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  • Online Resource  (18)
  • Proceedings of the National Academy of Sciences  (18)
  • 2015-2019  (18)
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  • Proceedings of the National Academy of Sciences  (18)
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  • 2015-2019  (18)
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  • 1
    Online Resource
    Online Resource
    Evidence for indigenous nitrogen in sedimentary and aeolian deposits from the Curiosity rover investigations at Gale crater, Mars
    Proceedings of the National Academy of Sciences ; 2015
    In:  Proceedings of the National Academy of Sciences Vol. 112, No. 14 ( 2015-04-07), p. 4245-4250
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 112, No. 14 ( 2015-04-07), p. 4245-4250
    Abstract: The Sample Analysis at Mars (SAM) investigation on the Mars Science Laboratory (MSL) Curiosity rover has detected oxidized nitrogen-bearing compounds during pyrolysis of scooped aeolian sediments and drilled sedimentary deposits within Gale crater. Total N concentrations ranged from 20 to 250 nmol N per sample. After subtraction of known N sources in SAM, our results support the equivalent of 110–300 ppm of nitrate in the Rocknest (RN) aeolian samples, and 70–260 and 330–1,100 ppm nitrate in John Klein (JK) and Cumberland (CB) mudstone deposits, respectively. Discovery of indigenous martian nitrogen in Mars surface materials has important implications for habitability and, specifically, for the potential evolution of a nitrogen cycle at some point in martian history. The detection of nitrate in both wind-drifted fines (RN) and in mudstone (JK, CB) is likely a result of N 2 fixation to nitrate generated by thermal shock from impact or volcanic plume lightning on ancient Mars. Fixed nitrogen could have facilitated the development of a primitive nitrogen cycle on the surface of ancient Mars, potentially providing a biochemically accessible source of nitrogen.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1420932112
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2015
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  • 2
    Online Resource
    Online Resource
    Gravity of human impacts mediates coral reef conservation gains
    Proceedings of the National Academy of Sciences ; 2018
    In:  Proceedings of the National Academy of Sciences Vol. 115, No. 27 ( 2018-07-03)
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 115, No. 27 ( 2018-07-03)
    Abstract: Coral reefs provide ecosystem goods and services for millions of people in the tropics, but reef conditions are declining worldwide. Effective solutions to the crisis facing coral reefs depend in part on understanding the context under which different types of conservation benefits can be maximized. Our global analysis of nearly 1,800 tropical reefs reveals how the intensity of human impacts in the surrounding seascape, measured as a function of human population size and accessibility to reefs (“gravity”), diminishes the effectiveness of marine reserves at sustaining reef fish biomass and the presence of top predators, even where compliance with reserve rules is high. Critically, fish biomass in high-compliance marine reserves located where human impacts were intensive tended to be less than a quarter that of reserves where human impacts were low. Similarly, the probability of encountering top predators on reefs with high human impacts was close to zero, even in high-compliance marine reserves. However, we find that the relative difference between openly fished sites and reserves (what we refer to as conservation gains) are highest for fish biomass (excluding predators) where human impacts are moderate and for top predators where human impacts are low. Our results illustrate critical ecological trade-offs in meeting key conservation objectives: reserves placed where there are moderate-to-high human impacts can provide substantial conservation gains for fish biomass, yet they are unlikely to support key ecosystem functions like higher-order predation, which is more prevalent in reserve locations with low human impacts.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1708001115
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2018
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    detail.hit.zdb_id: 1461794-8
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  • 3
    Online Resource
    Online Resource
    Blacklisting variants common in private cohorts but not in public databases optimizes human exome analysis
    Proceedings of the National Academy of Sciences ; 2019
    In:  Proceedings of the National Academy of Sciences Vol. 116, No. 3 ( 2019-01-15), p. 950-959
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 116, No. 3 ( 2019-01-15), p. 950-959
