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  • 1
    Online Resource
    Online Resource
    Alpha-kinase 1 is a cytosolic innate immune receptor for bacterial ADP-heptose
    Springer Science and Business Media LLC ; 2018
    In:  Nature Vol. 561, No. 7721 ( 2018-9), p. 122-126
    Details
    In: Nature, Springer Science and Business Media LLC, Vol. 561, No. 7721 ( 2018-9), p. 122-126
    Type of Medium: Online Resource
    ISSN: 0028-0836 , 1476-4687
    URL: Article
    DOI: 10.1038/s41586-018-0433-3
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    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2018
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  • 2
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    Revitalizing interface in protonic ceramic cells by acid etch
    Springer Science and Business Media LLC ; 2022
    In:  Nature Vol. 604, No. 7906 ( 2022-04-21), p. 479-485
    Details
    In: Nature, Springer Science and Business Media LLC, Vol. 604, No. 7906 ( 2022-04-21), p. 479-485
    Type of Medium: Online Resource
    ISSN: 0028-0836 , 1476-4687
    URL: Article
    DOI: 10.1038/s41586-022-04457-y
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    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2022
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  • 3
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    A multimodal cell census and atlas of the mammalian primary motor cortex
    Springer Science and Business Media LLC ; 2021
    In:  Nature Vol. 598, No. 7879 ( 2021-10-07), p. 86-102
    Details
    In: Nature, Springer Science and Business Media LLC, Vol. 598, No. 7879 ( 2021-10-07), p. 86-102
    Abstract: Here we report the generation of a multimodal cell census and atlas of the mammalian primary motor cortex as the initial product of the BRAIN Initiative Cell Census Network (BICCN). This was achieved by coordinated large-scale analyses of single-cell transcriptomes, chromatin accessibility, DNA methylomes, spatially resolved single-cell transcriptomes, morphological and electrophysiological properties and cellular resolution input–output mapping, integrated through cross-modal computational analysis. Our results advance the collective knowledge and understanding of brain cell-type organization 1–5 . First, our study reveals a unified molecular genetic landscape of cortical cell types that integrates their transcriptome, open chromatin and DNA methylation maps. Second, cross-species analysis achieves a consensus taxonomy of transcriptomic types and their hierarchical organization that is conserved from mouse to marmoset and human. Third, in situ single-cell transcriptomics provides a spatially resolved cell-type atlas of the motor cortex. Fourth, cross-modal analysis provides compelling evidence for the transcriptomic, epigenomic and gene regulatory basis of neuronal phenotypes such as their physiological and anatomical properties, demonstrating the biological validity and genomic underpinning of neuron types. We further present an extensive genetic toolset for targeting glutamatergic neuron types towards linking their molecular and developmental identity to their circuit function. Together, our results establish a unifying and mechanistic framework of neuronal cell-type organization that integrates multi-layered molecular genetic and spatial information with multi-faceted phenotypic properties.
    Type of Medium: Online Resource
    ISSN: 0028-0836 , 1476-4687
    URL: Article
    DOI: 10.1038/s41586-021-03950-0
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    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2021
    detail.hit.zdb_id: 120714-3
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  • 4
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    Probing CP symmetry and weak phases with entangled double-strange baryons
    Springer Science and Business Media LLC ; 2022
    In:  Nature Vol. 606, No. 7912 ( 2022-06-02), p. 64-69
    Details
    In: Nature, Springer Science and Business Media LLC, Vol. 606, No. 7912 ( 2022-06-02), p. 64-69
    Abstract: Though immensely successful, the standard model of particle physics does not offer any explanation as to why our Universe contains so much more matter than antimatter. A key to a dynamically generated matter–antimatter asymmetry is the existence of processes that violate the combined charge conjugation and parity (CP) symmetry 1 . As such, precision tests of CP symmetry may be used to search for physics beyond the standard model. However, hadrons decay through an interplay of strong and weak processes, quantified in terms of relative phases between the amplitudes. Although previous experiments constructed CP observables that depend on both strong and weak phases, we present an approach where sequential two-body decays of entangled multi-strange baryon–antibaryon pairs provide a separation between these phases. Our method, exploiting spin entanglement between the double-strange Ξ − baryon and its antiparticle 2 $${\bar{{\Xi }}}^{+}$$ Ξ ¯ + , has enabled a direct determination of the weak-phase difference, ( ξ P  −  ξ S ) = (1.2 ± 3.4 ± 0.8) × 10 −2  rad. Furthermore, three independent CP observables can be constructed from our measured parameters. The precision in the estimated parameters for a given data sample size is several orders of magnitude greater than achieved with previous methods 3 . Finally, we provide an independent measurement of the recently debated Λ decay parameter α Λ (refs.  4,5 ). The $${\Lambda }\bar{{\Lambda }}$$ Λ Λ ¯ asymmetry is in agreement with and compatible in precision to the most precise previous measurement 4 .
