3,883 research outputs found
Mutations in modified virus Ankara protein 183 render it a non-functional counterpart of B14, an inhibitor of nuclear factor κB activation
Vaccinia virus (VACV) encodes multiple proteins to evade host innate immunity, including B14, a virulence factor that binds to the inhibitor of κB kinase β (IKKβ) and blocks nuclear factor κB (NF-κB) activation. B14 shares 95 % amino acid identity with the 183 protein encoded by modified virus Ankara (MVA), an attenuated VACV strain being developed as a vaccine vector. To evaluate whether the immunogenicity of MVA might be increased by manipulation of MVA immunomodulatory proteins, the MVA counterpart of B14, protein 183, was characterized. Unlike B14, protein 183 was unstable in eukaryotic cells unless proteasome-mediated protein degradation was inhibited. Furthermore, 183 did not inhibit NF-κB activation in response to cytokine stimulation, and did not restore the virulence of VACV strain Western Reserve lacking gene B14R. The instability and non-functionality of 183 are probably explained by a deletion of 6 aa within α-helix 6 of the B14 crystal structure
Inhibition of IκB Kinase by Vaccinia Virus Virulence Factor B14
The IκB kinase (IKK) complex is a key regulator of signal transduction pathways leading to the induction of NF-κB-dependent gene expression and production of pro-inflammatory cytokines. It therefore represents a major target for the development of anti-inflammatory therapeutic drugs and may be targeted by pathogens seeking to diminish the host response to infection. Previously, the vaccinia virus (VACV) strain Western Reserve B14 protein was characterised as an intracellular virulence factor that alters the inflammatory response to infection by an unknown mechanism. Here we demonstrate that ectopic expression of B14 inhibited NF-κB activation in response to TNFα, IL-1β, poly(I:C), and PMA. In cells infected with VACV lacking gene B14R (vΔB14) there was a higher level of phosphorylated IκBα but a similar level of IκBα compared to cells infected with control viruses expressing B14, suggesting B14 affects IKK activity. Direct evidence for this was obtained by showing that B14 co-purified and co-precipitated with the endogenous IKK complex from human and mouse cells and inhibited IKK complex enzymatic activity. Notably, the interaction between B14 and the IKK complex required IKKβ but not IKKα, suggesting the interaction occurs via IKKβ. B14 inhibited NF-κB activation induced by overexpression of IKKα, IKKβ, and a constitutively active mutant of IKKα, S176/180E, but did not inhibit a comparable mutant of IKKβ, S177/181E. This suggested that phosphorylation of these serine residues in the activation loop of IKKβ is targeted by B14, and this was confirmed using Ab specific for phospho-IKKβ
The landscape of RNA polymerase II transcription initiation in C. elegans reveals promoter and enhancer architectures
RNA polymerase transcription initiation sites are largely unknown in Caenorhabditis elegans. The initial 5′ end of most protein-coding transcripts is removed by trans-splicing, and noncoding initiation sites have not been investigated. We characterized the landscape of RNA Pol II transcription initiation, identifying 73,500 distinct clusters of initiation. Bidirectional transcription is frequent, with a peak of transcriptional pairing at 120 bp. We assign transcription initiation sites to 7691 protein-coding genes and find that they display features typical of eukaryotic promoters. Strikingly, the majority of initiation events occur in regions with enhancer-like chromatin signatures. Based on the overlap of transcription initiation clusters with mapped transcription factor binding sites, we define 2361 transcribed intergenic enhancers. Remarkably, productive transcription elongation across these enhancers is predominantly in the same orientation as that of the nearest downstream gene. Directed elongation from an upstream enhancer toward a downstream gene could potentially deliver RNA polymerase II to a proximal promoter, or alternatively might function directly as a distal promoter. Our results provide a new resource to investigate transcription regulation in metazoans
Natural TTS Synthesis by Conditioning WaveNet on Mel Spectrogram Predictions
This paper describes Tacotron 2, a neural network architecture for speech
synthesis directly from text. The system is composed of a recurrent
sequence-to-sequence feature prediction network that maps character embeddings
to mel-scale spectrograms, followed by a modified WaveNet model acting as a
vocoder to synthesize timedomain waveforms from those spectrograms. Our model
achieves a mean opinion score (MOS) of comparable to a MOS of for
professionally recorded speech. To validate our design choices, we present
ablation studies of key components of our system and evaluate the impact of
using mel spectrograms as the input to WaveNet instead of linguistic, duration,
and features. We further demonstrate that using a compact acoustic
intermediate representation enables significant simplification of the WaveNet
architecture.Comment: Accepted to ICASSP 201
Tacotron: Towards End-to-End Speech Synthesis
A text-to-speech synthesis system typically consists of multiple stages, such
as a text analysis frontend, an acoustic model and an audio synthesis module.
Building these components often requires extensive domain expertise and may
contain brittle design choices. In this paper, we present Tacotron, an
end-to-end generative text-to-speech model that synthesizes speech directly
from characters. Given pairs, the model can be trained completely
from scratch with random initialization. We present several key techniques to
make the sequence-to-sequence framework perform well for this challenging task.
