be harnessed to read out lineage relationships after a single step of clonal barcoding. By considering a generalized multitype branching process, we determine the conditions under which the final distribution of barcodes over observed cell types encodes their bona fide lineage relationships. We then propose a method for inferring the order of fate decisions. Our theory predicts a set of symmetries of barcode covariance that serves as a consistency check for the validity of the method. We show that broken symmetries may be used to detect multiple paths of differentiation to the same cell types. We provide computational tools for general use. When applied to barcoding data in hematopoiesis, these tools reconstruct the classical hematopoietic hierarchy and detect couplings between monocytes and dendritic cells and between erythrocytes and basophils that suggest multiple pathways of differentiation for these lineages.

Keywords: branching processes; clonal barcodes; lineage tracing.

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

Conflict of interest statement
The authors declare no competing interest.

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8
Proc Natl Acad Sci U S A
. 2020 Jul 6;202007402. doi: 10.1073/pnas.2007402117. Online ahead of print.
Selective Amplification of ipRGC Signals Accounts for Interictal Photophobia in Migraine
Harrison McAdams 1, Eric A Kaiser 2, Aleksandra Igdalova 2, Edda B Haggerty 2, Brett Cucchiara 2, David H Brainard 3, Geoffrey K Aguirre 4
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PMID: 32632006 DOI: 10.1073/pnas.2007402117
Abstract
Second only to headache, photophobia is the most debilitating symptom reported by people with migraine. While the melanopsin-containing intrinsically photosensitive retinal ganglion cells (ipRGCs) are thought to play a role, how cone and melanopsin signals are integrated in this pathway to produce visual discomfort is poorly understood. We studied 60 people: 20 without headache and 20 each with interictal photophobia from migraine with or without visual aura. Participants viewed pulses of spectral change that selectively targeted melanopsin, the cones, or both and rated the degree of visual discomfort produced by these stimuli while we recorded pupil responses. We examined the data within a model that describes how cone and melanopsin signals are weighted and combined at the level of the retina and how this combined signal is transformed into a rating of discomfort or pupil response. Our results indicate that people with migraine do not differ from headache-free controls in the manner in which melanopsin and cone signals are combined. Instead, people with migraine demonstrate an enhanced response to integrated ipRGC signals for discomfort. This effect of migraine is selective for ratings of visual discomfort, in that an enhancement of pupil responses was not seen in the migraine group, nor were group differences found in surveys of other behaviors putatively linked to ipRGC function (chronotype, seasonal sensitivity, presence of a photic sneeze reflex). By revealing a dissociation in the amplification of discomfort vs. pupil response, our findings suggest a postretinal alteration in processing of ipRGC signals for photophobia in migraine.

Keywords: ipRGCs; melanopsin; migraine; photophobia.

Conflict of interest statement
Competing interest statement: E.A.K. has received royalties from a patent shared with Alder Biopharmaceuticals. The remaining authors declare that they have no relevant financial interests that relate to the research described in this paper.

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9
Proc Natl Acad Sci U S A
. 2020 Jul 6;202008373. doi: 10.1073/pnas.2008373117. Online ahead of print.
The Implications of Silent Transmission for the Control of COVID-19 Outbreaks
Seyed M Moghadas 1, Meagan C Fitzpatrick 2 3, Pratha Sah 2, Abhishek Pandey 2, Affan Shoukat 2, Burton H Singer 4, Alison P Galvani 5
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PMID: 32632012 DOI: 10.1073/pnas.2008373117
Abstract
Since the emergence of coronavirus disease 2019 (COVID-19), unprecedented movement restrictions and social distancing measures have been implemented worldwide. The socioeconomic repercussions have fueled calls to lift these measures. In the absence of population-wide restrictions, isolation of infected individuals is key to curtailing transmission. However, the effectiveness of symptom-based isolation in preventing a resurgence depends on the extent of presymptomatic and asymptomatic transmission. We evaluate the contribution of presymptomatic and asymptomatic transmission based on recent individual-level data regarding infectiousness prior to symptom onset and the asymptomatic proportion among all infections. We found that the majority of incidences may be attributable to silent transmission from a combination of the presymptomatic stage and asymptomatic infections. Consequently, even if all symptomatic cases are isolated, a vast outbreak may nonetheless unfold. We further quantified the effect of isolating silent infections in addition to symptomatic cases, finding that over one-third of silent infections must be isolated to suppress a future outbreak below 1% of the population. Our results indicate that symptom-based isolation must be supplemented by rapid contact tracing and testing that identifies asymptomatic and presymptomatic cases, in order to safely lift current restrictions and minimize the risk of resurgence.

Keywords: COVID-19; case isolation; contact tracing.

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

Conflict of interest statement
The authors declare no competing interest.

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10
Proc Natl Acad Sci U S A
. 2020 Jul 6;202007136. doi: 10.1073/pnas.2007136117. Online ahead of print.
Calpain Inhibitor and Ibudilast Rescue β Cell Functions in a Cellular Model of Wolfram Syndrome
Lien D Nguyen 1 2, Tom T Fischer 1 3, Damien Abreu 4 5, Alfredo Arroyo 1, Fumihiko Urano 4 6, Barbara E Ehrlich 7 2
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PMID: 32632005 DOI: 10.1073/pnas.2007136117
Abstract
Wolfram syndrome is a rare multisystem disease characterized by childhood-onset diabetes mellitus and progressive neurodegeneration. Most cases are attributed to pathogenic variants in a single gene, Wolfram syndrome 1 (WFS1). There currently is no disease-modifying treatment for Wolfram syndrome, as the molecular consequences of the loss of WFS1 remain elusive. Because diabetes mellitus is the first diagnosed symptom of Wolfram syndrome, we aimed to further examine the functions of WFS1 in pancreatic β cells in the context of hyperglycemia. Knockout (KO) of WFS1 in rat insulinoma (INS1) cells impaired calcium homeostasis and protein kinase B/Akt signaling and, subsequently, decreased cell viability and glucose-stimulated insulin secretion. Targeting calcium homeostasis with reexpression of WFS1, overexpression of WFS1's interacting partner neuronal calcium sensor-1 (NCS1), or treatment with calpain inhibitor and ibudilast reversed deficits observed in WFS1-KO cells. Collectively, our findings provide insight into the disease mechanism of Wolfram syndrome and highlight new targets and drug candidates to facilitate the development of a treatment for this disorder and similar diseases.

Keywords: Akt; calcium signaling; cell viability; diabetes; ibudilast.

Conflict of interest statement
Competing interest statement: B.E.E. is a cofounder of Osmol Therapeutics, a company that is targeting NCS1 for therapeutic purposes.

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11
Proc Natl Acad Sci U S A
. 2020 Jul 6;201922184. doi: 10.1073/pnas.1922184117. Online ahead of print.
Dopaminergic Neurodegeneration Induced by Parkinson's Disease-Linked G2019S LRRK2 Is Dependent on Kinase and GTPase Activity
An Phu Tran Nguyen 1, Elpida Tsika 2, Kaela Kelly 3, Nathan Levine 1, Xi Chen 1, Andrew B West 3, Sylviane Boularand 4, Pascal Barneoud 4, Darren J Moore 5
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PMID: 32631998 DOI: 10.1073/pnas.1922184117
Abstract
Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common cause of late-onset, autosomal-dominant familial Parkinson's disease (PD). LRRK2 functions as both a kinase and GTPase, and PD-linked mutations are known to influence both enzymatic activities. While PD-linked LRRK2 mutations can commonly induce neuronal damage in culture models, the mechanisms underlying these pathogenic effects remain uncertain. Rodent models containing familial LRRK2 mutations often lack robust PD-like neurodegenerative phenotypes. Here, we develop a robust preclinical model of PD in adult rats induced by the brain delivery of recombinant adenoviral vectors with neuronal-specific expression of human LRRK2 harboring the most common G2019S mutation. In this model, G2019S LRRK2 induces the robust degeneration of substantia nigra dopaminergic neurons, a pathological hallmark of PD. Introduction of a stable kinase-inactive mutation or administration of the selective kinase inhibitor, PF-360, attenuates neurodegeneration induced by G2019S LRRK2. Neuroprotection provided by pharmacological kinase inhibition is mediated by an unusual mechanism involving the robust destabilization of human LRRK2 protein in the brain relative to endogenous LRRK2. Our study further demonstrates that G2019S LRRK2-induced dopaminergic neurodegeneration critically requires normal GTPase activity, as hypothesis-testing mutations that increase GTP hydrolysis or impair GTP-binding activity provide neuroprotection although via distinct mechanisms. Taken together, our data demonstrate that G2019S LRRK2 induces neurodegeneration in vivo via a mechanism that is dependent on kinase and GTPase activity. Our study provides a robust rodent preclinical model of LRRK2-linked PD and nominates kinase inhibition and modulation of GTPase activity as promising disease-modifying therapeutic targets.

