显示样式:     当前期刊: PNAS    加入关注       排序: 导出
我的关注
我的收藏
您暂时未登录!
登录
  • Urban isolation and daytime neighborhood social composition from Twitter data [Letters (Online Only)]
    PNAS (IF 9.504) Pub Date : 2018-12-07
    Julie Vallée

    In a recent paper in PNAS, Wang et al. (1) investigate the key question of urban isolation in light of daily mobility. Urban isolation may actually be mitigated by individuals spending much of their everyday lives in neighborhoods where social composition and urban opportunities widely diverge from their home neighborhoods. From a large dataset composed of 128 million geotagged micromessages called tweets, sent by 392,000 Twitter users living in the 50 most populous American cities, the authors overcome the pervasive spatial assumption that social interactions are limited to home neighborhoods. However, they made one temporal assumption that merits further discussion. They classified neighborhoods into …

    更新日期:2018-12-08
  • Reply to Vallee: Different questions for different data [Letters (Online Only)]
    PNAS (IF 9.504) Pub Date : 2018-12-07
    Qi Wang, Nolan Edward Phillips, Mario L. Small, Robert J. Sampson

    Vallée (1) argues that “daily changes in neighborhood social composition” should be taken into account when analyzing social isolation. We agree that changes in neighborhoods’ compositions are important and have been largely omitted from research on neighborhood effects and activity spaces. We take this opportunity to clarify an issue and offer a commentary.

    更新日期:2018-12-08
  • Improving vaccines against Streptococcus pneumoniae using synthetic glycans [Medical Sciences]
    PNAS (IF 9.504) Pub Date : 2018-12-07
    Paulina Kaplonek, Naeem Khan, Katrin Reppe, Benjamin Schumann, Madhu Emmadi, Marilda P. Lisboa, Fei-Fei Xu, Adam D. J. Calow, Sharavathi G. Parameswarappa, Martin Witzenrath, Claney L. Pereira, Peter H. Seeberger

    Streptococcus pneumoniae remains a deadly disease in small children and the elderly even though conjugate and polysaccharide vaccines based on isolated capsular polysaccharides (CPS) are successful. The most common serotypes that cause infection are used in vaccines around the world, but differences in geographic and demographic serotype distribution compromises protection by leading vaccines. The medicinal chemistry approach to glycoconjugate vaccine development has helped to improve the stability and immunogenicity of synthetic vaccine candidates for several serotypes leading to the induction of higher levels of specific protective antibodies. Here, we show that marketed CPS-based glycoconjugate vaccines can be improved by adding synthetic glycoconjugates representing serotypes that are not covered by existing vaccines. Combination (coformulation) of synthetic glycoconjugates with the licensed vaccines Prevnar13 (13-valent) and Synflorix (10-valent) yields improved 15- and 13-valent conjugate vaccines, respectively, in rabbits. A pentavalent semisynthetic glycoconjugate vaccine containing five serotype antigens (sPCV5) elicits antibodies with strong in vitro opsonophagocytic activity. This study illustrates that synthetic oligosaccharides can be used in coformulation with both isolated polysaccharide glycoconjugates to expand protection from existing vaccines and each other to produce precisely defined multivalent conjugated vaccines.

    更新日期:2018-12-08
  • Fluctuating selection on migrant adaptive sodium transporter alleles in coastal Arabidopsis thaliana [Plant Biology]
    PNAS (IF 9.504) Pub Date : 2018-12-07
    Silvia Busoms, Pirita Paajanen, Sarah Marburger, Sian Bray, Xin-Yuan Huang, Charlotte Poschenrieder, Levi Yant, David E. Salt

    Stressors such as soil salinity and dehydration are major constraints on plant growth, causing worldwide crop losses. Compounding these insults, increasing climate volatility requires adaptation to fluctuating conditions. Salinity stress responses are relatively well understood in Arabidopsis thaliana, making this system suited for the rapid molecular dissection of evolutionary mechanisms. In a large-scale genomic analysis of Catalonian A. thaliana, we resequenced 77 individuals from multiple salinity gradients along the coast and integrated these data with 1,135 worldwide A. thaliana genomes for a detailed understanding of the demographic and evolutionary dynamics of naturally evolved salinity tolerance. This revealed that Catalonian varieties adapted to highly fluctuating soil salinity are not Iberian relicts but instead have immigrated to this region more recently. De novo genome assembly of three allelic variants of the high-affinity K+ transporter (HKT1;1) locus resolved structural variation between functionally distinct alleles undergoing fluctuating selection in response to seasonal changes in soil salinity. Plants harboring alleles responsible for low root expression of HKT1;1 and consequently high leaf sodium (HKT1;1HLS) were migrants that have moved specifically into areas where soil sodium levels fluctuate widely due to geography and rainfall variation. We demonstrate that the proportion of plants harboring HKT1;1HLS alleles correlates with soil sodium level over time, HKT1;1HLS-harboring plants are better adapted to intermediate levels of salinity, and the HKT1;1HLS allele clusters with high-sodium accumulator accessions worldwide. Together, our evidence suggests that HKT1;1 is under fluctuating selection in response to climate volatility and is a worldwide determinant in adaptation to saline conditions.

    更新日期:2018-12-08
  • Malleable folding of coiled-coils regulates kinesin-3 dimerization [Commentaries]
    PNAS (IF 9.504) Pub Date : 2018-12-07
    Jawdat Al-Bassam, Stanley Nithianantham

    Microtubules (MTs) form polarized intracellular fibers inside eukaryotic cells that organize the cytoplasm, form tracks for long-range vesicle transport, and generate forces to align and segregate chromosomes during cell division. The discovery of conventional kinesin (termed kinesin-1) over three decades ago revealed a vast superfamily dedicated to transporting a variety of intracellular cargos or generating forces in a variety of cellular functions (1). Kinesins are now organized into 14 subfamilies which share class-conserved motor domains that promote directional motility or MT dynamic polymerization/depolymerization by adenosine 3,5 triphosphate (ATP) hydrolysis-driven cyclical binding and release from the MT lattice (2, 3). The majority of kinesin subfamilies oligomerize into dimers or tetramers via coiled-coil folding of an α-helical region named the neck coil (NC), which lies in close proximity to the motor domain (4, 5). The NC dimerizes motor domains and couples their conformational changes driven by ATP hydrolysis via a connecting element termed the neck linkers (NLs) (6). Kinesins utilize these elements to couple dual-motor domains to undertake alternating steps in a persistent hand-over-hand walking mechanism along MTs (7). In the kinesin-1 subfamily, cargo-binding domains located at the opposite end of the polypeptide directly inhibit the motor domains to prevent wasteful motility and ATP hydrolysis in the absence of cargo (8).

    更新日期:2018-12-08
  • Approaching the adiabatic timescale with machine learning [Physics]
    PNAS (IF 9.504) Pub Date : 2018-12-07
    Bryce M. Henson, Dong K. Shin, Kieran F. Thomas, Jacob A. Ross, Michael R. Hush, Sean S. Hodgman, Andrew G. Truscott

    The control and manipulation of quantum systems without excitation are challenging, due to the complexities in fully modeling such systems accurately and the difficulties in controlling these inherently fragile systems experimentally. For example, while protocols to decompress Bose–Einstein condensates (BECs) faster than the adiabatic timescale (without excitation or loss) have been well developed theoretically, experimental implementations of these protocols have yet to reach speeds faster than the adiabatic timescale. In this work, we experimentally demonstrate an alternative approach based on a machine-learning algorithm which makes progress toward this goal. The algorithm is given control of the coupled decompression and transport of a metastable helium condensate, with its performance determined after each experimental iteration by measuring the excitations of the resultant BEC. After each iteration the algorithm adjusts its internal model of the system to create an improved control output for the next iteration. Given sufficient control over the decompression, the algorithm converges to a solution that sets the current speed record in relation to the adiabatic timescale, beating out other experimental realizations based on theoretical approaches. This method presents a feasible approach for implementing fast-state preparations or transformations in other quantum systems, without requiring a solution to a theoretical model of the system. Implications for fundamental physics and cooling are discussed.

    更新日期:2018-12-08
  • Combined molecular dynamics and neural network method for predicting protein antifreeze activity [Biophysics and Computational Biology]
    PNAS (IF 9.504) Pub Date : 2018-12-07
    Daniel J. Kozuch, Frank H. Stillinger, Pablo G. Debenedetti

    Antifreeze proteins (AFPs) are a diverse class of proteins that depress the kinetically observable freezing point of water. AFPs have been of scientific interest for decades, but the lack of an accurate model for predicting AFP activity has hindered the logical design of novel antifreeze systems. To address this, we perform molecular dynamics simulation for a collection of well-studied AFPs. By analyzing both the dynamic behavior of water near the protein surface and the geometric structure of the protein, we introduce a method that automatically detects the ice binding face of AFPs. From these data, we construct a simple neural network that is capable of quantitatively predicting experimentally observed thermal hysteresis from a trio of relevant physical variables. The model’s accuracy is tested against data for 17 known AFPs and 5 non-AFP controls.

    更新日期:2018-12-08
  • MTSS1/Src family kinase dysregulation underlies multiple inherited ataxias [Neuroscience]
    PNAS (IF 9.504) Pub Date : 2018-12-07
    Alexander S. Brown, Pratap Meera, Banu Altindag, Ravi Chopra, Emma M. Perkins, Sharan Paul, Daniel R. Scoles, Eric Tarapore, Jessica Magri, Haoran Huang, Mandy Jackson, Vikram G. Shakkottai, Thomas S. Otis, Stefan M. Pulst, Scott X. Atwood, Anthony E. Oro

    The genetically heterogeneous spinocerebellar ataxias (SCAs) are caused by Purkinje neuron dysfunction and degeneration, but their underlying pathological mechanisms remain elusive. The Src family of nonreceptor tyrosine kinases (SFK) are essential for nervous system homeostasis and are increasingly implicated in degenerative disease. Here we reveal that the SFK suppressor Missing-in-metastasis (MTSS1) is an ataxia locus that links multiple SCAs. MTSS1 loss results in increased SFK activity, reduced Purkinje neuron arborization, and low basal firing rates, followed by cell death. Surprisingly, mouse models for SCA1, SCA2, and SCA5 show elevated SFK activity, with SCA1 and SCA2 displaying dramatically reduced MTSS1 protein levels through reduced gene expression and protein translation, respectively. Treatment of each SCA model with a clinically approved Src inhibitor corrects Purkinje neuron basal firing and delays ataxia progression in MTSS1 mutants. Our results identify a common SCA therapeutic target and demonstrate a key role for MTSS1/SFK in Purkinje neuron survival and ataxia progression.

