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  • 1
    Online Resource
    Online Resource
    Wildfire prevention through prophylactic treatment of high-risk landscapes using viscoelastic retardant fluids
    Proceedings of the National Academy of Sciences ; 2019
    In:  Proceedings of the National Academy of Sciences Vol. 116, No. 42 ( 2019-10-15), p. 20820-20827
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 116, No. 42 ( 2019-10-15), p. 20820-20827
    Abstract: Polyphosphate fire retardants are a critical tactical resource for fighting fires in the wildland and in the wildland–urban interface. Yet, application of these retardants is limited to emergency suppression strategies because current formulations cannot retain fire retardants on target vegetation for extended periods of time through environmental exposure and weathering. New retardant formulations with persistent retention to target vegetation throughout the peak fire season would enable methodical, prophylactic treatment strategies of landscapes at high risk of wildfires through prolonged prevention of ignition and continual impediment to active flaming fronts. Here we develop a sprayable, environmentally benign viscoelastic fluid comprising biopolymers and colloidal silica to enhance adherence and retention of polyphosphate retardants on common wildfire-prone vegetation. These viscoelastic fluids exhibit appropriate wetting and rheological responses to enable robust retardant adherence to vegetation following spray application. Further, laboratory and pilot-scale burn studies establish that these materials drastically reduce ignition probability before and after simulated weathering events. Overall, these studies demonstrate how these materials actualize opportunities to shift the approach of retardant-based wildfire management from reactive suppression to proactive prevention at the source of ignitions.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1907855116
    RVK:
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    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2019
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  • 2
    Online Resource
    Online Resource
    The iron-regulated vacuolar Legionella pneumophila MavN protein is a transition-metal transporter
    Proceedings of the National Academy of Sciences ; 2019
    In:  Proceedings of the National Academy of Sciences Vol. 116, No. 36 ( 2019-09-03), p. 17775-17785
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 116, No. 36 ( 2019-09-03), p. 17775-17785
    Abstract: Legionella pneumophila causes a potentially fatal form of pneumonia by replicating within macrophages in the Legionella -containing vacuole (LCV). Bacterial survival and proliferation within the LCV rely on hundreds of secreted effector proteins comprising high functional redundancy. The vacuolar membrane-localized MavN, hypothesized to support iron transport, is unique among effectors because loss-of-function mutations result in severe intracellular growth defects. We show here an iron starvation response by L. pneumophila after infection of macrophages that was prematurely induced in the absence of MavN, consistent with MavN granting access to limiting cellular iron stores. MavN cysteine accessibilities to a membrane-impermeant label were determined during macrophage infections, revealing a topological pattern supporting multipass membrane transporter models. Mutations to several highly conserved residues that can take part in metal recognition and transport resulted in defective intracellular growth. Purified MavN and mutant derivatives were directly tested for transporter activity after heterologous purification and liposome reconstitution. Proteoliposomes harboring MavN exhibited robust transport of Fe 2+ , with the severity of defect of most mutants closely mimicking the magnitude of defects during intracellular growth. Surprisingly, MavN was equivalently proficient at transporting Fe 2+ , Mn 2+ , Co 2+ , or Zn 2+ . Consequently, flooding infected cells with either Mn 2+ or Zn 2+ allowed collaboration with iron to enhance intracellular growth of L. pneumophila Δ mavN strains, indicating a clear role for MavN in transporting each of these ions. These findings reveal that MavN is a transition-metal-ion transporter that plays a critical role in response to iron limitation during Legionella infection.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1902806116
    RVK:
    TA 1000
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    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2019
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  • 3
    Online Resource
    Online Resource
    Regulation of RAS oncogenicity by acetylation
    Proceedings of the National Academy of Sciences ; 2012
    In:  Proceedings of the National Academy of Sciences Vol. 109, No. 27 ( 2012-07-03), p. 10843-10848
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 109, No. 27 ( 2012-07-03), p. 10843-10848