Keywords: GTPase; LRRK2; Rab; kinase; neurodegeneration.

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

Conflict of interest statement
The authors declare no competing interest.

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12
Proc Natl Acad Sci U S A
. 2020 Jul 6;202002918. doi: 10.1073/pnas.2002918117. Online ahead of print.
Calibrating the Coevolution of Ediacaran Life and Environment
Alan D Rooney 1, Marjorie D Cantine 2, Kristin D Bergmann 3, Irene Gómez-Pérez 4, Badar Al Baloushi 4, Thomas H Boag 5, James F Busch 6, Erik A Sperling 5, Justin V Strauss 6
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PMID: 32632000 DOI: 10.1073/pnas.2002918117
Abstract
The rise of animals occurred during an interval of Earth history that witnessed dynamic marine redox conditions, potentially rapid plate motions, and uniquely large perturbations to global biogeochemical cycles. The largest of these perturbations, the Shuram carbon isotope excursion, has been invoked as a driving mechanism for Ediacaran environmental change, possibly linked with evolutionary innovation or extinction. However, there are a number of controversies surrounding the Shuram, including its timing, duration, and role in the concomitant biological and biogeochemical upheavals. Here we present radioisotopic dates bracketing the Shuram on two separate paleocontinents; our results are consistent with a global and synchronous event between 574.0 ± 4.7 and 567.3 ± 3.0 Ma. These dates support the interpretation that the Shuram is a primary and synchronous event postdating the Gaskiers glaciation. In addition, our Re-Os ages suggest that the appearance of Ediacaran macrofossils in northwestern Canada is identical, within uncertainty, to similar macrofossils from the Conception Group of Newfoundland, highlighting the coeval appearance of macroscopic metazoans across two paleocontinents. Our temporal framework for the terminal Proterozoic is a critical step for testing hypotheses related to extreme carbon isotope excursions and their role in the evolution of complex life.

Keywords: Ediacaran; Neoproterozoic; Re-Os geochronology; Shuram; carbon isotopes.

Conflict of interest statement
The authors declare no competing interest.

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13
Proc Natl Acad Sci U S A
. 2020 Jul 6;201922270. doi: 10.1073/pnas.1922270117. Online ahead of print.
Adiponectin and Related C1q/TNF-related Proteins Bind Selectively to Anionic Phospholipids and Sphingolipids
Jessica J Ye 1 2, Xin Bian 3 4, Jaechul Lim 1 2, Ruslan Medzhitov 5 2
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PMID: 32632018 DOI: 10.1073/pnas.1922270117
Abstract
Adiponectin (Acrp30) is an adipokine associated with protection from cardiovascular disease, insulin resistance, and inflammation. Although its effects are conventionally attributed to binding Adipor1/2 and T-cadherin, its abundance in circulation, role in ceramide metabolism, and homology to C1q suggest an overlooked role as a lipid-binding protein, possibly generalizable to other C1q/TNF-related proteins (CTRPs) and C1q family members. To investigate this, adiponectin, representative family members, and variants were expressed in Expi293 cells and tested for binding to lipids in liposomes using density centrifugation. Binding to physiological lipids were also analyzed using gradient ultracentrifugation, liquid chromatography-mass spectrometry, and shotgun lipidomics. Interestingly, adiponectin selectively bound several anionic phospholipids and sphingolipids, including phosphatidylserine, ceramide-1-phosphate, glucosylceramide, and sulfatide, via the C1q domain in an oligomerization-dependent fashion. Binding to lipids was observed in liposomes, low-density lipoproteins, cell membranes, and plasma. Other CTRPs and C1q family members (Cbln1, CTRP1, CTRP5, and CTRP13) also bound similar lipids. These findings suggest that adiponectin and CTRPs function not only as hormones, but also as lipid opsonins, as may other C1q family proteins.

Keywords: adipokine; adiponectin; lipid binding; opsonin.

Conflict of interest statement
The authors declare no competing interest.

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14
Proc Natl Acad Sci U S A
. 2020 Jul 6;201916805. doi: 10.1073/pnas.1916805117. Online ahead of print.
Self-emitted Surface Corrugations in Dynamic Fracture of Silicon Single Crystal
Meng Wang 1, Marion Fourmeau 1, Lv Zhao 2 3, Franck Legrand 1, Daniel Nélias 4
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PMID: 32631985 DOI: 10.1073/pnas.1916805117
Abstract
When a dynamic crack front travels through material heterogeneities, elastic waves are emitted, which perturb the crack and change the morphology of the fracture surface. For asperity-free crystalline materials, crack propagation along preferential cleavage planes is expected to present a smooth crack front and form a mirror-like fracture surface. Surprisingly, we show here that in single crystalline silicon without material asperities, the crack front presents a local kink during high-speed crack propagation. Meanwhile, local oscillations of the crack front, which can move along the crack front, emerge at the front kink position and generate periodic fracture surface corrugations. They grow from angstrom amplitude to a few hundred nanometers and propagate with a long lifetime at a frequency-dependent speed, while keeping a scale-independent shape. In particular, the local front oscillations collide in a particle-like manner rather than proceeding with a linear superposition upon interaction, which presents the characteristic of solitary waves. We propose that such a propagating mode of the crack front, which results from the fracture energy fluctuation at a critical crack speed in the silicon crystal, can be considered as nonlinear elastic waves that we call "corrugation waves."

Keywords: corrugation waves; crack front kink; dynamic fracture; silicon single crystal; solitary waves.

Conflict of interest statement
The authors declare no competing interest.

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15
Proc Natl Acad Sci U S A
. 2020 Jul 6;201922927. doi: 10.1073/pnas.1922927117. Online ahead of print.
Genomic Regions Influencing Aggressive Behavior in Honey Bees Are Defined by Colony Allele Frequencies
Arián Avalos 1, Miaoquan Fang 2, Hailin Pan 2 3, Aixa Ramirez Lluch 4, Alexander E Lipka 1 5, Sihai Dave Zhao 1 6, Tugrul Giray 4, Gene E Robinson 7 8 9, Guojie Zhang 10 3 11, Matthew E Hudson 7 5
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PMID: 32631983 DOI: 10.1073/pnas.1922927117
Abstract
For social animals, the genotypes of group members affect the social environment, and thus individual behavior, often indirectly. We used genome-wide association studies (GWAS) to determine the influence of individual vs. group genotypes on aggression in honey bees. Aggression in honey bees arises from the coordinated actions of colony members, primarily nonreproductive "soldier" bees, and thus, experiences evolutionary selection at the colony level. Here, we show that individual behavior is influenced by colony environment, which in turn, is shaped by allele frequency within colonies. Using a population with a range of aggression, we sequenced individual whole genomes and looked for genotype-behavior associations within colonies in a common environment. There were no significant correlations between individual aggression and specific alleles. By contrast, we found strong correlations between colony aggression and the frequencies of specific alleles within colonies, despite a small number of colonies. Associations at the colony level were highly significant and were very similar among both soldiers and foragers, but they covaried with one another. One strongly significant association peak, containing an ortholog of the Drosophila sensory gene dpr4 on linkage group (chromosome) 7, showed strong signals of both selection and admixture during the evolution of gentleness in a honey bee population. We thus found links between colony genetics and group behavior and also, molecular evidence for group-level selection, acting at the colony level. We conclude that group genetics dominates individual genetics in determining the fatal decision of honey bees to sting.

