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  • American Association for the Advancement of Science (AAAS)  (86)
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  • American Association for the Advancement of Science (AAAS)  (86)
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  • English  (86)
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  • 1
    Online Resource
    Online Resource
    American Association for the Advancement of Science (AAAS) ; 2023
    In:  Science Vol. 380, No. 6652 ( 2023-06-30), p. 1390-1396
    In: Science, American Association for the Advancement of Science (AAAS), Vol. 380, No. 6652 ( 2023-06-30), p. 1390-1396
    Abstract: Observations of the bright gamma-ray burst GRB 221009A at tera–electron volt energies show that it contained a very narrow jet.
    Type of Medium: Online Resource
    ISSN: 0036-8075 , 1095-9203
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    Language: English
    Publisher: American Association for the Advancement of Science (AAAS)
    Publication Date: 2023
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  • 2
    Online Resource
    Online Resource
    American Association for the Advancement of Science (AAAS) ; 2021
    In:  Science Vol. 373, No. 6553 ( 2021-07-23), p. 425-430
    In: Science, American Association for the Advancement of Science (AAAS), Vol. 373, No. 6553 ( 2021-07-23), p. 425-430
    Abstract: The Crab Nebula is a bright source of gamma rays powered by the Crab Pulsar’s rotational energy through the formation and termination of a relativistic electron-positron wind. We report the detection of gamma rays from this source with energies from 5 × 10 −4 to 1.1 peta–electron volts with a spectrum showing gradual steepening over three energy decades. The ultrahigh-energy photons imply the presence of a peta–electron volt electron accelerator (a pevatron) in the nebula, with an acceleration rate exceeding 15% of the theoretical limit. We constrain the pevatron’s size between 0.025 and 0.1 parsecs and the magnetic field to ≈110 microgauss. The production rate of peta–electron volt electrons, 2.5 × 10 36 ergs per second, constitutes 0.5% of the pulsar spin-down luminosity, although we cannot exclude a contribution of peta–electron volt protons to the production of the highest-energy gamma rays.
    Type of Medium: Online Resource
    ISSN: 0036-8075 , 1095-9203
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    Language: English
    Publisher: American Association for the Advancement of Science (AAAS)
    Publication Date: 2021
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  • 3
    In: Science, American Association for the Advancement of Science (AAAS), Vol. 338, No. 6114 ( 2012-12-21), p. 1576-1582
    Abstract: The ATLAS detector measured several characteristic decay products of the standard model Higgs boson, allowing its mass to be determined.
    Type of Medium: Online Resource
    ISSN: 0036-8075 , 1095-9203
    RVK:
    RVK:
    Language: English
    Publisher: American Association for the Advancement of Science (AAAS)
    Publication Date: 2012
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  • 4
    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
    RVK:
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    Language: English
    Publisher: American Association for the Advancement of Science (AAAS)
    Publication Date: 2023
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  • 5
    In: Science, American Association for the Advancement of Science (AAAS), Vol. 378, No. 6615 ( 2022-10-07)
    Abstract: Investment in Africa over the past year with regard to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) sequencing has led to a massive increase in the number of sequences, which, to date, exceeds 100,000 sequences generated to track the pandemic on the continent. These sequences have profoundly affected how public health officials in Africa have navigated the COVID-19 pandemic. RATIONALE We demonstrate how the first 100,000 SARS-CoV-2 sequences from Africa have helped monitor the epidemic on the continent, how genomic surveillance expanded over the course of the pandemic, and how we adapted our sequencing methods to deal with an evolving virus. Finally, we also examine how viral lineages have spread across the continent in a phylogeographic framework to gain insights into the underlying temporal and spatial transmission dynamics for several variants of concern (VOCs). RESULTS Our results indicate that the number of countries in Africa that can sequence the virus within their own borders is growing and that this is coupled with a shorter turnaround time from the time of sampling to sequence submission. Ongoing evolution necessitated the continual updating of primer sets, and, as a result, eight primer sets were designed in tandem with viral evolution and used to ensure effective sequencing of the virus. The pandemic unfolded through multiple waves of infection that were each driven by distinct genetic lineages, with B.1-like ancestral strains associated with the first pandemic wave of infections in 2020. Successive waves on the continent were fueled by different VOCs, with Alpha and Beta cocirculating in distinct spatial patterns during the second wave and Delta and Omicron affecting the whole continent during the third and fourth waves, respectively. Phylogeographic reconstruction points toward distinct differences in viral importation and exportation patterns associated with the Alpha, Beta, Delta, and Omicron variants and subvariants, when considering both Africa versus the rest of the world and viral dissemination within the continent. Our epidemiological and phylogenetic inferences therefore underscore the heterogeneous nature of the pandemic on the continent and highlight key insights and challenges, for instance, recognizing the limitations of low testing proportions. We also highlight the early warning capacity that genomic surveillance in Africa has had for the rest of the world with the detection of new lineages and variants, the most recent being the characterization of various Omicron subvariants. CONCLUSION Sustained investment for diagnostics and genomic surveillance in Africa is needed as the virus continues to evolve. This is important not only to help combat SARS-CoV-2 on the continent but also because it can be used as a platform to help address the many emerging and reemerging infectious disease threats in Africa. In particular, capacity building for local sequencing within countries or within the continent should be prioritized because this is generally associated with shorter turnaround times, providing the most benefit to local public health authorities tasked with pandemic response and mitigation and allowing for the fastest reaction to localized outbreaks. These investments are crucial for pandemic preparedness and response and will serve the health of the continent well into the 21st century. Expanse of SARS-CoV-2 sequencing capacity in Africa. ( A ) African countries (shaded in gray) and institutions (red circles) with on-site sequencing facilities that are capable of producing SARS-CoV-2 whole genomes locally. ( B ) The number of SARS-CoV-2 genomes produced per country and the proportion of those genomes that were produced locally, regionally within Africa, or abroad. ( C ) Decreased turnaround time of sequencing output in Africa to an almost real-time release of genomic data.
