991 research outputs found
Induction of microRNAs, mir-155, mir-222, mir-424 and mir-503, promotes monocytic differentiation through combinatorial regulation
Acute myeloid leukemia (AML) involves a block in terminal differentiation of
the myeloid lineage and uncontrolled proliferation of a progenitor state. Using
phorbol myristate acetate (PMA), it is possible to overcome this block in THP-1
cells (an M5-AML containing the MLL-MLLT3 fusion), resulting in differentiation
to an adherent monocytic phenotype. As part of FANTOM4, we used microarrays to
identify 23 microRNAs that are regulated by PMA. We identify four PMA-induced
micro- RNAs (mir-155, mir-222, mir-424 and mir-503) that when overexpressed
cause cell-cycle arrest and partial differentiation and when used in
combination induce additional changes not seen by any individual microRNA. We
further characterize these prodifferentiative microRNAs and show that mir-155
and mir-222 induce G2 arrest and apoptosis, respectively. We find mir-424 and
mir-503 are derived from a polycistronic precursor mir-424-503 that is under
repression by the MLL-MLLT3 leukemogenic fusion. Both of these microRNAs
directly target cell-cycle regulators and induce G1 cell-cycle arrest when
overexpressed in THP-1. We also find that the pro-differentiative mir-424 and
mir-503 downregulate the anti-differentiative mir-9 by targeting a site in its
primary transcript. Our study highlights the combinatorial effects of multiple
microRNAs within cellular systems.Comment: 45 pages 5 figure
Right-handed Sneutrino Dark Matter in Supersymmetric B-L Model
We show that the lightest right-handed sneutrino in TeV scale supersymmetric
B-L model with inverse seesaw mechanism is a viable candidate for cold dark
matter. We find that it accounts for the observed dark matter relic abundance
in a wide range of parameter space. The spin-independent cross section of B-L
right-handed sneutrino is consistent with the recent results CDMS II and XENON
experiments and it is detectable in future direct detection experiments.
Although the B-L right-handed sneutrinos annihilate into leptons, the PAMELA
results can not be explained in this model unless a huge boost factor is
considered. Also the muon flux generated by B-L right-handed sneutrino in the
galactic center is smaller than Super-Kamiokande's upper bound.Comment: 16 pages, 7 figures; version accepted for publication in Journal of
High Energy Physic
-Two Higgs Doublet Model and its Collider Phenomenology
Smallness of neutrino masses can be explained by introducing a tiny vacuum
expectation value of an extra-Higgs doublet which couples to right-handed
neutrinos (). This situation is naturally realized in -Two Higgs
Doublet Model (THDM), where a TeV-scale seesaw mechanism can work well. We
investigate observable phenomenology of THDM at LHC and ILC experiments.
Charged Higgs boson () in THDM is almost originated from the
extra-Higgs doublet and its coupling strength to neutrinos are not small. Then
this model induces rich phenomenology at the LHC, for example, when
, observable charged tracks can be induced from long lived
charged Higgs. On the other hand, when , right-handed
neutrinos can be long-lived, and secondary vertices may be tagged at the LHC.
The THDM also predicts observable lepton number violating process at the
ILC.Comment: 17 pages, 27 eps file
Probing the charged Higgs boson at the LHC in the CP-violating type-II 2HDM
We present a phenomenological study of a CP-violating two-Higgs-doublet Model
with type-II Yukawa couplings at the Large Hadron Collider (LHC). In the light
of recent LHC data, we focus on the parameter space that survives the current
and past experimental constraints as well as theoretical bounds on the model.
Once the phenomenological scenario is set, we analyse the scope of the LHC in
exploring this model through the discovery of a charged Higgs boson produced in
association with a W boson, with the former decaying into the lightest neutral
Higgs and a second W state, altogether yielding a b\bar b W^+W^- signature, of
which we exploit the W^+W^- semileptonic decays.Comment: 37 pages, 16 figures; v2 updated treatment of LHC constraint
Neurochemical Changes in the Mouse Hippocampus Underlying the Antidepressant Effect of Genetic Deletion of P2X7 Receptors.