Keywords: GWAS; aggression; behavioral genetics.

Conflict of interest statement
The authors declare no competing interest.

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16
Proc Natl Acad Sci U S A
. 2020 Jul 6;202002266. doi: 10.1073/pnas.2002266117. Online ahead of print.
Impaired Estrogen Signaling Underlies Regulatory T Cell Loss-Of-Function in the Chronically Inflamed Intestine
Wendy A Goodman 1, Sarah M Bedoyan 2, Hannah L Havran 2, Brian Richardson 3, Mark J Cameron 3, Theresa T Pizarro 1
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PMID: 32632016 DOI: 10.1073/pnas.2002266117
Abstract
Signaling of 17β-estradiol (estrogen) through its two nuclear receptors, α and β (ERα, ERβ), is an important mechanism of transcriptional regulation. Although ERs are broadly expressed by cells of the immune system, the mechanisms by which they modulate immune responses remain poorly understood. ERβ-specific signaling is reduced in patients with chronic inflammatory diseases, including systemic lupus erythematosus and inflammatory bowel disease, and our previous work suggests that dysregulation of ERβ-specific signaling contributes to enhanced intestinal inflammation in female SAMP/YitFC mice, a spontaneous model of Crohn's disease-like ileitis. The present study builds on these prior observations to identify a nonredundant, immunoprotective role for ERβ-specific signaling in TGF-β-dependent regulatory T cell (Treg) differentiation. Using a strain of congenic SAMP mice engineered to lack global expression of ERβ, we observed dramatic, female-specific exacerbation of intestinal inflammation accompanied by significant reductions in intestinal Treg frequency and function. Impaired Treg suppression in the absence of ERβ was associated with aberrant overexpression of Tsc22d3 (GILZ), a glucocorticoid-responsive transcription factor not normally expressed in mature Tregs, and ex vivo data reveal that forced overexpression of GILZ in mature Tregs inhibits their suppressive function. Collectively, our findings identify a pathway of estrogen-mediated immune regulation in the intestine, whereby homeostatic expression of ERβ normally functions to limit Treg-specific expression of GILZ, thereby maintaining effective immune suppression. Our data suggest that transcriptional cross-talk between glucocorticoid and steroid sex hormone signaling represents an important and understudied regulatory node in chronic inflammatory disease.

Keywords: Crohn’s disease; estrogen; inflammation; inflammatory bowel disease; regulatory T cell.

Conflict of interest statement
The authors declare no competing interest.

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17
Proc Natl Acad Sci U S A
. 2020 Jul 6;202002411. doi: 10.1073/pnas.2002411117. Online ahead of print.
Six Hundred Years of South American Tree Rings Reveal an Increase in Severe Hydroclimatic Events Since mid-20th Century
Mariano S Morales 1 2, Edward R Cook 3, Jonathan Barichivich 4 5, Duncan A Christie 5 6, Ricardo Villalba 7, Carlos LeQuesne 5, Ana M Srur 7, M Eugenia Ferrero 7, Álvaro González-Reyes 8, Fleur Couvreux 9, Vladimir Matskovsky 7 10, Juan C Aravena 11, Antonio Lara 5 6, Ignacio A Mundo 7 12, Facundo Rojas 7, María R Prieto 7, Jason E Smerdon 3, Lucas O Bianchi 7 13, Mariano H Masiokas 7, Rocio Urrutia-Jalabert 5 6 14, Milagros Rodriguez-Catón 7 3, Ariel A Muñoz 6 15, Moises Rojas-Badilla 5, Claudio Alvarez 5, Lidio Lopez 7, Brian H Luckman 16, David Lister 17, Ian Harris 17, Philip D Jones 17, A Park Williams 3, Gonzalo Velazquez 5, Diego Aliste 5 6, Isabella Aguilera-Betti 15 18, Eugenia Marcotti 7 19, Felipe Flores 5, Tomás Muñoz 5, Emilio Cuq 5, José A Boninsegna 7
Affiliations expand
PMID: 32632003 DOI: 10.1073/pnas.2002411117
Abstract
South American (SA) societies are highly vulnerable to droughts and pluvials, but lack of long-term climate observations severely limits our understanding of the global processes driving climatic variability in the region. The number and quality of SA climate-sensitive tree ring chronologies have significantly increased in recent decades, now providing a robust network of 286 records for characterizing hydroclimate variability since 1400 CE. We combine this network with a self-calibrated Palmer Drought Severity Index (scPDSI) dataset to derive the South American Drought Atlas (SADA) over the continent south of 12°S. The gridded annual reconstruction of austral summer scPDSI is the most spatially complete estimate of SA hydroclimate to date, and well matches past historical dry/wet events. Relating the SADA to the Australia-New Zealand Drought Atlas, sea surface temperatures and atmospheric pressure fields, we determine that the El Niño-Southern Oscillation (ENSO) and the Southern Annular Mode (SAM) are strongly associated with spatially extended droughts and pluvials over the SADA domain during the past several centuries. SADA also exhibits more extended severe droughts and extreme pluvials since the mid-20th century. Extensive droughts are consistent with the observed 20th-century trend toward positive SAM anomalies concomitant with the weakening of midlatitude Westerlies, while low-level moisture transport intensified by global warming has favored extreme rainfall across the subtropics. The SADA thus provides a long-term context for observed hydroclimatic changes and for 21st-century Intergovernmental Panel on Climate Change (IPCC) projections that suggest SA will experience more frequent/severe droughts and rainfall events as a consequence of increasing greenhouse gas emissions.

Keywords: South America hydroclimate; Southern Hemisphere climate modes; drought atlas; extreme hydroclimate events; palaeoclimate reconstruction.

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

Conflict of interest statement
The authors declare no competing interest.

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18
Proc Natl Acad Sci U S A
. 2020 Jul 6;202003852. doi: 10.1073/pnas.2003852117. Online ahead of print.
The Emergent Interactions That Govern Biodiversity Change
James S Clark 1 2 3, C Lane Scher 4, Margaret Swift 4
Affiliations expand
PMID: 32632009 DOI: 10.1073/pnas.2003852117
Abstract
Observational studies have not yet shown that environmental variables can explain pervasive nonlinear patterns of species abundance, because those patterns could result from (indirect) interactions with other species (e.g., competition), and models only estimate direct responses. The experiments that could extract these indirect effects at regional to continental scales are not feasible. Here, a biophysical approach quantifies environment- species interactions (ESI) that govern community change from field data. Just as species interactions depend on population abundances, so too do the effects of environment, as when drought is amplified by competition. By embedding dynamic ESI within framework that admits data gathered on different scales, we quantify responses that are induced indirectly through other species, including probabilistic uncertainty in parameters, model specification, and data. Simulation demonstrates that ESI are needed for accurate interpretation. Analysis demonstrates how nonlinear responses arise even when their direct responses to environment are linear. Applications to experimental lakes and the Breeding Bird Survey (BBS) yield contrasting estimates of ESI. In closed lakes, interactions involving phytoplankton and their zooplankton grazers play a large role. By contrast, ESI are weak in BBS, as expected where year-to-year movement degrades the link between local population growth and species interactions. In both cases, nonlinear responses to environmental gradients are induced by interactions between species. Stability analysis indicates stability in the closed-system lakes and instability in BBS. The probabilistic framework has direct application to conservation planning that must weigh risk assessments for entire habitats and communities against competing interests.

Keywords: GJAM; climate change; food web dynamics; species interactions.

Conflict of interest statement
The authors declare no competing interest.