    Abstract: Computational analyses of human patient exomes aim to filter out as many nonpathogenic genetic variants (NPVs) as possible, without removing the true disease-causing mutations. This involves comparing the patient’s exome with public databases to remove reported variants inconsistent with disease prevalence, mode of inheritance, or clinical penetrance. However, variants frequent in a given exome cohort, but absent or rare in public databases, have also been reported and treated as NPVs, without rigorous exploration. We report the generation of a blacklist of variants frequent within an in-house cohort of 3,104 exomes. This blacklist did not remove known pathogenic mutations from the exomes of 129 patients and decreased the number of NPVs remaining in the 3,104 individual exomes by a median of 62%. We validated this approach by testing three other independent cohorts of 400, 902, and 3,869 exomes. The blacklist generated from any given cohort removed a substantial proportion of NPVs (11–65%). We analyzed the blacklisted variants computationally and experimentally. Most of the blacklisted variants corresponded to false signals generated by incomplete reference genome assembly, location in low-complexity regions, bioinformatic misprocessing, or limitations inherent to cohort-specific private alleles (e.g., due to sequencing kits, and genetic ancestries). Finally, we provide our precalculated blacklists, together with ReFiNE, a program for generating customized blacklists from any medium-sized or large in-house cohort of exome (or other next-generation sequencing) data via a user-friendly public web server. This work demonstrates the power of extracting variant blacklists from private databases as a specific in-house but broadly applicable tool for optimizing exome analysis.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1808403116
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2019
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  • 4
    Online Resource
    Online Resource
    Global ensemble projections reveal trophic amplification of ocean biomass declines with climate change
    Proceedings of the National Academy of Sciences ; 2019
    In:  Proceedings of the National Academy of Sciences Vol. 116, No. 26 ( 2019-06-25), p. 12907-12912
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 116, No. 26 ( 2019-06-25), p. 12907-12912
    Abstract: While the physical dimensions of climate change are now routinely assessed through multimodel intercomparisons, projected impacts on the global ocean ecosystem generally rely on individual models with a specific set of assumptions. To address these single-model limitations, we present standardized ensemble projections from six global marine ecosystem models forced with two Earth system models and four emission scenarios with and without fishing. We derive average biomass trends and associated uncertainties across the marine food web. Without fishing, mean global animal biomass decreased by 5% (±4% SD) under low emissions and 17% (±11% SD) under high emissions by 2100, with an average 5% decline for every 1 °C of warming. Projected biomass declines were primarily driven by increasing temperature and decreasing primary production, and were more pronounced at higher trophic levels, a process known as trophic amplification. Fishing did not substantially alter the effects of climate change. Considerable regional variation featured strong biomass increases at high latitudes and decreases at middle to low latitudes, with good model agreement on the direction of change but variable magnitude. Uncertainties due to variations in marine ecosystem and Earth system models were similar. Ensemble projections performed well compared with empirical data, emphasizing the benefits of multimodel inference to project future outcomes. Our results indicate that global ocean animal biomass consistently declines with climate change, and that these impacts are amplified at higher trophic levels. Next steps for model development include dynamic scenarios of fishing, cumulative human impacts, and the effects of management measures on future ocean biomass trends.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1900194116
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2019
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  • 5
    Online Resource
    Online Resource
    Ancient pigs reveal a near-complete genomic turnover following their introduction to Europe
    Proceedings of the National Academy of Sciences ; 2019
    In:  Proceedings of the National Academy of Sciences Vol. 116, No. 35 ( 2019-08-27), p. 17231-17238
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 116, No. 35 ( 2019-08-27), p. 17231-17238
    Abstract: Archaeological evidence indicates that pig domestication had begun by ∼10,500 y before the present (BP) in the Near East, and mitochondrial DNA (mtDNA) suggests that pigs arrived in Europe alongside farmers ∼8,500 y BP. A few thousand years after the introduction of Near Eastern pigs into Europe, however, their characteristic mtDNA signature disappeared and was replaced by haplotypes associated with European wild boars. This turnover could be accounted for by substantial gene flow from local European wild boars, although it is also possible that European wild boars were domesticated independently without any genetic contribution from the Near East. To test these hypotheses, we obtained mtDNA sequences from 2,099 modern and ancient pig samples and 63 nuclear ancient genomes from Near Eastern and European pigs. Our analyses revealed that European domestic pigs dating from 7,100 to 6,000 y BP possessed both Near Eastern and European nuclear ancestry, while later pigs possessed no more than 4% Near Eastern ancestry, indicating that gene flow from European wild boars resulted in a near-complete disappearance of Near East ancestry. In addition, we demonstrate that a variant at a locus encoding black coat color likely originated in the Near East and persisted in European pigs. Altogether, our results indicate that while pigs were not independently domesticated in Europe, the vast majority of human-mediated selection over the past 5,000 y focused on the genomic fraction derived from the European wild boars, and not on the fraction that was selected by early Neolithic farmers over the first 2,500 y of the domestication process.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1901169116