    更新日期:2018-12-08
  • Virus-inclusive single-cell RNA sequencing reveals the molecular signature of progression to severe dengue [Medical Sciences]
    PNAS (IF 9.504) Pub Date : 2018-12-07
    Fabio Zanini, Makeda L. Robinson, Derek Croote, Malaya Kumar Sahoo, Ana Maria Sanz, Eliana Ortiz-Lasso, Ludwig Luis Albornoz, Fernando Rosso, Jose G. Montoya, Leslie Goo, Benjamin A. Pinsky, Stephen R. Quake, Shirit Einav

    Dengue virus (DENV) infection can result in severe complications. However, the understanding of the molecular correlates of severity is limited, partly due to difficulties in defining the peripheral blood mononuclear cells (PBMCs) that contain DENV RNA in vivo. Accordingly, there are currently no biomarkers predictive of progression to severe dengue (SD). Bulk transcriptomics data are difficult to interpret because blood consists of multiple cell types that may react differently to infection. Here, we applied virus-inclusive single-cell RNA-seq approach (viscRNA-Seq) to profile transcriptomes of thousands of single PBMCs derived early in the course of disease from six dengue patients and four healthy controls and to characterize distinct leukocyte subtypes that harbor viral RNA (vRNA). Multiple IFN response genes, particularly MX2 in naive B cells and CD163 in CD14+ CD16+ monocytes, were up-regulated in a cell-specific manner before progression to SD. The majority of vRNA-containing cells in the blood of two patients who progressed to SD were naive IgM B cells expressing the CD69 and CXCR4 receptors and various antiviral genes, followed by monocytes. Bystander, non-vRNA–containing B cells also demonstrated immune activation, and IgG1 plasmablasts from two patients exhibited clonal expansions. Lastly, assembly of the DENV genome sequence revealed diversity at unexpected sites. This study presents a multifaceted molecular elucidation of natural dengue infection in humans with implications for any tissue and viral infection and proposes candidate biomarkers for prediction of SD.

    更新日期:2018-12-08
  • Rethinking pneumonia: A paradigm shift with practical utility [Commentaries]
    PNAS (IF 9.504) Pub Date : 2018-12-07
    Rishi Chanderraj, Robert P. Dickson

    We associate the founders of germ theory, Louis Pasteur and Robert Koch, with a dusty, bygone age: gray beards, sepia tones, and antiquated techniques. However, in their own time, both Pasteur and Koch were what we would now call “early adopters,” embracing and advancing the leading edge of available technology in their efforts to identify microbes. Among his many innovations, Pasteur invented anaerobic cultivation and derived a variety of selective culture media. Koch pioneered the use of solid growth media, developed the techniques of pure culture to isolate individual species, and was the first to apply oil-immersion microscopy to respiratory specimens. [Rudolph Virchow, then the revered “Pope of Medicine,” was an old-guard skeptic. When presented with Koch’s oil-immersion discoveries, he scoffed that “What I can not see with my dry lens, I do not need to see” (1).] Though rightfully celebrated for their own scientific genius, both Pasteur and Koch were beneficiaries of recent advances in technology and both propelled their field forward with their own methodological innovations.

    更新日期:2018-12-08
  • Role of gene body methylation in acclimatization and adaptation in a basal metazoan [Genetics]
    PNAS (IF 9.504) Pub Date : 2018-12-07
    Groves Dixon, Yi Liao, Line K. Bay, Mikhail V. Matz

    Gene body methylation (GBM) has been hypothesized to modulate responses to environmental change, including transgenerational plasticity, but the evidence thus far has been lacking. Here we show that coral fragments reciprocally transplanted between two distant reefs respond predominantly by increase or decrease in genome-wide GBM disparity: The range of methylation levels between lowly and highly methylated genes becomes either wider or narrower. Remarkably, at a broad functional level this simple adjustment correlated very well with gene expression change, reflecting a shifting balance between expressions of environmentally responsive and housekeeping genes. In our experiment, corals in a lower-quality habitat up-regulated genes involved in environmental responses, while corals in a higher-quality habitat invested more in housekeeping genes. Transplanted fragments showing closer GBM match to local corals attained higher fitness characteristics, which supports GBM’s role in acclimatization. Fixed differences in GBM between populations did not align with plastic GBM changes and were mostly observed in genes with elevated FST, which suggests that they arose predominantly through genetic divergence. However, we cannot completely rule out transgenerational inheritance of acquired GBM states.

    更新日期:2018-12-08
  • Profiling proliferative cells and their progeny in damaged murine hearts [Cell Biology]
    PNAS (IF 9.504) Pub Date : 2018-12-07
    Kai Kretzschmar, Yorick Post, Marie Bannier-Hélaouët, Andrea Mattiotti, Jarno Drost, Onur Basak, Vivian S. W. Li, Maaike van den Born, Quinn D. Gunst, Danielle Versteeg, Lieneke Kooijman, Stefan van der Elst, Johan H. van Es, Eva van Rooij, Maurice J. B. van den Hoff, Hans Clevers

    The significance of cardiac stem cell (CSC) populations for cardiac regeneration remains disputed. Here, we apply the most direct definition of stem cell function (the ability to replace lost tissue through cell division) to interrogate the existence of CSCs. By single-cell mRNA sequencing and genetic lineage tracing using two Ki67 knockin mouse models, we map all proliferating cells and their progeny in homoeostatic and regenerating murine hearts. Cycling cardiomyocytes were only robustly observed in the early postnatal growth phase, while cycling cells in homoeostatic and damaged adult myocardium represented various noncardiomyocyte cell types. Proliferative postdamage fibroblasts expressing follistatin-like protein 1 (FSTL1) closely resemble neonatal cardiac fibroblasts and form the fibrotic scar. Genetic deletion of Fstl1 in cardiac fibroblasts results in postdamage cardiac rupture. We find no evidence for the existence of a quiescent CSC population, for transdifferentiation of other cell types toward cardiomyocytes, or for proliferation of significant numbers of cardiomyocytes in response to cardiac injury.

    更新日期:2018-12-08
  • Modulation of HIF-2{alpha} PAS-B domain contributes to physiological responses [Biochemistry]
    PNAS (IF 9.504) Pub Date : 2018-12-06
    Zhihui Feng, Xuan Zou, Yaomin Chen, Hanzhi Wang, Yingli Duan, Richard K. Bruick

    Hypoxia-inducible factors (HIFs) are transcription factors in the basic helix–loop–helix PER-ARNT-SIM (bHLH-PAS) protein family that contain internal hydrophobic cavities within their PAS-A and PAS-B domains. Among HIFs, the HIF-2α PAS-B domain contains a relatively large cavity exploited for the development of specific artificial ligands such as PT2399. Administration of PT2399 could suppress HIF-2α target gene expression without affecting HIF-1 activity in mice under hypoxia conditions. A single mutation (S305M) within the HIF-2α PAS-B domain suppressed HIF-2α activity while conferring resistance to PT2399 in vivo, indicating the vital role of PAS-B domain in HIF-2α hypoxia response. In contrast, the mutant mice did not phenocopy PT2399 intervention in wild-type mice under metabolic stress. Under a high-fat diet (HFD), the mutant mice exert enhanced adipogenesis and obtain larger adipose mass and body weight gain compared to wild type. However, administration of PT2399 along with HFD feeding sufficiently suppressed HFD-induced body weight and adipose mass increase through suppression of adipogenesis and lipogenesis. The accompanying decreased lipid accumulation in the liver and improved glucose tolerance in wild-type mice were not observed in the mutant mice indicating negative regulation of HIF-2α on obesity and a complex role for the PAS-B domain in metabolic regulation. Notably, short-term administration of PT2399 to obese mice decreased adipose mass and improved metabolic condition. These results indicate a regulatory role for HIF-2α in obesity progression and suggest a therapeutic opportunity for PT2399 in obesity and associated metabolic disorders.

    更新日期:2018-12-07
  • Persistence of false paradigms in low-power sciences [Social Sciences]
    PNAS (IF 9.504) Pub Date : 2018-12-06
    George A. Akerlof, Pascal Michaillat

    We develop a model describing how false paradigms may persist, hindering scientific progress. The model features two paradigms, one describing reality better than the other. Tenured scientists display homophily: They favor tenure candidates who adhere to their paradigm. As in statistics, power is the probability (absent any bias) of denying tenure to scientists adhering to the false paradigm. The model shows that because of homophily, when power is low, the false paradigm may prevail. Then, only an increase in power can ignite convergence to the true paradigm. Historical case studies suggest that low power comes either from lack of empirical evidence or from reluctance to base tenure decisions on available evidence.

    更新日期:2018-12-07
  • Quantitative conformational profiling of kinase inhibitors reveals origins of selectivity for Aurora kinase activation states [Biochemistry]
    PNAS (IF 9.504) Pub Date : 2018-12-05
    Eric W. Lake, Joseph M. Muretta, Andrew R. Thompson, Damien M. Rasmussen, Abir Majumdar, Erik B. Faber, Emily F. Ruff, David D. Thomas, Nicholas M. Levinson

    Protein kinases undergo large-scale structural changes that tightly regulate function and control recognition by small-molecule inhibitors. Methods for quantifying the conformational effects of inhibitors and linking them to an understanding of selectivity patterns have long been elusive. We have developed an ultrafast time-resolved fluorescence methodology that tracks structural movements of the kinase activation loop in solution with angstrom-level precision, and can resolve multiple structural states and quantify conformational shifts between states. Profiling a panel of clinically relevant Aurora kinase inhibitors against the mitotic kinase Aurora A revealed a wide range of conformational preferences, with all inhibitors promoting either the active DFG-in state or the inactive DFG-out state, but to widely differing extents. Remarkably, these conformational preferences explain broad patterns of inhibitor selectivity across different activation states of Aurora A, with DFG-out inhibitors preferentially binding Aurora A activated by phosphorylation on the activation loop, which dynamically samples the DFG-out state, and DFG-in inhibitors binding preferentially to Aurora A constrained in the DFG-in state by its allosteric activator Tpx2. The results suggest that many inhibitors currently in clinical development may be capable of differentiating between Aurora A signaling pathways implicated in normal mitotic control and in melanoma, neuroblastoma, and prostate cancer. The technology is applicable to a wide range of clinically important kinases and could provide a wealth of valuable structure–activity information for the development of inhibitors that exploit differences in conformational dynamics to achieve enhanced selectivity.

    更新日期:2018-12-06
  • Calditol-linked membrane lipids are required for acid tolerance in Sulfolobus acidocaldarius [Microbiology]
    PNAS (IF 9.504) Pub Date : 2018-12-05
    Zhirui Zeng, Xiao-Lei Liu, Jeremy H. Wei, Roger E. Summons, Paula V. Welander

    Archaea have many unique physiological features of which the lipid composition of their cellular membranes is the most striking. Archaeal ether-linked isoprenoidal membranes can occur as bilayers or monolayers, possess diverse polar head groups, and a multiplicity of ring structures in the isoprenoidal cores. These lipid structures are proposed to provide protection from the extreme temperature, pH, salinity, and nutrient-starved conditions that many archaea inhabit. However, many questions remain regarding the synthesis and physiological role of some of the more complex archaeal lipids. In this study, we identify a radical S-adenosylmethionine (SAM) protein in Sulfolobus acidocaldarius required for the synthesis of a unique cyclopentyl head group, known as calditol. Calditol-linked glycerol dibiphytanyl glycerol tetraethers (GDGTs) are membrane spanning lipids in which calditol is ether bonded to the glycerol backbone and whose production is restricted to a subset of thermoacidophilic archaea of the Sulfolobales order within the Crenarchaeota phylum. Several studies have focused on the enzymatic mechanism for the synthesis of the calditol moiety, but to date no protein that catalyzes this reaction has been discovered. Phylogenetic analyses of this putative calditol synthase (Cds) reveal the genetic potential for calditol–GDGT synthesis in phyla other than the Crenarchaeota, including the Korarchaeota and Marsarchaeota. In addition, we identify Cds homologs in metagenomes predominantly from acidic ecosystems. Finally, we demonstrate that deletion of calditol synthesis renders S. acidocaldarius sensitive to extremely low pH, indicating that calditol plays a critical role in protecting archaeal cells from acidic stress.