Recent investigations have revealed that the genetic deletion of P2X7 receptors (P2rx7) results in an antidepressant phenotype in mice. However, the link between the deficiency of P2rx7 and changes in behavior has not yet been explored. In the present study, we studied the effect of genetic deletion of P2rx7 on neurochemical changes in the hippocampus that might underlie the antidepressant phenotype. P2X7 receptor deficient mice (P2rx7-/-) displayed decreased immobility in the tail suspension test (TST) and an attenuated anhedonia response in the sucrose preference test (SPT) following bacterial endotoxin (LPS) challenge. The attenuated anhedonia was reproduced through systemic treatments with P2rx7 antagonists. The activation of P2rx7 resulted in the concentration-dependent release of [3H]glutamate in P2rx7+/+ but not P2rx7-/- mice, and the NR2B subunit mRNA and protein was upregulated in the hippocampus of P2rx7-/- mice. The brain-derived neurotrophic factor (BDNF) expression was higher in saline but not LPS-treated P2rx7-/- mice; the P2rx7 antagonist Brilliant blue G elevated and the P2rx7 agonist benzoylbenzoyl ATP (BzATP) reduced BDNF level. This effect was dependent on the activation of NMDA and non-NMDA receptors but not on Group I metabotropic glutamate receptors (mGluR1,5). An increased 5-bromo-2-deoxyuridine (BrdU) incorporation was also observed in the dentate gyrus derived from P2rx7-/- mice. Basal level of 5-HT was increased, whereas the 5HIAA/5-HT ratio was lower in the hippocampus of P2rx7-/- mice, which accompanied the increased uptake of [3H]5-HT and an elevated number of [3H]citalopram binding sites. The LPS-induced elevation of 5-HT level was absent in P2rx7-/- mice. In conclusion there are several potential mechanisms for the antidepressant phenotype of P2rx7-/- mice, such as the absence of P2rx7-mediated glutamate release, elevated basal BDNF production, enhanced neurogenesis and increased 5-HT bioavailability in the hippocampus
Detection of regulator genes and eQTLs in gene networks
Genetic differences between individuals associated to quantitative phenotypic
traits, including disease states, are usually found in non-coding genomic
regions. These genetic variants are often also associated to differences in
expression levels of nearby genes (they are "expression quantitative trait
loci" or eQTLs for short) and presumably play a gene regulatory role, affecting
the status of molecular networks of interacting genes, proteins and
metabolites. Computational systems biology approaches to reconstruct causal
gene networks from large-scale omics data have therefore become essential to
understand the structure of networks controlled by eQTLs together with other
regulatory genes, and to generate detailed hypotheses about the molecular
mechanisms that lead from genotype to phenotype. Here we review the main
analytical methods and softwares to identify eQTLs and their associated genes,
to reconstruct co-expression networks and modules, to reconstruct causal
Bayesian gene and module networks, and to validate predicted networks in
silico.Comment: minor revision with typos corrected; review article; 24 pages, 2
figure
Absence of system xcâť on immune cells invading the central nervous system alleviates experimental autoimmune encephalitis
Background: Multiple sclerosis (MS) is an autoimmune demyelinating disease that affects the central nervous system (CNS), leading to neurodegeneration and chronic disability. Accumulating evidence points to a key role for neuroinflammation, oxidative stress, and excitotoxicity in this degenerative process. System x(c)- or the cystine/glutamate antiporter could tie these pathological mechanisms together: its activity is enhanced by reactive oxygen species and inflammatory stimuli, and its enhancement might lead to the release of toxic amounts of glutamate, thereby triggering excitotoxicity and neurodegeneration.