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2019
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
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  • 6
    Online Resource
    Online Resource
    Immunoreceptor tyrosine-based inhibitory motif–dependent functions of an MHC class I-specific NK cell receptor
    Proceedings of the National Academy of Sciences ; 2017
    In:  Proceedings of the National Academy of Sciences Vol. 114, No. 40 ( 2017-10-03)
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 114, No. 40 ( 2017-10-03)
    Abstract: Natural killer (NK) cells express MHC class I (MHC-I)-specific receptors, such as Ly49A, that inhibit killing of cells expressing self–MHC-I. Self–MHC-I also “licenses” NK cells to become responsive to activating stimuli and regulates the surface level of NK-cell inhibitory receptors. However, the mechanisms of action resulting from these interactions of the Ly49s with their MHC-I ligands, particularly in vivo, have been controversial. Definitive studies could be derived from mice with targeted mutations in inhibitory Ly49s, but there are inherent challenges in specifically altering a single gene within a multigene family. Herein, we generated a knock-in mouse with a targeted mutation in the immunoreceptor tyrosine-based inhibitory motif (ITIM) of Ly49A that abolished the inhibitory function of Ly49A in cytotoxicity assays. This mutant Ly49A caused a licensing defect in NK cells, but the surface expression of Ly49A was unaltered. Moreover, NK cells that expressed this mutant Ly49A exhibited an altered inhibitory receptor repertoire. These results demonstrate that Ly49A ITIM signaling is critical for NK-cell effector inhibition, licensing, and receptor repertoire development.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1713064114
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2017
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  • 7
    Online Resource
    Online Resource
    Distance from sub-Saharan Africa predicts mutational load in diverse human genomes
    Proceedings of the National Academy of Sciences ; 2016
    In:  Proceedings of the National Academy of Sciences Vol. 113, No. 4 ( 2016-01-26)
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 113, No. 4 ( 2016-01-26)
    Abstract: The Out-of-Africa (OOA) dispersal ∼50,000 y ago is characterized by a series of founder events as modern humans expanded into multiple continents. Population genetics theory predicts an increase of mutational load in populations undergoing serial founder effects during range expansions. To test this hypothesis, we have sequenced full genomes and high-coverage exomes from seven geographically divergent human populations from Namibia, Congo, Algeria, Pakistan, Cambodia, Siberia, and Mexico. We find that individual genomes vary modestly in the overall number of predicted deleterious alleles. We show via spatially explicit simulations that the observed distribution of deleterious allele frequencies is consistent with the OOA dispersal, particularly under a model where deleterious mutations are recessive. We conclude that there is a strong signal of purifying selection at conserved genomic positions within Africa, but that many predicted deleterious mutations have evolved as if they were neutral during the expansion out of Africa. Under a model where selection is inversely related to dominance, we show that OOA populations are likely to have a higher mutation load due to increased allele frequencies of nearly neutral variants that are recessive or partially recessive.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1510805112
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2016
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  • 8
    Online Resource
    Online Resource
    Dynamically stiffened matrix promotes malignant transformation of mammary epithelial cells via collective mechanical signaling
    Proceedings of the National Academy of Sciences ; 2019
    In:  Proceedings of the National Academy of Sciences Vol. 116, No. 9 ( 2019-02-26), p. 3502-3507
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 116, No. 9 ( 2019-02-26), p. 3502-3507
