Proceedings of the Natural Academy of Sciences

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  • Connectivity dynamics and seizure onset zone [Neuroscience]
    [Dec 2014]

    The human brain is a dynamic networked system. Patients with partial epileptic seizures have focal regions that periodically diverge from normal brain network dynamics during seizures. We studied the evolution of brain connectivity before, during, and after seizures with graph-theoretic techniques on continuous electrocorticographic (ECoG) recordings (5.4 ± 1.7 d...
    Categories: Journal Articles
  • Evolution of Bantu kinship [Anthropology]
    [Dec 2014]

    Kinship provides the fundamental structure of human society: descent determines the inheritance pattern between generations, whereas residence rules govern the location a couple moves to after they marry. In turn, descent and residence patterns determine other key relationships such as alliance, trade, and marriage partners. Hunter-gatherer kinship patterns are viewed...
    Categories: Journal Articles
  • Splice site correction by engineered U2AF65 [Applied Biological Sciences]
    [Dec 2014]

    Purine interruptions of polypyrimidine (Py) tract splice site signals contribute to human genetic diseases. The essential splicing factor U2AF65 normally recognizes a Py tract consensus sequence preceding the major class of 3′ splice sites. We found that neurofibromatosis- or retinitis pigmentosa-causing mutations in the 5′ regions of Py tracts severely...
    Categories: Journal Articles
  • Osteoinductivity of devitalized cartilage template [Applied Biological Sciences]
    [Dec 2014]

    The role of cell-free extracellular matrix (ECM) in triggering tissue and organ regeneration has gained increased recognition, yet current approaches are predominantly based on the use of ECM from fully developed native tissues at nonhomologous sites. We describe a strategy to generate customized ECM, designed to activate endogenous regenerative programs...
    Categories: Journal Articles
  • Volumetric superresolution imaging [Applied Physical Sciences]
    [Dec 2014]

    Single molecule-based superresolution imaging has become an essential tool in modern cell biology. Because of the limited depth of field of optical imaging systems, one of the major challenges in superresolution imaging resides in capturing the 3D nanoscale morphology of the whole cell. Despite many previous attempts to extend the...
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  • Protein kinase IKK{beta} activates IRF5 [Biochemistry]
    [Dec 2014]

    The siRNA knockdown of IFN Regulatory Factor 5 (IRF5) in the human plasmacytoid dendritic cell line Gen2.2 prevented IFNβ production induced by compound CL097, a ligand for Toll-like receptor 7 (TLR7). CL097 also stimulated the phosphorylation of IRF5 at Ser462 and stimulated the nuclear translocation of wild-type IRF5, but not...
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  • IKK{beta} phosphorylates and activates IRF5 [Biochemistry]
    [Dec 2014]

    The transcription factor interferon regulatory factor 5 (IRF5) is essential for the induction of inflammatory cytokines, but the mechanism by which IRF5 is activated is not well understood. Here we present evidence that the kinase IKKβ phosphorylates and activates IRF5 in response to stimulation in several inflammatory pathways, including those...
    Categories: Journal Articles
  • Structure of the Crumbs-PALS1 complex [Biochemistry]
    [Dec 2014]

    The Crumbs (Crb) complex, formed by Crb, PALS1, and PATJ, is evolutionarily conserved in metazoans and acts as a master cell-growth and -polarity regulator at the apical membranes in polarized epithelia. Crb intracellular functions, including its direct binding to PALS1, are mediated by Crb’s highly conserved 37-residue cytoplasmic tail. However,...
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  • Lipolysis inhibits adipocyte glucose uptake [Biochemistry]
    [Dec 2014]

    Anabolic and catabolic signaling oppose one another in adipose tissue to maintain cellular and organismal homeostasis, but these pathways are often dysregulated in metabolic disorders. Although it has long been established that stimulation of the β-adrenergic receptor inhibits insulin-stimulated glucose uptake in adipocytes, the mechanism has remained unclear. Here we...
    Categories: Journal Articles
  • UbcH7 regulates 53BP1 stability [Biochemistry]
    [Dec 2014]

    DNA double-strand break (DSB) repair is not only key to genome stability but is also an important anticancer target. Through an shRNA library-based screening, we identified ubiquitin-conjugating enzyme H7 (UbcH7, also known as Ube2L3), a ubiquitin E2 enzyme, as a critical player in DSB repair. UbcH7 regulates both the steady-state...
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  • How HCMV Exo mutations cause GCV resistance [Biochemistry]
    [Dec 2014]

