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  • Proceedings of the National Academy of Sciences  (17)
  • English  (17)
  • 1
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    Online Resource
    Multiancestry analysis of the HLA locus in Alzheimer’s and Parkinson’s diseases uncovers a shared adaptive immune response mediated by HLA-DRB1*04 subtypes
    Proceedings of the National Academy of Sciences ; 2023
    In:  Proceedings of the National Academy of Sciences Vol. 120, No. 36 ( 2023-09-05)
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 120, No. 36 ( 2023-09-05)
    Abstract: Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson’s disease (PD) and Alzheimer’s disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1 *04 subtypes best accounted for the association, strongest with HLA-DRB1 *04:04 and HLA-DRB1 *04:07, and intermediary with HLA-DRB1 *04:01 and HLA-DRB1 *04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased Aβ42. Protective HLA-DRB1 *04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1 *04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.2302720120
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    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2023
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  • 2
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    MRI-localized biopsies reveal subtype-specific differences in molecular and cellular composition at the margins of glioblastoma
    Proceedings of the National Academy of Sciences ; 2014
    In:  Proceedings of the National Academy of Sciences Vol. 111, No. 34 ( 2014-08-26), p. 12550-12555
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 111, No. 34 ( 2014-08-26), p. 12550-12555
    Abstract: Glioblastomas (GBMs) diffusely infiltrate the brain, making complete removal by surgical resection impossible. The mixture of neoplastic and nonneoplastic cells that remain after surgery form the biological context for adjuvant therapeutic intervention and recurrence. We performed RNA-sequencing (RNA-seq) and histological analysis on radiographically guided biopsies taken from different regions of GBM and showed that the tissue contained within the contrast-enhancing (CE) core of tumors have different cellular and molecular compositions compared with tissue from the nonenhancing (NE) margins of tumors. Comparisons with the The Cancer Genome Atlas dataset showed that the samples from CE regions resembled the proneural, classical, or mesenchymal subtypes of GBM, whereas the samples from the NE regions predominantly resembled the neural subtype. Computational deconvolution of the RNA-seq data revealed that contributions from nonneoplastic brain cells significantly influence the expression pattern in the NE samples. Gene ontology analysis showed that the cell type-specific expression patterns were functionally distinct and highly enriched in genes associated with the corresponding cell phenotypes. Comparing the RNA-seq data from the GBM samples to that of nonneoplastic brain revealed that the differentially expressed genes are distributed across multiple cell types. Notably, the patterns of cell type-specific alterations varied between the different GBM subtypes: the NE regions of proneural tumors were enriched in oligodendrocyte progenitor genes, whereas the NE regions of mesenchymal GBM were enriched in astrocytic and microglial genes. These subtype-specific patterns provide new insights into molecular and cellular composition of the infiltrative margins of GBM.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1405839111
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    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2014
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  • 3
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    Global collision-risk hotspots of marine traffic and the world’s largest fish, the whale shark
    Proceedings of the National Academy of Sciences ; 2022
    In:  Proceedings of the National Academy of Sciences Vol. 119, No. 20 ( 2022-05-17)
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 119, No. 20 ( 2022-05-17)
    Abstract: Marine traffic is increasing globally yet collisions with endangered megafauna such as whales, sea turtles, and planktivorous sharks go largely undetected or unreported. Collisions leading to mortality can have population-level consequences for endangered species. Hence, identifying simultaneous space use of megafauna and shipping throughout ranges may reveal as-yet-unknown spatial targets requiring conservation. However, global studies tracking megafauna and shipping occurrences are lacking. Here we combine satellite-tracked movements of the whale shark, Rhincodon typus , and vessel activity to show that 92% of sharks’ horizontal space use and nearly 50% of vertical space use overlap with persistent large vessel ( 〉 300 gross tons) traffic. Collision-risk estimates correlated with reported whale shark mortality from ship strikes, indicating higher mortality in areas with greatest overlap. Hotspots of potential collision risk were evident in all major oceans, predominantly from overlap with cargo and tanker