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19
Proc Natl Acad Sci U S A
. 2020 Jul 6;201918964. doi: 10.1073/pnas.1918964117. Online ahead of print.
Adversarial Super-Resolution of Climatological Wind and Solar Data
Karen Stengel 1, Andrew Glaws 1, Dylan Hettinger 2, Ryan N King 3
Affiliations expand
PMID: 32631993 DOI: 10.1073/pnas.1918964117
Abstract
Accurate and high-resolution data reflecting different climate scenarios are vital for policy makers when deciding on the development of future energy resources, electrical infrastructure, transportation networks, agriculture, and many other societally important systems. However, state-of-the-art long-term global climate simulations are unable to resolve the spatiotemporal characteristics necessary for resource assessment or operational planning. We introduce an adversarial deep learning approach to super resolve wind velocity and solar irradiance outputs from global climate models to scales sufficient for renewable energy resource assessment. Using adversarial training to improve the physical and perceptual performance of our networks, we demonstrate up to a [Formula: see text] resolution enhancement of wind and solar data. In validation studies, the inferred fields are robust to input noise, possess the correct small-scale properties of atmospheric turbulent flow and solar irradiance, and retain consistency at large scales with coarse data. An additional advantage of our fully convolutional architecture is that it allows for training on small domains and evaluation on arbitrarily-sized inputs, including global scale. We conclude with a super-resolution study of renewable energy resources based on climate scenario data from the Intergovernmental Panel on Climate Change's Fifth Assessment Report.

Keywords: adversarial training; climate downscaling; deep learning.

Conflict of interest statement
The authors declare no competing interest.

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20
Proc Natl Acad Sci U S A
. 2020 Jul 6;202001230. doi: 10.1073/pnas.2001230117. Online ahead of print.
Adherence to Suicide Reporting Guidelines by News Shared on a Social Networking Platform
Steven A Sumner 1, Moira Burke 2, Farshad Kooti 2
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PMID: 32631982 DOI: 10.1073/pnas.2001230117
Abstract
Rates of suicide in the United States are at a more than 20-y high. Suicide contagion, or spread of suicide-related thoughts and behaviors through exposure to sensationalized and harmful content is a well-recognized phenomenon. Health authorities have published guidelines for news media reporting on suicide to help prevent contagion; however, uptake of recommendations remains limited. A key barrier to widespread voluntary uptake of suicide-reporting guidelines is that more sensational content is perceived to be more engaging to readers and thus enhances publisher visibility and engagement; however, no empirical information exists on the actual influence of adherence to safe-reporting practices on reader engagement. Hence, we conducted a study to analyze adherence to suicide-reporting guidelines on news shared on social media and to assess how adherence affects reader engagement. Our analysis of Facebook data revealed that harmful elements were prevalent in news articles about suicide shared on social media while the presence of protective elements was generally rare. Contrary to popular perception, closer adherence to safe-reporting practices was associated with a greater likelihood of an article being reshared (adjusted odds ratio [AOR] = 1.19, 95% confidence interval [CI] = 1.10 to 1.27) and receiving positive engagement ("love" reactions) (AOR = 1.20, 95% CI = 1.13 to 1.26). Mean safe-reporting scores were lower in the US than other English-speaking nations and variation existed by publisher characteristics. Our results provide empirical evidence that improved adherence to suicide-reporting guidelines may benefit not only the health of individuals, but also support publisher goals of reach and engagement.

Keywords: Facebook; contagion; news reporting; social networks; suicide.

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

Conflict of interest statement
Competing interest statement: M.B. and F.K. are Facebook employees.

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21
Proc Natl Acad Sci U S A
. 2020 Jul 6;202000065. doi: 10.1073/pnas.2000065117. Online ahead of print.
Forgoing Earned Incentives to Signal Pure Motives
Erika L Kirgios 1, Edward H Chang 2, Emma E Levine 3, Katherine L Milkman 2, Judd B Kessler 4
Affiliations expand
PMID: 32631987 DOI: 10.1073/pnas.2000065117
Abstract
Policy makers, employers, and insurers often provide financial incentives to encourage citizens, employees, and customers to take actions that are good for them or for society (e.g., energy conservation, healthy living, safe driving). Although financial incentives are often effective at inducing good behavior, they've been shown to have self-image costs: Those who receive incentives view their actions less positively due to the perceived incompatibility between financial incentives and intrinsic motives. We test an intervention that allows organizations and individuals to resolve this tension: We use financial rewards to kick-start good behavior and then offer individuals the opportunity to give up some or all of their earned financial rewards in order to boost their self-image. Two preregistered studies-an incentivized online experiment (n = 763) on prosocial behavior and a large field experiment (n = 17,968) on exercise-provide evidence that emphasizing the intrinsic rewards of a past action leads individuals to forgo or donate earned financial rewards. Our intervention allows individuals to retroactively signal that they acted for the right reason, which we call "motivation laundering." We discuss the implications of motivation laundering for the design of incentive systems and behavioral change.

Keywords: incentives; motivation laundering; self-signaling.

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

Conflict of interest statement
The authors declare no competing interest.

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22
Proc Natl Acad Sci U S A
. 2020 Jul 6;202002201. doi: 10.1073/pnas.2002201117. Online ahead of print.
Active Photonic Wireless Power Transfer Into Live Tissues
Juho Kim 1 2, Jimin Seo 1, Dongwuk Jung 1 2, Taeyeon Lee 1 2, Hunpyo Ju 1, Junkyu Han 1, Namyun Kim 1, Jinmo Jeong 1 2, Sungbum Cho 1 2, Jae Hun Seol 1, Jongho Lee 3 2
Affiliations expand
PMID: 32632002 DOI: 10.1073/pnas.2002201117
Abstract
Recent advances in soft materials and mechanics activate development of many new types of electrical medical implants. Electronic implants that provide exceptional functions, however, usually require more electrical power, resulting in shorter period of usages although many approaches have been suggested to harvest electrical power in human bodies by resolving the issues related to power density, biocompatibility, tissue damage, and others. Here, we report an active photonic power transfer approach at the level of a full system to secure sustainable electrical power in human bodies. The active photonic power transfer system consists of a pair of the skin-attachable photon source patch and the photovoltaic device array integrated in a flexible medical implant. The skin-attachable patch actively emits photons that can penetrate through live tissues to be captured by the photovoltaic devices in a medical implant. The wireless power transfer system is very simple, e.g., active power transfer in direct current (DC) to DC without extra circuits, and can be used for implantable medical electronics regardless of weather, covering by clothes, in indoor or outdoor at day and night. We demonstrate feasibility of the approach by presenting thermal and mechanical compatibility with soft live tissues while generating enough electrical power in live bodies through in vivo animal experiments. We expect that the results enable long-term use of currently available implants in addition to accelerating emerging types of electrical implants that require higher power to provide diverse convenient diagnostic and therapeutic functions in human bodies.

Keywords: bioelectronics; biomedical implants; flexible electronics; photonic power transfer.

Conflict of interest statement
The authors declare no competing interest.

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23
Proc Natl Acad Sci U S A
. 2020 Jul 6;202001105. doi: 10.1073/pnas.2001105117. Online ahead of print.
How Frequency Hopping Suppresses Pulse-Echo Ambiguity in Bat Biosonar
Chen Ming 1, Mary E Bates 2, James A Simmons 3
Affiliations expand
PMID: 32632013 DOI: 10.1073/pnas.2001105117
Abstract
Big brown bats transmit wideband FM biosonar sounds that sweep from 55 to 25 kHz (first harmonic, FM1) and from 110 to 50 kHz (second harmonic, FM2). FM1 is required to perceive echo delay for target ranging; FM2 contributes only if corresponding FM1 frequencies are present. We show that echoes need only the lowest FM1 broadcast frequencies of 25 to 30 kHz for delay perception. If these frequencies are removed, no delay is perceived. Bats begin echo processing at the lowest frequencies and accumulate perceptual acuity over successively higher frequencies, but they cannot proceed without the low-frequency starting point in their broadcasts. This reveals a solution to pulse-echo ambiguity, a serious problem for radar or sonar. In dense, extended biosonar scenes, bats have to emit sounds rapidly to avoid collisions with near objects. But if a new broadcast is emitted when echoes of the previous broadcast still are arriving, echoes from both broadcasts intermingle, creating ambiguity about which echo corresponds to which broadcast. Frequency hopping by several kilohertz from one broadcast to the next can segregate overlapping narrowband echo streams, but wideband FM echoes ordinarily do not segregate because their spectra still overlap. By starting echo processing at the lowest frequencies in frequency-hopped broadcasts, echoes of the higher hopped broadcast are prevented from being accepted by lower hopped broadcasts, and ambiguity is avoided. The bat-inspired spectrogram correlation and transformation (SCAT) model also begins at the lowest frequencies; echoes that lack them are eliminated from processing of delay and no longer cause ambiguity.

