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  • 1
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    Coherent control of plasma dynamics by feedback-optimized wavefront manipulationa) (2015)
    American Institute of Physics (AIP)
    Details
    Publication Date: 2015-05-16
    Description: Plasmas generated by an intense laser pulse can support coherent structures such as large amplitude wakefield that can affect the outcome of an experiment. We investigate the coherent control of plasma dynamics by feedback-optimized wavefront manipulation using a deformable mirror. The experimental outcome is directly used as feedback in an evolutionary algorithm for optimization of the phase front of the driving laser pulse. In this paper, we applied this method to two different experiments: (i) acceleration of electrons in laser driven plasma waves and (ii) self-compression of optical pulses induced by ionization nonlinearity. The manipulation of the laser wavefront leads to orders of magnitude improvement to electron beam properties such as the peak charge, beam divergence, and transverse emittance. The demonstration of coherent control for plasmas opens new possibilities for future laser-based accelerators and their applications.
    Print ISSN: 1070-664X
    Electronic ISSN: 1089-7674
    Topics: Physics
    Published by American Institute of Physics (AIP)
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  • 2
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    3D nanofabrication by volumetric deposition and controlled shrinkage of patterned scaffolds (2018)
    American Association for the Advancement of Science (AAAS)
    In: Science
    Details
    Publication Date: 2018
    Description: 〈p〉Lithographic nanofabrication is often limited to successive fabrication of two-dimensional (2D) layers. We present a strategy for the direct assembly of 3D nanomaterials consisting of metals, semiconductors, and biomolecules arranged in virtually any 3D geometry. We used hydrogels as scaffolds for volumetric deposition of materials at defined points in space. We then optically patterned these scaffolds in three dimensions, attached one or more functional materials, and then shrank and dehydrated them in a controlled way to achieve nanoscale feature sizes in a solid substrate. We demonstrate that our process, Implosion Fabrication (ImpFab), can directly write highly conductive, 3D silver nanostructures within an acrylic scaffold via volumetric silver deposition. Using ImpFab, we achieve resolutions in the tens of nanometers and complex, non–self-supporting 3D geometries of interest for optical metamaterials.〈/p〉
    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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  • 3
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    Molecular basis for pore blockade of human Na+ channel Nav1.2 by the {mu}-conotoxin KIIIA (2019)
    American Association for the Advancement of Science (AAAS)
    In: Science
    Details
    Publication Date: 2019
    Description: 〈p〉The voltage-gated sodium channel Na〈sub〉v〈/sub〉1.2 is responsible for the initiation and propagation of action potentials in the central nervous system. We report the cryo–electron microscopy structure of human Na〈sub〉v〈/sub〉1.2 bound to a peptidic pore blocker, the μ-conotoxin KIIIA, in the presence of an auxiliary subunit, β2, to an overall resolution of 3.0 angstroms. The immunoglobulin domain of β2 interacts with the shoulder of the pore domain through a disulfide bond. The 16-residue KIIIA interacts with the extracellular segments in repeats I to III, placing Lys〈sup〉7〈/sup〉 at the entrance to the selectivity filter. Many interacting residues are specific to Na〈sub〉v〈/sub〉1.2, revealing a molecular basis for KIIIA specificity. The structure establishes a framework for the rational design of subtype-specific blockers for Na〈sub〉v〈/sub〉 channels.〈/p〉
    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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  • 4
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    HIPK2 is necessary for type I interferon-mediated antiviral immunity (2019)
    The American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2019