    Abstract: Members of the RAS small GTPase family regulate cellular responses to extracellular stimuli by mediating the flux through downstream signal transduction cascades. RAS activity is strongly dependent on its subcellular localization and its nucleotide-binding status, both of which are modulated by posttranslational modification. We have determined that RAS is posttranslationally acetylated on lysine 104. Molecular dynamics simulations suggested that this modification affects the conformational stability of the Switch II domain, which is critical for the ability of RAS to interact with guanine nucleotide exchange factors. Consistent with this model, an acetylation-mimetic mutation in K-RAS4B suppressed guanine nucleotide exchange factor-induced nucleotide exchange and inhibited in vitro transforming activity. These data suggest that lysine acetylation is a negative regulatory modification on RAS. Because mutations in RAS family members are extremely common in cancer, modulation of RAS acetylation may constitute a therapeutic approach.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1201487109
    RVK:
    TA 1000
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    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2012
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  • 4
    Online Resource
    Online Resource
    Probing the active site tightness of DNA polymerase in subangstrom increments
    Proceedings of the National Academy of Sciences ; 2005
    In:  Proceedings of the National Academy of Sciences Vol. 102, No. 44 ( 2005-11), p. 15803-15808
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 102, No. 44 ( 2005-11), p. 15803-15808
    Abstract: We describe the use of a series of gradually expanded thymine nucleobase analogs in probing steric effects in DNA polymerase efficiency and fidelity. In these nonpolar compounds, the base size was increased incrementally over a 1.0-Å range by use of variably sized atoms (H, F, Cl, Br, and I) to replace the oxygen molecules of thymine. Kinetics studies with DNA Pol I (Klenow fragment, exonuclease-deficient) in vitro showed that replication efficiency opposite adenine increased through the series, reaching a peak at the chlorinated compound. Efficiency then dropped markedly as a steric tightness limit was apparently reached. Importantly, fidelity also followed this trend, with the fidelity maximum at dichlorotoluene, the largest compound that fits without apparent repulsion. The fidelity at this point approached that of wild-type thymine. Surprisingly, the maximum fidelity and efficiency was found at a base pair size significantly larger than the natural size. Parallel bypass and mutagenesis experiments were then carried out in vivo with a bacterial assay for replication. The cellular results were virtually the same as those seen in solution. The results provide direct evidence for the importance of a tight steric fit on DNA replication fidelity. In addition, the results suggest that even high-fidelity replicative enzymes have more steric room than necessary, possibly to allow for an evolutionarily advantageous mutation rate.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.0505113102
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2005
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  • 5
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    Online Resource
    Inhibition of influenza virus replication via small molecules that induce the formation of higher-order nucleoprotein oligomers
    Proceedings of the National Academy of Sciences ; 2011
    In:  Proceedings of the National Academy of Sciences Vol. 108, No. 37 ( 2011-09-13), p. 15366-15371
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 108, No. 37 ( 2011-09-13), p. 15366-15371
    Abstract: Influenza nucleoprotein (NP) plays multiple roles in the virus life cycle, including an essential function in viral replication as an integral component of the ribonucleoprotein complex, associating with viral RNA and polymerase within the viral core. The multifunctional nature of NP makes it an attractive target for antiviral intervention, and inhibitors targeting this protein have recently been reported. In a parallel effort, we discovered a structurally similar series of influenza replication inhibitors and show that they interfere with NP-dependent processes via formation of higher-order NP oligomers. Support for this unique mechanism is provided by site-directed mutagenesis studies, biophysical characterization of the oligomeric ligand:NP complex, and an X-ray cocrystal structure of an NP dimer of trimers (or hexamer) comprising three NP_A:NP_B dimeric subunits. Each NP_A:NP_B dimeric subunit contains two ligands that bridge two composite, protein-spanning binding sites in an antiparallel orientation to form a stable quaternary complex. Optimization of the initial screening hit produced an analog that protects mice from influenza-induced weight loss and mortality by reducing viral titers to undetectable levels throughout the course of treatment.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1107906108
    RVK:
    TA 1000
