922 research outputs found
On dynamic network entropy in cancer
The cellular phenotype is described by a complex network of molecular
interactions. Elucidating network properties that distinguish disease from the
healthy cellular state is therefore of critical importance for gaining
systems-level insights into disease mechanisms and ultimately for developing
improved therapies. By integrating gene expression data with a protein
interaction network to induce a stochastic dynamics on the network, we here
demonstrate that cancer cells are characterised by an increase in the dynamic
network entropy, compared to cells of normal physiology. Using a fundamental
relation between the macroscopic resilience of a dynamical system and the
uncertainty (entropy) in the underlying microscopic processes, we argue that
cancer cells will be more robust to random gene perturbations. In addition, we
formally demonstrate that gene expression differences between normal and cancer
tissue are anticorrelated with local dynamic entropy changes, thus providing a
systemic link between gene expression changes at the nodes and their local
network dynamics. In particular, we also find that genes which drive
cell-proliferation in cancer cells and which often encode oncogenes are
associated with reductions in the dynamic network entropy. In summary, our
results support the view that the observed increased robustness of cancer cells
to perturbation and therapy may be due to an increase in the dynamic network
entropy that allows cells to adapt to the new cellular stresses. Conversely,
genes that exhibit local flux entropy decreases in cancer may render cancer
cells more susceptible to targeted intervention and may therefore represent
promising drug targets.Comment: 10 pages, 3 figures, 4 tables. Submitte
Conserved presence of G-quadruplex forming sequences in the Long Terminal Repeat Promoter of Lentiviruses
G-quadruplexes (G4s) are secondary structures of nucleic acids that epigenetically regulate cellular processes. In the human immunodeficiency lentivirus 1 (HIV-1), dynamic G4s are located in the unique viral LTR promoter. Folding of HIV-1 LTR G4s inhibits viral transcription; stabilization by G4 ligands intensifies this effect. Cellular proteins modulate viral transcription by inducing/unfolding LTR G4s. We here expanded our investigation on the presence of LTR G4s to all lentiviruses. G4s in the 5'-LTR U3 region were completely conserved in primate lentiviruses. A G4 was also present in a cattle-infecting lentivirus. All other non-primate lentiviruses displayed hints of less stable G4s. In primate lentiviruses, the possibility to fold into G4s was highly conserved among strains. LTR G4 sequences were very similar among phylogenetically related primate viruses, while they increasingly differed in viruses that diverged early from a common ancestor. A strong correlation between primate lentivirus LTR G4s and Sp1/NF\u3baB binding sites was found. All LTR G4s folded: their complexity was assessed by polymerase stop assay. Our data support a role of the lentiviruses 5'-LTR G4 region as control centre of viral transcription, where folding/unfolding of G4s and multiple recruitment of factors based on both sequence and structure may take place
Tumor innate immunity primed by specific interferon-stimulated endogenous retroviruses.
Mesenchymal tumor subpopulations secrete pro-tumorigenic cytokines and promote treatment resistance1-4. This phenomenon has been implicated in chemorefractory small cell lung cancer and resistance to targeted therapies5-8, but remains incompletely defined. Here, we identify a subclass of endogenous retroviruses (ERVs) that engages innate immune signaling in these cells. Stimulated 3 prime antisense retroviral coding sequences (SPARCS) are oriented inversely in 3' untranslated regions of specific genes enriched for regulation by STAT1 and EZH2. Derepression of these loci results in double-stranded RNA generation following IFN-γ exposure due to bi-directional transcription from the STAT1-activated gene promoter and the 5' long terminal repeat of the antisense ERV. Engagement of MAVS and STING activates downstream TBK1, IRF3, and STAT1 signaling, sustaining a positive feedback loop. SPARCS induction in human tumors is tightly associated with major histocompatibility complex class 1 expression, mesenchymal markers, and downregulation of chromatin modifying enzymes, including EZH2. Analysis of cell lines with high inducible SPARCS expression reveals strong association with an AXL/MET-positive mesenchymal cell state. While SPARCS-high tumors are immune infiltrated, they also exhibit multiple features of an immune-suppressed microenviroment. Together, these data unveil a subclass of ERVs whose derepression triggers pathologic innate immune signaling in cancer, with important implications for cancer immunotherapy
Children, parents and pets exercising together (CPET) : exploratory randomised controlled trial