Keywords: bat biosonar; clutter suppression; echo ambiguity; echolocation; sonar image.

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 Jul 6;202001779. doi: 10.1073/pnas.2001779117. Online ahead of print.
Noninvasive Acoustic Manipulation of Objects in a Living Body
Mohamed A Ghanem 1, Adam D Maxwell 2 3, Yak-Nam Wang 2, Bryan W Cunitz 2, Vera A Khokhlova 2 4, Oleg A Sapozhnikov 2 4, Michael R Bailey 2 3
Affiliations expand
PMID: 32631991 DOI: 10.1073/pnas.2001779117
Abstract
In certain medical applications, transmitting an ultrasound beam through the skin to manipulate a solid object within the human body would be beneficial. Such applications include, for example, controlling an ingestible camera or expelling a kidney stone. In this paper, ultrasound beams of specific shapes were designed by numerical modeling and produced using a phased array. These beams were shown to levitate and electronically steer solid objects (3-mm-diameter glass spheres), along preprogrammed paths, in a water bath, and in the urinary bladders of live pigs. Deviation from the intended path was on average <10%. No injury was found on the bladder wall or intervening tissue.

Keywords: acoustic radiation force; acoustic tweezers; kidney stones.

Conflict of interest statement
Competing interest statement: A.D.M., B.W.C., and M.R.B. have equity and consult for SonoMotion, Inc. which has licensed technology related to this work from the University of Washington for commercialization.

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25
Proc Natl Acad Sci U S A
. 2020 Jul 6;201918953. doi: 10.1073/pnas.1918953117. Online ahead of print.
Flat Latitudinal Diversity Gradient Caused by the Permian-Triassic Mass Extinction
Haijun Song 1, Shan Huang 2, Enhao Jia 3, Xu Dai 3, Paul B Wignall 4, Alexander M Dunhill 4
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PMID: 32631978 DOI: 10.1073/pnas.1918953117
Abstract
The latitudinal diversity gradient (LDG) is recognized as one of the most pervasive, global patterns of present-day biodiversity. However, the controlling mechanisms have proved difficult to identify because many potential drivers covary in space. The geological record presents a unique opportunity for understanding the mechanisms which drive the LDG by providing a direct window to deep-time biogeographic dynamics. Here we used a comprehensive database containing 52,318 occurrences of marine fossils to show that the shape of the LDG changed greatly during the Permian-Triassic mass extinction from showing a significant tropical peak to a flattened LDG. The flat LDG lasted for the entire Early Triassic (∼5 My) before reverting to a modern-like shape in the Middle Triassic. The environmental extremes that prevailed globally, especially the dramatic warming, likely induced selective extinction in low latitudes and accumulation of diversity in high latitudes through origination and poleward migration, which combined together account for the flat LDG of the Early Triassic.

Keywords: biodiversity; biogeography; end-Permian mass extinction; global warming; ocean anoxia.

Conflict of interest statement
The authors declare no competing interest.

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26
Proc Natl Acad Sci U S A
. 2020 Jul 6;202000523. doi: 10.1073/pnas.2000523117. Online ahead of print.
Inhibition of Impulsive Action by Projection-Defined Prefrontal Pyramidal Neurons
Bing Li 1 2, Thao Phuong Nguyen 3, Chenyan Ma 1 2, Yang Dan 4 2
Affiliations expand
PMID: 32631999 DOI: 10.1073/pnas.2000523117
Abstract
The prefrontal cortex (PFC) plays a critical role in curbing impulsive behavior, but the underlying circuit mechanism remains incompletely understood. Here we show that a subset of dorsomedial PFC (dmPFC) layer 5 pyramidal neurons, which project to the subthalamic nucleus (STN) of the basal ganglia, play a key role in inhibiting impulsive responses in a go/no-go task. Projection-specific labeling and calcium imaging showed that the great majority of STN-projecting neurons were preferentially active in no-go trials when the mouse successfully withheld licking responses, but lateral hypothalamus (LH)-projecting neurons were more active in go trials with licking; visual cortex (V1)-projecting neurons showed only weak task-related activity. Optogenetic activation and inactivation of STN-projecting neurons reduced and increased inappropriate licking, respectively, partly through their direct innervation of the STN, but manipulating LH-projecting neurons had the opposite effects. These results identify a projection-defined subtype of PFC pyramidal neurons as key mediators of impulse control.

Keywords: impulsive behavior; lateral hypothalamus; prefrontal cortex; subthalamic nucleus; two-photon calcium imaging.

Conflict of interest statement
The authors declare no competing interest.

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27
Proc Natl Acad Sci U S A
. 2020 Jul 6;202008030. doi: 10.1073/pnas.2008030117. Online ahead of print.
Structural Basis for Autophagy Inhibition by the Human Rubicon-Rab7 Complex
Hersh K Bhargava 1 2, Keisuke Tabata 3, Jordan M Byck 1 2, Maho Hamasaki 4, Daniel P Farrell 5 6, Ivan Anishchenko 5 6, Frank DiMaio 5 6, Young Jun Im 7, Tamotsu Yoshimori 3 4, James H Hurley 8 2 9
Affiliations expand
PMID: 32632011 DOI: 10.1073/pnas.2008030117
Abstract
Rubicon is a potent negative regulator of autophagy and a potential target for autophagy-inducing therapeutics. Rubicon-mediated inhibition of autophagy requires the interaction of the C-terminal Rubicon homology (RH) domain of Rubicon with Rab7-GTP. Here we report the 2.8-Å crystal structure of the Rubicon RH domain in complex with Rab7-GTP. Our structure reveals a fold for the RH domain built around four zinc clusters. The switch regions of Rab7 insert into pockets on the surface of the RH domain in a mode that is distinct from those of other Rab-effector complexes. Rubicon residues at the dimer interface are required for Rubicon and Rab7 to colocalize in living cells. Mutation of Rubicon RH residues in the Rab7-binding site restores efficient autophagic flux in the presence of overexpressed Rubicon, validating the Rubicon RH domain as a promising therapeutic target.

Keywords: Rab GTPase; autophagy; crystal structure.

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

Conflict of interest statement
Competing interest statement: The authors declare a competing interest. J.H.H. is a cofounder of Casma Therapeutics.

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28
Proc Natl Acad Sci U S A
. 2020 Jul 6;201918304. doi: 10.1073/pnas.1918304117. Online ahead of print.
Bayesian Inference of Reassortment Networks Reveals Fitness Benefits of Reassortment in Human Influenza Viruses
Nicola F Müller 1 2 3, Ugnė Stolz 4 2, Gytis Dudas 5, Tanja Stadler 4 2, Timothy G Vaughan 1 2
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PMID: 32631984 DOI: 10.1073/pnas.1918304117
Abstract
Reassortment is an important source of genetic diversity in segmented viruses and is the main source of novel pathogenic influenza viruses. Despite this, studying the reassortment process has been constrained by the lack of a coherent, model-based inference framework. Here, we introduce a coalescent-based model that allows us to explicitly model the joint coalescent and reassortment process. In order to perform inference under this model, we present an efficient Markov chain Monte Carlo algorithm to sample rooted networks and the embedding of phylogenetic trees within networks. This algorithm provides the means to jointly infer coalescent and reassortment rates with the reassortment network and the embedding of segments in that network from full-genome sequence data. Studying reassortment patterns of different human influenza datasets, we find large differences in reassortment rates across different human influenza viruses. Additionally, we find that reassortment events predominantly occur on selectively fitter parts of reassortment networks showing that on a population level, reassortment positively contributes to the fitness of human influenza viruses.