    更新日期:2018-12-06
  • Fenestrations control resting-state block of a voltage-gated sodium channel [Biophysics and Computational Biology]
    PNAS (IF 9.504) Pub Date : 2018-12-05
    Tamer M. Gamal El-Din, Michael J. Lenaeus, Ning Zheng, William A. Catterall

    Potency of drug action is usually determined by binding to a specific receptor site on target proteins. In contrast to this conventional paradigm, we show here that potency of local anesthetics (LAs) and antiarrhythmic drugs (AADs) that block sodium channels is controlled by fenestrations that allow drug access to the receptor site directly from the membrane phase. Voltage-gated sodium channels initiate action potentials in nerve and cardiac muscle, where their hyperactivity causes pain and cardiac arrhythmia, respectively. LAs and AADs selectively block sodium channels in rapidly firing nerve and muscle cells to relieve these conditions. The structure of the ancestral bacterial sodium channel NaVAb, which is also blocked by LAs and AADs, revealed fenestrations connecting the lipid phase of the membrane to the central cavity of the pore. We cocrystallized lidocaine and flecainide with NavAb, which revealed strong drug-dependent electron density in the central cavity of the pore. Mutation of the contact residue T206 greatly reduced drug potency, confirming this site as the receptor for LAs and AADs. Strikingly, mutations of the fenestration cap residue F203 changed fenestration size and had graded effects on resting-state block by flecainide, lidocaine, and benzocaine, the potencies of which were altered from 51- to 2.6-fold in order of their molecular size. These results show that conserved fenestrations in the pores of sodium channels are crucial pharmacologically and determine the level of resting-state block by widely used drugs. Fine-tuning drug access through fenestrations provides an unexpected avenue for structure-based design of ion-channel–blocking drugs.

    更新日期:2018-12-06
  • Hybrid prevalence estimation: Method to improve intervention coverage estimations [Medical Sciences]
    PNAS (IF 9.504) Pub Date : 2018-12-05
    Caroline Jeffery, Marcello Pagano, Janet Hemingway, Joseph J. Valadez

    Delivering excellent health services requires accurate health information systems (HIS) data. Poor-quality data can lead to poor judgments and outcomes. Unlike probability surveys, which are representative of the population and carry accuracy estimates, HIS do not, but in many countries the HIS is the primary source of data used for administrative estimates. However, HIS are not structured to detect gaps in service coverage and leave communities exposed to unnecessary health risks. Here we propose a method to improve informatics by combining HIS and probability survey data to construct a hybrid estimator. This technique provides a more accurate estimator than either data source alone and facilitates informed decision-making. We use data from vitamin A and polio vaccination campaigns in children from Madagascar and Benin to demonstrate the effect. The hybrid estimator is a weighted average of two measurements and produces SEs and 95% confidence intervals (CIs) for the hybrid and HIS estimators. The estimates of coverage proportions using the combined data and the survey estimates differ by no more than 3%, while decreasing the SE by 1–6%; the administrative estimates from the HIS and combined data estimates are very different, with 3–25 times larger CI, questioning the value of administrative estimates. Estimators of unknown accuracy may lead to poorly formulated policies and wasted resources. The hybrid estimator technique can be applied to disease prevention services for which population coverages are measured. This methodology creates more accurate estimators, alongside measured HIS errors, to improve tracking the public’s health.

    更新日期:2018-12-06
  • VIPER is a genetically encoded peptide tag for fluorescence and electron microscopy [Chemistry]
    PNAS (IF 9.504) Pub Date : 2018-12-05
    Julia K. Doh, Jonathan D. White, Hannah K. Zane, Young Hwan Chang, Claudia S. López, Caroline A. Enns, Kimberly E. Beatty

    Many discoveries in cell biology rely on making specific proteins visible within their native cellular environment. There are various genetically encoded tags, such as fluorescent proteins, developed for fluorescence microscopy (FM). However, there are almost no genetically encoded tags that enable cellular proteins to be observed by both FM and electron microscopy (EM). Herein, we describe a technology for labeling proteins with diverse chemical reporters, including bright organic fluorophores for FM and electron-dense nanoparticles for EM. Our technology uses versatile interacting peptide (VIP) tags, a class of genetically encoded tag. We present VIPER, which consists of a coiled-coil heterodimer formed between the genetic tag, CoilE, and a probe-labeled peptide, CoilR. Using confocal FM, we demonstrate that VIPER can be used to highlight subcellular structures or to image receptor-mediated iron uptake. Additionally, we used VIPER to image the iron uptake machinery by correlative light and EM (CLEM). VIPER compared favorably with immunolabeling for imaging proteins by CLEM, and is an enabling technology for protein targets that cannot be immunolabeled. VIPER is a versatile peptide tag that can be used to label and track proteins with diverse chemical reporters observable by both FM and EM instrumentation.

    更新日期:2018-12-06
  • Dengue type 1 viruses circulating in humans are highly infectious and poorly neutralized by human antibodies [Microbiology]
    PNAS (IF 9.504) Pub Date : 2018-12-05
    Rajendra Raut, Kizzmekia S. Corbett, Rashika N. Tennekoon, Sunil Premawansa, Ananda Wijewickrama, Gayani Premawansa, Piotr Mieczkowski, Claudia Rückert, Gregory D. Ebel, Aruna D. De Silva, Aravinda M. de Silva

    The four dengue virus (DENV) serotypes are mosquito-borne flaviviruses of humans. The interactions between DENVs and the human host that lead to asymptomatic, mild, or severe disease are poorly understood, in part, because laboratory models are poor surrogates for human DENV disease. Virologists are interested in how the properties of DENVs replicating in people compare with virions propagated on laboratory cell lines, which are widely used for research and vaccine development. Using clinical samples from a DENV type 1 epidemic in Sri Lanka and new ultrasensitive assays, we compared the properties of DENVs in human plasma and after one passage on laboratory cell lines. DENVs in plasma were 50- to 700-fold more infectious than cell culture-grown viruses. DENVs produced by laboratory cell lines were structurally immature and hypersensitive to neutralization by human antibodies compared with DENVs circulating in people. Human plasma and cell culture-derived virions had identical genome sequences, indicating that these phenotypic differences were due to the mature state of plasma virions. Several dengue vaccines are under development. Recent studies indicate that vaccine-induced antibodies that neutralized DENVs in cell culture assays were not sufficient for protecting people from DENV infections. Our results about structural differences between DENVs produced in humans versus cell lines may be key to understanding vaccine failure and developing better models for vaccine evaluation.

    更新日期:2018-12-06
  • Correction to Supporting Information for Nobori et al., Transcriptome landscape of a bacterial pathogen under plant immunity [SI Corrections]
    PNAS (IF 9.504) Pub Date : 2018-12-04
    National Academy of Sciences

    PLANT BIOLOGY Correction to Supporting Information for “Transcriptome landscape of a bacterial pathogen under plant …

    更新日期:2018-12-05
  • Correction to Supporting Information for Kwon et al., Coiled-coil structure-dependent interactions between polyQ proteins and Foxo lead to dendrite pathology and behavioral defects [SI Corrections]
    PNAS (IF 9.504) Pub Date : 2018-12-04
    National Academy of Sciences

    NEUROSCIENCE Correction to Supporting Information for “Coiled-coil structure-dependent interactions between polyQ proteins and Foxo lead to dendrite pathology and behavioral defects,” by Min Jee Kwon, Myeong Hoon Han, Joshua A. Bagley, Do Young Hyeon, Byung Su …

    更新日期:2018-12-05
  • Correction to Supporting Information for Alix-Garcia et al., Payments for environmental services supported social capital while increasing land management [SI Corrections]
    PNAS (IF 9.504) Pub Date : 2018-12-04
    National Academy of Sciences

    SUSTAINABILITY SCIENCE Correction to Supporting Information for “Payments for environmental services supported social capital while increasing land management,” by Jennifer M. Alix-Garcia, Katharine R. E. Sims, Victor H. Orozco-Olvera, Laura E. Costica, Jorge David Fernández Medina, and Sofía Romo Monroy, which was first published June 14, 2018; 10.1073/pnas.1720873115 (Proc Natl …

    更新日期:2018-12-05
  • Correction for Benej et al., Papaverine and its derivatives radiosensitize solid tumors by inhibiting mitochondrial metabolism [Corrections]
    PNAS (IF 9.504) Pub Date : 2018-12-04
    National Academy of Sciences

    MEDICAL SCIENCES Correction for “Papaverine and its derivatives radiosensitize solid tumors by inhibiting mitochondrial metabolism,” by Martin Benej, Xiangqian Hong, Sandip Vibhute, Sabina Scott, Jinghai …

    更新日期:2018-12-05
  • Opinion: Flood-risk reduction: Structural measures and diverse strategies [Sustainability Science]
    PNAS (IF 9.504) Pub Date : 2018-12-04
    Z. W. Kundzewicz, D. L. T. Hegger, P. Matczak, P. P. J. Driessen

    Floods continue to hit many countries, both less developed and industrialized, bringing human suffering and immense economic damage (see floodobservatory.colorado.edu/). Hurricane Florence and Typhoon Mangkhut were just the most recent reminders of the disruption that flooding can bring. Hence, striving to improve the flood-risk governance system has broad relevance. Yet, the reduction of flood risk, understood globally as a combination of hazard, exposure, and vulnerability, is a rather distant goal (Fig. 1).

    更新日期:2018-12-05
  • Generalizability of heterogeneous treatment effect estimates across samples [Social Sciences]
    PNAS (IF 9.504) Pub Date : 2018-12-04
    Alexander Coppock, Thomas J. Leeper, Kevin J. Mullinix

    The extent to which survey experiments conducted with nonrepresentative convenience samples are generalizable to target populations depends critically on the degree of treatment effect heterogeneity. Recent inquiries have found a strong correspondence between sample average treatment effects estimated in nationally representative experiments and in replication studies conducted with convenience samples. We consider here two possible explanations: low levels of effect heterogeneity or high levels of effect heterogeneity that are unrelated to selection into the convenience sample. We analyze subgroup conditional average treatment effects using 27 original–replication study pairs (encompassing 101,745 individual survey responses) to assess the extent to which subgroup effect estimates generalize. While there are exceptions, the overwhelming pattern that emerges is one of treatment effect homogeneity, providing a partial explanation for strong correspondence across both unconditional and conditional average treatment effect estimates.