Levels of physical activity (PA) in UK children are much lower than recommended and novel approaches to its promotion are needed. The Children, Parents and Pets Exercising Together (CPET) study is the first exploratory randomised controlled trial (RCT) to develop and evaluate an intervention aimed at dog-based PA promotion in families. CPET aimed to assess the feasibility, acceptability and potential efficacy of a theory-driven, family-based, dog walking intervention for 9-11 year olds
Microbial Activities and Dissolved Organic Matter Dynamics in Oil-Contaminated Surface Seawater from the Deepwater Horizon Oil Spill Site
The Deepwater Horizon oil spill triggered a complex cascade of microbial responses that reshaped the dynamics of heterotrophic carbon degradation and the turnover of dissolved organic carbon (DOC) in oil contaminated waters. Our results from 21-day laboratory incubations in rotating glass bottles (roller bottles) demonstrate that microbial dynamics and carbon flux in oil-contaminated surface water sampled near the spill site two weeks after the onset of the blowout were greatly affected by activities of microbes associated with macroscopic oil aggregates. Roller bottles with oil-amended water showed rapid formation of oil aggregates that were similar in size and appearance compared to oil aggregates observed in surface waters near the spill site. Oil aggregates that formed in roller bottles were densely colonized by heterotrophic bacteria, exhibiting high rates of enzymatic activity (lipase hydrolysis) indicative of oil degradation. Ambient waters surrounding aggregates also showed enhanced microbial activities not directly associated with primary oil-degradation (β-glucosidase; peptidase), as well as a twofold increase in DOC. Concurrent changes in fluorescence properties of colored dissolved organic matter (CDOM) suggest an increase in oil-derived, aromatic hydrocarbons in the DOC pool. Thus our data indicate that oil aggregates mediate, by two distinct mechanisms, the transfer of hydrocarbons to the deep sea: a microbially-derived flux of oil-derived DOC from sinking oil aggregates into the ambient water column, and rapid sedimentation of the oil aggregates themselves, serving as vehicles for oily particulate matter as well as oil aggregate-associated microbial communities
Brane-World Gravity
The observable universe could be a 1+3-surface (the "brane") embedded in a
1+3+\textit{d}-dimensional spacetime (the "bulk"), with Standard Model
particles and fields trapped on the brane while gravity is free to access the
bulk. At least one of the \textit{d} extra spatial dimensions could be very
large relative to the Planck scale, which lowers the fundamental gravity scale,
possibly even down to the electroweak ( TeV) level. This revolutionary
picture arises in the framework of recent developments in M theory. The
1+10-dimensional M theory encompasses the known 1+9-dimensional superstring
theories, and is widely considered to be a promising potential route to quantum
gravity. At low energies, gravity is localized at the brane and general
relativity is recovered, but at high energies gravity "leaks" into the bulk,
behaving in a truly higher-dimensional way. This introduces significant changes
to gravitational dynamics and perturbations, with interesting and potentially
testable implications for high-energy astrophysics, black holes, and cosmology.
Brane-world models offer a phenomenological way to test some of the novel
predictions and corrections to general relativity that are implied by M theory.
This review analyzes the geometry, dynamics and perturbations of simple
brane-world models for cosmology and astrophysics, mainly focusing on warped
5-dimensional brane-worlds based on the Randall--Sundrum models. We also cover
the simplest brane-world models in which 4-dimensional gravity on the brane is
modified at \emph{low} energies -- the 5-dimensional Dvali--Gabadadze--Porrati
models. Then we discuss co-dimension two branes in 6-dimensional models.Comment: A major update of Living Reviews in Relativity 7:7 (2004)
"Brane-World Gravity", 119 pages, 28 figures, the update contains new
material on RS perturbations, including full numerical solutions of
gravitational waves and scalar perturbations, on DGP models, and also on 6D
models. A published version in Living Reviews in Relativit
Medial prefrontal cortex serotonin 1A and 2A receptor binding interacts to predict threat-related amygdala reactivity
Background\ud
The amygdala and medial prefrontal cortex (mPFC) comprise a key corticolimbic circuit that helps shape individual differences in sensitivity to threat and the related risk for psychopathology. Although serotonin (5-HT) is known to be a key modulator of this circuit, the specific receptors mediating this modulation are unclear. The colocalization of 5-HT1A and 5-HT2A receptors on mPFC glutamatergic neurons suggests that their functional interactions may mediate 5-HT effects on this circuit through top-down regulation of amygdala reactivity. Using a multimodal neuroimaging strategy in 39 healthy volunteers, we determined whether threat-related amygdala reactivity, assessed with blood oxygen level-dependent functional magnetic resonance imaging, was significantly predicted by the interaction between mPFC 5-HT1A and 5-HT2A receptor levels, assessed by positron emission tomography.\ud