vessels, and were concentrated in gulf regions, where dense traffic co-occurred with seasonal shark movements. Nearly a third of whale shark hotspots overlapped with the highest collision-risk areas, with the last known locations of tracked sharks coinciding with busier shipping routes more often than expected. Depth-recording tags provided evidence for sinking, likely dead, whale sharks, suggesting substantial “cryptic” lethal ship strikes are possible, which could explain why whale shark population declines continue despite international protection and low fishing-induced mortality. Mitigation measures to reduce ship-strike risk should be considered to conserve this species and other ocean giants that are likely experiencing similar impacts from growing global vessel traffic.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.2117440119
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    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2022
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  • 4
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    Complementarity in the provision of ecosystem services reduces the cost of mitigating amplified natural disturbance events
    Proceedings of the National Academy of Sciences ; 2014
    In:  Proceedings of the National Academy of Sciences Vol. 111, No. 47 ( 2014-11-25), p. 16718-16723
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 111, No. 47 ( 2014-11-25), p. 16718-16723
    Abstract: Climate change has been implicated as a root cause of the recent surge in natural disturbance events such as storms, wildfires, and insect outbreaks. This climate-based surge has led to a greater focus on disturbance-mitigating benefits of ecosystem management. Quantifying these benefits requires knowledge of the relationship between natural and anthropogenic disturbances, which is lacking at the temporal and spatial scales needed to inform ecosystem-based management. This study investigates a specific relationship between timber harvesting and climate-amplified outbreaks of mountain pine beetle. If harvesting is located to mitigate long-distance insect dispersal, there is potential for a win–win outcome in which both timber production and forest conservation can be increased. This spatially targeted harvesting strategy lowers the cost of providing disturbance-mitigating ecosystem services, because valuable timber products are also produced. Mitigating long-distance dispersal also produces net gains in forest conservation across various stakeholder groups. These results speak to ongoing federal efforts to encourage forest vegetation removal on public forestlands to improve forest health. These efforts will lower the cost of responding to climate-amplified natural disturbance events but only if vegetation removal efforts are spatially located to reduce disturbance risk. Otherwise, efforts to improve forest health may be converting forest conservation services to timber services.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1407381111
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    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2014
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  • 5
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    Divergent sensory and immune gene evolution in sea turtles with contrasting demographic and life histories
    Proceedings of the National Academy of Sciences ; 2023
    In:  Proceedings of the National Academy of Sciences Vol. 120, No. 7 ( 2023-02-14)
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 120, No. 7 ( 2023-02-14)
    Abstract: Sea turtles represent an ancient lineage of marine vertebrates that evolved from terrestrial ancestors over 100 Mya. The genomic basis of the unique physiological and ecological traits enabling these species to thrive in diverse marine habitats remains largely unknown. Additionally, many populations have drastically declined due to anthropogenic activities over the past two centuries, and their recovery is a high global conservation priority. We generated and analyzed high-quality reference genomes for the leatherback ( Dermochelys coriacea ) and green ( Chelonia mydas ) turtles, representing the two extant sea turtle families. These genomes are highly syntenic and homologous, but localized regions of noncollinearity were associated with higher copy numbers of immune, zinc-finger, and olfactory receptor (OR) genes in green turtles, with ORs related to waterborne odorants greatly expanded in green turtles. Our findings suggest that divergent evolution of these key gene families may underlie immunological and sensory adaptations assisting navigation, occupancy of neritic versus pelagic environments, and diet specialization. Reduced collinearity was especially prevalent in microchromosomes, with greater gene content, heterozygosity, and genetic distances between species, supporting their critical role in vertebrate evolutionary adaptation. Finally, diversity and demographic histories starkly contrasted between species, indicating that leatherback turtles have had a low yet stable effective population size, exhibit extremely low diversity compared with other reptiles, and harbor a higher genetic load compared with green turtles, reinforcing concern over their persistence under future climate scenarios. These genomes provide invaluable resources for advancing our understanding of evolution and conservation best practices in an imperiled vertebrate lineage.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.2201076120
