1,088 research outputs found
Characterization of the lncRNA transcriptome in mESC-derived motor neurons: Implications for FUS-ALS
Long non-coding RNAs (lncRNAs) are currently recognized as crucial players in nervous system development,
function and pathology. In Amyotrophic Lateral Sclerosis (ALS), identification of causative mutations in FUS
and TDP-43 or hexanucleotide repeat expansion in C9ORF72 point to the essential role of aberrant RNA metabolism
in neurodegeneration. In this study, by taking advantage of an in vitro differentiation system generating
mouse motor neurons (MNs) from embryonic stem cells, we identified and characterized the long non-coding
transcriptome of MNs. Moreover, by using mutant mouse MNs carrying the equivalent of one of the most severe
ALS-associated FUS alleles (P517L), we identified lncRNAs affected by this mutation. Comparative analysis with
humanMNs derived in vitro frominduced pluripotent stemcells indicated that candidate lncRNAs are conserved
between mouse and human. Our work provides a global view of the long non-coding transcriptome of MN, as a
prerequisite toward the comprehension of the still poorly characterized non-coding side ofMNphysiopatholog
A Regulatory Circuitry Between Gria2, miR-409, and miR-495 Is Affected by ALS FUS Mutation in ESC-Derived Motor Neurons
Mutations in fused in sarcoma (FUS) cause amyotrophic lateral sclerosis (ALS). FUS is a multifunctional protein involved in the
biogenesis and activity of several types of RNAs, and its role in the pathogenesis of ALS may involve both direct effects of
disease-associated mutations through gain- and loss-of-function mechanisms and indirect effects due to the cross talk between
different classes of FUS-dependent RNAs. To explore how FUS mutations impinge on motor neuron-specific RNA-based
circuitries, we performed transcriptome profiling of small and long RNAs of motor neurons (MNs) derived from mouse
embryonic stem cells carrying a FUS-P517L knock-in mutation, which is equivalent to human FUS-P525L, associated with a
severe and juvenile-onset form of ALS. Combining ontological, predictive and molecular analyses, we found an inverse correlation
between several classes of deregulated miRNAs and their corresponding mRNA targets in both homozygous and heterozygous
P517L MNs. We validated a circuitry in which the upregulation of miR-409-3p and miR-495-3p, belonging to a brainspecific
miRNA subcluster implicated in several neurodevelopmental disorders, produced the downregulation of Gria2, a subunit
of the glutamate αâaminoâ3âhydroxyâ5âmethyl-4-isoxazole propionic acid (AMPA) receptor with a significant role in excitatory
neurotransmission. Moreover, we found that FUS was involved in mediating such miRNA repression. Gria2 alteration has been
proposed to be implicated in MN degeneration, through disturbance of Ca2+ homeostasis, which triggers a cascade of damaging
âexcitotoxicâ events. The molecular cross talk identified highlights a role for FUS in excitotoxicity and in miRNA-dependent
regulation of Gria2. This circuitry also proved to be deregulated in heterozygosity, which matches the human condition perfectly
FUS affects circular RNA expression in murine embryonic stem cell-derived motor neurons
The RNA-binding protein FUS participates in several RNA biosynthetic processes and has
been linked to the pathogenesis of amyotrophic lateral sclerosis (ALS) and frontotemporal
dementia. Here we report that FUS controls back-splicing reactions leading to circular RNA
(circRNA) production. We identified circRNAs expressed in
in vitro
-derived mouse motor
neurons (MNs) and determined that the production of a considerable number of these
circRNAs is regulated by FUS. Using RNAi and overexpression of wild-type and ALS-asso-
ciated FUS mutants, we directly correlate the modulation of circRNA biogenesis with
alteration of FUS nuclear levels and with putative toxic gain of function activities. We also
demonstrate that FUS regulates circRNA biogenesis by binding the introns flanking the
back-splicing junctions and that this control can be reproduced with artificial constructs. Most
circRNAs are conserved in humans and specific ones are deregulated in human-induced
pluripotent stem cell-derived MNs carrying the FUS
P525L
mutation associated with AL
