Nucleolin is a c-Myc-induced gene product with defined roles in ribosomal RNA processing and the inhibition of chromosomal DNA replication following stress. Here we find that changes in nucleolin ...protein levels in unstressed cells cause parallel changes in the amount of p53 protein. Alterations in p53 levels arise from nucleolin binding to the p53 antagonist Hdm2, resulting in the inhibition of both p53 ubiquitination and Hdm2 auto-ubiquitination. Nucleolin does not alter p53 ubiquitination by human papillomavirus E6, indicating that the effect is specific for Hdm2. Although the inhibition of ligase activity would be expected to stabilize Hdm2, we instead find that nucleolin also reduces Hdm2 protein levels, demonstrating that nucleolin inhibits Hdm2 using multiple mechanisms. Increases in nucleolin levels in unstressed cells led to higher expression of p21(cip1/waf1), a reduced rate of cellular proliferation, and an increase in apoptosis. Thus, nucleolin has a number of properties in common with the tumor suppressor ARF (alternate reading frame). We propose that nucleolin, like ARF, responds to hyperproliferative signals by upregulation of p53 through Hdm2 inhibition.
Nanoparticle (NP) toxicity assessment is a critical step in assessing the health impacts of NP exposure to both consumers and occupational workers.
assessment models comprising cells cultured in a ...two-dimensional tissue culture plate (2D-TCP) are an efficient and cost-effective choice for estimating the safety risks of NPs. However,
culture of cells in 2D-TCPs distorts cell-integrin and cell-cell interactions and is not able to replicate an
phenotype. Three-dimensional (3D)
platforms provide a unique alternative to bridge the gap between traditional 2D
and
models. In this study, novel microcapsules of alginate hydrogel incorporated with natural polymeric nanofibers (chitin nanofibrils) and synthetic polymeric nanofibers poly(lactide-
-glycolide) are designed as a 3D
platform. This study demonstrates for the first time that electrodynamic assisted self-assembled fibrous 3D hydrogel (3D-SAF hydrogel) microcapsules with a size in the range of 300-500 μm in diameter with a Young's modulus of 12.7-42 kPa can be obtained by varying the amount of nanofibers in the hydrogel precursor solutions. The 3D-SAF microcapsules were found to mimic the
cellular microenvironment for cells to grow, as evaluated using A549 cells. Higher cellular spreading and prolonged proliferation of A549 cells were observed in 3D-SAF microcapsules compared to control microcapsules without the nanofibers. The 3D-SAF microcapsule integrated well plate was used to assess the toxicity of model NPs,
, Al
O
and ZnO. The toxicity levels of the model NPs were found to be dependent on the chemistry of the NPs and their physical agglomeration in the test media. Our results demonstrate that 3D-SAF microcapsules with an
mimicking microenvironment can be developed as a physiologically relevant platform for high-throughput toxicity screening of NPs or pharmaceutical drugs.
Neuroblastoma (NB) and the Ewing sarcoma (ES)/peripheral primitive neuroectodermal tumor (PNET) family are pediatric cancers derived from neural crest cells. Although NBs display features of the ...sympathetic nervous system, ES/PNETs express markers consistent with parasympathetic differentiation. To examine the control of these differentiation markers, we generated NB x ES/PNET somatic cell hybrids. NB-specific markers were suppressed in the hybrids, whereas ES/PNET-specific markers were unaffected. These results suggested that the Ews/Fli-1 fusion gene, resulting from a translocation unique to ES/PNETs, might account for the loss of NB-specific markers. To test this hypothesis, we generated two different NB cell lines that stably expressed the Ews/Fli-1 gene. We observed that heterologous expression of the Ews/Fli-1 protein led to the suppression of NB-specific markers and de novo expression of ES/PNET markers. To determine the extent of changes in differentiation, we used the Affymetrix GeneChip Array system to observe global transcriptional changes of genes. This analysis revealed that the gene expression pattern of the Ews/Fli-1-expressing NB cells resembled that observed in pooled ES/PNET cell lines and differed significantly from the NB parental cells. Therefore, we propose that Ews/Fli-1 contributes to the etiology of ES/PNET by subverting the differentiation program of its neural crest precursor cell to a less differentiated and more proliferative state.