Keywords: BEAST; MCMC; infectious diseases; phylodynamics; phylogenetics.

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 Jul 6;202000635. doi: 10.1073/pnas.2000635117. Online ahead of print.
Individual Differences Determine the Strength of Ecological Interactions
Jason I Griffiths 1 2, Dylan Z Childs 3, Ronald D Bassar 4, Tim Coulson 5, David N Reznick 6, Mark Rees 3
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PMID: 32631995 DOI: 10.1073/pnas.2000635117
Abstract
Biotic interactions are central to both ecological and evolutionary dynamics. In the vast majority of empirical studies, the strength of intraspecific interactions is estimated by using simple measures of population size. Biologists have long known that these are crude metrics, with experiments and theory suggesting that interactions between individuals should depend on traits, such as body size. Despite this, it has been difficult to estimate the impact of traits on competitive ability from ecological field data, and this explains why the strength of biotic interactions has empirically been treated in a simplistic manner. Using long-term observational data from four different populations, we show that large Trinidadian guppies impose a significantly larger competitive pressure on conspecifics than individuals that are smaller; in other words, competition is asymmetric. When we incorporate this asymmetry into integral projection models, the predicted size structure is much closer to what we see in the field compared with models where competition is independent of body size. This difference in size structure translates into a twofold difference in reproductive output. This demonstrates how the nature of ecological interactions drives the size structure, which, in turn, will have important implications for both the ecological and evolutionary dynamics.

Keywords: Trinidadian guppies; asymmetric competition; size structure.

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

Conflict of interest statement
The authors declare no competing interest.

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30
Proc Natl Acad Sci U S A
. 2020 Jul 6;202003267. doi: 10.1073/pnas.2003267117. Online ahead of print.
Evolution of Abiotic Cubane Chemistries in a Nucleic Acid Aptamer Allows Selective Recognition of a Malaria Biomarker
Yee-Wai Cheung 1, Pascal Röthlisberger 2, Ariel E Mechaly 3, Patrick Weber 3, Fabienne Levi-Acobas 2, Young Lo 1, Alvin W C Wong 1, Andrew B Kinghorn 1, Ahmed Haouz 3, G Paul Savage 4, Marcel Hollenstein 5, Julian A Tanner 6
Affiliations expand
PMID: 32631977 DOI: 10.1073/pnas.2003267117
Abstract
Nucleic acid aptamers selected through systematic evolution of ligands by exponential enrichment (SELEX) fold into exquisite globular structures in complex with protein targets with diverse translational applications. Varying the chemistry of nucleotides allows evolution of nonnatural nucleic acids, but the extent to which exotic chemistries can be integrated into a SELEX selection to evolve nonnatural macromolecular binding interfaces is unclear. Here, we report the identification of a cubane-modified aptamer (cubamer) against the malaria biomarker Plasmodium vivax lactate dehydrogenase (PvLDH). The crystal structure of the complex reveals an unprecedented binding mechanism involving a multicubane cluster within a hydrophobic pocket. The binding interaction is further stabilized through hydrogen bonding via cubyl hydrogens, previously unobserved in macromolecular binding interfaces. This binding mechanism allows discriminatory recognition of P. vivax over Plasmodium falciparum lactate dehydrogenase, thereby distinguishing these highly conserved malaria biomarkers for diagnostic applications. Together, our data demonstrate that SELEX can be used to evolve exotic nucleic acids bearing chemical functional groups which enable remarkable binding mechanisms which have never been observed in biology. Extending to other exotic chemistries will open a myriad of possibilities for functional nucleic acids.

Keywords: SELEX; X-ray crystallography; cubane; malaria diagnosis; modified aptamer.

Conflict of interest statement
Competing interest statement: J.A.T. is a scientific advisor for Zio Health, and J.A.T. and A.B.K. are founders of Jushan Bio.

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31
Proc Natl Acad Sci U S A
. 2020 Jul 6;201914430. doi: 10.1073/pnas.1914430117. Online ahead of print.
A Molecular Mechanism for Probabilistic Bet Hedging and Its Role in Viral Latency
Sonali Chaturvedi 1, Jonathan Klein 1, Noam Vardi 1, Cynthia Bolovan-Fritts 1, Marie Wolf 1, Kelvin Du 1, Luwanika Mlera 2, Meredith Calvert 1, Nathaniel J Moorman 3, Felicia Goodrum 2, Bo Huang 4 5, Leor S Weinberger 6 4 5
Affiliations expand
PMID: 32632017 DOI: 10.1073/pnas.1914430117
Abstract
Probabilistic bet hedging, a strategy to maximize fitness in unpredictable environments by matching phenotypic variability to environmental variability, is theorized to account for the evolution of various fate-specification decisions, including viral latency. However, the molecular mechanisms underlying bet hedging remain unclear. Here, we report that large variability in protein abundance within individual herpesvirus virion particles enables probabilistic bet hedging between viral replication and latency. Superresolution imaging of individual virions of the human herpesvirus cytomegalovirus (CMV) showed that virion-to-virion levels of pp71 tegument protein-the major viral transactivator protein-exhibit extreme variability. This super-Poissonian tegument variability promoted alternate replicative strategies: high virion pp71 levels enhance viral replicative fitness but, strikingly, impede silencing, whereas low virion pp71 levels reduce fitness but promote silencing. Overall, the results indicate that stochastic tegument packaging provides a mechanism enabling probabilistic bet hedging between viral replication and latency.

Keywords: fate selection; herpesvirus; latency; stochastic variability; tegument.

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

Conflict of interest statement
The authors declare no competing interest.

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32
Proc Natl Acad Sci U S A
. 2020 Jul 6;201921689. doi: 10.1073/pnas.1921689117. Online ahead of print.
Upper Midwest Lakes Are Supersaturated With N 2
Brianna M Loeks-Johnson 1, James B Cotner 2
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PMID: 32631997 DOI: 10.1073/pnas.1921689117
Abstract
Little is known about the exchange of gaseous nitrogen (N2) with the atmosphere in freshwater systems. Although the exchange of N2, driven by excess or deficiencies relative to saturation values, has little relevance to the atmospheric N2 pool due to its large size, it does play an important role in freshwater and marine nitrogen (N) cycling. N-fixation converts N2 to ammonia, which can be used by microbes and phytoplankton, while denitrification/anammox effectively removes it by converting oxidized, inorganic N to N2 We examined N2 saturation to infer net biological nitrogen processes in 34 lakes across 5° latitude varying in trophic status, mixing regime, and bathymetry. Here, we report that nearly all lakes examined in the upper Midwest (USA) were supersaturated with N2 (>85% of samples, n = 248), suggesting lakes are continuously releasing nitrogen to the atmosphere. The traditional paradigm is that freshwaters compensate for N-limitation through N-fixation, but these results indicate that lakes were constantly losing N to the atmosphere via denitrification and/or anammox, suggesting that terrestrial N inputs are needed to balance the internal N cycle.

Keywords: biogeochemistry; denitrification; nitrogen cycling; nitrogen fixation.

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

Conflict of interest statement
The authors declare no competing interest.

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33
Proc Natl Acad Sci U S A
. 2020 Jul 6;202005238. doi: 10.1073/pnas.2005238117. Online ahead of print.
Default-mode Network Streams for Coupling to Language and Control Systems
Evan M Gordon 1 2 3, Timothy O Laumann 4, Scott Marek 5, Ryan V Raut 6, Caterina Gratton 7, Dillan J Newbold 5, Deanna J Greene 4 6, Rebecca S Coalson 5 6, Abraham Z Snyder 5 6, Bradley L Schlaggar 8 9 10, Steven E Petersen 5 6 11 12, Nico U F Dosenbach 5 6 13 14 15, Steven M Nelson 16 2 3 17
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PMID: 32632019 DOI: 10.1073/pnas.2005238117
Abstract
The human brain is organized into large-scale networks identifiable using resting-state functional connectivity (RSFC). These functional networks correspond with broad cognitive domains; for example, the Default-mode network (DMN) is engaged during internally oriented cognition. However, functional networks may contain hierarchical substructures corresponding with more specific cognitive functions. Here, we used individual-specific precision RSFC to test whether network substructures could be identified in 10 healthy human brains. Across all subjects and networks, individualized network subdivisions were more valid-more internally homogeneous and better matching spatial patterns of task activation-than canonical networks. These measures of validity were maximized at a hierarchical scale that contained ∼83 subnetworks across the brain. At this scale, nine DMN subnetworks exhibited topographical similarity across subjects, suggesting that this approach identifies homologous neurobiological circuits across individuals. Some DMN subnetworks matched known features of brain organization corresponding with cognitive functions. Other subnetworks represented separate streams by which DMN couples with other canonical large-scale networks, including language and control networks. Together, this work provides a detailed organizational framework for studying the DMN in individual humans.