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    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2023
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  • 6
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    Rationalizing spatial exploration patterns of wild animals and humans through a temporal discounting framework
    Proceedings of the National Academy of Sciences ; 2016
    In:  Proceedings of the National Academy of Sciences Vol. 113, No. 31 ( 2016-08-02), p. 8747-8752
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 113, No. 31 ( 2016-08-02), p. 8747-8752
    Abstract: Understanding the exploration patterns of foragers in the wild provides fundamental insight into animal behavior. Recent experimental evidence has demonstrated that path lengths (distances between consecutive turns) taken by foragers are well fitted by a power law distribution. Numerous theoretical contributions have posited that “Lévy random walks”—which can produce power law path length distributions—are optimal for memoryless agents searching a sparse reward landscape. It is unclear, however, whether such a strategy is efficient for cognitively complex agents, from wild animals to humans. Here, we developed a model to explain the emergence of apparent power law path length distributions in animals that can learn about their environments. In our model, the agent’s goal during search is to build an internal model of the distribution of rewards in space that takes into account the cost of time to reach distant locations (i.e., temporally discounting rewards). For an agent with such a goal, we find that an optimal model of exploration in fact produces hyperbolic path lengths, which are well approximated by power laws. We then provide support for our model by showing that humans in a laboratory spatial exploration task search space systematically and modify their search patterns under a cost of time. In addition, we find that path length distributions in a large dataset obtained from free-ranging marine vertebrates are well described by our hyperbolic model. Thus, we provide a general theoretical framework for understanding spatial exploration patterns of cognitively complex foragers.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1601664113
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    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2016
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  • 7
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    Genome-wide functional screen identifies a compendium of genes affecting sensitivity to tamoxifen
    Proceedings of the National Academy of Sciences ; 2012
    In:  Proceedings of the National Academy of Sciences Vol. 109, No. 8 ( 2012-02-21), p. 2730-2735
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 109, No. 8 ( 2012-02-21), p. 2730-2735
    Abstract: Therapies that target estrogen signaling have made a very considerable contribution to reducing mortality from breast cancer. However, resistance to tamoxifen remains a major clinical problem. Here we have used a genome-wide functional profiling approach to identify multiple genes that confer resistance or sensitivity to tamoxifen. Combining whole-genome shRNA screening with massively parallel sequencing, we have profiled the impact of more than 56,670 RNA interference reagents targeting 16,487 genes on the cellular response to tamoxifen. This screen, along with subsequent validation experiments, identifies a compendium of genes whose silencing causes tamoxifen resistance (including BAP1 , CLPP , GPRC5D , NAE1 , NF1 , NIPBL , NSD1 , RAD21 , RARG , SMC3 , and UBA3 ) and also a set of genes whose silencing causes sensitivity to this endocrine agent ( C10orf72 , C15orf55/NUT , EDF1 , ING5 , KRAS , NOC3L , PPP1R15B , RRAS2 , TMPRSS2 , and TPM4 ). Multiple individual genes, including NF1 , a regulator of RAS signaling, also correlate with clinical outcome after tamoxifen treatment.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1018872108
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    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2012
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  • 8
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    Hierarchical random walks in trace fossils and the origin of optimal search behavior
    Proceedings of the National Academy of Sciences ; 2014
    In:  Proceedings of the National Academy of Sciences Vol. 111, No. 30 ( 2014-07-29), p. 11073-11078
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 111, No. 30 ( 2014-07-29), p. 11073-11078
