Upregulation of Id1 by Epstein-Barr Virus-encoded LMP1 confers resistance to TGFβ-mediated growth inhibition

BACKGROUND: Epstein-Barr virus (EBV)-encoded LMP1 protein is commonly expressed in nasopharyngeal carcinoma (NPC). LMP1 is a prime candidate for driving tumourigenesis given its ability to activate multiple signalling pathways and to alter the expression and activity of variety of downstream targets. Resistance to TGFβ-mediated cytostasis is one of the growth transforming effects of LMP1. Of the downstream targets manipulated by LMP1, the induction of Id1 and inactivation of Foxo3a appear particularly relevant to LMP1-mediated effects. Id1, a HLH protein is implicated in cell transformation and plays a role in cell proliferation, whilst Foxo3a, a transcription factor controls cell integrity and homeostasis by regulating apoptosis. The mechanism(s) by which LMP1 induces these effects have not been fully characterised. RESULTS: In this study, we demonstrate that the ability of LMP1 to induce the phosphorylation and inactivation of Foxo3a is linked to the upregulation of Id1. Furthermore, we show that the induction of Id1 is essential for the transforming function of LMP1 as over-expression of Id1 increases cell proliferation, attenuates TGFβ-SMAD-mediated transcription and renders cells refractory to TGFβ-mediated cytostasis. Id1 silencing in LMP1-expressing epithelial cells abolishes the inhibitory effect of LMP1 on TGFβ-mediated cell growth arrest and reduces the ability of LMP1 to attenuate SMAD transcriptional activity. In response to TGFβ stimulation, LMP1 does not abolish SMAD phosphorylation but inhibits p21 protein expression. In addition, we found the induction of Id1 in LMP1-expressing cells upon stimulation by TGFβ. We provide evidence that LMP1 suppresses the transcriptional repressor ATF3, possibly leading to the TGFβ-induced Id1 upregulation. CONCLUSION: The current data provide novel information regarding the mechanisms by which LMP1 suppresses TGFβ-induced cytostasis, highlighting the importance of Id1 in LMP1 mediated cell transformatio

DCE-MRI for pre-treatment prediction and post-treatment assessment of treatment response in sites of squamous cell carcinoma in the head and neck

Background and Purpose It is important to identify patients with head and neck squamous cell carcinoma (SCC) who fail to respond to chemoradiotherapy so that they can undergo post-treatment salvage surgery while the disease is still operable. This study aimed to determine the diagnostic performance of dynamic contrast enhanced (DCE)-MRI using a pharmacokinetic model for pre-treatment predictive imaging, as well as post-treatment diagnosis, of residual SCC at primary and nodal sites in the head and neck. Material and Methods Forty-nine patients with 83 SCC sites (primary and/or nodal) underwent pre-treatment DCEMRI, and 43 patients underwent post-treatment DCE-MRI, of which 33 SCC sites had a residual mass amenable to analysis. Pre-treatment, post-treatment and %change in the mean Ktrans, kep, ve and AUGC were obtained from SCC sites. Logistic regression was used to correlate DCE parameters at each SCC site with treatment response at the same site, based on clinical outcome at that site at a minimum of two years. Results None of the pre-treatment DCE-MRI parameters showed significant correlations with SCC site failure (SF) (29/83 sites) or site control (SC) (54/83 sites). Post-treatment residual masses with SF (14/33) had significantly higher kep (p = 0.05), higher AUGC (p = 0.02), and lower % reduction in AUGC (p = 0.02), than residual masses with SC (19/33), with the% change in AUGC remaining significant on multivariate analysis. Conclusion Pre-treatment DCE-MRI did not predict which SCC sites would fail treatment, but post-treatment DCE-MRI showed potential for identifying residual masses that had failed treatment

DCE-MRI for pre-treatment prediction and post-treatment assessment of treatment response in sites of squamous cell carcinoma in the head and neck