    Type of Medium: Online Resource
    ISSN: 0036-8075 , 1095-9203
    RVK:
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    Language: English
    Publisher: American Association for the Advancement of Science (AAAS)
    Publication Date: 2022
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  • 6
    In: Science, American Association for the Advancement of Science (AAAS), Vol. 296, No. 5573 ( 2002-05-31), p. 1661-1671
    Abstract: The high degree of similarity between the mouse and human genomes is demonstrated through analysis of the sequence of mouse chromosome 16 (Mmu 16), which was obtained as part of a whole-genome shotgun assembly of the mouse genome. The mouse genome is about 10% smaller than the human genome, owing to a lower repetitive DNA content. Comparison of the structure and protein-coding potential of Mmu 16 with that of the homologous segments of the human genome identifies regions of conserved synteny with human chromosomes (Hsa) 3, 8, 12, 16, 21, and 22. Gene content and order are highly conserved between Mmu 16 and the syntenic blocks of the human genome. Of the 731 predicted genes on Mmu 16, 509 align with orthologs on the corresponding portions of the human genome, 44 are likely paralogous to these genes, and 164 genes have homologs elsewhere in the human genome; there are 14 genes for which we could find no human counterpart.
    Type of Medium: Online Resource
    ISSN: 0036-8075 , 1095-9203
    RVK:
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    Language: English
    Publisher: American Association for the Advancement of Science (AAAS)
    Publication Date: 2002
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  • 7
    In: Science, American Association for the Advancement of Science (AAAS), Vol. 291, No. 5507 ( 2001-02-16), p. 1304-1351
    Abstract: A 2.91-billion base pair (bp) consensus sequence of the euchromatic portion of the human genome was generated by the whole-genome shotgun sequencing method. The 14.8-billion bp DNA sequence was generated over 9 months from 27,271,853 high-quality sequence reads (5.11-fold coverage of the genome) from both ends of plasmid clones made from the DNA of five individuals. Two assembly strategies—a whole-genome assembly and a regional chromosome assembly—were used, each combining sequence data from Celera and the publicly funded genome effort. The public data were shredded into 550-bp segments to create a 2.9-fold coverage of those genome regions that had been sequenced, without including biases inherent in the cloning and assembly procedure used by the publicly funded group. This brought the effective coverage in the assemblies to eightfold, reducing the number and size of gaps in the final assembly over what would be obtained with 5.11-fold coverage. The two assembly strategies yielded very similar results that largely agree with independent mapping data. The assemblies effectively cover the euchromatic regions of the human chromosomes. More than 90% of the genome is in scaffold assemblies of 100,000 bp or more, and 25% of the genome is in scaffolds of 10 million bp or larger. Analysis of the genome sequence revealed 26,588 protein-encoding transcripts for which there was strong corroborating evidence and an additional ∼12,000 computationally derived genes with mouse matches or other weak supporting evidence. Although gene-dense clusters are obvious, almost half the genes are dispersed in low G+C sequence separated by large tracts of apparently noncoding sequence. Only 1.1% of the genome is spanned by exons, whereas 24% is in introns, with 75% of the genome being intergenic DNA. Duplications of segmental blocks, ranging in size up to chromosomal lengths, are abundant throughout the genome and reveal a complex evolutionary history. Comparative genomic analysis indicates vertebrate expansions of genes associated with neuronal function, with tissue-specific developmental regulation, and with the hemostasis and immune systems. DNA sequence comparisons between the consensus sequence and publicly funded genome data provided locations of 2.1 million single-nucleotide polymorphisms (SNPs). A random pair of human haploid genomes differed at a rate of 1 bp per 1250 on average, but there was marked heterogeneity in the level of polymorphism across the genome. Less than 1% of all SNPs resulted in variation in proteins, but the task of determining which SNPs have functional consequences remains an open challenge.