    Abstract: Efficient searching is crucial for timely location of food and other resources. Recent studies show that diverse living animals use a theoretically optimal scale-free random search for sparse resources known as a Lévy walk, but little is known of the origins and evolution of foraging behavior and the search strategies of extinct organisms. Here, using simulations of self-avoiding trace fossil trails, we show that randomly introduced strophotaxis (U-turns)—initiated by obstructions such as self-trail avoidance or innate cueing—leads to random looping patterns with clustering across increasing scales that is consistent with the presence of Lévy walks. This predicts that optimal Lévy searches may emerge from simple behaviors observed in fossil trails. We then analyzed fossilized trails of benthic marine organisms by using a novel path analysis technique and find the first evidence, to our knowledge, of Lévy-like search strategies in extinct animals. Our results show that simple search behaviors of extinct animals in heterogeneous environments give rise to hierarchically nested Brownian walk clusters that converge to optimal Lévy patterns. Primary productivity collapse and large-scale food scarcity characterizing mass extinctions evident in the fossil record may have triggered adaptation of optimal Lévy-like searches. The findings suggest that Lévy-like behavior has been used by foragers since at least the Eocene but may have a more ancient origin, which might explain recent widespread observations of such patterns among modern taxa.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1405966111
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    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2014
    detail.hit.zdb_id: 209104-5
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  • 9
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    Characterization of a 34-kDa soybean binding protein for the syringolide elicitors
    Proceedings of the National Academy of Sciences ; 1998
    In:  Proceedings of the National Academy of Sciences Vol. 95, No. 6 ( 1998-03-17), p. 3306-3311
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 95, No. 6 ( 1998-03-17), p. 3306-3311
    Abstract: Syringolides are water-soluble, low-molecular-weight elicitors that trigger defense responses in soybean cultivars carrying the Rpg4 disease-resistance gene but not in rpg 4 cultivars. 125 I-syringolide 1 previously was shown to bind to a soluble protein(s) in extracts from soybean leaves. A 34-kDa protein that accounted for 125 I-syringolide 1 binding activity was isolated with a syringolide affinity-gel column. Partial sequences of internal peptides of the 34-kDa protein were identical to P34, a previously described soybean seed allergen. In soybean seeds, P34 is processed from a 46-kDa precursor protein and was shown to have homology with thiol proteases. P34 is a moderately abundant protein in soybean seeds and cotyledons but its level in leaves is low. cDNAs encoding 46-, 34-, and 32-kDa forms of the soybean protein were cloned into the baculovirus vector, pVL1392, and expressed in insect cells. The resulting 32- and 34-kDa proteins, but not the 46-kDa protein, exhibited ligand-specific 125 I-syringolide binding activity. These results suggest that P34 may be the receptor that mediates syringolide signaling.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.95.6.3306
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    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 1998
    detail.hit.zdb_id: 209104-5
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  • 10
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    An ontogenetic switch drives the positive and negative selection of B cells
    Proceedings of the National Academy of Sciences ; 2020
    In:  Proceedings of the National Academy of Sciences Vol. 117, No. 7 ( 2020-02-18), p. 3718-3727
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 117, No. 7 ( 2020-02-18), p. 3718-3727
    Abstract: Developing B cells can be positively or negatively selected by self-antigens, but the mechanisms that determine these outcomes are incompletely understood. Here, we show that a B cell intrinsic switch between positive and negative selection during ontogeny is determined by a change from Lin28b to let-7 gene expression. Ectopic expression of a Lin28b transgene in murine B cells restored the positive selection of autoreactive B-1 B cells by self-antigen in adult bone marrow. Analysis of antigen-specific immature B cells in early and late ontogeny identified Lin28b-dependent genes associated with B-1 B cell development, including Arid3a and Bhleh41 , and Lin28b-independent effects are associated with the presence or absence of self-antigen. These findings identify cell intrinsic and extrinsic determinants of B cell fate during ontogeny and reconcile lineage and selection theories of B cell development. They explain how changes in the balance of positive and negative selection may be able to adapt to meet the immunological needs of an individual during its lifetime.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1915247117
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    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2020
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
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