New sets of CMS underlying-event parameters (“tunes”) are presented for the
pythia
8 event generator. These tunes use the NNPDF3.1 parton distribution functions (PDFs) at leading (LO), ...next-to-leading (NLO), or next-to-next-to-leading (NNLO) orders in perturbative quantum chromodynamics, and the strong coupling evolution at LO or NLO. Measurements of charged-particle multiplicity and transverse momentum densities at various hadron collision energies are fit simultaneously to determine the parameters of the tunes. Comparisons of the predictions of the new tunes are provided for observables sensitive to the event shapes at LEP, global underlying event, soft multiparton interactions, and double-parton scattering contributions. In addition, comparisons are made for observables measured in various specific processes, such as multijet, Drell–Yan, and top quark-antiquark pair production including jet substructure observables. The simulation of the underlying event provided by the new tunes is interfaced to a higher-order matrix-element calculation. For the first time, predictions from
pythia
8 obtained with tunes based on NLO or NNLO PDFs are shown to reliably describe minimum-bias and underlying-event data with a similar level of agreement to predictions from tunes using LO PDF sets.
A
bstract
A search for narrow and broad resonances with masses greater than 1.8 TeV decaying to a pair of jets is presented. The search uses proton-proton collision data at
s
= 13 TeV collected at ...the LHC, corresponding to an integrated luminosity of 137 fb
−
1
. The background arising from standard model processes is predicted with the fit method used in previous publications and with a new method. The dijet invariant mass spectrum is well described by both data-driven methods, and no significant evidence for the production of new particles is observed. Model independent upper limits are reported on the production cross sections of narrow resonances, and broad resonances with widths up to 55% of the resonance mass. Limits are presented on the masses of narrow resonances from various models: string resonances, scalar diquarks, axigluons, colorons, excited quarks, color-octet scalars, W′ and Z′ bosons, Randall-Sundrum gravitons, and dark matter mediators. The limits on narrow resonances are improved by 200 to 800 GeV relative to those reported in previous CMS dijet resonance searches. The limits on dark matter mediators are presented as a function of the resonance mass and width, and on the associated coupling strength as a function of the mediator mass. These limits exclude at 95% confidence level a dark matter mediator with a mass of 1.8 TeV and width 1% of its mass or higher, up to one with a mass of 4.8 TeV and a width 45% of its mass or higher.
A
bstract
A measurement of the inelastic proton-proton cross section with the CMS detector at a center-of-mass energy of
s
=
13
TeV is presented. The analysis is based on events with energy deposits ...in the forward calorimeters, which cover pseudorapidities of −6
.
6
< η <
−3
.
0 and +3
.
0
< η <
+5
.
2. An inelastic cross section of 68
.
6 ± 0
.
5(syst) ± 1
.
6(lumi) mb is obtained for events with
M
X
>
4
.
1 GeV and/or
M
Y
>
13 GeV, where
M
X
and
M
Y
are the masses of the diffractive dissociation systems at negative and positive pseudorapidities, respectively. The results are compared with those from other experiments as well as to predictions from high-energy hadron-hadron interaction models.
A
bstract
Properties of the Higgs boson are measured in the H → ZZ → 4ℓ (ℓ = e,
μ
) decay channel. A data sample of proton-proton collisions at
s
=
13
TeV, collected with the CMS detector at the LHC ...and corresponding to an integrated luminosity of 35.9 fb
−1
is used. The signal strength modifier
μ
, defined as the ratio of the observed Higgs boson rate in the H → ZZ → 4ℓ decay channel to the standard model expectation, is measured to be
μ
= 1.05
− 0.17
+ 0.19
at
m
H
= 125.09 GeV, the combined ATLAS and CMS measurement of the Higgs boson mass. The signal strength modifiers for the individual Higgs boson production modes are also measured. The cross section in the fiducial phase space defined by the requirements on lepton kinematics and event topology is measured to be 2. 92
− 0.44
+ 0.48
(stat)
− 0.24
+ 0.28
(syst)fb, which is compatible with the standard model prediction of 2.76 ± 0.14 fb. Differential cross sections are reported as a function of the transverse momentum of the Higgs boson, the number of associated jets, and the transverse momentum of the leading associated jet. The Higgs boson mass is measured to be
m
H
= 125.26 ± 0.21 GeV and the width is constrained using the on-shell invariant mass distribution to be Γ
H
< 1.10 GeV, at 95% confidence level.
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