    更新日期:2018-12-05
  • Arc/Arg3.1 mediates a critical period for spatial learning and hippocampal networks [Neuroscience]
    PNAS (IF 9.504) Pub Date : 2018-12-04
    Xiaoyan Gao, Sergio Castro-Gomez, Jasper Grendel, Sabine Graf, Ute Süsens, Lars Binkle, Daniel Mensching, Dirk Isbrandt, Dietmar Kuhl, Ora Ohana

    During early postnatal development, sensory regions of the brain undergo periods of heightened plasticity which sculpt neural networks and lay the foundation for adult sensory perception. Such critical periods were also postulated for learning and memory but remain elusive and poorly understood. Here, we present evidence that the activity-regulated and memory-linked gene Arc/Arg3.1 is transiently up-regulated in the hippocampus during the first postnatal month. Conditional removal of Arc/Arg3.1 during this period permanently alters hippocampal oscillations and diminishes spatial learning capacity throughout adulthood. In contrast, post developmental removal of Arc/Arg3.1 leaves learning and network activity patterns intact. Long-term memory storage continues to rely on Arc/Arg3.1 expression throughout life. These results demonstrate that Arc/Arg3.1 mediates a critical period for spatial learning, during which Arc/Arg3.1 fosters maturation of hippocampal network activity necessary for future learning and memory storage.

    更新日期:2018-12-05
  • Acyl-CoA synthetase 6 enriches the neuroprotective omega-3 fatty acid DHA in the brain [Neuroscience]
    PNAS (IF 9.504) Pub Date : 2018-12-04
    Regina F. Fernandez, Sora Q. Kim, Yingwei Zhao, Rachel M. Foguth, Marcus M. Weera, Jessica L. Counihan, Daniel K. Nomura, Julia A. Chester, Jason R. Cannon, Jessica M. Ellis

    Docosahexaenoic acid (DHA) is an omega-3 fatty acid that is highly abundant in the brain and confers protection against numerous neurological diseases, yet the fundamental mechanisms regulating the enrichment of DHA in the brain remain unknown. Here, we have discovered that a member of the long-chain acyl-CoA synthetase family, Acsl6, is required for the enrichment of DHA in the brain by generating an Acsl6-deficient mouse (Acsl6−/−). Acsl6 is highly enriched in the brain and lipid profiling of Acsl6−/− tissues reveals consistent reductions in DHA-containing lipids in tissues highly abundant with Acsl6. Acsl6−/− mice demonstrate motor impairments, altered glutamate metabolism, and increased astrogliosis and microglia activation. In response to a neuroinflammatory lipopolysaccharide injection, Acsl6−/− brains show similar increases in molecular and pathological indices of astrogliosis compared with controls. These data demonstrate that Acsl6 is a key mediator of neuroprotective DHA enrichment in the brain.

    更新日期:2018-12-05
  • The Pseudomonas aeruginosa T6SS-VgrG1b spike is topped by a PAAR protein eliciting DNA damage to bacterial competitors [Microbiology]
    PNAS (IF 9.504) Pub Date : 2018-12-04
    Panayiota Pissaridou, Luke P. Allsopp, Sarah Wettstadt, Sophie A. Howard, Despoina A. I. Mavridou, Alain Filloux

    The type VI secretion system (T6SS) is a supramolecular complex involved in the delivery of potent toxins during bacterial competition. Pseudomonas aeruginosa possesses three T6SS gene clusters and several hcp and vgrG gene islands, the latter encoding the spike at the T6SS tip. The vgrG1b cluster encompasses seven genes whose organization and sequences are highly conserved in P. aeruginosa genomes, except for two genes that we called tse7 and tsi7. We show that Tse7 is a Tox-GHH2 domain nuclease which is distinct from other T6SS nucleases identified thus far. Expression of this toxin induces the SOS response, causes growth arrest and ultimately results in DNA degradation. The cytotoxic domain of Tse7 lies at its C terminus, while the N terminus is a predicted PAAR domain. We find that Tse7 sits on the tip of the VgrG1b spike and that specific residues at the PAAR–VgrG1b interface are essential for VgrG1b-dependent delivery of Tse7 into bacterial prey. We also show that the delivery of Tse7 is dependent on the H1-T6SS cluster, and injection of the nuclease into bacterial competitors is deployed for interbacterial competition. Tsi7, the cognate immunity protein, protects the producer from the deleterious effect of Tse7 through a direct protein–protein interaction so specific that toxin/immunity pairs are effective only if they originate from the same P. aeruginosa isolate. Overall, our study highlights the diversity of T6SS effectors, the exquisite fitting of toxins on the tip of the T6SS, and the specificity in Tsi7-dependent protection, suggesting a role in interstrain competition.

    更新日期:2018-12-05
  • Artemisinin resistance phenotypes and K13 inheritance in a Plasmodium falciparum cross and Aotus model [Microbiology]
    PNAS (IF 9.504) Pub Date : 2018-12-04
    Juliana M. Sá, Sarah R. Kaslow, Michael A. Krause, Viviana A. Melendez-Muniz, Rebecca E. Salzman, Whitney A. Kite, Min Zhang, Roberto R. Moraes Barros, Jianbing Mu, Paul K. Han, J. Patrick Mershon, Christine E. Figan, Ramoncito L. Caleon, Rifat S. Rahman, Tyler J. Gibson, Chanaki Amaratunga, Erika P. Nishiguchi, Kimberly F. Breglio, Theresa M. Engels, Soundarapandian Velmurugan, Stacy Ricklefs, Judith Straimer, Nina F. Gnädig, Bingbing Deng, Anna Liu, Ababacar Diouf, Kazutoyo Miura, Gregory S. Tullo, Richard T. Eastman, Sumana Chakravarty, Eric R. James, Kenneth Udenze, Suzanne Li, Daniel E. Sturdevant, Robert W. Gwadz, Stephen F. Porcella, Carole A. Long, David A. Fidock, Marvin L. Thomas, Michael P. Fay, B. Kim Lee Sim, Stephen L. Hoffman, John H. Adams, Rick M. Fairhurst, Xin-zhuan Su, Thomas E. Wellems

    Concerns about malaria parasite resistance to treatment with artemisinin drugs (ARTs) have grown with findings of prolonged parasite clearance t1/2s (>5 h) and their association with mutations in Plasmodium falciparum Kelch-propeller protein K13. Here, we describe a P. falciparum laboratory cross of K13 C580Y mutant with C580 wild-type parasites to investigate ART response phenotypes in vitro and in vivo. After genotyping >400 isolated progeny, we evaluated 20 recombinants in vitro: IC50 measurements of dihydroartemisinin were at similar low nanomolar levels for C580Y- and C580-type progeny (mean ratio, 1.00; 95% CI, 0.62–1.61), whereas, in a ring-stage survival assay, the C580Y-type progeny had 19.6-fold (95% CI, 9.76–39.2) higher average counts. In splenectomized Aotus monkeys treated with three daily doses of i.v. artesunate, t1/2 calculations by three different methods yielded mean differences of 0.01 h (95% CI, −3.66 to 3.67), 0.80 h (95% CI, −0.92 to 2.53), and 2.07 h (95% CI, 0.77–3.36) between C580Y and C580 infections. Incidences of recrudescence were 57% in C580Y (4 of 7) versus 70% in C580 (7 of 10) infections (−13% difference; 95% CI, −58% to 35%). Allelic substitution of C580 in a C580Y-containing progeny clone (76H10) yielded a transformant (76H10C580Rev) that, in an infected monkey, recrudesced regularly 13 times over 500 d. Frequent recrudescences of ART-treated P. falciparum infections occur with or without K13 mutations and emphasize the need for improved partner drugs to effectively eliminate the parasites that persist through the ART component of combination therapy.

    更新日期:2018-12-05
  • Model metabolic strategy for heterotrophic bacteria in the cold ocean based on Colwellia psychrerythraea 34H [Microbiology]
    PNAS (IF 9.504) Pub Date : 2018-12-04
    Jeffrey J. Czajka, Mary H. Abernathy, Veronica T. Benites, Edward E. K. Baidoo, Jody W. Deming, Yinjie J. Tang

    Colwellia psychrerythraea 34H is a model psychrophilic bacterium found in the cold ocean—polar sediments, sea ice, and the deep sea. Although the genomes of such psychrophiles have been sequenced, their metabolic strategies at low temperature have not been quantified. We measured the metabolic fluxes and gene expression of 34H at 4 °C (the mean global-ocean temperature and a normal-growth temperature for 34H), making comparative analyses at room temperature (above its upper-growth temperature of 18 °C) and with mesophilic Escherichia coli. When grown at 4 °C, 34H utilized multiple carbon substrates without catabolite repression or overflow byproducts; its anaplerotic pathways increased flux network flexibility and enabled CO2 fixation. In glucose-only medium, the Entner–Doudoroff (ED) pathway was the primary glycolytic route; in lactate-only medium, gluconeogenesis and the glyoxylate shunt became active. In comparison, E. coli, cold stressed at 4 °C, had rapid glycolytic fluxes but no biomass synthesis. At their respective normal-growth temperatures, intracellular concentrations of TCA cycle metabolites (α-ketoglutarate, succinate, malate) were 4–17 times higher in 34H than in E. coli, while levels of energy molecules (ATP, NADH, NADPH) were 10- to 100-fold lower. Experiments with E. coli mutants supported the thermodynamic advantage of the ED pathway at cold temperature. Heat-stressed 34H at room temperature (2 hours) revealed significant down-regulation of genes associated with glycolytic enzymes and flagella, while 24 hours at room temperature caused irreversible cellular damage. We suggest that marine heterotrophic bacteria in general may rely upon simplified metabolic strategies to overcome thermodynamic constraints and thrive in the cold ocean.

    更新日期:2018-12-05
  • Roles of mucus adhesion and cohesion in cough clearance [Medical Sciences]
    PNAS (IF 9.504) Pub Date : 2018-12-04
    Brian Button, Henry P. Goodell, Eyad Atieh, Yu-Cheng Chen, Robert Williams, Siddharth Shenoy, Elijah Lackey, Nathan T. Shenkute, Li-Heng Cai, Robert G. Dennis, Richard C. Boucher, Michael Rubinstein

    Clearance of intrapulmonary mucus by the high-velocity airflow generated by cough is the major rescue clearance mechanism in subjects with mucoobstructive diseases and failed cilial-dependent mucus clearance, e.g., subjects with cystic fibrosis (CF) or chronic obstructive pulmonary disease (COPD). Previous studies have investigated the mechanical forces generated at airway surfaces by cough but have not considered the effects of mucus biophysical properties on cough efficacy. Theoretically, mucus can be cleared by cough from the lung by an adhesive failure, i.e., breaking mucus-cell surface adhesive bonds and/or by cohesive failure, i.e., directly fracturing mucus. Utilizing peel-testing technologies, mucus-epithelial surface adhesive and mucus cohesive strengths were measured. Because both mucus concentration and pH have been reported to alter mucus biophysical properties in disease, the effects of mucus concentration and pH on adhesion and cohesion were compared. Both adhesive and cohesive strengths depended on mucus concentration, but neither on physiologically relevant changes in pH nor bicarbonate concentration. Mucus from bronchial epithelial cultures and patient sputum samples exhibited similar adhesive and cohesive properties. Notably, the magnitudes of both adhesive and cohesive strength exhibited similar velocity and concentration dependencies, suggesting that viscous dissipation of energy within mucus during cough determines the efficiency of cough clearance of diseased, hyperconcentrated, mucus. Calculations of airflow-induced shear forces on airway mucus related to mucus concentration predicted substantially reduced cough clearance in small versus large airways. Studies designed to improve cough clearance in subjects with mucoobstructive diseases identified reductions of mucus concentration and viscous dissipation as key therapeutic strategies.