    Description: 〈p〉Precise control of interferons (IFNs) is crucial to maintain immune homeostasis. Here, we demonstrated that homeodomain-interacting protein kinase 2 (HIPK2) was required for the production of type I IFNs in response to RNA virus infection. HIPK2 deficiency markedly impaired IFN production in macrophages after vesicular stomatitis virus (VSV) infection, and HIPK2-deficient mice were more susceptible to lethal VSV disease than were wild-type mice. After VSV infection, HIPK2 was cleaved by active caspases, which released a hyperactive, N-terminal fragment that translocated to the nucleus and further augmented antiviral responses. In part, HIPK2 interacted with ELF4 and promoted its phosphorylation at Ser〈sup〉369〈/sup〉, which enabled 〈i〉Ifn-〈/i〉b transcription. In addition, HIPK2 production was stimulated by type I IFNs to further enhance antiviral immunity. These data suggest that the kinase activity and nuclear localization of HIPK2 are essential for the production of type I IFNs.〈/p〉
    Print ISSN: 1945-0877
    Electronic ISSN: 1937-9145
    Topics: Biology , Medicine
    Published by The American Association for the Advancement of Science (AAAS)
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  • 5
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    Host resistance to intranasal Acinetobacter baumannii reinfection in mice (2016)
    Oxford University Press
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    Publication Date: 2016-06-04
    Description: Acinetobacter baumannii is a major causative agent of healthcare-associated infection and develops multidrug resistance rapidly. However, little is known in the host defense mechanisms against this infection. In this study, we examined if mice recovered from a previous intranasal A. baumannii infection (recovered mice) are fully protected against a subsequent reinfection. We found that, despite the presence of specific serum IgG and mucosal IgA responses prior to the reinfection, the recovered mice were only marginally better protected against intranasal challenge with low doses of homologous or heterologous A. baumannii strains than the naïve mice. Post-challenge immune and inflammatory (cells and cytokines) responses were generally comparable between recovered and naïve mice although the recovered mice produced significantly higher amounts of IFN- and IL-17 and had higher percentages and numbers of resident lung CD44 hi CD62L – CD4 + and CD19 + B lymphocytes. Taken together, our results suggest that mice recovered from a previous A. baumannii infection remain susceptible to reinfection, indicating the complexity of immune protection mechanism for this Gram-negative, multidrug-resistant emerging pathogen.
    Print ISSN: 0928-8244
    Topics: Biology , Medicine
    Published by Oxford University Press
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  • 6
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    Important roles of brain-specific carnitine palmitoyltransferase and ceramide metabolism in leptin hypothalamic control of feeding [Neuroscience] (2011)
    National Academy of Sciences
    Details
    Publication Date: 2011-06-08
    Description: Brain-specific carnitine palmitoyltransferase-1 (CPT-1c) is implicated in CNS control of food intake. In this article, we explore the role of hypothalamic CPT-1c in leptin's anorexigenic actions. We first show that adenoviral overexpression of CPT-1c in hypothalamic arcuate nucleus of rats increases food intake and concomitantly up-regulates orexigenic neuropeptide Y (NPY) and Bsx (a transcription factor of NPY). Then, we demonstrate that this overexpression antagonizes the anorectic actions induced by central leptin or compound cerulenin (an inhibitor of fatty acid synthase). The overexpression of CPT-1c also blocks leptin-induced down-regulations of NPY and Bsx. Furthermore, the anorectic actions of central leptin or cerulenin are impaired in mice with brain CPT-1c deleted. Both anorectic effects require elevated levels of hypothalamic arcuate nucleus (Arc) malonyl-CoA, a fatty acid-metabolism intermediate that has emerged as a mediator in hypothalamic control of food intake. Thus, these data suggest that CPT-1c is implicated in malonyl-CoA action in leptin's hypothalamic anorectic signaling pathways. Moreover, ceramide metabolism appears to play a role in leptin's central control of feeding. Leptin treatment decreases Arc ceramide levels, with the decrease being important in leptin-induced anorectic actions and down-regulations of NPY and Bsx. Of interest, our data indicate that leptin impacts ceramide metabolism through malonyl-CoA and CPT-1c, and ceramide de novo biosynthesis acts downstream of both malonyl-CoA and CPT-1c in mediating their effects on feeding and expressions of NPY and Bsx. In summary, we provide insights into the important roles of malonyl-CoA, CPT-1c, and ceramide metabolism in leptin's hypothalamic signaling pathways.
