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With Mornefull Musique: Funeral Elegies in Early Modern England. By K. Dawn Grapes. (Music in Britain, 1600-2000.) Woodbridge, Suffolk: Boydell, 2018. [xi, 276 p. ISBN 9781783273515 (hardcover), $99; ISBN 9781787443242 [...]

Jas, Eric. 2018. Piety and Polyphony in Sixteenth-Century Holland: The Choirbooks of St Peter's Church, Leiden. Studies in Medieval and Renaissance Music, 18. Woodbridge: The Boydell Press The six choirbooks [...]

Author(s): Kristina M Adams Waldorf (corresponding author) [1, 2, 3, 4]; Branden R Nelson [5]; Jennifer E Stencel-Baerenwald [2, 6]; Colin Studholme [7, 8, 9]; Raj P Kapur [10, 11]; [...]

Type I IFNs promote cellular responses to viruses, and IFN receptor (IFNAR) signaling regulates the responses of endothelial cells of the blood-brain barrier (BBB) during neurotropic viral infection. However, the role of astrocytes in innate immune responses of the BBB during viral infection of the CNS remains to be fully elucidated. Here, we have demonstrated that type I IFNAR signaling in astrocytes regulates BBB permeability and protects the cerebellum from infection and immunopathology. Mice with astrocyte-specific loss of IFNAR signaling showed decreased survival after West Nile virus infection. Accelerated mortality was not due to expanded viral tropism or increased replication. Rather, viral entry increased specifically in the hindbrain of IFNAR-deficient mice, suggesting that IFNAR signaling critically regulates BBB permeability in this brain region. Pattern recognition receptors and IFN-stimulated genes had higher basal and IFN-induced expression in human and mouse cerebellar astrocytes than did cerebral cortical astrocytes, suggesting that IFNAR signaling has brain region-specific roles in CNS immune responses. Taken together, our data identify cerebellar astrocytes as key responders to viral infection and highlight the existence of distinct innate immune programs in astrocytes from evolutionarily disparate regions of the CNS., Introduction Type I IFNs (IFN[alpha]/[beta]) promote the expression of antiviral molecules in response to induction by several different transmembrane and cytosolic pattern recognition receptors (PRRs). Cellular responses to type I [...]

Author(s): Abigail Jarret [1]; Adelle P McFarland [1]; Stacy M Horner [1]; Alison Kell [1]; Johannes Schwerk [1]; MeeAe Hong [1]; Samantha Badil [1]; Rochelle C Joslyn [1]; Darren P [...]

Author(s): Kristina M Adams Waldorf (corresponding author) [1]; Jennifer E Stencel-Baerenwald [2, 3]; Raj P Kapur [4, 5]; Colin Studholme [6, 7, 8]; Erica Boldenow [6, 9]; Jay Vornhagen [9, [...]

Hepatitis C virus (HCV) and triglyceride-rich very low-density lipoproteins (VLDLs) both are secreted uniquely by hepatocytes and circulate in blood in a complex. Here, we isolated from human hepatoma cells the membrane vesicles in which HCV replicates. These vesicles, which contain the HCV replication complex, are highly enriched in proteins required for VLDL assembly, including apolipoprotein B (apoB), apoE, and microsomal triglyceride transfer protein. In hepatoma cells that constitutively produce infectious HCV, HCV production is reduced by two agents that block VLDL assembly: an inhibitor of microsomal triglyceride transfer protein and siRNA directed against apoB. These results provide a possible explanation for the restriction of HCV production to the liver and suggest new cellular targets for treatment of HCV infection. apolipoprotein B | microsomal triglyceride transfer protein