    更新日期:2018-12-05
  • Redox dysregulation as a link between childhood trauma and psychopathological and neurocognitive profile in patients with early psychosis [Medical Sciences]
    PNAS (IF 9.504) Pub Date : 2018-12-04
    Luis Alameda, Margot Fournier, Ines Khadimallah, Alessandra Griffa, Martine Cleusix, Raoul Jenni, Carina Ferrari, Paul Klauser, Philipp S. Baumann, Michel Cuenod, Patric Hagmann, Philippe Conus, Kim Q. Do

    Exposure to childhood trauma (CT) increases the risk for psychosis and affects the development of brain structures, possibly through oxidative stress. As oxidative stress is also linked to psychosis, it may interact with CT, leading to a more severe clinical phenotype. In 133 patients with early psychosis (EPP), we explored the relationships between CT and hippocampal, amygdala, and intracranial volume (ICV); blood antioxidant defenses [glutathione peroxidase (GPx) and thioredoxin/peroxiredoxin (Trx/Prx)]; psychopathological results; and neuropsychological results. Nonadjusted hippocampal volume correlated negatively with GPx activity in patients with CT, but not in patients without CT. In patients with CT with high GPx activity (high-GPx+CT), hippocampal volume was decreased compared with that in patients with low-GPx+CT and patients without CT, who had similar hippocampal volumes. Patients with high-GPx+CT had more severe positive and disorganized symptoms than other patients. Interestingly, Trx and oxidized Prx levels correlated negatively with GPx only in patients with low-GPx+CT. Moreover, patients with low-GPx+CT performed better than other patients on cognitive tasks. Discriminant analysis combining redox markers, hippocampal volume, clinical scores, and cognitive scores allowed for stratification of the patients into subgroups. In conclusion, traumatized EPP with high peripheral oxidation status (high-GPx activity) had smaller hippocampal volumes and more severe symptoms, while those with lower oxidation status (low-GPx activity) showed better cognition and regulation of GPx and Trx/Prx systems. These results suggest that maintained regulation of various antioxidant systems allowed for compensatory mechanisms preventing long-term neuroanatomical and clinical impacts. The redox marker profile may thus represent important biomarkers for defining treatment strategies in patients with psychosis.

    更新日期:2018-12-05
  • Targeted exon skipping of a CEP290 mutation rescues Joubert syndrome phenotypes in vitro and in a murine model [Medical Sciences]
    PNAS (IF 9.504) Pub Date : 2018-12-04
    Simon A. Ramsbottom, Elisa Molinari, Shalabh Srivastava, Flora Silberman, Charline Henry, Sumaya Alkanderi, Laura A. Devlin, Kathryn White, David H. Steel, Sophie Saunier, Colin G. Miles, John A. Sayer

    Genetic treatments of renal ciliopathies leading to cystic kidney disease would provide a real advance in current therapies. Mutations in CEP290 underlie a ciliopathy called Joubert syndrome (JBTS). Human disease phenotypes include cerebral, retinal, and renal disease, which typically progresses to end stage renal failure (ESRF) within the first two decades of life. While currently incurable, there is often a period of years between diagnosis and ESRF that provides a potential window for therapeutic intervention. By studying patient biopsies, patient-derived kidney cells, and a mouse model, we identify abnormal elongation of primary cilia as a key pathophysiological feature of CEP290-associated JBTS and show that antisense oligonucleotide (ASO)-induced splicing of the mutated exon (41, G1890*) restores protein expression in patient cells. We demonstrate that ASO-induced splicing leading to exon skipping is tolerated, resulting in correct localization of CEP290 protein to the ciliary transition zone, and restoration of normal cilia length in patient kidney cells. Using a gene trap Cep290 mouse model of JBTS, we show that systemic ASO treatment can reduce the cystic burden of diseased kidneys in vivo. These findings indicate that ASO treatment may represent a promising therapeutic approach for kidney disease in CEP290-associated ciliopathy syndromes.

    更新日期:2018-12-05
  • MARCH3 attenuates IL-1{beta}-triggered inflammation by mediating K48-linked polyubiquitination and degradation of IL-1RI [Immunology and Inflammation]
    PNAS (IF 9.504) Pub Date : 2018-12-04
    Heng Lin, Deng Gao, Ming-Ming Hu, Man Zhang, Xiao-Xia Wu, Lu Feng, Wen-Hua Xu, Qing Yang, Xuan Zhong, Jin Wei, Zhi-Sheng Xu, Hong-Xia Zhang, Ze-Min Song, Qian Zhou, Wen Ye, Ying Liu, Shu Li, Hong-Bing Shu

    The proinflammatory cytokine IL-1β plays critical roles in inflammatory and autoimmune diseases. IL-1β signaling is tightly regulated to avoid excessive inflammatory response. In this study, we identified the E3 ubiquitin ligase membrane-associated RING-CH-type finger 3 (MARCH3) as a critical negative regulator of IL-1β–triggered signaling. Overexpression of MARCH3 inhibited IL-1β–triggered activation of NF-κB as well as expression of inflammatory genes, whereas MARCH3 deficiency had the opposite effects. MARCH3-deficient mice produced higher levels of serum inflammatory cytokines and were more sensitive to inflammatory death upon IL-1β injection or Listeria monocytogenes infection. Mechanistically, MARCH3 was associated with IL-1 receptor I (IL-1RI) and mediated its K48-linked polyubiquitination at K409 and lysosomal-dependent degradation. Furthermore, IL-1β stimulation triggered dephosphorylation of MARCH3 by CDC25A and activation of its E3 ligase activity. Our findings suggest that MARCH3-mediated IL-1RI degradation is an important mechanism for attenuating IL-1β–triggered inflammatory response.

    更新日期:2018-12-05
  • Biological sex affects vaccine efficacy and protection against influenza in mice [Immunology and Inflammation]
    PNAS (IF 9.504) Pub Date : 2018-12-04
    Ashley L. Fink, Kyrra Engle, Rebecca L. Ursin, Wan-Yee Tang, Sabra L. Klein

    Biological sex affects adaptive immune responses, which could impact influenza infection and vaccine efficacy. Infection of mice with 2009 H1N1 induced antibody responses, CD4+ T cell and CD8+ T cell memory responses that were greater in females than males; both sexes, however, were equally protected against secondary challenge with an H1N1 drift variant virus. To test whether greater antibody in females is sufficient for protection against influenza, males and females were immunized with an inactivated H1N1 vaccine that induced predominantly antibody-mediated immunity. Following vaccination, females had greater antibody responses and protection against challenge with an H1N1 drift variant virus than males. Antibody derived from vaccinated females was better at protecting both naïve males and females than antibody from males, and this protection was associated with increased antibody specificity and avidity to the H1N1 virus. The expression of Tlr7 was greater in B cells from vaccinated females than males and was associated with reduced DNA methylation in the Tlr7 promoter region, higher neutralizing antibody, class switch recombination, and antibody avidity in females. Deletion of Tlr7 reduced sex differences in vaccine-induced antibody responses and protection following challenge and had a greater impact on responses in females than males. Taken together, these data illustrate that greater TLR7 activation and antibody production in females improves the efficacy of vaccination against influenza.

    更新日期:2018-12-05
  • Narrow thermal tolerance and low dispersal drive higher speciation in tropical mountains [Evolution]
    PNAS (IF 9.504) Pub Date : 2018-12-04
    Nicholas R. Polato, Brian A. Gill, Alisha A. Shah, Miranda M. Gray, Kayce L. Casner, Antoine Barthelet, Philipp W. Messer, Mark P. Simmons, Juan M. Guayasamin, Andrea C. Encalada, Boris C. Kondratieff, Alexander S. Flecker, Steven A. Thomas, Cameron K. Ghalambor, N. LeRoy Poff, W. Chris Funk, Kelly R. Zamudio

    Species richness is greatest in the tropics, and much of this diversity is concentrated in mountains. Janzen proposed that reduced seasonal temperature variation selects for narrower thermal tolerances and limited dispersal along tropical elevation gradients [Janzen DH (1967) Am Nat 101:233–249]. These locally adapted traits should, in turn, promote reproductive isolation and higher speciation rates in tropical mountains compared with temperate ones. Here, we show that tropical and temperate montane stream insects have diverged in thermal tolerance and dispersal capacity, two key traits that are drivers of isolation in montane populations. Tropical species in each of three insect clades have markedly narrower thermal tolerances and lower dispersal than temperate species, resulting in significantly greater population divergence, higher cryptic diversity, higher tropical speciation rates, and greater accumulation of species over time. Our study also indicates that tropical montane species, with narrower thermal tolerance and reduced dispersal ability, will be especially vulnerable to rapid climate change.

    更新日期:2018-12-05
  • Testing the retroelement invasion hypothesis for the emergence of the ancestral eukaryotic cell [Evolution]
    PNAS (IF 9.504) Pub Date : 2018-12-04
    Gloria Lee, Nicholas A. Sherer, Neil H. Kim, Ema Rajic, Davneet Kaur, Niko Urriola, K. Michael Martini, Chi Xue, Nigel Goldenfeld, Thomas E. Kuhlman

    Phylogenetic evidence suggests that the invasion and proliferation of retroelements, selfish mobile genetic elements that copy and paste themselves within a host genome, was one of the early evolutionary events in the emergence of eukaryotes. Here we test the effects of this event by determining the pressures retroelements exert on simple genomes. We transferred two retroelements, human LINE-1 and the bacterial group II intron Ll.LtrB, into bacteria, and find that both are functional and detrimental to growth. We find, surprisingly, that retroelement lethality and proliferation are enhanced by the ability to perform eukaryotic-like nonhomologous end-joining (NHEJ) DNA repair. We show that the only stable evolutionary consequence in simple cells is maintenance of retroelements in low numbers, suggesting how retrotransposition rates and costs in early eukaryotes could have been constrained to allow proliferation. Our results suggest that the interplay between NHEJ and retroelements may have played a fundamental and previously unappreciated role in facilitating the proliferation of retroelements, elements of which became the ancestors of the spliceosome components in eukaryotes.

