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  • 1
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    Discovery of phosphonates by genome mining [Chemistry] (2015)
    National Academy of Sciences
    Details
    Publication Date: 2015-09-30
    Description: Although natural products have been a particularly rich source of human medicines, activity-based screening results in a very high rate of rediscovery of known molecules. Based on the large number of natural product biosynthetic genes in microbial genomes, many have proposed “genome mining” as an alternative approach for discovery efforts;...
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
    Published by National Academy of Sciences
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  • 2
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    Insulinotropic treatments exacerbate metabolic syndrome in mice lacking MeCP2 function (2013)
    Oxford University Press
    Details
    Publication Date: 2013-06-07
    Description: Rett syndrome (RTT), an X-linked postnatal disorder, results from mutations in Methyl CpG-binding protein 2 ( MECP2 ). Survival and breathing in Mecp2 NULL/Y animals are improved by an N-terminal tripeptide of insulin-like growth factor I (IGF-I) treatment. We determined that Mecp2 NULL/Y animals also have a metabolic syndrome and investigated whether IGF-I treatment might improve this phenotype. Mecp2 NULL/Y mice were treated with a full-length IGF-I modified with the addition of polyethylene glycol (PEG-IGF-I), which improves pharmacological properties. Low-dose PEG-IGF-I treatment slightly improved lifespan and heart rate in Mecp2 NULL/Y mice; however, high-dose PEG-IGF-I decreased lifespan. To determine whether insulinotropic off-target effects of PEG-IGF-I caused the detrimental effect, we treated Mecp2 NULL/Y mice with insulin, which also decreased lifespan. Thus, the clinical benefit of IGF-I treatment in RTT may critically depend on the dose used, and caution should be taken when initiating clinical trials with these compounds because the beneficial therapeutic window is narrow.
    Print ISSN: 0964-6906
    Electronic ISSN: 1460-2083
    Topics: Biology , Medicine
    Published by Oxford University Press
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  • 3
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    Formation of high-field magnetic white dwarfs from common envelopes [Astronomy] (2011)
    National Academy of Sciences
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    Publication Date: 2011-02-23
    Description: The origin of highly magnetized white dwarfs has remained a mystery since their initial discovery. Recent observations indicate that the formation of high-field magnetic white dwarfs is intimately related to strong binary interactions during post-main-sequence phases of stellar evolution. If a low-mass companion, such as a planet, brown dwarf, or low-mass star, is engulfed by a post-main-sequence giant, gravitational torques in the envelope of the giant lead to a reduction of the companion’s orbit. Sufficiently low-mass companions in-spiral until they are shredded by the strong gravitational tides near the white dwarf core. Subsequent formation of a super-Eddington accretion disk from the disrupted companion inside a common envelope can dramatically amplify magnetic fields via a dynamo. Here, we show that these disk-generated fields are sufficiently strong to explain the observed range of magnetic field strengths for isolated, high-field magnetic white dwarfs. A higher-mass binary analogue may also contribute to the origin of magnetar fields.
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
    Published by National Academy of Sciences
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  • 4
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    Pharmacologically induced mouse model of adult spinal muscular atrophy to evaluate effectiveness of therapeutics after disease onset (2016)
    Oxford University Press
    Details
    Publication Date: 2016-02-16
    Description: Spinal muscular atrophy (SMA) is a genetic disease characterized by atrophy of muscle and loss of spinal motor neurons. SMA is caused by deletion or mutation of the survival motor neuron 1 ( SMN1 ) gene, and the nearly identical SMN2 gene fails to generate adequate levels of functional SMN protein due to a splicing defect. Currently, several therapeutics targeted to increase SMN protein are in clinical trials. An outstanding issue in the field is whether initiating treatment in symptomatic older patients would confer a therapeutic benefit, an important consideration as the majority of patients with milder forms of SMA are diagnosed at an older age. An SMA mouse model that recapitulates the disease phenotype observed in adolescent and adult SMA patients is needed to address this important question. We demonstrate here that 7 mice, a model of severe SMA, treated with a suboptimal dose of an SMN2 splicing modifier show increased SMN protein, survive into adulthood and display SMA disease-relevant pathologies. Increasing the dose of the splicing modifier after the disease symptoms are apparent further mitigates SMA histopathological features in suboptimally dosed adult 7 mice. In addition, inhibiting myostatin using intramuscular injection of AAV1-follistatin ameliorates muscle atrophy in suboptimally dosed 7 mice. Taken together, we have developed a new murine model of symptomatic SMA in adolescents and adult mice that is induced pharmacologically from a more severe model and demonstrated efficacy of both SMN2 splicing modifiers and a myostatin inhibitor in mice at later disease stages.