    Type of Medium: Online Resource
    ISSN: 0028-0836 , 1476-4687
    URL: Article
    DOI: 10.1038/s41586-022-04624-1
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    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2022
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  • 5
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    Impacts of species richness on productivity in a large-scale subtropical forest experiment
    American Association for the Advancement of Science (AAAS) ; 2018
    In:  Science Vol. 362, No. 6410 ( 2018-10-05), p. 80-83
    Details
    In: Science, American Association for the Advancement of Science (AAAS), Vol. 362, No. 6410 ( 2018-10-05), p. 80-83
    Abstract: Biodiversity experiments have shown that species loss reduces ecosystem functioning in grassland. To test whether this result can be extrapolated to forests, the main contributors to terrestrial primary productivity, requires large-scale experiments. We manipulated tree species richness by planting more than 150,000 trees in plots with 1 to 16 species. Simulating multiple extinction scenarios, we found that richness strongly increased stand-level productivity. After 8 years, 16-species mixtures had accumulated over twice the amount of carbon found in average monocultures and similar amounts as those of two commercial monocultures. Species richness effects were strongly associated with functional and phylogenetic diversity. A shrub addition treatment reduced tree productivity, but this reduction was smaller at high shrub species richness. Our results encourage multispecies afforestation strategies to restore biodiversity and mitigate climate change.
    Type of Medium: Online Resource
    ISSN: 0036-8075 , 1095-9203
    URL: Article
    DOI: 10.1126/science.aat6405
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    Language: English
    Publisher: American Association for the Advancement of Science (AAAS)
    Publication Date: 2018
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  • 6
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    Comparative genomic investigation of high-elevation adaptation in ectothermic snakes
    Proceedings of the National Academy of Sciences ; 2018
    In:  Proceedings of the National Academy of Sciences Vol. 115, No. 33 ( 2018-08-14), p. 8406-8411
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 115, No. 33 ( 2018-08-14), p. 8406-8411
    Abstract: Several previous genomic studies have focused on adaptation to high elevations, but these investigations have been largely limited to endotherms. Snakes of the genus Thermophis are endemic to the Tibetan plateau and therefore present an opportunity to study high-elevation adaptations in ectotherms. Here, we report the de novo assembly of the genome of a Tibetan hot-spring snake ( Thermophis baileyi ) and then compare its genome to the genomes of the other two species of Thermophis , as well as to the genomes of two related species of snakes that occur at lower elevations. We identify 308 putative genes that appear to be under positive selection in Thermophis . We also identified genes with shared amino acid replacements in the high-elevation hot-spring snakes compared with snakes and lizards that live at low elevations, including the genes for proteins involved in DNA damage repair ( FEN1 ) and response to hypoxia ( EPAS1 ). Functional assays of the FEN1 alleles reveal that the Thermophis allele is more stable under UV radiation than is the ancestral allele found in low-elevation lizards and snakes. Functional assays of EPAS1 alleles suggest that the Thermophis protein has lower transactivation activity than the low-elevation forms. Our analysis identifies some convergent genetic mechanisms in high-elevation adaptation between endotherms (based on studies of mammals) and ectotherms (based on our studies of Thermophis ).