RIG-I is an RNA helicase containing caspase activation and recruitment domains (CARDs). RNA binding and signaling by RIG-I are implicated in pathogen recognition and triggering of IFN-[alpha]/[beta] immune defenses that impact cell permissiveness for hepatitis C virus (HCV). Here we evaluated the processes that control RIG-I signaling. RNA binding studies and analysis of cells lacking RIG-I, or the related MDA5 protein, demonstrated that RIG-I, but not MDA5, efficiently binds to secondary structured HCV RNA to confer induction of IFN-[beta] expression. We also found that LGP2, a helicase related to RIG-I and MDA5 but lacking CARDs and functioning as a negative regulator of host defense, binds HCV RNA. In resting cells, RIG-I is maintained as a monomer in an autoinhibited state, but during virus infection and RNA binding it undergoes a conformation shift that promotes self-association and CARD interactions with the IPS-1 adaptor protein to signal IFN regulatory factor 3- and NF-[kappa]B-responsive genes. This reaction is governed by an internal repressor domain (RD) that controls RIG-I multimerization and IPS-1 interaction. Deletion of the RIG-I RD resulted in constitutive signaling to the IFN-[beta] promoter, whereas RD expression alone prevented signaling and increased cellular permissiveness to HCV. We identified an analogous RD within LGP2 that interacts in trans with RIG-I to ablate self-association and signaling. Thus, RIG-I is a cytoplasmic sensor of HCV and is governed by RD interactions that are shared with LGP2 as an on/off switch controlling innate defenses. Modulation of RIG-I/LGP2 interaction dynamics may have therapeutic implications for immune regulation. hepatitis C virus | IFN lIPS-1 | MAVS | Cardif

Viral signaling through retinoic acid-inducible gene-I (RIG-I) and its adaptor protein, IFN promoter-stimulator 1 (IPS-1), activates IFN regulatory factor-3 (IRF-3) and the host IFN-[alpha]/[beta] response that limits virus infection. The hepatitis C virus (HCV) NS3/4A protease cleaves IPS-1 to block RIG-I signaling, but how this regulation controls the host response to HCV is not known. Moreover, endogenous IPS-1 cleavage has not been demonstrated in the context of HCV infection in vitro or in vivo. Here, we show that HCV infection transiently induces RIG-I- and IPS-1-dependent IRF-3 activation. This host response limits HCV production and constrains cellular permissiveness to infection. However, HCV disrupts this response early in infection by NS3/4A cleavage of IPS-1 at C508, releasing IPS-1 from the mitochondrial membrane. Cleavage results in subcellular redistribution of IPS-1 and loss of interaction with RIG-I, thereby preventing downstream activation of IRF-3 and IFN-[beta] induction. Liver tissues from chronically infected patients similarly demonstrate subcellular redistribution of IPS-1 in infected hepatocytes and IPS-1 cleavage associated with a lack of ISG15 expression and conjugation of target proteins in vivo. Importantly, small-molecule inhibitors of NS3/4A prevent cleavage and restore RIG-I signaling of IFN-[beta] induction. Our results suggest a dynamic model in which early activation of IRF-3 and induction of antiviral genes are reversed by IPS-1 proteolysis and abrogation of RIG-I signaling as NS3/4A accumulates in newly infected cells. HCV protease inhibitors effectively prevent IPS-1 proteolysis, suggesting they may be capable of restoring this innate host response in clinical practice. CARDIF | MAVS | VISA

Toll-like receptors (TLRs) bind pathogen-specific ligands early in infection, initiating signaling pathways that lead to expression of multiple protective cellular genes. Many viruses have evolved strategies that block the effector mechanisms induced through these signaling pathways, but viral interference with critical proximal receptor interactions has not been described. We show here that the NS3/4A serine protease of hepatitis C virus (HCV), a virus notorious for its ability to establish persistent intrahepatic infection, causes specific proteolysis of Toll-IL-1 receptor domain-containing adaptor inducing IFN-[beta] (TRIF or TICAM-1), an adaptor protein linking TLR3 to kinases responsible for activating IFN regulatory factor 3 (IRF-3) and NF-[kappa]B, transcription factors controlling a multiplicity of antiviral defenses. NS3/4A-mediated cleavage of TRIF reduces its abundance and inhibits polyl:C-activated signaling through the TLR3 pathway before its bifurcation to IRF-3 and NF-[kappa]B. This uniquely broad mechanism of immune evasion potentially limits expression of multiple host defense genes, thereby promoting persistent infections with this medically important virus. innate immunity | IFN | IFN regulatory factor 3 | NF-[kappa]B | protease inhibitor

