630 research outputs found
Lead optimisation of dehydroemetine for repositioned use in malaria
Drug repositioning offers an effective alternative to de novo drug design to tackle the urgent need for novel anti-malarial treatments. The anti-amoebic compound, emetine dihydrochloride, has been identified as a potent in-vitro inhibitor of the multi-drug resistant strain K1 of Plasmodium falciparum (IC50: 47 nM ± 2.1 nM). Dehydroemetine, a synthetic analogue of emetine dihydrochloride has been reported to have less cardiotoxic effects than emetine. The structures of two diastereomers of dehydroemetine were modelled on the published emetine binding site on cryo-EM structure 3J7A (Pf 80S ribosome in complex with emetine) and it was found that (-)-R,S-dehydroemetine mimicked the bound pose of emetine more closely than (-)-S,S-dehydroisoemetine. (-)-R,S-dehydroemetine (IC50 71.03 ± 6.1 nM) was also found to be highly potent against the multi-drug resistant K1 strain of P. falciparum in comparison with (-)-S,S-dehydroisoemetine (IC50 2.07 ± 0.26 μM), which loses its potency due to the change of configuration at C-1′. In addition to its effect on the asexual erythrocytic stages of P. falciparum, the compounds exhibited gametocidal properties with no cross-resistance against any of the multi-drug resistant strains tested. Drug interaction studies showed (-)-R,S-dehydroemetine to have synergistic antimalarial activity with atovaquone and proguanil. Emetine dihydrochloride, and (-)-R,S-dehydroemetine failed to show any inhibition of the hERG potassium channel and displayed activity on the mitochondrial membrane potential indicating a possible multi-modal mechanism of action. [Abstract copyright: Copyright © 2020 Panwar et al.
Dynamical tunneling in molecules: Quantum routes to energy flow
Dynamical tunneling, introduced in the molecular context, is more than two
decades old and refers to phenomena that are classically forbidden but allowed
by quantum mechanics. On the other hand the phenomenon of intramolecular
vibrational energy redistribution (IVR) has occupied a central place in the
field of chemical physics for a much longer period of time. Although the two
phenomena seem to be unrelated several studies indicate that dynamical
tunneling, in terms of its mechanism and timescales, can have important
implications for IVR. Examples include the observation of local mode doublets,
clustering of rotational energy levels, and extremely narrow vibrational
features in high resolution molecular spectra. Both the phenomena are strongly
influenced by the nature of the underlying classical phase space. This work
reviews the current state of understanding of dynamical tunneling from the
phase space perspective and the consequences for intramolecular vibrational
energy flow in polyatomic molecules.Comment: 37 pages and 23 figures (low resolution); Int. Rev. Phys. Chem.
(Review to appear in Oct. 2007
Neonatal umbilical cord blood transplantation halts skeletal disease progression in the murine model of MPS-I
Umbilical cord blood (UCB) is a promising source of stem cells to use in early haematopoietic stem
cell transplantation (HSCT) approaches for several genetic diseases that can be diagnosed at birth. Mucopolysaccharidosis type I (MPS-I) is a progressive multi-system disorder caused by deficiency
of lysosomal enzyme α-L-iduronidase, and patients treated with allogeneic HSCT at the onset
have improved outcome, suggesting to administer such therapy as early as possible. Given that
the best characterized MPS-I murine model is an immunocompetent mouse, we here developed a transplantation system based on murine UCB. With the final aim of testing the therapeutic efficacy of UCB in MPS-I mice transplanted at birth, we first defined the features of murine UCB cells and demonstrated that they are capable of multi-lineage haematopoietic repopulation of myeloablated adult mice similarly to bone marrow cells. We then assessed the effectiveness of murine UCB cells transplantation in busulfan-conditioned newborn MPS-I mice. Twenty weeks after treatment, iduronidase activity was increased in visceral organs of MPS-I animals, glycosaminoglycans storage was reduced, and skeletal phenotype was ameliorated. This study explores a potential therapy for MPS-I at a very early stage in life and represents a novel model to test UCB-based transplantation approaches for various diseases
Nanostructured lipid carriers deliver resveratrol, restoring attenuated dilation in small coronary arteries, via the AMPK pathway