    更新日期:2018-12-05
  • Diverse segments of the US public underestimate the environmental concerns of minority and low-income Americans [Environmental Sciences]
    PNAS (IF 9.504) Pub Date : 2018-12-04
    Adam R. Pearson, Jonathon P. Schuldt, Rainer Romero-Canyas, Matthew T. Ballew, Dylan Larson-Konar

    In a nationally representative survey experiment, diverse segments of the US public underestimated the environmental concerns of nonwhite and low-income Americans and misperceived them as lower than those of white and more affluent Americans. Moreover, both whites and nonwhites and higher- and lower-income respondents associated the term “environmentalist” with whites and the well-educated, suggesting that shared cultural stereotypes may drive these misperceptions. This environmental belief paradox—a tendency to misperceive groups that are among the most environmentally concerned and most vulnerable to a wide range of environmental impacts as least concerned about the environment—was largely invariant across demographic groups and also extended to the specific issue of climate change. Suggesting these beliefs are malleable, exposure to images of a racially diverse (vs. nondiverse) environmental organization in an embedded randomized experiment reduced the perceived gap between whites’ and nonwhites’ environmental concerns and strengthened associations between nonwhites and the category “environmentalists” among minority respondents. These findings suggest that stereotypes about others’ environmental attitudes may pose a barrier to broadening public engagement with environmental initiatives, particularly among populations most vulnerable to negative environmental impacts.

    更新日期:2018-12-05
  • Smoke radiocarbon measurements from Indonesian fires provide evidence for burning of millennia-aged peat [Environmental Sciences]
    PNAS (IF 9.504) Pub Date : 2018-12-04
    Elizabeth B. Wiggins, Claudia I. Czimczik, Guaciara M. Santos, Yang Chen, Xiaomei Xu, Sandra R. Holden, James T. Randerson, Charles F. Harvey, Fuu Ming Kai, Liya E. Yu

    In response to a strong El Niño, fires in Indonesia during September and October 2015 released a large amount of carbon dioxide and created a massive regional smoke cloud that severely degraded air quality in many urban centers across Southeast Asia. Although several lines of evidence indicate that peat burning was a dominant contributor to emissions in the region, El Niño-induced drought is also known to increase deforestation fires and agricultural waste burning in plantations. As a result, uncertainties remain with respect to partitioning emissions among different ecosystem and fire types. Here we measured the radiocarbon content (14C) of carbonaceous aerosol samples collected in Singapore from September 2014 through October 2015, with the aim of identifying the age and origin of fire-emitted fine particulate matter (particulate matter with an aerodynamic diameter less than or equal to 2.5 μm). The Δ14C of fire-emitted aerosol was −76 ± 51‰, corresponding to a carbon pool of combusted organic matter with a mean turnover time of 800 ± 420 y. Our observations indicated that smoke plumes reaching Singapore originated primarily from peat burning (∼85%), and not from deforestation fires or waste burning. Atmospheric transport modeling confirmed that fires in Sumatra and Borneo were dominant contributors to elevated PM2.5 in Singapore during the fire season. The mean age of the carbonaceous aerosol, which predates the Industrial Revolution, highlights the importance of improving peatland fire management during future El Niño events for meeting climate mitigation and air quality commitments.

    更新日期:2018-12-05
  • Detecting and explaining why aquifers occasionally become degraded near hydraulically fractured shale gas wells [Environmental Sciences]
    PNAS (IF 9.504) Pub Date : 2018-12-04
    Josh Woda, Tao Wen, David Oakley, David Yoxtheimer, Terry Engelder, M. Clara Castro, Susan L. Brantley

    Extensive development of shale gas has generated some concerns about environmental impacts such as the migration of natural gas into water resources. We studied high gas concentrations in waters at a site near Marcellus Shale gas wells to determine the geological explanations and geochemical implications. The local geology may explain why methane has discharged for 7 years into groundwater, a stream, and the atmosphere. Gas may migrate easily near the gas wells in this location where the Marcellus Shale dips significantly, is shallow (∼1 km), and is more fractured. Methane and ethane concentrations in local water wells increased after gas development compared with predrilling concentrations reported in the region. Noble gas and isotopic evidence are consistent with the upward migration of gas from the Marcellus Formation in a free-gas phase. This upflow results in microbially mediated oxidation near the surface. Iron concentrations also increased following the increase of natural gas concentrations in domestic water wells. After several months, both iron and SO42− concentrations dropped. These observations are attributed to iron and SO42− reduction associated with newly elevated concentrations of methane. These temporal trends, as well as data from other areas with reported leaks, document a way to distinguish newly migrated methane from preexisting sources of gas. This study thus documents both geologically risky areas and geochemical signatures of iron and SO42− that could distinguish newly leaked methane from older methane sources in aquifers.

    更新日期:2018-12-05
  • Dynamic effects of enforcement on cooperation [Economic Sciences]
    PNAS (IF 9.504) Pub Date : 2018-12-04
    Roberto Galbiati, Emeric Henry, Nicolas Jacquemet

    In situations where social payoffs are not aligned with private incentives, enforcement with fines can be a way to sustain cooperation. In this paper we show, by the means of a laboratory experiment, that past fines can have an effect on current behavior even when no longer in force. We document two mechanisms: (i) Past fines affect directly individuals’ future propensity to cooperate, and (ii) when fines for noncooperation are in place in the past, individuals experience higher levels of cooperation from partners and, consistent with indirect reciprocity motives, are in turn nicer toward others once these fines have been removed. This second mechanism is empirically prevalent and, in contrast with the first one, induces a snowball effect of past enforcement. Our results can inform the design of costly enforcement policies.

    更新日期:2018-12-05
  • Partitioning mortality into growth-dependent and growth-independent hazards across 203 tropical tree species [Ecology]
    PNAS (IF 9.504) Pub Date : 2018-12-04
    James S. Camac, Richard Condit, Richard G. FitzJohn, Lachlan McCalman, Daniel Steinberg, Mark Westoby, S. Joseph Wright, Daniel S. Falster

    Tree death drives population dynamics, nutrient cycling, and evolution within plant communities. Mortality variation across species is thought to be influenced by different factors relative to variation within species. The unified model provided here separates mortality rates into growth-dependent and growth-independent hazards. This model creates the opportunity to simultaneously estimate these hazards both across and within species. Moreover, it provides the ability to examine how species traits affect growth-dependent and growth-independent hazards. We derive this unified mortality model using cross-validated Bayesian methods coupled with mortality data collected over three census intervals for 203 tropical rainforest tree species at Barro Colorado Island (BCI), Panama. We found that growth-independent mortality tended to be higher in species with lower wood density, higher light requirements, and smaller maximum diameter at breast height (dbh). Mortality due to marginal carbon budget as measured by near-zero growth rate tended to be higher in species with lower wood density and higher light demand. The total mortality variation attributable to differences among species was large relative to variation explained by these traits, emphasizing that much remains to be understood. This additive hazards model strengthens our capacity to parse and understand individual-level mortality in highly diverse tropical forests and hence to predict its consequences.

    更新日期:2018-12-05
  • Large changes in biomass burning over the last millennium inferred from paleoatmospheric ethane in polar ice cores [Earth, Atmospheric, and Planetary Sciences]
    PNAS (IF 9.504) Pub Date : 2018-12-04
    Melinda R. Nicewonger, Murat Aydin, Michael J. Prather, Eric S. Saltzman

    Biomass burning drives changes in greenhouse gases, climate-forcing aerosols, and global atmospheric chemistry. There is controversy about the magnitude and timing of changes in biomass burning emissions on millennial time scales from preindustrial to present and about the relative importance of climate change and human activities as the underlying cause. Biomass burning is one of two notable sources of ethane in the preindustrial atmosphere. Here, we present ice core ethane measurements from Antarctica and Greenland that contain information about changes in biomass burning emissions since 1000 CE (Common Era). The biomass burning emissions of ethane during the Medieval Period (1000–1500 CE) were higher than present day and declined sharply to a minimum during the cooler Little Ice Age (1600–1800 CE). Assuming that preindustrial atmospheric reactivity and transport were the same as in the modern atmosphere, we estimate that biomass burning emissions decreased by 30 to 45% from the Medieval Period to the Little Ice Age. The timing and magnitude of this decline in biomass burning emissions is consistent with that inferred from ice core methane stable carbon isotope ratios but inconsistent with histories based on sedimentary charcoal and ice core carbon monoxide measurements. This study demonstrates that biomass burning emissions have exceeded modern levels in the past and may be highly sensitive to changes in climate.

    更新日期:2018-12-05
  • Potential shift from a carbon sink to a source in Amazonian peatlands under a changing climate [Earth, Atmospheric, and Planetary Sciences]
    PNAS (IF 9.504) Pub Date : 2018-12-04
    Sirui Wang, Qianlai Zhuang, Outi Lähteenoja, Frederick C. Draper, Hinsby Cadillo-Quiroz

    Amazonian peatlands store a large amount of soil organic carbon (SOC), and its fate under a future changing climate is unknown. Here, we use a process-based peatland biogeochemistry model to quantify the carbon accumulation for peatland and nonpeatland ecosystems in the Pastaza-Marañon foreland basin (PMFB) in the Peruvian Amazon from 12,000 y before present to AD 2100. Model simulations indicate that warming accelerates peat SOC loss, while increasing precipitation accelerates peat SOC accumulation at millennial time scales. The uncertain parameters and spatial variation of climate are significant sources of uncertainty to modeled peat carbon accumulation. Under warmer and presumably wetter conditions over the 21st century, SOC accumulation rate in the PMFB slows down to 7.9 (4.3–12.2) g⋅C⋅m−2⋅y−1 from the current rate of 16.1 (9.1–23.7) g⋅C⋅m−2⋅y−1, and the region may turn into a carbon source to the atmosphere at −53.3 (−66.8 to −41.2) g⋅C⋅m−2⋅y−1 (negative indicates source), depending on the level of warming. Peatland ecosystems show a higher vulnerability than nonpeatland ecosystems, as indicated by the ratio of their soil carbon density changes (ranging from 3.9 to 5.8). This is primarily due to larger peatlands carbon stocks and more dramatic responses of their aerobic and anaerobic decompositions in comparison with nonpeatland ecosystems under future climate conditions. Peatland and nonpeatland soils in the PMFB may lose up to 0.4 (0.32–0.52) Pg⋅C by AD 2100 with the largest loss from palm swamp. The carbon-dense Amazonian peatland may switch from a current carbon sink into a source in the 21st century.