Hepatitis C virus (HCV) is a major human pathogen that infects 170 million people. A hallmark of HCV is its ability to establish persistent infections reflecting the evasion of host immunity and interference with [alpha]/[beta]-IFN innate immune defenses. We demonstrate that disruption of retinoic acid-inducible gene I (RIG-I) signaling by the viral NS3/4A protease contributes to the ability of HCV to control innate antiviral defenses. RIG-I was essential for virus or HCV RNA-induced signaling to the IFN-[beta] promoter in human hepatoma cells. This signaling was disrupted by the protease activity of NS3/4A, which ablates RIG-I signaling of downstream IFN regulatory factor 3 and NF-[kappa]B activation, attenuating expression of host antiviral defense genes and interrupting an IFN amplification loop that otherwise suppresses HCV replication. Treatment of cells with an active site inhibitor of the NS3/4A protease relieved this suppression and restored intracellular antiviral defenses. Thus, NS3/4A control of RIG-I supports HCV persistence by preventing IFN regulatory factor 3 and NF-[kappa]B activation. Our results demonstrate that these processes are amenable to restoration through pharmacologic inhibition of viral protease function. interferon | protease | host response | infection | NF-[kappa]B

Hepatitis C virus (HCV) RNA replication depends on viral protein association with intracellular membranes, but the influence of membrane composition on viral replication is unclear. We report that HCV RNA replication and assembly of the viral replication complex require geranylgeranylation of one or more host proteins. In cultured hepatoma cells, HCV RNA replication was disrupted by treatment with lovastatin, an inhibitor of 3-hydroxy-3-methyglutaryl CoA reductase, or with an inhibitor of protein geranylgeranyl transferase I, each of which induced the dissolution of the HCV replication complex. Viral replication was not affected by treatment of cells with an inhibitor of farnesyl transferase. When added to lovastatin-treated cells, geranylgeraniol, but not farnesol, restored replication complex assembly and viral replication. Inasmuch as the HCV genome does not encode a canonical geranylgeranylated protein, the data suggest the involvement of a geranylgeranylated host protein in HCV replication. Inhibition of its geranylgeranylation affords a therapeutic strategy for treatment of HCV infection.

The P52(sup)rIPK regulates P(sup)IPK in a manner that the former functions as an upstream regulator of PKR, eIF2, and mRNA translation by interacting with the latter. Research delineates the domains of the two proteins that are involved in such an interaction and supports that P52(sup)rIPK functions as a signal transducer and regulates P58(sup)IPK under cytoplasmic stress conditions.

Research shows that the J domain of P58(sup)IPK replaces the J domain of prokaryotic DnaJ and eukaryotic Ydj1 during cell growth. Data reveal that inhibition of interferon-induced protein kinase activity or mRNA translation strimulation do not require J domain of the DnaJ molecular cheperones.

The virus-host interactions that influence hepatitis C virus (HCV) replication are largely unknown but are thought to involve those that disrupt components of the innate intracellular antiviral response. Here we examined cellular antiviral pathways that are triggered during HCV RNA replication. We report that (i) RNA replication of HCV subgenomic replicons stimulated double-stranded RNA (dsRNA) signaling pathways within cultured human hepatoma cells, and (ii) viral RNA replication efficiency corresponded with an ability to block a key cellular antiviral effector pathway that is triggered by dsRNA and includes IFN regulatory factor-1 (IRF-1) and protein kinase R (PKR). The block to dsRNA signaling was mapped to the viral nonstructural 5A (NS5A) protein, which colocalized with PKR and suppressed the dsRNA activation of PKR during HCV RNA replication. NS5A alone was sufficient to block both the activation of IRF-1 and the induction of an IRF-1-dependent cellular promoter by dsRNA. Mutations that clustered in or adjacent to the PKR-binding domain of NS5A relieved the blockade to this IRF-1 regulatory pathway, resulting in induction of IRF-1-dependent antiviral effector genes and the concomitant reduction in HCV RNA replication efficiency. Our results provide further evidence to support a role for PKR in dsRNA signaling processes that activate IRF-1 during virus infection and suggest that NS5A may influence HCV persistence by blocking IRF-1 activation and disrupting a host antiviral pathway that plays a role in suppressing virus replication.