    Type of Medium: Online Resource
    ISSN: 0036-8075 , 1095-9203
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    Language: English
    Publisher: American Association for the Advancement of Science (AAAS)
    Publication Date: 2001
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  • 8
    In: Science, American Association for the Advancement of Science (AAAS), Vol. 361, No. 6399 ( 2018-07-20), p. 278-281
    Abstract: Atmospheric new particle formation (NPF) is an important global phenomenon that is nevertheless sensitive to ambient conditions. According to both observation and theoretical arguments, NPF usually requires a relatively high sulfuric acid (H 2 SO 4 ) concentration to promote the formation of new particles and a low preexisting aerosol loading to minimize the sink of new particles. We investigated NPF in Shanghai and were able to observe both precursor vapors (H 2 SO 4 ) and initial clusters at a molecular level in a megacity. High NPF rates were observed to coincide with several familiar markers suggestive of H 2 SO 4 –dimethylamine (DMA)–water (H 2 O) nucleation, including sulfuric acid dimers and H 2 SO 4 -DMA clusters. In a cluster kinetics simulation, the observed concentration of sulfuric acid was high enough to explain the particle growth to ~3 nanometers under the very high condensation sink, whereas the subsequent higher growth rate beyond this size is believed to result from the added contribution of condensing organic species. These findings will help in understanding urban NPF and its air quality and climate effects, as well as in formulating policies to mitigate secondary particle formation in China.
    Type of Medium: Online Resource
    ISSN: 0036-8075 , 1095-9203
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    Language: English
    Publisher: American Association for the Advancement of Science (AAAS)
    Publication Date: 2018
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  • 9
    In: Science, American Association for the Advancement of Science (AAAS), Vol. 298, No. 5591 ( 2002-10-04), p. 129-149
    Abstract: Anopheles gambiae is the principal vector of malaria, a disease that afflicts more than 500 million people and causes more than 1 million deaths each year. Tenfold shotgun sequence coverage was obtained from the PEST strain of A. gambiae and assembled into scaffolds that span 278 million base pairs. A total of 91% of the genome was organized in 303 scaffolds; the largest scaffold was 23.1 million base pairs. There was substantial genetic variation within this strain, and the apparent existence of two haplotypes of approximately equal frequency (“dual haplotypes”) in a substantial fraction of the genome likely reflects the outbred nature of the PEST strain. The sequence produced a conservative inference of more than 400,000 single-nucleotide polymorphisms that showed a markedly bimodal density distribution. Analysis of the genome sequence revealed strong evidence for about 14,000 protein-encoding transcripts. Prominent expansions in specific families of proteins likely involved in cell adhesion and immunity were noted. An expressed sequence tag analysis of genes regulated by blood feeding provided insights into the physiological adaptations of a hematophagous insect.
    Type of Medium: Online Resource
    ISSN: 0036-8075 , 1095-9203
    RVK:
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    Language: English
    Publisher: American Association for the Advancement of Science (AAAS)
    Publication Date: 2002
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    detail.hit.zdb_id: 2066996-3
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  • 10
    Online Resource
    Online Resource
    American Association for the Advancement of Science (AAAS) ; 2023
    In:  Science Vol. 380, No. 6648 ( 2023-06-02), p. 913-924
    In: Science, American Association for the Advancement of Science (AAAS), Vol. 380, No. 6648 ( 2023-06-02), p. 913-924
    Abstract: Comparative analysis of primate genomes within a phylogenetic context is essential for understanding the evolution of human genetic architecture and primate diversity. We present such a study of 50 primate species spanning 38 genera and 14 families, including 27 genomes first reported here, with many from previously less well represented groups, the New World monkeys and the Strepsirrhini. Our analyses reveal heterogeneous rates of genomic rearrangement and gene evolution across primate lineages. Thousands of genes under positive selection in different lineages play roles in the nervous, skeletal, and digestive systems and may have contributed to primate innovations and adaptations. Our study reveals that many key genomic innovations occurred in the Simiiformes ancestral node and may have had an impact on the adaptive radiation of the Simiiformes and human evolution.
    Type of Medium: Online Resource
    ISSN: 0036-8075 , 1095-9203
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    Language: English
    Publisher: American Association for the Advancement of Science (AAAS)
    Publication Date: 2023
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    detail.hit.zdb_id: 2066996-3
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    SSG: 11
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