Short locked nucleic acid antisense oligonucleotides potently reduce apolipoprotein B mRNA and serum cholesterol in mice and non-human primates

The potency and specificity of locked nucleic acid (LNA) antisense oligonucleotides was investigated as a function of length and affinity. The oligonucleotides were designed to target apolipoprotein B (apoB) and were investigated both in vitro and in vivo. The high affinity of LNA enabled the design of short antisense oligonucleotides (12- to 13-mers) that possessed high affinity and increased potency both in vitro and in vivo compared to longer oligonucleotides. The short LNA oligonucleotides were more target specific, and they exhibited the same biodistribution and tissue half-life as longer oligonucleotides. Pharmacology studies in both mice and non-human primates were conducted with a 13-mer LNA oligonucleotide against apoB, and the data showed that repeated dosing of the 13-mer at 1–2 mg/kg/week was sufficient to provide a significant and long lasting lowering of non-high-density lipoprotein (non-HDL) cholesterol without increasing serum liver toxicity markers. The data presented here show that oligonucleotide length as a parameter needs to be considered in the design of antisense oligonucleotide and that potent short oligonucleotides with sufficient target affinity can be generated using the LNA chemistry. Conclusively, we present a 13-mer LNA oligonucleotide with therapeutic potential that produce beneficial cholesterol lowering effect in non-human primates

Inclusive and multiplicity dependent production of electrons from heavy-flavour hadron decays in pp and p−-Pb collisions

International audienceMeasurements of the production of electrons from heavy-flavour hadron decays in pp collisions at $\sqrt{s} = 13$ TeV at midrapidity with the ALICE detector are presented down to a transverse momentum ($p_{\rm T}$) of 0.2 GeV$/c$ and up to $p_{\rm T} = 35$ GeV$/c$, which is the largest momentum range probed for inclusive electron measurements in ALICE. In p$-$Pb collisions, the production cross section and the nuclear modification factor of electrons from heavy-flavour hadron decays are measured in the $p_{\rm T}$ range $0.5 < p_{\rm T} < 26$ GeV$/c$ at $\sqrt{s_{\rm NN}} = 8.16$ TeV. The nuclear modification factor is found to be consistent with unity within the statistical and systematic uncertainties. In both collision systems, first measurements of the yields of electrons from heavy-flavour hadron decays in different multiplicity intervals normalised to the multiplicity-integrated yield (self-normalised yield) at midrapidity are reported as a function of the self-normalised charged-particle multiplicity estimated at midrapidity. The self-normalised yields in pp and p$-$Pb collisions grow faster than linear with the self-normalised multiplicity. A strong $p_{\rm T}$ dependence is observed in pp collisions, where the yield of high-$p_{\rm T}$ electrons increases faster as a function of multiplicity than the one of low-$p_{\rm T}$ electrons. The measurement in p$-$Pb collisions shows no $p_{\rm T}$ dependence within uncertainties. The self-normalised yields in pp and p$-$Pb collisions are compared with measurements of other heavy-flavour, light-flavour, and strange particles, and with Monte Carlo simulations

Inclusive and multiplicity dependent production of electrons from heavy-flavour hadron decays in pp and p–Pb collisions

Measurements of the production of electrons from heavy-flavour hadron decays in pp collisions at s√=13 TeV at midrapidity with the ALICE detector are presented down to a transverse momentum (pT) of 0.2 GeV/c and up to pT=35 GeV/c, which is the largest momentum range probed for inclusive electron measurements in ALICE. In p−Pb collisions, the production cross section and the nuclear modification factor of electrons from heavy-flavour hadron decays are measured in the pT range 0.5<pT<26 GeV/c at sNN−−−√=8.16 TeV. The nuclear modification factor is found to be consistent with unity within the statistical and systematic uncertainties. In both collision systems, first measurements of the yields of electrons from heavy-flavour hadron decays in different multiplicity intervals normalised to the multiplicity-integrated yield (self-normalised yield) at midrapidity are reported as a function of the self-normalised charged-particle multiplicity estimated at midrapidity. The self-normalised yields in pp and p−Pb collisions grow faster than linear with the self-normalised multiplicity. A strong pT dependence is observed in pp collisions, where the yield of high-pT electrons increases faster as a function of multiplicity than the one of low-pT electrons. The measurement in p−Pb collisions shows no pT dependence within uncertainties. The self-normalised yields in pp and p−Pb collisions are compared with measurements of other heavy-flavour, light-flavour, and strange particles, and with Monte Carlo simulations