    更新日期:2018-12-05
  • Change in household fuels dominates the decrease in PM2.5 exposure and premature mortality in China in 2005-2015 [Earth, Atmospheric, and Planetary Sciences]
    PNAS (IF 9.504) Pub Date : 2018-12-04
    Bin Zhao, Haotian Zheng, Shuxiao Wang, Kirk R. Smith, Xi Lu, Kristin Aunan, Yu Gu, Yuan Wang, Dian Ding, Jia Xing, Xiao Fu, Xudong Yang, Kuo-Nan Liou, Jiming Hao

    To tackle the severe fine particle (PM2.5) pollution in China, the government has implemented stringent control policies mainly on power plants, industry, and transportation since 2005, but estimates of the effectiveness of the policy and the temporal trends in health impacts are subject to large uncertainties. By adopting an integrated approach that combines chemical transport simulation, ambient/household exposure evaluation, and health-impact assessment, we find that the integrated population-weighted exposure to PM2.5 (IPWE) decreased by 47% (95% confidence interval, 37–55%) from 2005 [180 (146–219) μg/m3] to 2015 [96 (83–111) μg/m3]. Unexpectedly, 90% (86–93%) of such reduction is attributed to reduced household solid-fuel use, primarily resulting from rapid urbanization and improved incomes rather than specific control policies. The IPWE due to household fuels for both cooking and heating decreased, but the impact of cooking is significantly larger. The reduced household-related IPWE is estimated to avoid 0.40 (0.25–0.57) million premature deaths annually, accounting for 33% of the PM2.5-induced mortality in 2015. The IPWE would be further reduced by 63% (57–68%) if the remaining household solid fuels were replaced by clean fuels, which would avoid an additional 0.51 (0.40–0.64) million premature deaths. Such a transition to clean fuels, especially for heating, requires technology innovation and policy support to overcome the barriers of high cost of distribution systems, as is recently being attempted in the Beijing–Tianjin–Hebei area. We suggest that household-fuel use be more highly prioritized in national control policies, considering its effects on PM2.5 exposures.

    更新日期:2018-12-05
  • Bots increase exposure to negative and inflammatory content in online social systems [Computer Sciences]
    PNAS (IF 9.504) Pub Date : 2018-12-04
    Massimo Stella, Emilio Ferrara, Manlio De Domenico

    Societies are complex systems, which tend to polarize into subgroups of individuals with dramatically opposite perspectives. This phenomenon is reflected—and often amplified—in online social networks, where, however, humans are no longer the only players and coexist alongside with social bots—that is, software-controlled accounts. Analyzing large-scale social data collected during the Catalan referendum for independence on October 1, 2017, consisting of nearly 4 millions Twitter posts generated by almost 1 million users, we identify the two polarized groups of Independentists and Constitutionalists and quantify the structural and emotional roles played by social bots. We show that bots act from peripheral areas of the social system to target influential humans of both groups, bombarding Independentists with violent contents, increasing their exposure to negative and inflammatory narratives, and exacerbating social conflict online. Our findings stress the importance of developing countermeasures to unmask these forms of automated social manipulation.

    更新日期:2018-12-05
  • Structural analysis of transient reaction intermediate in formic acid dehydrogenation catalysis using two-dimensional IR spectroscopy [Chemistry]
    PNAS (IF 9.504) Pub Date : 2018-12-04
    Yufan Zhang, Xin Chen, Bin Zheng, Xunmin Guo, Yupeng Pan, Hailong Chen, Huaifeng Li, Shixiong Min, Chao Guan, Kuo-Wei Huang, Junrong Zheng

    The molecular structure of a catalytically active key intermediate is determined in solution by employing 2D IR spectroscopy measuring vibrational cross-angles. The formate intermediate (2) in the formic acid dehydrogenation reaction catalyzed by a phosphorus–nitrogen PN3P–Ru catalyst is elucidated. Our spectroscopic studies show that the complex features a formate ion directly attached to the Ru center as a ligand, and a proton added to the imine arm of the dearomatized PN3P* ligand. During the catalytic process, the imine arms are not only reversibly protonated and deprotonated, but also interacting with the protic substrate molecules, effectively serving as the local proton buffer to offer remarkable stability with a turnover number (TON) over one million.

    更新日期:2018-12-05
  • Elastic and Li-ion-percolating hybrid membrane stabilizes Li metal plating [Chemistry]
    PNAS (IF 9.504) Pub Date : 2018-12-04
    Quan Pang, Laidong Zhou, Linda F. Nazar

    Lithium metal batteries are capable of revolutionizing the battery marketplace for electrical vehicles, owing to the high capacity and low voltage offered by Li metal. Current exploitation of Li metal electrodes, however, is plagued by their exhaustive parasitic reactions with liquid electrolytes and dendritic growth, which pose concerns to both cell performance and safety. We demonstrate that a hybrid membrane, both elastic and Li+-ion percolating, can stabilize Li plating/stripping with high Coulombic efficiency. The compact packing of a Li+ solid electrolyte phase offers percolated Li+-conducting channels and the consequent infiltration of an elastic polymer endows membrane flexibility to accommodate volume changes. The protected electrode allows Li plating with 95.8% efficiency for 200 cycles and stable operation of an LTO|Li cell for 2,000 cycles. This rationally structured membrane represents an interface engineering approach toward stabilized Li metal electrodes.

    更新日期:2018-12-05
  • Receptor selectivity from minimal backbone modification of a polypeptide agonist [Chemistry]
    PNAS (IF 9.504) Pub Date : 2018-12-04
    Shi Liu, Ross W. Cheloha, Tomoyuki Watanabe, Thomas J. Gardella, Samuel H. Gellman

    Human parathyroid hormone (PTH) and N-terminal fragments thereof activate two receptors, hPTHR1 and hPTHR2, which share ∼51% sequence similarity. A peptide comprising the first 34 residues of PTH is fully active at both receptors and is used to treat osteoporosis. We have used this system to explore the hypothesis that backbone modification of a promiscuous peptidic agonist can provide novel receptor-selective agonists. We tested this hypothesis by preparing a set of variants of PTH(1–34)-NH2 that contained a single β-amino-acid residue replacement at each of the first eight positions. These homologs, each containing one additional backbone methylene unit relative to PTH(1–34)-NH2 itself, displayed a wide range of potencies in cell-based assays for PTHR1 or PTHR2 activation. The β-scan series allowed us to identify two homologs, each containing two α→β replacements, that were highly selective, one for PTHR1 and the other for PTHR2. These findings suggest that backbone modification of peptides may provide a general strategy for achieving activation selectivity among polypeptide-modulated receptors, and that success requires consideration of both β2- and β3-residues, which differ in terms of side-chain location.

    更新日期:2018-12-05
  • Probabilistic control of HIV latency and transactivation by the Tat gene circuit [Biophysics and Computational Biology]
    PNAS (IF 9.504) Pub Date : 2018-12-04
    Youfang Cao, Xue Lei, Ruy M. Ribeiro, Alan S. Perelson, Jie Liang

    The reservoir of HIV latently infected cells is the major obstacle for eradication of HIV infection. The “shock-and-kill” strategy proposed earlier aims to reduce the reservoir by activating cells out of latency. While the intracellular HIV Tat gene circuit is known to play important roles in controlling latency and its transactivation in HIV-infected cells, the detailed control mechanisms are not well understood. Here we study the mechanism of probabilistic control of the latent and the transactivated cell phenotypes of HIV-infected cells. We reconstructed the probability landscape, which is the probability distribution of the Tat gene circuit states, by directly computing the exact solution of the underlying chemical master equation. Results show that the Tat circuit exhibits a clear bimodal probability landscape (i.e., there are two distinct probability peaks, one associated with the latent cell phenotype and the other with the transactivated cell phenotype). We explore potential modifications to reactions in the Tat gene circuit for more effective transactivation of latent cells (i.e., the shock-and-kill strategy). Our results suggest that enhancing Tat acetylation can dramatically increase Tat and viral production, while increasing the Tat–transactivation response binding affinity can transactivate latent cells more rapidly than other manipulations. Our results further explored the “block and lock” strategy toward a functional cure for HIV. Overall, our study demonstrates a general approach toward discovery of effective therapeutic strategies and druggable targets by examining control mechanisms of cell phenotype switching via exactly computed probability landscapes of reaction networks.

    更新日期:2018-12-05
  • Cats use hollow papillae to wick saliva into fur [Biophysics and Computational Biology]
    PNAS (IF 9.504) Pub Date : 2018-12-04
    Alexis C. Noel, David L. Hu

    The cat tongue is covered in sharp, rear-facing spines called papillae, the precise function of which is a mystery. In this combined experimental and theoretical study, we use high-speed film, grooming force measurements, and computed tomography (CT) scanning to elucidate the mechanism by which papillae are used to groom fur. We examine the tongues of six species of cats from domestic cat to lion, spanning 30-fold in body weight. The papillae of these cats each feature a hollow cavity at the tip that spontaneously wicks saliva from the mouth and then releases it onto hairs. The unique shape of the cat’s papillae may inspire ways to clean complex hairy surfaces. We demonstrate one such application with the tongue-inspired grooming (TIGR) brush, which incorporates 3D-printed cat papillae into a silicone substrate. The TIGR brush experiences lower grooming forces than a normal hairbrush and is easier to clean.

    更新日期:2018-12-05
  • Differential growth and shape formation in plant organs [Biophysics and Computational Biology]
    PNAS (IF 9.504) Pub Date : 2018-12-04
    Changjin Huang, Zilu Wang, David Quinn, Subra Suresh, K. Jimmy Hsia

    Morphogenesis is a phenomenon by which a wide variety of functional organs are formed in biological systems. In plants, morphogenesis is primarily driven by differential growth of tissues. Much effort has been devoted to identifying the role of genetic and biomolecular pathways in regulating cell division and cell expansion and in influencing shape formation in plant organs. However, general principles dictating how differential growth controls the formation of complex 3D shapes in plant leaves and flower petals remain largely unknown. Through quantitative measurements on live plant organs and detailed finite-element simulations, we show how the morphology of a growing leaf is determined by both the maximum value and the spatial distribution of growth strain. With this understanding, we develop a broad scientific framework for a morphological phase diagram that is capable of rationalizing four configurations commonly found in plant organs: twisting, helical twisting, saddle bending, and edge waving. We demonstrate the robustness of these findings and analyses by recourse to synthetic reproduction of all four configurations using controlled polymerization of a hydrogel. Our study points to potential approaches to innovative geometrical design and actuation in such applications as building architecture, soft robotics and flexible electronics.

    更新日期:2018-12-05
  • SIR proteins create compact heterochromatin fibers [Biochemistry]
    PNAS (IF 9.504) Pub Date : 2018-12-04
    Sarah G. Swygert, Subhadip Senapati, Mehmet F. Bolukbasi, Scot A. Wolfe, Stuart Lindsay, Craig L. Peterson

    Heterochromatin is a silenced chromatin region essential for maintaining genomic stability and driving developmental processes. The complicated structure and dynamics of heterochromatin have rendered it difficult to characterize. In budding yeast, heterochromatin assembly requires the SIR proteins—Sir3, believed to be the primary structural component of SIR heterochromatin, and the Sir2–4 complex, responsible for the targeted recruitment of SIR proteins and the deacetylation of lysine 16 of histone H4. Previously, we found that Sir3 binds but does not compact nucleosomal arrays. Here we reconstitute chromatin fibers with the complete complement of SIR proteins and use sedimentation velocity, molecular modeling, and atomic force microscopy to characterize the stoichiometry and conformation of SIR chromatin fibers. In contrast to fibers with Sir3 alone, our results demonstrate that SIR arrays are highly compact. Strikingly, the condensed structure of SIR heterochromatin fibers requires both the integrity of H4K16 and an interaction between Sir3 and Sir4. We propose a model in which a dimer of Sir3 bridges and stabilizes two adjacent nucleosomes, while a Sir2–4 heterotetramer interacts with Sir3 associated with a nucleosomal trimer, driving fiber compaction.