    Print ISSN: 0964-6906
    Electronic ISSN: 1460-2083
    Topics: Biology , Medicine
    Published by Oxford University Press
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  • 5
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    Growth factors engineered for super-affinity to the extracellular matrix enhance tissue healing (2014)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2014-02-22
    Description: Growth factors (GFs) are critical in tissue repair, but their translation to clinical use has been modest. Physiologically, GF interactions with extracellular matrix (ECM) components facilitate localized and spatially regulated signaling; therefore, we reasoned that the lack of ECM binding in their clinically used forms could underlie the limited translation. We discovered that a domain in placenta growth factor-2 (PlGF-2(123-144)) binds exceptionally strongly and promiscuously to ECM proteins. By fusing this domain to the GFs vascular endothelial growth factor-A, platelet-derived growth factor-BB, and bone morphogenetic protein-2, we generated engineered GF variants with super-affinity to the ECM. These ECM super-affinity GFs induced repair in rodent models of chronic wounds and bone defects that was greatly enhanced as compared to treatment with the wild-type GFs, demonstrating that this approach may be useful in several regenerative medicine applications.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Martino, Mikael M -- Briquez, Priscilla S -- Guc, Esra -- Tortelli, Federico -- Kilarski, Witold W -- Metzger, Stephanie -- Rice, Jeffrey J -- Kuhn, Gisela A -- Muller, Ralph -- Swartz, Melody A -- Hubbell, Jeffrey A -- New York, N.Y. -- Science. 2014 Feb 21;343(6173):885-8. doi: 10.1126/science.1247663.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institute of Bioengineering, School of Life Sciences and School of Engineering, Ecole Polytechnique Federale de Lausanne, CH-1015 Lausanne, Switzerland.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24558160" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Bone Morphogenetic Protein 2/chemistry/genetics/metabolism ; Disease Models, Animal ; Extracellular Matrix/*metabolism ; Extracellular Matrix Proteins/chemistry/metabolism ; Heparitin Sulfate/chemistry/metabolism ; Humans ; Intercellular Signaling Peptides and Proteins/chemistry/genetics/*metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Pregnancy Proteins/chemistry/genetics/metabolism ; Protein Engineering ; Protein Structure, Tertiary ; Proto-Oncogene Proteins c-sis/chemistry/genetics/metabolism ; Vascular Endothelial Growth Factor A/chemistry/genetics/metabolism ; *Wound Healing
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
    Published by American Association for the Advancement of Science (AAAS)
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  • 6
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    Structure and mechanism of the LPLAT enzyme LpxM [Biochemistry] (2016)
    National Academy of Sciences
    Details
    Publication Date: 2016-10-12
    Description: Gram-negative bacteria possess a characteristic outer membrane, of which the lipid A constituent elicits a strong host immune response through the Toll-like receptor 4 complex, and acts as a component of the permeability barrier to prevent uptake of bactericidal compounds. Lipid A species comprise the bulk of the outer leaflet...
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
    Published by National Academy of Sciences
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  • 7
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    Size distribution of Parkfield's microearthquakes reflects changes in surface creep rate (2013)
    Oxford University Press
    Details
    Publication Date: 2013-05-09
    Description: The nucleation area of the series of M 6 events in Parkfield has been shown to be characterized by low b -values throughout the seismic cycle. Since low b -values represent high differential stresses, the asperity structure seems to be always stably stressed and even unaffected by the latest main shock in 2004. However, because fault loading rates and applied shear stress vary with time, some degree of temporal variability of the b -value within stable blocks is to be expected. We discuss in this study adequate techniques and uncertainty treatment for a detailed analysis of the temporal evolution of b -values. We show that the derived signal for the Parkfield asperity correlates with changes in surface creep, suggesting a sensitive time resolution of the b -value stress meter, and confirming near-critical loading conditions within the Parkfield asperity.
    Print ISSN: 0956-540X
    Electronic ISSN: 1365-246X
    Topics: Geosciences
    Published by Oxford University Press on behalf of The Deutsche Geophysikalische Gesellschaft (DGG) and the Royal Astronomical Society (RAS).
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  • 8
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    Tectonic interaction between the Pamir and Tien Shan observed by GPS (2016)
    Wiley
    In: Tectonics
    Details
    Publication Date: 2016-01-18
    Description: The complex tectonic interplay between the Central Asian Southwest Tien Shan and the north-advancing Pamir as well as the role of the Pamir Frontal Thrust (PFT) separating these two orogens along the intervening Alai valley is yet unclear. In this paper we present data of the newly installed Western Alai GPS profile (WAGP), capturing the deformation signal of both mountain ranges. The 20 km long WAGP records a maximum displacement rate of 9.3 ± 0.8 mm yr −1 . The lion's share of displacement (6.0 ± 0.8 mm yr −1 ) is accommodated between the two stations located directly north and south of the PFT in 5 km distance. The WAGP data nicely complement the existing South Tien Shan and the Pamir GPS network data, which we present here in a combined reference frame and use it as input for horizontal block rotation/strain models. The model results show that both the Southwest Tien Shan and the Pamir behave as uniformly strained blocks and rotate counterclockwise (with respect to Eurasia) by 0.93 ± 0.11° Myr −1 and 0.62 ± 0.05° Myr −1 , respectively. The Southwest Tien Shan undergoes NNE-SSW shortening of −22.1 ± 1.5 x 10 −9 yr −1 with an insignificant perpendicular extension. The Pamir is shortening with a rate of −10.2 ± 3.8 x 10 −9 yr −1 in a NNE-SSW direction, which is nearly 2.5 times less than its lateral extension rate. A band of increased deformation along the PFT is bounded to the North by the northern rim of the Alai valley and extends up to 30–50 km south into the Pamir.
    Print ISSN: 0278-7407
    Electronic ISSN: 1944-9194
    Topics: Geosciences
    Published by Wiley on behalf of American Geophysical Union (AGU).
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