Keywords: Default network; brain networks; fMRI; functional connectivity; individual variability.

Conflict of interest statement
Competing interest statement: N.U.F.D. is cofounder of Nous Imaging.

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34
Proc Natl Acad Sci U S A
. 2020 Jul 6;202002352. doi: 10.1073/pnas.2002352117. Online ahead of print.
Label-free Optical Detection of Bioelectric Potentials Using Electrochromic Thin Films
Felix S Alfonso 1, Yuecheng Zhou 1, Erica Liu 1, Allister F McGuire 1, Yang Yang 1, Husniye Kantarci 2, Dong Li 2, Eric Copenhaver 3 4, J Bradley Zuchero 2, Holger Müller 5 4, Bianxiao Cui 6
Affiliations expand
PMID: 32632007 DOI: 10.1073/pnas.2002352117
Abstract
Understanding how a network of interconnected neurons receives, stores, and processes information in the human brain is one of the outstanding scientific challenges of our time. The ability to reliably detect neuroelectric activities is essential to addressing this challenge. Optical recording using voltage-sensitive fluorescent probes has provided unprecedented flexibility for choosing regions of interest in recording neuronal activities. However, when recording at a high frame rate such as 500 to 1,000 Hz, fluorescence-based voltage sensors often suffer from photobleaching and phototoxicity, which limit the recording duration. Here, we report an approach called electrochromic optical recording (ECORE) that achieves label-free optical recording of spontaneous neuroelectrical activities. ECORE utilizes the electrochromism of poly(3,4-ethylenedioxythiophene) polystyrene sulfonate (PEDOT:PSS) thin films, whose optical absorption can be modulated by an applied voltage. Being based on optical reflection instead of fluorescence, ECORE offers the flexibility of an optical probe without suffering from photobleaching or phototoxicity. Using ECORE, we optically recorded spontaneous action potentials in cardiomyocytes, cultured hippocampal and dorsal root ganglion neurons, and brain slices. With minimal perturbation to cells, ECORE allows long-term optical recording over multiple days.

Keywords: PEDOT:PSS; action potential; electrochromic; neurons; optical electrophysiology.

Conflict of interest statement
The authors declare no competing interest.

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35
Proc Natl Acad Sci U S A
. 2020 Jul 6;201920321. doi: 10.1073/pnas.1920321117. Online ahead of print.
Original Antigenic Sin Priming of Influenza Virus Hemagglutinin Stalk Antibodies
Claudia P Arevalo 1, Valerie Le Sage 2, Marcus J Bolton 1, Theresa Eilola 1, Jennifer E Jones 2, Karen A Kormuth 2, Eric Nturibi 2, Angel Balmaseda 3, Aubree Gordon 4, Seema S Lakdawala 2 5, Scott E Hensley 6
Affiliations expand
PMID: 32631992 DOI: 10.1073/pnas.1920321117
Abstract
Immunity to influenza viruses can be long-lived, but reinfections with antigenically distinct viral strains and subtypes are common. Reinfections can boost antibody responses against viral strains first encountered in childhood through a process termed "original antigenic sin." It is unknown how initial childhood exposures affect the induction of antibodies against the hemagglutinin (HA) stalk domain of influenza viruses. This is an important consideration since broadly reactive HA stalk antibodies can protect against infection, and universal vaccine platforms are being developed to induce these antibodies. Here we show that experimentally infected ferrets and naturally infected humans establish strong "immunological imprints" against HA stalk antigens first encountered during primary influenza virus infections. We found that HA stalk antibodies are surprisingly boosted upon subsequent infections with antigenically distinct influenza A virus subtypes. Paradoxically, these heterosubtypic-boosted HA stalk antibodies do not bind efficiently to the boosting influenza virus strain. Our results demonstrate that an individual's HA stalk antibody response is dependent on the specific subtype of influenza virus that they first encounter early in life. We propose that humans are susceptible to heterosubtypic influenza virus infections later in life since these viruses boost HA stalk antibodies that do not bind efficiently to the boosting antigen.

Keywords: hemagglutinin; influenza virus; original antigenic sin.

Conflict of interest statement
Competing interest statement: S.E.H. reports receiving consulting fees from Sanofi Pasteur, Lumen, Novavax, and Merck for work unrelated to this manuscript.

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36
Proc Natl Acad Sci U S A
. 2020 Jul 6;202002729. doi: 10.1073/pnas.2002729117. Online ahead of print.
Children Drinking Private Well Water Have Higher Blood Lead Than Those With City Water
Jacqueline MacDonald Gibson 1, Michael Fisher 2, Allison Clonch 2, John M MacDonald 3, Philip J Cook 4
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PMID: 32631989 DOI: 10.1073/pnas.2002729117
Abstract
Although the Flint, Michigan, water crisis renewed concerns about lead (Pb) in city drinking water, little attention has been paid to Pb in private wells, which provide drinking water for 13% of the US population. This study evaluates the risk of Pb exposure in children in households relying on private wells. It is based on a curated dataset of blood Pb records from 59,483 North Carolina children matched with household water source information. We analyze the dataset for statistical associations between children's blood Pb and household drinking water source. The analysis shows that children in homes relying on private wells have 25% increased odds (95% CI 6.2 to 48%, P < 0.01) of elevated blood Pb, compared with children in houses served by a community water system that is regulated under the Safe Drinking Water Act. This increased Pb exposure is likely a result of corrosion of household plumbing and well components, because homes relying on private wells rarely treat their water to prevent corrosion. In contrast, corrosion control is required in regulated community water systems. These findings highlight the need for targeted outreach to prevent Pb exposure for the 42.5 million Americans depending on private wells for their drinking water.

Keywords: blood lead; children’s health; drinking water; lead exposure; private well.

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

Conflict of interest statement
The authors declare no competing interest.

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37
Proc Natl Acad Sci U S A
. 2020 Jul 6;201918584. doi: 10.1073/pnas.1918584117. Online ahead of print.
Contrasting Effects of Climate Change on Seasonal Survival of a Hibernating Mammal
Line S Cordes 1, Daniel T Blumstein 2 3, Kenneth B Armitage 4, Paul J CaraDonna 3 5, Dylan Z Childs 6, Brian D Gerber 7, Julien G A Martin 8, Madan K Oli 9, Arpat Ozgul 10
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PMID: 32631981 DOI: 10.1073/pnas.1918584117
Abstract
Seasonal environmental conditions shape the behavior and life history of virtually all organisms. Climate change is modifying these seasonal environmental conditions, which threatens to disrupt population dynamics. It is conceivable that climatic changes may be beneficial in one season but result in detrimental conditions in another because life-history strategies vary between these time periods. We analyzed the temporal trends in seasonal survival of yellow-bellied marmots (Marmota flaviventer) and explored the environmental drivers using a 40-y dataset from the Colorado Rocky Mountains (USA). Trends in survival revealed divergent seasonal patterns, which were similar across age-classes. Marmot survival declined during winter but generally increased during summer. Interestingly, different environmental factors appeared to drive survival trends across age-classes. Winter survival was largely driven by conditions during the preceding summer and the effect of continued climate change was likely to be mainly negative, whereas the likely outcome of continued climate change on summer survival was generally positive. This study illustrates that seasonal demographic responses need disentangling to accurately forecast the impacts of climate change on animal population dynamics.