Nanostructured lipid carriers (NLCs) are an emerging drug delivery platform for improved drug stability and the bioavailability of antihypertensive drugs and vasoprotective nutraceutical compounds, such as resveratrol (RV). The objective of this study was to ascertain NLCs’ potential to deliver RV and restore attenuated dilator function, using an ex vivo model of acute hyperten-sion. Trimyristin–triolein NLCs were synthesized and loaded with RV. The uptake of RV-NLCs by human coronary artery endothelial cells (HCAECs) maintained their viability and reduced both mitochondrial and cytosolic superoxide levels. Acute pressure elevation in isolated coronary arteries significantly attenuated endothelial-dependent dilator responses, which were reversed following incubation in RV-NLCs, superoxide dismutase or apocynin (p < 0.0001). RV-NLCs demonstrated a five-fold increase in potency in comparison to RV solution. At elevated pressure, in the presence of RV-NLCs, incubation with Nω-nitro-l-arginine (L-NNA) or indomethacin resulted in a significant reduction in the restored dilator component (p < 0.0001), whereas apamin and TRAM-34 had no overall effect. Incubation with the adenosine monophosphate-activated protein kinase (AMPK) inhibitor dorsomorphin significantly attenuated dilator responses (p < 0.001), whereas the SIRT-1 inhibitor EX-527 had no effect. RV-NLCs improved the impaired endothelial-dependent dilation of small coronary arteries, following acute pressure elevation, via NO and downstream COX elements, mediated by AMPK. We suggest that RV-NLCs are an effective delivery modality for improved potency and sustained drug release into the vasculature. Our findings have important implications for the future design and implementation of antihypertensive treatment strategies
Higher-order multipole amplitudes in charmonium radiative transitions
Using 24 million decays in CLEO-c, we have searched
for higher multipole admixtures in electric-dipole-dominated radiative
transitions in charmonia. We find good agreement between our data and
theoretical predictions for magnetic quadrupole (M2) amplitudes in the
transitions and ,
in striking contrast to some previous measurements. Let and
denote the normalized M2 amplitudes in the respective aforementioned decays,
where the superscript refers to the angular momentum of the . By
performing unbinned maximum likelihood fits to full five-parameter angular
distributions, we determine the ratios and , where
the theoretical predictions are independent of the charmed quark magnetic
moment and are and .Comment: 32 pages, 7 figures, acceptance updat
Search for D0 to p e- and D0 to pbar e+
Using data recorded by CLEO-c detector at CESR, we search for simultaneous
baryon and lepton number violating decays of the D^0 meson, specifically, D^0
--> p-bar e^+, D^0-bar --> p-bar e^+, D^0 --> p e^- and D^0-bar --> p e^-. We
set the following branching fraction upper limits: D^0 --> p-bar e^+ (D^0-bar
--> p-bar e^+) p e^- (D^0-bar --> p e^-) < 1.2 *
10^{-5}, both at 90% confidence level.Comment: 10 pages, available through http://www.lns.cornell.edu/public/CLNS/,
submitted to PRD. Comments: changed abstract, added reference for section 1,
vertical axis in Fig.5 changed (starts from 1.5 rather than 2.0), fixed typo
Dalitz Plot Analysis of Ds to K+K-pi+
We perform a Dalitz plot analysis of the decay Ds to K+K-pi+ with the CLEO-c
data set of 586/pb of e+e- collisions accumulated at sqrt(s) = 4.17 GeV. This
corresponds to about 0.57 million D_s+D_s(*)- pairs from which we select 14400
candidates with a background of roughly 15%. In contrast to previous
measurements we find good agreement with our data only by including an
additional f_0(1370)pi+ contribution. We measure the magnitude, phase, and fit
fraction of K*(892) K+, phi(1020)pi+, K0*(1430)K+, f_0(980)pi+, f_0(1710)pi+,
and f_0(1370)pi+ contributions and limit the possible contributions of other KK
and Kpi resonances that could appear in this decay.Comment: 21 Pages,available through http://www.lns.cornell.edu/public/CLNS/,
submitted to PR
Charmonium decays to gamma pi0, gamma eta, and gamma eta'
Using data acquired with the CLEO-c detector at the CESR e+e- collider, we
measure branching fractions for J/psi, psi(2S), and psi(3770) decays to gamma
pi0, gamma eta, and gamma eta'. Defining R_n = B[ psi(nS)-->gamma eta ]/B[
psi(nS)-->gamma eta' ], we obtain R_1 = (21.1 +- 0.9)% and, unexpectedly, an
order of magnitude smaller limit, R_2 < 1.8% at 90% C.L. We also use
J/psi-->gamma eta' events to determine branching fractions of improved
precision for the five most copious eta' decay modes.Comment: 14 pages, available through http://www.lns.cornell.edu/public/CLNS/,
published in Physical Review
Precision Measurement of the Mass of the h_c(1P1) State of Charmonium
A precision measurement of the mass of the h_c(1P1) state of charmonium has
been made using a sample of 24.5 million psi(2S) events produced in e+e-
annihilation at CESR. The reaction used was psi(2S) -> pi0 h_c, pi0 -> gamma
gamma, h_c -> gamma eta_c, and the reaction products were detected in the
CLEO-c detector.
Data have been analyzed both for the inclusive reaction and for the exclusive
reactions in which eta_c decays are reconstructed in fifteen hadronic decay
channels. Consistent results are obtained in the two analyses. The averaged
results of the present measurements are M(h_c)=3525.28+-0.19 (stat)+-0.12(syst)
MeV, and B(psi(2S) -> pi0 h_c)xB(h_c -> gamma eta_c)= (4.19+-0.32+-0.45)x10^-4.
Using the 3PJ centroid mass, Delta M_hf(1P)= - M(h_c) =
+0.02+-0.19+-0.13 MeV.Comment: 9 pages, available through http://www.lns.cornell.edu/public/CLNS/,
submitted to PR
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