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1805348115
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    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2018
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  • 7
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    De novo mutations across 1,465 diverse genomes reveal mutational insights and reductions in the Amish founder population
    Proceedings of the National Academy of Sciences ; 2020
    In:  Proceedings of the National Academy of Sciences Vol. 117, No. 5 ( 2020-02-04), p. 2560-2569
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 117, No. 5 ( 2020-02-04), p. 2560-2569
    Abstract: De novo mutations (DNMs), or mutations that appear in an individual despite not being seen in their parents, are an important source of genetic variation whose impact is relevant to studies of human evolution, genetics, and disease. Utilizing high-coverage whole-genome sequencing data as part of the Trans-Omics for Precision Medicine (TOPMed) Program, we called 93,325 single-nucleotide DNMs across 1,465 trios from an array of diverse human populations, and used them to directly estimate and analyze DNM counts, rates, and spectra. We find a significant positive correlation between local recombination rate and local DNM rate, and that DNM rate explains a substantial portion (8.98 to 34.92%, depending on the model) of the genome-wide variation in population-level genetic variation from 41K unrelated TOPMed samples. Genome-wide heterozygosity does correlate with DNM rate, but only explains 〈 1% of variation. While we are underpowered to see small differences, we do not find significant differences in DNM rate between individuals of European, African, and Latino ancestry, nor across ancestrally distinct segments within admixed individuals. However, we did find significantly fewer DNMs in Amish individuals, even when compared with other Europeans, and even after accounting for parental age and sequencing center. Specifically, we found significant reductions in the number of C→A and T→C mutations in the Amish, which seem to underpin their overall reduction in DNMs. Finally, we calculated near-zero estimates of narrow sense heritability ( h 2 ), which suggest that variation in DNM rate is significantly shaped by nonadditive genetic effects and the environment.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1902766117
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    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2020
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  • 8
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    Modulation of the proteostasis network promotes tumor resistance to oncogenic KRAS inhibitors
    American Association for the Advancement of Science (AAAS) ; 2023
    In:  Science Vol. 381, No. 6662 ( 2023-09-08)
    Details
    In: Science, American Association for the Advancement of Science (AAAS), Vol. 381, No. 6662 ( 2023-09-08)
    Abstract: KRAS is one of the most frequently mutated genes in human cancer. Despite advances in the development of inhibitors that directly target mutant KRAS and the approval of KRAS G12C inhibitors sotorasib and adagrasib for the treatment of KRAS G12C -mutant non–small cell lung cancer (NSCLC) patients, multiple lines of clinical and preclinical evidence demonstrate that adaptive resistance to KRAS inhibitors (KRASi) is rapid and almost inevitable. The heterogeneous resistance mechanisms in patients and dose-limiting toxicity associated with targeting multiple KRASi resistance pathways—such as receptor tyrosine kinases (RTKs), extracellular signal–regulated kinase (ERK), and AKT–remain a major barrier to progress. RATIONALE Most cancers require a balanced protein homeostasis (proteostasis) network to maintain oncogenic growth. Therapeutic insults often disrupt proteostasis and induce proteotoxic stresses. Residual drug-tolerant cells must overcome imbalances in the proteostasis network to maintain survival. How a proteostasis network is orchestrated by driver oncogenes and the proteostasis reprogramming mechanisms that bypass oncogene addiction and allow for acquired resistance to targeted therapies remain largely unknown. In this study, we investigated the regulation of proteostasis by oncogenic KRAS and the rewiring of proteostasis network underlying the acquired resistance to KRAS inhibition. RESULTS We show that oncogenic KRAS is critical for protein quality control in cancer cells. Genetic or pharmacological inhibition of oncogenic KRAS rapidly inactivated both cytosolic and endoplasmic reticulum (ER) protein quality control machinery, two essential components of the proteostasis network, through inhibition of the master regulators heat shock factor 1 (HSF1) and inositol-requiring enzyme 1α (IRE1α). However, residue cancer cells that survive KRASi directly reactivated IRE1α through an ER stress–independent phosphorylation mechanism that reestablished proteostasis and sustained acquired resistance to KRAS inhibition. We identified four oncogenic signaling–regulated phosphorylation sites in IRE1α (Ser 525 , Ser 529 , Ser 549 , and Thr 973 ) that are distinct from IRE1α autophosphorylation sites but are required for enhanced protein stability. The phosphorylation of IRE1α at these sites prevents IRE1α binding with the SEL1L/HRD1 E3 ligase complex, thus impairing the ubiquitination-dependent degradation of IRE1α and stabilizing the protein. These sites are the convergence points of multiple resistance mechanisms in KRASi-resistant tumors. RTK-mediated reactivation of ERK and hyperactivation of AKT sustained the unconventional phosphorylation of IRE1α in the KRASi-resistant tumors, which consequently restored its protein stability and reestablished proteostasis. Genetic or pharmacological suppression of IRE1α collapsed the rewired proteostasis network and overcame resistance to KRAS–MAPK (mitogen-activated protein kinase) inhibitors. CONCLUSION This study reveals the direct cross-talk between oncogenic signaling and the protein quality control machinery and uncovers the mechanisms that account for the proteostasis rewiring in response to KRAS inhibition. Multiple resistance mechanisms converge on IRE1α through ER stress–independent phosphorylation to restore proteostasis and promote KRASi-resistant tumor growth. Targeting this key convergence point represents an effective therapeutic strategy to overcome KRASi resistance. Proteostasis reprogramming upon KRAS inhibition. Inhibition of oncogenic KRAS inactivates both cytosolic and ER protein quality control machinery by inhibiting HSF1 and IRE1α. Residual cells that survive KRASi directly restore IRE1α phosphorylation through receptor tyrosine kinase–mediated reactivation of ERK and hyperactivation of AKT, preventing IRE1α from SEL1L/HRD1–mediated ubiquitination and degradation. Multiple heterogeneous resistance pathways converge on IRE1α to reestablish proteostasis and promote resistance to KRASi.