    更新日期:2018-12-05
  • Oscillating path between self-similarities in liquid pinch-off [Applied Physical Sciences]
    PNAS (IF 9.504) Pub Date : 2018-12-04
    Antoine Lagarde, Christophe Josserand, Suzie Protière

    Many differential equations involved in natural sciences show singular behaviors; i.e., quantities in the model diverge as the solution goes to zero. Nonetheless, the evolution of the singularity can be captured with self-similar solutions, several of which may exist for a given system. How to characterize the transition from one self-similar regime to another remains an open question. By studying the classic example of the pinch-off of a viscous liquid thread, we show experimentally that the geometry of the system and external perturbations play an essential role in the transition from a symmetric to an asymmetric solution. Moreover, this transient regime undergoes unexpected log-scale oscillations that delay dramatically the onset of the final self-similar solution. This result sheds light on the strong impact external constraints can have on predictions established to explain the formation of satellite droplets or on the rheological tests applied on a fluid, for example.

    更新日期:2018-12-05
  • Mesoscale structure, mechanics, and transport properties of source rocks’ organic pore networks [Applied Physical Sciences]
    PNAS (IF 9.504) Pub Date : 2018-12-04
    Jeremie Berthonneau, Amaël Obliger, Pierre-Louis Valdenaire, Olivier Grauby, Daniel Ferry, Damien Chaudanson, Pierre Levitz, Jae Jin Kim, Franz-Josef Ulm, Roland J.-M. Pellenq

    Organic matter is responsible for the generation of hydrocarbons during the thermal maturation of source rock formation. This geochemical process engenders a network of organic hosted pores that governs the flow of hydrocarbons from the organic matter to fractures created during the stimulation of production wells. Therefore, it can be reasonably assumed that predictions of potentially recoverable confined hydrocarbons depend on the geometry of this pore network. Here, we analyze mesoscale structures of three organic porous networks at different thermal maturities. We use electron tomography with subnanometric resolution to characterize their morphology and topology. Our 3D reconstructions confirm the formation of nanopores and reveal increasingly tortuous and connected pore networks in the process of thermal maturation. We then turn the binarized reconstructions into lattice models including information from atomistic simulations to derive mechanical and confined fluid transport properties. Specifically, we highlight the influence of adsorbed fluids on the elastic response. The resulting elastic energy concentrations are localized at the vicinity of macropores at low maturity whereas these concentrations present more homogeneous distributions at higher thermal maturities, due to pores’ topology. The lattice models finally allow us to capture the effect of sorption on diffusion mechanisms with a sole input of network geometry. Eventually, we corroborate the dominant impact of diffusion occurring within the connected nanopores, which constitute the limiting factor of confined hydrocarbon transport in source rocks.

    更新日期:2018-12-05
  • Resistance protein Pit interacts with the GEF OsSPK1 to activate OsRac1 and trigger rice immunity [Plant Biology]
    PNAS (IF 9.504) Pub Date : 2018-12-04
    Qiong Wang, Yuying Li, Kazuya Ishikawa, Ken-ichi Kosami, Kazumi Uno, Shingo Nagawa, Li Tan, Jiamu Du, Ko Shimamoto, Yoji Kawano

    Resistance (R) genes encode intracellular nucleotide-binding/leucine-rich repeat-containing (NLR) family proteins that serve as critical plant immune receptors to induce effector-triggered immunity (ETI). NLR proteins possess a tripartite domain architecture consisting of an N-terminal variable region, a central nucleotide-binding domain, and a C-terminal leucine-rich repeat. N-terminal coiled-coil (CC) or Toll-interleukin 1 receptor (TIR) domains of R proteins appear to serve as platforms to trigger immune responses, because overexpression of the CC or TIR domain of some R proteins is sufficient to induce an immune response. Because direct downstream signaling molecules of R proteins remain obscure, the molecular mechanisms by which R proteins regulate downstream signaling are largely unknown. We reported previously that a rice R protein named Pit triggers ETI through a small GTPase, OsRac1, although how Pit activates OsRac1 is unclear. Here, we identified OsSPK1, a DOCK family guanine nucleotide exchange factor, as an interactor of Pit and activator for OsRac1. OsSPK1 contributes to signaling by two disease-resistance genes, Pit and Pia, against the rice blast fungus Magnaporthe oryzae and facilitates OsRac1 activation in vitro and in vivo. The CC domain of Pit is required for its binding to OsSPK1, OsRac1 activation, and the induction of cell death. Overall, we conclude that OsSPK1 is a direct and key signaling target of Pit-mediated immunity. Our results shed light on how R proteins trigger ETI through direct downstream molecules.

    更新日期:2018-12-05
  • Interlinked regulatory loops of ABA catabolism and biosynthesis coordinate fruit growth and ripening in woodland strawberry [Plant Biology]
    PNAS (IF 9.504) Pub Date : 2018-12-04
    Xiong Liao, Mengsi Li, Bin Liu, Miaoling Yan, Xiaomin Yu, Hailing Zi, Renyi Liu, Chizuko Yamamuro

    Fruit growth and ripening are controlled by multiple phytohormones. How these hormones coordinate and interact with each other to control these processes at the molecular level is unclear. We found in the early stages of Fragaria vesca (woodland strawberry) fruit development, auxin increases both widths and lengths of fruits, while gibberellin [gibberellic acid (GA)] mainly promotes their longitudinal elongation. Auxin promoted GA biosynthesis and signaling by activating GA biosynthetic and signaling genes, suggesting auxin function is partially dependent on GA function. To prevent the repressive effect of abscisic acid (ABA) on fruit growth, auxin and GA suppressed ABA accumulation during early fruit development by activating the expression of FveCYP707A4a encoding cytochrome P450 monooxygenase that catalyzes ABA catabolism. At the onset of fruit ripening, both auxin and GA levels decreased, leading to a steep increase in the endogenous level of ABA that drives fruit ripening. ABA repressed the expression of FveCYP707A4a but promoted that of FveNCED, a rate-limiting step in ABA biosynthesis. Accordingly, altering FveCYP707A4a expression changed the endogenous ABA levels and affected FveNCED expression. Hence, ABA catabolism and biosynthesis are tightly linked by feedback and feedforward loops to limit ABA contents for fruit growth and to quickly increase ABA contents for the onset of fruit ripening. These results indicate that FveCYP707A4a not only regulates ABA accumulation but also provides a hub to coordinate fruit size and ripening times by relaying auxin, GA, and ABA signals.

    更新日期:2018-12-05
  • Genetic deletion of vesicular glutamate transporter in dopamine neurons increases vulnerability to MPTP-induced neurotoxicity in mice [Neuroscience]
    PNAS (IF 9.504) Pub Date : 2018-12-04
    Hui Shen, Rosa Anna M. Marino, Ross A. McDevitt, Guo-Hua Bi, Kai Chen, Graziella Madeo, Pin-Tse Lee, Ying Liang, Lindsay M. De Biase, Tsung-Ping Su, Zheng-Xiong Xi, Antonello Bonci

    A subset of midbrain dopamine (DA) neurons express vesicular glutamate transporter 2 (VgluT2), which facilitates synaptic vesicle loading of glutamate. Recent studies indicate that such expression can modulate DA-dependent reward behaviors, but little is known about functional consequences of DA neuron VgluT2 expression in neurodegenerative diseases like Parkinson’s disease (PD). Here, we report that selective deletion of VgluT2 in DA neurons in conditional VgluT2-KO (VgluT2-cKO) mice abolished glutamate release from DA neurons, reduced their expression of brain-derived neurotrophic factor (BDNF) and tyrosine receptor kinase B (TrkB), and exacerbated the pathological effects of exposure to the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Furthermore, viral rescue of VgluT2 expression in DA neurons of VglutT2-cKO mice restored BDNF/TrkB expression and attenuated MPTP-induced DA neuron loss and locomotor impairment. Together, these findings indicate that VgluT2 expression in DA neurons is neuroprotective. Genetic or environmental factors causing reduced expression or function of VgluT2 in DA neurons may place some individuals at increased risk for DA neuron degeneration. Therefore, maintaining physiological expression and function of VgluT2 in DA neurons may represent a valid molecular target for the development of preventive therapeutic interventions for PD.

    更新日期:2018-12-05
  • Excessive endosomal TLR signaling causes inflammatory disease in mice with defective SMCR8-WDR41-C9ORF72 complex function [Immunology and Inflammation]
    PNAS (IF 9.504) Pub Date : 2018-12-04
    William McAlpine, Lei Sun, Kuan-wen Wang, Aijie Liu, Ruchi Jain, Miguel San Miguel, Jianhui Wang, Zhao Zhang, Braden Hayse, Sarah Grace McAlpine, Jin Huk Choi, Xue Zhong, Sara Ludwig, Jamie Russell, Xiaoming Zhan, Mihwa Choi, Xiaohong Li, Miao Tang, Eva Marie Y. Moresco, Bruce Beutler, Emre Turer

    The SMCR8-WDR41-C9ORF72 complex is a regulator of autophagy and lysosomal function. Autoimmunity and inflammatory disease have been ascribed to loss-of-function mutations of Smcr8 or C9orf72 in mice. In humans, autoimmunity has been reported to precede amyotrophic lateral sclerosis caused by mutations of C9ORF72. However, the cellular and molecular mechanisms underlying autoimmunity and inflammation caused by C9ORF72 or SMCR8 deficiencies remain unknown. Here, we show that splenomegaly, lymphadenopathy, and activated circulating T cells observed in Smcr8−/− mice were rescued by triple knockout of the endosomal Toll-like receptors (TLRs) TLR3, TLR7, and TLR9. Myeloid cells from Smcr8−/− mice produced excessive inflammatory cytokines in response to endocytosed TLR3, TLR7, or TLR9 ligands administered in the growth medium and in response to TLR2 or TLR4 ligands internalized by phagocytosis. These defects likely stem from prolonged TLR signaling caused by accumulation of LysoTracker-positive vesicles and by delayed phagosome maturation, both of which were observed in Smcr8−/− macrophages. Smcr8−/− mice also showed elevated susceptibility to dextran sodium sulfate-induced colitis, which was not associated with increased TLR3, TLR7, or TLR9 signaling. Deficiency of WDR41 phenocopied loss of SMCR8. Our findings provide evidence that excessive endosomal TLR signaling resulting from prolonged ligand–receptor contact causes inflammatory disease in SMCR8-deficient mice.

    更新日期:2018-12-05
Some contents have been Reproduced with permission of the American Chemical Society.
Some contents have been Reproduced by permission of The Royal Society of Chemistry.
化学 • 材料 期刊列表