Keywords: Marmota flaviventer; demography; environmental conditions; individual-based; mark–recapture.

Conflict of interest statement
The authors declare no competing interest.

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38
Proc Natl Acad Sci U S A
. 2020 Jul 6;202005648. doi: 10.1073/pnas.2005648117. Online ahead of print.
The Environmental Stress Response Causes Ribosome Loss in Aneuploid Yeast Cells
Allegra Terhorst 1, Arzu Sandikci 1, Abigail Keller 2, Charles A Whittaker 1, Maitreya J Dunham 2, Angelika Amon 3
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PMID: 32632008 DOI: 10.1073/pnas.2005648117
Abstract
Aneuploidy, a condition characterized by whole chromosome gains and losses, is often associated with significant cellular stress and decreased fitness. However, how cells respond to the aneuploid state has remained controversial. In aneuploid budding yeast, two opposing gene-expression patterns have been reported: the "environmental stress response" (ESR) and the "common aneuploidy gene-expression" (CAGE) signature, in which many ESR genes are oppositely regulated. Here, we investigate this controversy. We show that the CAGE signature is not an aneuploidy-specific gene-expression signature but the result of normalizing the gene-expression profile of actively proliferating aneuploid cells to that of euploid cells grown into stationary phase. Because growth into stationary phase is among the strongest inducers of the ESR, the ESR in aneuploid cells was masked when stationary phase euploid cells were used for normalization in transcriptomic studies. When exponentially growing euploid cells are used in gene-expression comparisons with aneuploid cells, the CAGE signature is no longer evident in aneuploid cells. Instead, aneuploid cells exhibit the ESR. We further show that the ESR causes selective ribosome loss in aneuploid cells, providing an explanation for the decreased cellular density of aneuploid cells. We conclude that aneuploid budding yeast cells mount the ESR, rather than the CAGE signature, in response to aneuploidy-induced cellular stresses, resulting in selective ribosome loss. We propose that the ESR serves two purposes in aneuploid cells: protecting cells from aneuploidy-induced cellular stresses and preventing excessive cellular enlargement during slowed cell cycles by down-regulating translation capacity.

Keywords: CAGE; ESR; aneuploidy; ribosome loss.

Conflict of interest statement
The authors declare no competing interest.

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39
Proc Natl Acad Sci U S A
. 2020 Jul 6;202002887. doi: 10.1073/pnas.2002887117. Online ahead of print.
Vision Perceptually Restores Auditory Spectral Dynamics in Speech
John Plass 1 2, David Brang 3, Satoru Suzuki 2 4, Marcia Grabowecky 2 4
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PMID: 32632010 DOI: 10.1073/pnas.2002887117
Abstract
Visual speech facilitates auditory speech perception, but the visual cues responsible for these benefits and the information they provide remain unclear. Low-level models emphasize basic temporal cues provided by mouth movements, but these impoverished signals may not fully account for the richness of auditory information provided by visual speech. High-level models posit interactions among abstract categorical (i.e., phonemes/visemes) or amodal (e.g., articulatory) speech representations, but require lossy remapping of speech signals onto abstracted representations. Because visible articulators shape the spectral content of speech, we hypothesized that the perceptual system might exploit natural correlations between midlevel visual (oral deformations) and auditory speech features (frequency modulations) to extract detailed spectrotemporal information from visual speech without employing high-level abstractions. Consistent with this hypothesis, we found that the time-frequency dynamics of oral resonances (formants) could be predicted with unexpectedly high precision from the changing shape of the mouth during speech. When isolated from other speech cues, speech-based shape deformations improved perceptual sensitivity for corresponding frequency modulations, suggesting that listeners could exploit this cross-modal correspondence to facilitate perception. To test whether this type of correspondence could improve speech comprehension, we selectively degraded the spectral or temporal dimensions of auditory sentence spectrograms to assess how well visual speech facilitated comprehension under each degradation condition. Visual speech produced drastically larger enhancements during spectral degradation, suggesting a condition-specific facilitation effect driven by cross-modal recovery of auditory speech spectra. The perceptual system may therefore use audiovisual correlations rooted in oral acoustics to extract detailed spectrotemporal information from visual speech.

Keywords: audiovisual speech; multisensory; spectrotemporal; speech perception.

Conflict of interest statement
The authors declare no competing interest.

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40
Proc Natl Acad Sci U S A
. 2020 Jul 6;202005633. doi: 10.1073/pnas.2005633117. Online ahead of print.
Functionally Distinct Purkinje Cell Types Show Temporal Precision in Encoding Locomotion
Weipang Chang 1, Andrea Pedroni 1, Victoria Hohendorf 1, Stefania Giacomello 2, Masahiko Hibi 3, Reinhard W Köster 4, Konstantinos Ampatzis 5
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PMID: 32632015 DOI: 10.1073/pnas.2005633117
Abstract
Purkinje cells, the principal neurons of cerebellar computations, are believed to comprise a uniform neuronal population of cells, each with similar functional properties. Here, we show an undiscovered heterogeneity of adult zebrafish Purkinje cells, revealing the existence of anatomically and functionally distinct cell types. Dual patch-clamp recordings showed that the cerebellar circuit contains all Purkinje cell types that cross-communicate extensively using chemical and electrical synapses. Further activation of spinal central pattern generators (CPGs) revealed unique phase-locked activity from each Purkinje cell type during the locomotor cycle. Thus, we show intricately organized Purkinje cell networks in the adult zebrafish cerebellum that encode the locomotion rhythm differentially, and we suggest that these organizational properties may also apply to other cerebellar functions.

Keywords: Purkinje cells; central pattern generator; cerebellum; locomotion; zebrafish.

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 Jul 6;202011873. doi: 10.1073/pnas.2011873117. Online ahead of print.
Correction to Supporting Information for Halpern Et Al., Opinion: Putting All Foods on the Same Table: Achieving Sustainable Food Systems Requires Full Accounting
No authors listed
PMID: 32631988 DOI: 10.1073/pnas.2011873117
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42
Published Erratum Proc Natl Acad Sci U S A
. 2020 Jul 6;202011246. doi: 10.1073/pnas.2011246117. Online ahead of print.
Correction for Mastrangelo Et Al., Twin-chain Polymer Hydrogels Based on Poly(vinyl Alcohol) as New Advanced Tool for the Cleaning of Modern and Contemporary Art
No authors listed
PMID: 32631990 DOI: 10.1073/pnas.2011246117
Erratum for
Twin-chain polymer hydrogels based on poly(vinyl alcohol) as new advanced tool for the cleaning of modern and contemporary art.
Mastrangelo R, Chelazzi D, Poggi G, Fratini E, Pensabene Buemi L, Petruzzellis ML, Baglioni P.
Proc Natl Acad Sci U S A. 2020 Mar 31;117(13):7011-7020. doi: 10.1073/pnas.1911811117. Epub 2020 Mar 9.
PMID: 32152095 Free PMC article.
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43
Published Erratum Proc Natl Acad Sci U S A
. 2020 Jul 6;202010186. doi: 10.1073/pnas.2010186117. Online ahead of print.
Correction for Luther Et Al., Hepatic Gap Junctions Amplify Alcohol Liver Injury by Propagating cGAS-mediated IRF3 Activation
No authors listed
PMID: 32631979 DOI: 10.1073/pnas.2010186117
Erratum for
Hepatic gap junctions amplify alcohol liver injury by propagating cGAS-mediated IRF3 activation.
Luther J, Khan S, Gala MK, Kedrin D, Sridharan G, Goodman RP, Garber JJ, Masia R, Diagacomo E, Adams D, King KR, Piaker S, Reinecker HC, Yarmush ML, Argemi J, Bataller R, Dienstag JL, Chung RT, Patel SJ.
Proc Natl Acad Sci U S A. 2020 May 26;117(21):11667-11673. doi: 10.1073/pnas.1911870117. Epub 2020 May 11.
PMID: 32393626 Free PMC article.
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