Methods: Semi-quantitative Western blotting served to study protein expression of xCT, the specific subunit of system x(c)-, as well as of regulators of xCT transcription, in the normal appearing white matter (NAWM) of MS patients and in the CNS and spleen of mice exposed to experimental autoimmune encephalomyelitis (EAE), an accepted mouse model of MS. We next compared the clinical course of the EAE disease, the extent of demyelination, the infiltration of immune cells and microglial activation in xCT-knockout (xCT(-/-)) mice and irradiated mice reconstituted in xCT(-/-) bone marrow (BM), to their proper wild type (xCT(+/+)) controls.
Results: xCT protein expression levels were upregulated in the NAWM of MS patients and in the brain, spinal cord, and spleen of EAE mice. The pathways involved in this upregulation in NAWM of MS patients remain unresolved. Compared to xCT(+/+) mice, xCT(-/-) mice were equally susceptible to EAE, whereas mice transplanted with xCT(-/-) BM, and as such only exhibiting loss of xCT in their immune cells, were less susceptible to EAE. In none of the above-described conditions, demyelination, microglial activation, or infiltration of immune cells were affected.
Conclusions: Our findings demonstrate enhancement of xCT protein expression in MS pathology and suggest that system x(c)- on immune cells invading the CNS participates to EAE. Since a total loss of system x(c)- had no net beneficial effects, these results have important implications for targeting system x(c)- for treatment of MS
Essential versus accessory aspects of cell death: recommendations of the NCCD 2015
Cells exposed to extreme physicochemical or mechanical stimuli die in an uncontrollable manner, as a result of their immediate structural breakdown. Such an unavoidable variant of cellular demise is generally referred to as âaccidental cell deathâ (ACD). In most settings, however, cell death is initiated by a genetically encoded apparatus, correlating with the fact that its course can be altered by pharmacologic or genetic interventions. âRegulated cell deathâ (RCD) can occur as part of physiologic programs or can be activated once adaptive responses to perturbations of the extracellular or intracellular microenvironment fail. The biochemical phenomena that accompany RCD may be harnessed to classify it into a few subtypes, which often (but not always) exhibit stereotyped morphologic features. Nonetheless, efficiently inhibiting the processes that are commonly thought to cause RCD, such as the activation of executioner caspases in the course of apoptosis, does not exert true cytoprotective effects in the mammalian system, but simply alters the kinetics of cellular demise as it shifts its morphologic and biochemical correlates. Conversely, bona fide cytoprotection can be achieved by inhibiting the transduction of lethal signals in the early phases of the process, when adaptive responses are still operational. Thus, the mechanisms that truly execute RCD may be less understood, less inhibitable and perhaps more homogeneous than previously thought. Here, the Nomenclature Committee on Cell Death formulates a set of recommendations to help scientists and researchers to discriminate between essential and accessory aspects of cell death
Performance of CMS muon reconstruction in pp collision events at sqrt(s) = 7 TeV
The performance of muon reconstruction, identification, and triggering in CMS
has been studied using 40 inverse picobarns of data collected in pp collisions
at sqrt(s) = 7 TeV at the LHC in 2010. A few benchmark sets of selection
criteria covering a wide range of physics analysis needs have been examined.
For all considered selections, the efficiency to reconstruct and identify a
muon with a transverse momentum pT larger than a few GeV is above 95% over the
whole region of pseudorapidity covered by the CMS muon system, abs(eta) < 2.4,
while the probability to misidentify a hadron as a muon is well below 1%. The
efficiency to trigger on single muons with pT above a few GeV is higher than
90% over the full eta range, and typically substantially better. The overall
momentum scale is measured to a precision of 0.2% with muons from Z decays. The
transverse momentum resolution varies from 1% to 6% depending on pseudorapidity
for muons with pT below 100 GeV and, using cosmic rays, it is shown to be
better than 10% in the central region up to pT = 1 TeV. Observed distributions
of all quantities are well reproduced by the Monte Carlo simulation.Comment: Replaced with published version. Added journal reference and DO
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