    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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    Epigenetic regulation of differential HLA-A allelic expression levels (2015)
    Oxford University Press
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    Publication Date: 2015-07-07
    Description: MHC class I expression levels influence the strength of immune responses and represent another variable in determining outcome to disease beyond peptide binding alone. Identification of the HLA loci that vary in allelic expression levels and delineating the mechanism responsible for expression variation may provide the opportunity to modify their expression therapeutically. We have examined the expression levels of allelic lineages at the HLA-A locus in a sample of 216 European Americans using a real-time polymerase chain reaction assay, which amplifies all HLA-A lineages specifically with equal efficiency, and observed a gradient of expression that associates with HLA-A allelic lineage ( R = 0.6, P = 5 x 10 –25 ). DNA methylation of the HLA-A gene appears to contribute to the variation in HLA-A mRNA expression levels, as a significant inverse correlation was observed between HLA-A mRNA expression levels in untreated cells and the degree to which expression is increased after treatment of the cells with a DNA methyltransferase inhibitor ( R = 0.6, P = 2.8 x 10 –6 ). Further, deep-sequencing and immunoprecipitation assays revealed allelic lineage-specific methylation patterns within the HLA-A promoter region where increased DNA methylation levels correlated significantly with reduced HLA-A expression levels ( R = 0.89, P = 3.7 x 10 –9 ). These data demonstrate HLA-A allelic lineage-specific variation in expression levels, and DNA methylation as a likely factor in contributing to this variation.
    Print ISSN: 0964-6906
    Electronic ISSN: 1460-2083
    Topics: Biology , Medicine
    Published by Oxford University Press
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  • 8
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    CD83-stimulated monocytes suppress T-cell immune responses through production of prostaglandin E2 [Immunology] (2011)
    National Academy of Sciences
    Details
    Publication Date: 2011-11-16
    Description: CD83 is commonly known as a specific marker for mature dendritic cells. It has been shown to be important for CD4+ T-cell development in the thymus. However, its function in the peripheral immune system remains enigmatic. Here, we show that CD83 inhibits proliferation and production of IL-2 and IFN-γ by T cells, and the inhibitory effect of CD83 is mediated by monocytes. Prostaglandin E2 (PGE2), but not IL-10 or TGF-β, was up-regulated specifically by CD83 in monocytes. Consistent with high levels of PGE2, expression of COX-2 also was increased upon CD83 treatment. NF-κB activation also is required for induction of PGE2 by CD83. Finally, application of the COX-2–selective inhibitor NS-398 fully prevented CD83-triggered inhibition of T-cell responses. Our study establishes an immune-regulatory mechanism by CD83 via stimulation of PGE2 production in monocytes.
    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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  • 9
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    Leptin is an effective treatment for hypothalamic amenorrhea [Medical Sciences] (2011)
    National Academy of Sciences
    Details
    Publication Date: 2011-04-20
    Description: Hypothalamic amenorrhea (HA) is associated with dysfunction of the hypothalamic-pituitary-peripheral endocrine axes, leading to infertility and bone loss, and usually is caused by chronic energy deficiency secondary to strenuous exercise and/or decreased food intake. Energy deficiency also leads to hypoleptinemia, which has been proposed, on the basis of observational studies as well as an open-label study, to mediate the neuroendocrine abnormalities associated with this condition. To prove definitively a causal role of leptin in the pathogenesis of HA, we performed a randomized, double-blinded, placebo-controlled trial of human recombinant leptin (metreleptin) in replacement doses over 36 wk in women with HA. We assessed its effects on reproductive outcomes, neuroendocrine function, and bone metabolism. Leptin replacement resulted in recovery of menstruation and corrected the abnormalities in the gonadal, thyroid, growth hormone, and adrenal axes. We also demonstrated changes in markers of bone metabolism suggestive of bone formation, but no changes in bone mineral density were detected over the short duration of this study. If these data are confirmed, metreleptin administration in replacement doses to normalize circulating leptin levels may prove to be a safe and effective therapy for women with HA.
    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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  • 10
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    aPKC activates Smo and Ci through phosphorylation [Developmental Biology] (2014)
    National Academy of Sciences
    Details
    Publication Date: 2014-11-12
    Description: Smoothened (Smo) is essential for transduction of the Hedgehog (Hh) signal in both insects and vertebrates. Cell surface/cilium accumulation of Smo is thought to play an important role in Hh signaling, but how the localization of Smo is controlled remains poorly understood. In this study, we demonstrate that atypical PKC...
    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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