\ud
Results\ud
5-HT1A binding in the mPFC significantly moderated an inverse correlation between mPFC 5-HT2A binding and threat-related amygdala reactivity. Specifically, mPFC 5-HT2A binding was significantly inversely correlated with amygdala reactivity only when mPFC 5-HT1A binding was relatively low.\ud
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Conclusions\ud
Our findings provide evidence that 5-HT1A and 5-HT2A receptors interact to shape serotonergic modulation of a functional circuit between the amygdala and mPFC. The effect of the interaction between mPFC 5-HT1A and 5-HT2A binding and amygdala reactivity is consistent with the colocalization of these receptors on glutamatergic neurons in the mPFC
The Strathclyde Evaluation of Children's Active Travel (SE-CAT): study rationale and methods
Peer reviewedPublisher PD
Cluster Lenses
Clusters of galaxies are the most recently assembled, massive, bound
structures in the Universe. As predicted by General Relativity, given their
masses, clusters strongly deform space-time in their vicinity. Clusters act as
some of the most powerful gravitational lenses in the Universe. Light rays
traversing through clusters from distant sources are hence deflected, and the
resulting images of these distant objects therefore appear distorted and
magnified. Lensing by clusters occurs in two regimes, each with unique
observational signatures. The strong lensing regime is characterized by effects
readily seen by eye, namely, the production of giant arcs, multiple-images, and
arclets. The weak lensing regime is characterized by small deformations in the
shapes of background galaxies only detectable statistically. Cluster lenses
have been exploited successfully to address several important current questions
in cosmology: (i) the study of the lens(es) - understanding cluster mass
distributions and issues pertaining to cluster formation and evolution, as well
as constraining the nature of dark matter; (ii) the study of the lensed objects
- probing the properties of the background lensed galaxy population - which is
statistically at higher redshifts and of lower intrinsic luminosity thus
enabling the probing of galaxy formation at the earliest times right up to the
Dark Ages; and (iii) the study of the geometry of the Universe - as the
strength of lensing depends on the ratios of angular diameter distances between
the lens, source and observer, lens deflections are sensitive to the value of
cosmological parameters and offer a powerful geometric tool to probe Dark
Energy. In this review, we present the basics of cluster lensing and provide a
current status report of the field.Comment: About 120 pages - Published in Open Access at:
http://www.springerlink.com/content/j183018170485723/ . arXiv admin note:
text overlap with arXiv:astro-ph/0504478 and arXiv:1003.3674 by other author
Vitamin D and the hepatitis B vaccine response: a prospective cohort study and a randomized, placebo-controlled oral vitamin D3 and simulated sunlight supplementation trial in healthy adults.
PURPOSE: To determine serum 25(OH)D and 1,25(OH)2D relationship with hepatitis B vaccination (study 1). Then, to investigate the effects on hepatitis B vaccination of achieving vitamin D sufficiency (serum 25(OH)D ≥ 50 nmol/L) by a unique comparison of simulated sunlight and oral vitamin D3 supplementation in wintertime (study 2). METHODS: Study 1 involved 447 adults. In study 2, 3 days after the initial hepatitis B vaccination, 119 men received either placebo, simulated sunlight (1.3 × standard-erythema dose, 3 × /week for 4 weeks and then 1 × /week for 8 weeks) or oral vitamin D3 (1000 IU/day for 4 weeks and 400 IU/day for 8 weeks). We measured hepatitis B vaccination efficacy as percentage of responders with anti-hepatitis B surface antigen immunoglobulin G ≥ 10 mIU/mL. RESULTS: In study 1, vaccine response was poorer in persons with low vitamin D status (25(OH)D ≤ 40 vs 41-71 nmol/L mean difference [95% confidence interval] - 15% [- 26, - 3%]; 1,25(OH)2D ≤ 120 vs ≥ 157 pmol/L - 12% [- 24%, - 1%]). Vaccine response was also poorer in winter than summer (- 18% [- 31%, - 3%]), when serum 25(OH)D and 1,25(OH)2D were at seasonal nadirs, and 81% of persons had serum 25(OH)D < 50 nmol/L. In study 2, vitamin D supplementation strategies were similarly effective in achieving vitamin D sufficiency from the winter vitamin D nadir in almost all (~ 95%); however, the supplementation beginning 3 days after the initial vaccination did not effect the vaccine response (vitamin D vs placebo 4% [- 21%, 14%]). CONCLUSION: Low vitamin D status at initial vaccination was associated with poorer hepatitis B vaccine response (study 1); however, vitamin D supplementation commencing 3 days after vaccination (study 2) did not influence the vaccination response. CLINICAL TRIAL REGISTRY NUMBER: Study 1 NCT02416895; https://clinicaltrials.gov/ct2/show/study/NCT02416895; Study 2 NCT03132103; https://clinicaltrials.gov/ct2/show/NCT03132103
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