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    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2011
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  • 6
    Online Resource
    Online Resource
    Transitions to catalytically inactive conformations in EGFR kinase
    Proceedings of the National Academy of Sciences ; 2013
    In:  Proceedings of the National Academy of Sciences Vol. 110, No. 18 ( 2013-04-30), p. 7270-7275
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 110, No. 18 ( 2013-04-30), p. 7270-7275
    Abstract: The epidermal growth factor receptor (EGFR) is a key protein in cellular signaling, and its kinase domain (EGFR kinase) is an intensely pursued target of small-molecule drugs. Although both catalytically active and inactive conformations of EGFR kinase have been resolved crystallographically, experimental characterization of the transitions between these conformations remains difficult. Using unbiased, all-atom molecular dynamics simulations, we observed EGFR kinase spontaneously transition from the active to the so-called “Src-like inactive” conformation by way of two sets of intermediate conformations: One corresponds to a previously identified locally disordered state and the other to previously undescribed “extended” conformations, marked by the opening of the ATP-binding site between the two lobes of the kinase domain. We also simulated the protonation-dependent transition of EGFR kinase to another [“Asp-Phe-Gly-out” (“DFG-out”)] inactive conformation and observed similar intermediate conformations. A key element observed in the simulated transitions is local unfolding, or “cracking,” which supports a prediction of energy landscape theory. We used hydrogen–deuterium (H/D) exchange measurements to corroborate our simulations and found that the simulated intermediate conformations correlate better with the H/D exchange data than existing active or inactive EGFR kinase crystal structures. The intermediate conformations revealed by our simulations of the transition process differ significantly from the existing crystal structures and may provide unique possibilities for structure-based drug discovery.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1220843110
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2013
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  • 7
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    Online Resource
    Multimessenger observations of a flaring blazar coincident with high-energy neutrino IceCube-170922A
    American Association for the Advancement of Science (AAAS) ; 2018
    In:  Science Vol. 361, No. 6398 ( 2018-07-13)
    Details
    In: Science, American Association for the Advancement of Science (AAAS), Vol. 361, No. 6398 ( 2018-07-13)
    Type of Medium: Online Resource
    ISSN: 0036-8075 , 1095-9203
    URL: Article
    DOI: 10.1126/science.aat1378
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    Language: English
    Publisher: American Association for the Advancement of Science (AAAS)
    Publication Date: 2018
    detail.hit.zdb_id: 128410-1
    detail.hit.zdb_id: 2066996-3
    detail.hit.zdb_id: 2060783-0
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  • 8
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    Online Resource
    Morphometricity as a measure of the neuroanatomical signature of a trait
    Proceedings of the National Academy of Sciences ; 2016
    In:  Proceedings of the National Academy of Sciences Vol. 113, No. 39 ( 2016-09-27)
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 113, No. 39 ( 2016-09-27)
    Abstract: Complex physiological and behavioral traits, including neurological and psychiatric disorders, often associate with distributed anatomical variation. This paper introduces a global metric, called morphometricity, as a measure of the anatomical signature of different traits. Morphometricity is defined as the proportion of phenotypic variation that can be explained by macroscopic brain morphology. We estimate morphometricity via a linear mixed-effects model that uses an anatomical similarity matrix computed based on measurements derived from structural brain MRI scans. We examined over 3,800 unique MRI scans from nine large-scale studies to estimate the morphometricity of a range of phenotypes, including clinical diagnoses such as Alzheimer’s disease, and nonclinical traits such as measures of cognition. Our results demonstrate that morphometricity can provide novel insights about the neuroanatomical correlates of a diverse set of traits, revealing associations that might not be detectable through traditional statistical techniques.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1604378113
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2016
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  • 9
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    Anatomically interpretable deep learning of brain age captures domain-specific cognitive impairment
    Proceedings of the National Academy of Sciences ; 2023
    In:  Proceedings of the National Academy of Sciences Vol. 120, No. 2 ( 2023-01-10)