    Many antiviral and anticancer drugs are nucleoside analogs that target polymerases and cause DNA chain termination. Interestingly, ganciclovir (GCV), the first line of therapy for human cytomegalovirus (HCMV) infections, induces chain termination despite containing the equivalent of a 3′-hydroxyl group. Certain HCMV GCV resistance (GCVr) mutations, including ones associated with...
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  • Respiration triggers heme transfer in mitochondria [Biochemistry]
    [Dec 2014]

    In exponentially growing yeast, the heme enzyme, cytochrome c peroxidase (Ccp1) is targeted to the mitochondrial intermembrane space. When the fermentable source (glucose) is depleted, cells switch to respiration and mitochondrial H2O2 levels rise. It has long been assumed that CCP activity detoxifies mitochondrial H2O2 because of the efficiency of...
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  • Collagen fiber degradation by cathepsin K [Biochemistry]
    [Dec 2014]

    Cathepsin K is the major collagenolytic protease in bone that facilitates physiological as well as pathological bone degradation. Despite its key role in bone remodeling and for being a highly sought-after drug target for the treatment of osteoporosis, the mechanism of collagen fiber degradation by cathepsin K remained elusive. Here,...
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  • Trajectories of the ribosome as a nanomachine [Biophysics and Computational Biology]
    [Dec 2014]

    A Brownian machine, a tiny device buffeted by the random motions of molecules in the environment, is capable of exploiting these thermal motions for many of the conformational changes in its work cycle. Such machines are now thought to be ubiquitous, with the ribosome, a molecular machine responsible for protein...
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  • Distinct regulatory roles of PsbS and zeaxanthin [Biophysics and Computational Biology]
    [Dec 2014]

    The photosystem II (PSII) protein PsbS and the enzyme violaxanthin deepoxidase (VDE) are known to influence the dynamics of energy-dependent quenching (qE), the component of nonphotochemical quenching (NPQ) that allows plants to respond to fast fluctuations in light intensity. Although the absence of PsbS and VDE has been shown to...
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  • NMR {Delta}{delta}NH/{Delta}T to design orally bioavailable peptides [Biophysics and Computational Biology]
    [Dec 2014]

    Enhancing the oral bioavailability of peptide drug leads is a major challenge in drug design. As such, methods to address this challenge are highly sought after by the pharmaceutical industry. Here, we propose a strategy to identify appropriate amides for N-methylation using temperature coefficients measured by NMR to identify exposed...
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  • Electric fingerprint of voltage sensor domains [Biophysics and Computational Biology]
    [Dec 2014]

    A dynamic transmembrane voltage field has been suggested as an intrinsic element in voltage sensor (VS) domains. Here, the dynamic field contribution to the VS energetics was analyzed via electrostatic calculations applied to a number of atomistic structures made available recently. We find that the field is largely static along...
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  • Chorismate mutase catalysis revisited [Biophysics and Computational Biology]
    [Dec 2014]

    For more than half a century, transition state theory has provided a useful framework for understanding the origins of enzyme catalysis. As proposed by Pauling, enzymes accelerate chemical reactions by binding transition states tighter than substrates, thereby lowering the activation energy compared with that of the corresponding uncatalyzed process. This...
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  • GABA{rho} in cerebellar GFAP+ cells [Cell Biology]
    [Dec 2014]

    GABA-A receptors mediating synaptic or extrasynaptic transmission are molecularly and functionally distinct, and glial cells are known to express a plethora of GABA-A subunits. Here we demonstrate that GFAP+ cells of the granular layer of cerebellum express GABAρ subunits during early postnatal development, thereby conferring peculiar pharmacologic characteristics to GABA...
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  • Mechanical-biochemical signaling remodels actin [Cell Biology]
    [Dec 2014]

    Cytoskeletal actin assemblies transmit mechanical stresses that molecular sensors transduce into biochemical signals to trigger cytoskeletal remodeling and other downstream events. How mechanical and biochemical signaling cooperate to orchestrate complex remodeling tasks has not been elucidated. Here, we studied remodeling of contractile actomyosin stress fibers. When fibers spontaneously fractured, they...
    Categories: Journal Articles