Background and Purpose It is important to identify patients with head and neck squamous cell carcinoma (SCC) who fail to respond to chemoradiotherapy so that they can undergo post-treatment salvage surgery while the disease is still operable. This study aimed to determine the diagnostic performance of dynamic contrast enhanced (DCE)-MRI using a pharmacokinetic model for pre-treatment predictive imaging, as well as post-treatment diagnosis, of residual SCC at primary and nodal sites in the head and neck. Material and Methods Forty-nine patients with 83 SCC sites (primary and/or nodal) underwent pre-treatment DCEMRI, and 43 patients underwent post-treatment DCE-MRI, of which 33 SCC sites had a residual mass amenable to analysis. Pre-treatment, post-treatment and %change in the mean Ktrans, kep, ve and AUGC were obtained from SCC sites. Logistic regression was used to correlate DCE parameters at each SCC site with treatment response at the same site, based on clinical outcome at that site at a minimum of two years. Results None of the pre-treatment DCE-MRI parameters showed significant correlations with SCC site failure (SF) (29/83 sites) or site control (SC) (54/83 sites). Post-treatment residual masses with SF (14/33) had significantly higher kep (p = 0.05), higher AUGC (p = 0.02), and lower % reduction in AUGC (p = 0.02), than residual masses with SC (19/33), with the% change in AUGC remaining significant on multivariate analysis. Conclusion Pre-treatment DCE-MRI did not predict which SCC sites would fail treatment, but post-treatment DCE-MRI showed potential for identifying residual masses that had failed treatment

IL-33 ameliorates Alzheimer’s disease-like pathology and cognitive decline

Alzheimer’s disease (AD) is a devastating condition with no known effective treatment. AD is characterized by memory loss as well as impaired locomotor ability, reasoning, and judgment. Emerging evidence suggests that the innate immune response plays a major role in the pathogenesis of AD. In AD, the accumulation of β-amyloid (Aβ) in the brain perturbs physiological functions of the brain, including synaptic and neuronal dysfunction, microglial activation, and neuronal loss. Serum levels of soluble ST2 (sST2), a decoy receptor for interleukin (IL)-33, increase in patients with mild cognitive impairment, suggesting that impaired IL-33/ST2 signaling may contribute to the pathogenesis of AD. Therefore, we investigated the potential therapeutic role of IL-33 in AD, using transgenic mouse models. Here we report that IL-33 administration reverses synaptic plasticity impairment and memory deficits in APP/PS1 mice. IL-33 administration reduces soluble Aβ levels and amyloid plaque deposition by promoting the recruitment and Aβ phagocytic activity of microglia; this is mediated by ST2/p38 signaling activation. Furthermore, IL-33 injection modulates the innate immune response by polarizing microglia/macrophages toward an antiinflammatory phenotype and reducing the expression of proinflammatory genes, including IL-1β, IL-6, and NLRP3, in the cortices of APP/PS1 mice. Collectively, our results demonstrate a potential therapeutic role for IL-33 in AD

Detection of co-eluted peptides using database search methods

<p>Abstract</p> <p>Background</p> <p>Current experimental techniques, especially those applying liquid chromatography mass spectrometry, have made high-throughput proteomic studies possible. The increase in throughput however also raises concerns on the accuracy of identification or quantification. Most experimental procedures select in a given MS scan only a few relatively most intense parent ions, each to be fragmented (MS²) separately, and most other minor co-eluted peptides that have similar chromatographic retention times are ignored and their information lost.</p> <p>Results</p> <p>We have computationally investigated the possibility of enhancing the information retrieval during a given LC/MS experiment by selecting the two or three most intense parent ions for simultaneous fragmentation. A set of spectra is created via superimposing a number of MS²spectra, each can be identified by all search methods tested with high confidence, to mimick the spectra of co-eluted peptides. The generated convoluted spectra were used to evaluate the capability of several database search methods – SEQUEST, Mascot, X!Tandem, OMSSA, and RAId_DbS – in identifying true peptides from superimposed spectra of co-eluted peptides. We show that using these simulated spectra, all the database search methods will gain eventually in the number of true peptides identified by using the compound spectra of co-eluted peptides.</p> <p>Open peer review</p> <p>Reviewed by Vlad Petyuk (nominated by Arcady Mushegian), King Jordan and Shamil Sunyaev. For the full reviews, please go to the Reviewers' comments section.</p