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 120, No. 2 ( 2023-01-10)
    Abstract: The gap between chronological age (CA) and biological brain age, as estimated from magnetic resonance images (MRIs), reflects how individual patterns of neuroanatomic aging deviate from their typical trajectories. MRI-derived brain age (BA) estimates are often obtained using deep learning models that may perform relatively poorly on new data or that lack neuroanatomic interpretability. This study introduces a convolutional neural network (CNN) to estimate BA after training on the MRIs of 4,681 cognitively normal (CN) participants and testing on 1,170 CN participants from an independent sample. BA estimation errors are notably lower than those of previous studies. At both individual and cohort levels, the CNN provides detailed anatomic maps of brain aging patterns that reveal sex dimorphisms and neurocognitive trajectories in adults with mild cognitive impairment (MCI, N  = 351) and Alzheimer’s disease (AD, N  = 359). In individuals with MCI (54% of whom were diagnosed with dementia within 10.9 y from MRI acquisition), BA is significantly better than CA in capturing dementia symptom severity, functional disability, and executive function. Profiles of sex dimorphism and lateralization in brain aging also map onto patterns of neuroanatomic change that reflect cognitive decline. Significant associations between BA and neurocognitive measures suggest that the proposed framework can map, systematically, the relationship between aging-related neuroanatomy changes in CN individuals and in participants with MCI or AD. Early identification of such neuroanatomy changes can help to screen individuals according to their AD risk.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.2214634120
    RVK:
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    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2023
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  • 10
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    Characteristics of amnestic patients with hypometabolism patterns suggestive of Lewy body pathology
    Oxford University Press (OUP) ; 2023
    In:  Brain ( 2023-06-07)
    Details
    In: Brain, Oxford University Press (OUP), ( 2023-06-07)
    Abstract: A clinical diagnosis of Alzheimer’s disease dementia (ADD) encompasses considerable pathological and clinical heterogeneity. While Alzheimer’s disease patients typically show a characteristic temporo-parietal pattern of glucose hypometabolism on 18F-fluorodeoxyglucose (FDG)-PET imaging, previous studies have identified a subset of patients showing a distinct posterior-occipital hypometabolism pattern associated with Lewy body pathology. Here, we aimed to improve the understanding of the clinical relevance of these posterior-occipital FDG-PET patterns in patients with Alzheimer’s disease-like amnestic presentations. Our study included 1214 patients with clinical diagnoses of ADD (n = 305) or amnestic mild cognitive impairment (aMCI, n = 909) from the Alzheimer’s Disease Neuroimaging Initiative, who had FDG-PET scans available. Individual FDG-PET scans were classified as being suggestive of Alzheimer’s (AD-like) or Lewy body (LB-like) pathology by using a logistic regression classifier trained on a separate set of patients with autopsy-confirmed Alzheimer’s disease or Lewy body pathology. AD- and LB-like subgroups were compared on amyloid-β and tau-PET, domain-specific cognitive profiles (memory versus executive function performance), as well as the presence of hallucinations and their evolution over follow-up (≈6 years for aMCI, ≈3 years for ADD). Around 12% of the aMCI and ADD patients were classified as LB-like. For both aMCI and ADD patients, the LB-like group showed significantly lower regional tau-PET burden than the AD-like subgroup, but amyloid-β load was only significantly lower in the aMCI LB-like subgroup. LB- and AD-like subgroups did not significantly differ in global cognition (aMCI: d = 0.15, P = 0.16; ADD: d = 0.02, P = 0.90), but LB-like patients exhibited a more dysexecutive cognitive profile relative to the memory deficit (aMCI: d = 0.35, P = 0.01; ADD: d = 0.85 P & lt; 0.001), and had a significantly higher risk of developing hallucinations over follow-up [aMCI: hazard ratio = 1.8, 95% confidence interval = (1.29, 3.04), P = 0.02; ADD: hazard ratio = 2.2, 95% confidence interval = (1.53, 4.06) P = 0.01]. In summary, a sizeable group of clinically diagnosed ADD and aMCI patients exhibit posterior-occipital FDG-PET patterns typically associated with Lewy body pathology, and these also show less abnormal Alzheimer’s disease biomarkers as well as specific clinical features typically associated with dementia with Lewy bodies.
    Type of Medium: Online Resource
    ISSN: 0006-8950 , 1460-2156
    URL: Article
    DOI: 10.1093/brain/awad194
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    XA 10000
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2023
    detail.hit.zdb_id: 1474117-9
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