Advances in molecular and genome analyses have paved the way for studying the mechanisms of translational control of viral gene expression in eukaryotic systems. This review discusses RNA-protein interaction, environmental influence on viral and cellular gene expression, parallel identification of transcriptionally and translationally regulated mRNAs with reference to herpes and influenza viruses.

New wheat grain varieties grown during the 1960s and 1970s are shorter, resistant to wind and rain damage and increase grain yield. Their shortness is a response to gibberellin, the plant growth hormome, which is conferred by mutant dwarfing alleles at one of two Reduced height-1 (Rht-B1 and Rht-D1) loci. It is shown that RhtB1/D1 and maize dwarf-8 (d8) are orthologues of the Araidopsis Gibberellin Insensitive (GA1) gene, which encode proteins resembling nuclear transcription factors.

The fabrication of continuous-relief diffractive optical elements by direct laser beam writing in photoresist is analyzed. The main limitation and tolerances are identified, and their influence on optical performance is quantified. Fabricated structures show rounded profile steps resulting from the convolution of the desired profile with the writing beam. This leads to a reduction in diffraction efficiency. Optimization techniques are presented to minimize this effect. Scaling the profile depth by a factor of [Mu] > 1 increases the first-order diffraction efficiency for blazed elements. This method is also applied to suppress the zeroth diffraction order in computer-generated holograms. A nonlinear compensation of the exposure data for the Gaussian beam convolution results in an 18% increase of the diffraction efficiency for a blazed grating with a 10-[[micro]meter] period to a value of 79%.

Genetic mapping of wheat, maize, and rice and other grass species with common DNA probes has revealed remarkable conservation of gene content and gene order over the 60 million years of radiation of Poaceae. The linear organization of genes in some nine different genomes differing in basic chromosome number from 5 to 12 and nuclear DNA amount from 400 to 6,000 Mb, can be described in terms of only 25 'rice linkage blocks.' The extent to which this intergenomic colinearity is confounded at the micro level by gene duplication and micro-rearrangements is still an open question. Nevertheless, it is clear that the elucidation of the organization of the economically important grasses with larger genomes, such as maize (2n = 10, 4,500 Mb DNA), will, to a greater or lesser extent, be predicted from sequence analysis of smaller genomes such as rice, with only 400 Mb, which in turn may be greatly aided by knowledge of the entire sequence of Arabidopsis, which may be available as soon as the turn of the century. Comparative genetics will provide the key to unlock the genomic secrets of crop plants with bigger genomes than Homo sapiens.

Continuous surface-relief diffractive optical elements for two-dimensional array generation (fan-out) are designed and fabricated. Separable and nonseparable solutions for the two-dimensional element design are compared. The phase-grating microstructures are generated by laser-beam writing lithography in a single exposure step and converted to nickel shims by electroplating, enabling low-cost replicas to be produced by using laboratory and commercial replication processes. Results are presented for a 9 X 9 fan-out diffractive optical element with a measured efficiency of 94% and an overall uniformity within plus or minus 8%; replicas in epoxy have the same efficiency and a uniformity of plus or minus 15%.

The relative contribution of RalGTPase effector proteins to Ral function in normal and tumorigenic human epithelial cells were investigated in order to define the regulatory pathway directly engaged by RalB to support tumor cell survival. The study observations define the mechanistic contribution of RalGTPases to cancer cell survival and reveal the RalB/Sec5 effector complex as a component of TBK1-dependent innate immune signaling.