Live view of gonadotropin-releasing hormone containing neuron migration

Neurons that synthesize GnRH control the reproductive axis and migrate over long distances and through different environments during development. Prior studies provided strong clues for the types of molecules encountered and movements expected along the migratory route. However, our studies provide the first real-time views of the behavior of GnRH neurons in the context of an in vitro preparation that maintains conditions comparable to those in vivo. The live views provide direct evidence of the changing behavior of GnRH neurons in their different environments, showing that GnRH neurons move with greater frequency and with more changes in direction after they enter the brain. Perturbations of guiding fibers distal to moving GnRH neurons in the nasal compartment influenced movement without detectable changes in the fibers in the immediate vicinity of moving GnRH neurons. This suggests that the use of fibers by GnRH neurons for guidance may entail selective signaling in addition to mechanical guidance. These studies establish a model to evaluate the influences of specific molecules that are important for their migration

Longitudinal and transverse dissipation in a simple model for the vortex lattice with screening

Transport properties of the vortex lattice in high temperature superconductors are studied using numerical simulations in the case in which the non-local interactions between vortex lines are dismissed. The results obtained for the longitudinal and transverse resistivities in the presence of quenched disorder are compared with the results of experimental measurements and other numerical simulations where the full interaction is considered. This work shows that the dependence on temperature of the resistivities is well described by the model without interactions, thus indicating that many of the transport characteristics of the vortex structure in real materials are mainly a consequence of the topological configuration of the vortex structure only. In addition, for highly anisotropic samples, a regime is obtained where longitudinal coherence is lost at temperatures where transverse coherence is still finite. I discuss the possibility of observing this regime in real samples.Comment: 9 pages, 7 figures included using epsf.st

Absence of the Transition into Abrikosov Vortex State of Two-Dimensional Type-II Superconductor with Weak Pinning

The resistive properties of thin amorphous NbO_{x} films with weak pinning were investigated experimentally above and below the second critical field H_{c2}. As opposed to bulk type II superconductors with weak pinning where a sharp change of resistive properties at the transition into the Abrikosov state is observed at H_{c4}, some percent below H_{c2} (V.A.Marchenko and A.V.Nikulov, 1981), no qualitative change of resistive properties is observed down to a very low magnetic field, H_{c4} < 0.006 H_{c2}, in thin films with weak pinning. The smooth dependencies of the resistivity observed in these films can be described by paraconductivity theory both above and below H_{c2}. This means that the fluctuation superconducting state without phase coherence remains appreciably below H_{c2} in the two-dimensional superconductor with weak pinning. The difference the H_{c4}/H_{c2} values, i.e. position of the transition into the Abrikosov state, in three- and two-dimensional superconductors conforms to the Maki-Takayama result 1971 year according to which the Abrikosov solution 1957 year is valid only for a superconductor with finite dimensions. Because of the fluctuation this solution obtained in the mean field approximation is not valid in a relatively narrow region below H_{c2} for bulk superconductors with real dimensions and much below H_{c2} for thin films with real dimensions. The superconducting state without phase coherence should not be identified with the mythical vortex liquid because the vortex, as a singularity in superconducting state with phase coherence, can not exist without phase coherence.Comment: 4 pages, 4 figure

Editorial: Recent Advancements in Structural Equation Modeling (SEM): From Both Methodological and Application Perspectives

10.3389/fpsyg.2018.01936Frontiers in Psychology9OCT193