    Abstract: Breast cancer development is associated with increasing tissue stiffness over years. To more accurately mimic the onset of gradual matrix stiffening, which is not feasible with conventional static hydrogels, mammary epithelial cells (MECs) were cultured on methacrylated hyaluronic acid hydrogels whose stiffness can be dynamically modulated from “normal” ( 〈 150 Pascals) to “malignant” ( 〉 3,000 Pascals) via two-stage polymerization. MECs form and remain as spheroids, but begin to lose epithelial characteristics and gain mesenchymal morphology upon matrix stiffening. However, both the degree of matrix stiffening and culture time before stiffening play important roles in regulating this conversion as, in both cases, a subset of mammary spheroids remained insensitive to local matrix stiffness. This conversion depended neither on colony size nor cell density, and MECs did not exhibit “memory” of prior niche when serially cultured through cycles of compliant and stiff matrices. Instead, the transcription factor Twist1, transforming growth factor β (TGFβ), and YAP activation appeared to modulate stiffness-mediated signaling; when stiffness-mediated signals were blocked, collective MEC phenotypes were reduced in favor of single MECs migrating away from spheroids. These data indicate a more complex interplay of time-dependent stiffness signaling, spheroid structure, and soluble cues that regulates MEC plasticity than suggested by previous models.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1814204116
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2019
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
    SSG: 11
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  • 9
    Online Resource
    Online Resource
    Asymmetric percolation drives a double transition in sexual contact networks
    Proceedings of the National Academy of Sciences ; 2017
    In:  Proceedings of the National Academy of Sciences Vol. 114, No. 34 ( 2017-08-22), p. 8969-8973
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 114, No. 34 ( 2017-08-22), p. 8969-8973
    Abstract: Zika virus (ZIKV) exhibits unique transmission dynamics in that it is concurrently spread by a mosquito vector and through sexual contact. Due to the highly asymmetric durations of infectiousness between males and females—it is estimated that males are infectious for periods up to 10 times longer than females—we show that this sexual component of ZIKV transmission behaves akin to an asymmetric percolation process on the network of sexual contacts. We exactly solve the properties of this asymmetric percolation on random sexual contact networks and show that this process exhibits two epidemic transitions corresponding to a core–periphery structure. This structure is not present in the underlying contact networks, which are not distinguishable from random networks, and emerges because of the asymmetric percolation. We provide an exact analytical description of this double transition and discuss the implications of our results in the context of ZIKV epidemics. Most importantly, our study suggests a bias in our current ZIKV surveillance, because the community most at risk is also one of the least likely to get tested.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1703073114
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2017
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
    SSG: 11
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  • 10
    Online Resource
    Online Resource
    Human pluripotent stem cells as a model of trophoblast differentiation in both normal development and disease
    Proceedings of the National Academy of Sciences ; 2016
    In:  Proceedings of the National Academy of Sciences Vol. 113, No. 27 ( 2016-07-05)
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 113, No. 27 ( 2016-07-05)
    Abstract: Trophoblast is the primary epithelial cell type in the placenta, a transient organ required for proper fetal growth and development. Different trophoblast subtypes are responsible for gas/nutrient exchange (syncytiotrophoblasts, STBs) and invasion and maternal vascular remodeling (extravillous trophoblasts, EVTs). Studies of early human placental development are severely hampered by the lack of a representative trophoblast stem cell (TSC) model with the capacity for self-renewal and the ability to differentiate into both STBs and EVTs. Primary cytotrophoblasts (CTBs) isolated from early-gestation (6–8 wk) human placentas are bipotential, a phenotype that is lost with increasing gestational age. We have identified a CDX2 + /p63 + CTB subpopulation in the early postimplantation human placenta that is significantly reduced later in gestation. We describe a reproducible protocol, using defined medium containing bone morphogenetic protein 4 by which human pluripotent stem cells (hPSCs) can be differentiated into CDX2 + /p63 + CTB stem-like cells. These cells can be replated and further differentiated into STB- and EVT-like cells, based on marker expression, hormone secretion, and invasive ability. As in primary CTBs, differentiation of hPSC-derived CTBs in low oxygen leads to reduced human chorionic gonadotropin secretion and STB-associated gene expression, instead promoting differentiation into HLA-G + EVTs in an hypoxia-inducible, factor-dependent manner. To validate further the utility of hPSC-derived CTBs, we demonstrated that differentiation of trisomy 21 (T21) hPSCs recapitulates the delayed CTB maturation and blunted STB differentiation seen in T21 placentae. Collectively, our data suggest that hPSCs are a valuable model of human placental development, enabling us to recapitulate processes that result in both normal and diseased pregnancies.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1604747113
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2016
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
    SSG: 11
    SSG: 12
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