Tacotron achieves a 3.82 subjective 5-scale mean opinion score on US English,
outperforming a production parametric system in terms of naturalness. In
addition, since Tacotron generates speech at the frame level, it's
substantially faster than sample-level autoregressive methods.Comment: Submitted to Interspeech 2017. v2 changed paper title to be
consistent with our conference submission (no content change other than typo
fixes
Electrical Control of Plasmon Resonance with Graphene
Surface plasmon, with its unique capability to concentrate light into
sub-wavelength volume, has enabled great advances in photon science, ranging
from nano-antenna and single-molecule Raman scattering to plasmonic waveguide
and metamaterials. In many applications it is desirable to control the surface
plasmon resonance in situ with electric field. Graphene, with its unique
tunable optical properties, provides an ideal material to integrate with
nanometallic structures for realizing such control. Here we demonstrate
effective modulation of the plasmon resonance in a model system composed of
hybrid graphene-gold nanorod structure. Upon electrical gating the strong
optical transitions in graphene can be switched on and off, which leads to
significant modulation of both the resonance frequency and quality factor of
plasmon resonance in gold nanorods. Hybrid graphene-nanometallic structures, as
exemplified by this combination of graphene and gold nanorod, provide a general
and powerful way for electrical control of plasmon resonances. It holds promise
for novel active optical devices and plasmonic circuits at the deep
subwavelength scale
NASA Light Emitting Diode Medical Applications from Deep Space to Deep Sea
This work is supported and managed through the NASA Marshall Space Flight Center-SBIR Program. LED-technology developed for NASA plant growth experiments in space shows promise for delivering light deep into tissues of the body to promote wound healing and human tissue growth. We present the results of LED-treatment of cells grown in culture and the effects of LEDs on patients’ chronic and acute wounds. LED-technology is also biologically optimal for photodynamic therapy of cancer and we discuss our successes using LEDs in conjunction with light-activated chemotherapeutic drugs
Mechanism of Activation and Inhibition of the HER4/ErbB4 Kinase
SummaryHER4/ErbB4 is a ubiquitously expressed member of the EGF/ErbB family of receptor tyrosine kinases that is essential for normal development of the heart, nervous system, and mammary gland. We report here crystal structures of the ErbB4 kinase domain in active and lapatinib-inhibited forms. Active ErbB4 kinase adopts an asymmetric dimer conformation essentially identical to that observed to be important for activation of the EGF receptor/ErbB1 kinase. Mutagenesis studies of intact ErbB4 in Ba/F3 cells confirm the importance of this asymmetric dimer for activation of intact ErbB4. Lapatinib binds to an inactive form of the ErbB4 kinase in a mode equivalent to its interaction with the EGF receptor. All ErbB4 residues contacted by lapatinib are conserved in the EGF receptor and HER2/ErbB2, which lapatinib also targets. These results demonstrate that key elements of kinase activation and inhibition are conserved among ErbB family members
Intratumor Heterogeneity of the Estrogen Receptor and the Long-term Risk of Fatal Breast Cancer.
Background:Breast cancer patients with estrogen receptor (ER)-positive disease have a continuous long-term risk for fatal breast cancer, but the biological factors influencing this risk are unknown. We aimed to determine whether high intratumor heterogeneity of ER predicts an increased long-term risk (25 years) of fatal breast cancer. Methods:The STO-3 trial enrolled 1780 postmenopausal lymph node-negative breast cancer patients randomly assigned to receive adjuvant tamoxifen vs not. The fraction of cancer cells for each ER intensity level was scored by breast cancer pathologists, and intratumor heterogeneity of ER was calculated using Rao's quadratic entropy and categorized into high and low heterogeneity using a predefined cutoff at the second tertile (67%). Long-term breast cancer-specific survival analyses by intra-tumor heterogeneity of ER were performed using Kaplan-Meier and multivariable Cox proportional hazard modeling adjusting for patient and tumor characteristics. Results:A statistically significant difference in long-term survival by high vs low intratumor heterogeneity of ER was seen for all ER-positive patients (P < .001) and for patients with luminal A subtype tumors (P = .01). In multivariable analyses, patients with high intratumor heterogeneity of ER had a twofold increased long-term risk as compared with patients with low intratumor heterogeneity (ER-positive: hazard ratio [HR] = 1.98, 95% confidence interval [CI] = 1.31 to 3.00; luminal A subtype tumors: HR = 2.43, 95% CI = 1.18 to 4.99). Conclusions:Patients with high intratumor heterogeneity of ER had an increased long-term risk of fatal breast cancer. Interestingly, a similar long-term risk increase was seen in patients with luminal A subtype tumors. Our findings suggest that intratumor heterogeneity of ER is an independent long-term prognosticator with potential to change clinical management, especially for patients with luminal A tumors
Saturation of electrical resistivity
Resistivity saturation is observed in many metallic systems with a large
resistivity, i.e., when the resistivity has reached a critical value, its
further increase with temperature is substantially reduced. This typically
happens when the apparent mean free path is comparable to the interatomic
separations - the Ioffe-Regel condition. Recently, several exceptions to this
rule have been found. Here, we review experimental results and early theories
of resistivity saturation. We then describe more recent theoretical work,
addressing cases both where the Ioffe-Regel condition is satisfied and where it
is violated. In particular we show how the (semiclassical) Ioffe-Regel
condition can be derived quantum-mechanically under certain assumptions about
the system and why these assumptions are violated for high-Tc cuprates and
alkali-doped fullerides.Comment: 16 pages, RevTeX, 15 eps figures, additional material available at
http://www.mpi-stuttgart.mpg.de/andersen/saturation
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