    Type of Medium: Online Resource
    ISSN: 0036-8075 , 1095-9203
    URL: Article
    DOI: 10.1126/science.abn4180
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    Language: English
    Publisher: American Association for the Advancement of Science (AAAS)
    Publication Date: 2023
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  • 9
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    Cross-host evolution of severe acute respiratory syndrome coronavirus in palm civet and human
    Proceedings of the National Academy of Sciences ; 2005
    In:  Proceedings of the National Academy of Sciences Vol. 102, No. 7 ( 2005-02-15), p. 2430-2435
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 102, No. 7 ( 2005-02-15), p. 2430-2435
    Abstract: The genomic sequences of severe acute respiratory syndrome coronaviruses from human and palm civet of the 2003/2004 outbreak in the city of Guangzhou, China, were nearly identical. Phylogenetic analysis suggested an independent viral invasion from animal to human in this new episode. Combining all existing data but excluding singletons, we identified 202 single-nucleotide variations. Among them, 17 are polymorphic in palm civets only. The ratio of nonsynonymous/synonymous nucleotide substitution in palm civets collected 1 yr apart from different geographic locations is very high, suggesting a rapid evolving process of viral proteins in civet as well, much like their adaptation in the human host in the early 2002–2003 epidemic. Major genetic variations in some critical genes, particularly the Spike gene, seemed essential for the transition from animal-to-human transmission to human-to-human transmission, which eventually caused the first severe acute respiratory syndrome outbreak of 2002/2003.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.0409608102
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    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2005
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  • 10
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    Versatile pathway-centric approach based on high-throughput sequencing to anticancer drug discovery
    Proceedings of the National Academy of Sciences ; 2012
    In:  Proceedings of the National Academy of Sciences Vol. 109, No. 12 ( 2012-03-20), p. 4609-4614
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 109, No. 12 ( 2012-03-20), p. 4609-4614
    Abstract: The advent of powerful genomics technologies has uncovered many fundamental aspects of biology, including the mechanisms of cancer; however, it has not been appropriately matched by the development of global approaches to discover new medicines against human diseases. Here we describe a unique high-throughput s creening strategy by high-throughput sequencing, referred to as HTS 2 , to meet this challenge. This technology enables large-scale and quantitative analysis of gene matrices associated with specific disease phenotypes, therefore allowing screening for small molecules that can specifically intervene with disease-linked gene-expression events. By initially applying this multitarget strategy to the pressing problem of hormone-refractory prostate cancer, which tends to be accelerated by the current antiandrogen therapy, we identify Peruvoside, a cardiac glycoside, which can potently inhibit both androgen-sensitive and -resistant prostate cancer cells without triggering severe cytotoxicity. We further show that, despite transcriptional reprogramming in prostate cancer cells at different disease stages, the compound can effectively block androgen receptor-dependent gene expression by inducing rapid androgen receptor degradation via the proteasome pathway. These findings establish a genomics-based phenotypic screening approach capable of quickly connecting pathways of phenotypic response to the molecular mechanism of drug action, thus offering a unique pathway-centric strategy for drug discovery.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1200305109
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    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2012
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