Autonomous Mower Saves Energy and Improves Quality of Tall Fescue Lawn
Battery-powered autonomous mowers are designed to reduce the need of
labor for lawn mowing compared with traditional endothermic engine mowers and
at the same time to abate local emissions and noise. The aim of this research was to
compare autonomous mower with traditional rotary mower on a tall fescue (Festuca
arundinacea) lawn under different nitrogen (N) rates. A two-way factor experimental
design with three replications was adopted. In the study, fourNrates (0, 50,
100, and 150 kghaL1) and two mowing systems (autonomous mower vs. gasolinepowered
walk-behind rotary mower equipped for mulching) were used. As
expected, N fertilization increased turf quality. At the end of the trial, the
autonomous mower increased turf density (3.2 shoots/cm2) compared with the
rotary mower (2.1 shoots/cm2) and decreased average leaf width (2.1 mm)
compared with the rotary mower (2.7 mm). Increased density and decreased leaf
width with autonomous mowing yielded higher quality turf (7.3) compared with
the rotary mower (6.4) and a lower weed incidence (6% and 9% cover for
autonomous mower and rotary mower, respectively). Disease incidence and
mowing quality were unaffected by the mowing system. The autonomous mower
working time was set to 10 hours per day (7.8 hours for mowing and 2.2 hours for
recharging) for a surface of 1296 m2. The traditional rotary mower working time
for the same surface was 1.02 hours per week. The estimated primary energy
consumption for autonomous mower was about 4.80 kWh/week compared with
12.60 kWh/week for gasoline-powered rotary mowing. Based on turf quality
aspects and energy consumption, the use of autonomous mowers could be
a promising alternative to traditional mowers
Bile Acid Recognition by NAPE-PLD
The membrane-associated enzyme NAPE-PLD (N-acyl phosphatidylethanolamine specific-phospholipase D) generates the endogenous cannabinoid arachidonylethanolamide and other lipid signaling amides, including oleoylethanolamide and palmitoylethanolamide. These bioactive molecules play important roles in several physiological pathways including stress and pain response, appetite and lifespan. Recently, we reported the crystal structure of human NAPE-PLD and discovered specific binding sites for the bile acid deoxycholic acid. In this study we demonstrate that in the presence of this secondary bile acid, the stiffness of the protein measured by elastic neutron scattering increases, and NAPE-PLD results ~7 times faster to catalyze the hydrolysis of the more unsaturated substrate N-arachidonyl-phosphatidylethanolamine, compared with N-palmitoyl-phosphatidylethanolamine. Chenodeoxycholic acid and glyco- or tauro-dihydroxy conjugates can also bind to NAPE-PLD and drive its activation. The only natural monohydroxy bile acid, lithocholic acid, shows an affinity of ~20 ÎŒM and acts instead as a reversible inhibitor (IC(50) â 68 ÎŒM). Overall, these findings provide important insights into the allosteric regulation of the enzyme mediated by bile acid cofactors, and reveal that NAPE-PLD responds primarily to the number and position of their hydroxyl groups
Measurement of the top quark forward-backward production asymmetry and the anomalous chromoelectric and chromomagnetic moments in pp collisions at âs = 13 TeV
Abstract The parton-level top quark (t) forward-backward asymmetry and the anomalous chromoelectric (dÌ t) and chromomagnetic (ÎŒÌ t) moments have been measured using LHC pp collisions at a center-of-mass energy of 13 TeV, collected in the CMS detector in a data sample corresponding to an integrated luminosity of 35.9 fbâ1. The linearized variable AFB(1) is used to approximate the asymmetry. Candidate t t ÂŻ events decaying to a muon or electron and jets in final states with low and high Lorentz boosts are selected and reconstructed using a fit of the kinematic distributions of the decay products to those expected for t t ÂŻ final states. The values found for the parameters are AFB(1)=0.048â0.087+0.095(stat)â0.029+0.020(syst),ÎŒÌt=â0.024â0.009+0.013(stat)â0.011+0.016(syst), and a limit is placed on the magnitude of | dÌ t| < 0.03 at 95% confidence level. [Figure not available: see fulltext.
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