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Gas phase conformational basicity of carvedilol fragment B, 2(S)-1-(ethylamonium)propane-2-ol: An ab initio study on a protonophoretic of oxidative phosphorylation uncoupling

Carvedilol is cardiovascular drug of proven efficacy. It is believed that carvedilol exerts cardio-protective effects by acting as a mild uncoupler of mitochondrial oxidative phosphorylation, thereby protecting mitochondria from oxidative stress and preserving proper bioenergetics and cardiac function. This uncoupling occurs via a proton-shuttling mechanism involving the amino group of carvedilol's side-chain. However, the molecular details of carvedilol's proton affinity have not yet been completely worked out, especially with regards to the attributes of molecular conformation. In the present study, the full conformational basicity of a fragment of carvedilol, 2(S)-1-(ethylamonium)propane-2-ol (Fragment B), is presented to illustrate the protonophoretic character of carvedilol. Full gas phase geometry optimizations were performed at the ab initio, RHF/3-21G, level of theory for the entire potential energy hypersurface (PEHS) of Fragment B. Subsequently, since deprotonation can occur via two different protons, a two-prong methodology was applied to calculate vertical and adiabatic energies of deprotonation. A total of 18 out of a possible 81 minima converged and the dominant characteristic in all protonated and deprotonated conformers was a gauche plus effect in the rotation about the C-OH bond at the Fragment B stereocentre. Optimized energies of deprotonation ranged from 245 to 262 kcal mol-1 while protons involved in internal hydrogen bonding required an extra 6-8 kcal mol-1 for deprotonation compared to protons that were oriented away from the backbone structure. The overall trend indicates that conformers devoid of significant stabilization interactions possessed lower energies of deprotonation; in other words, as the relative conformer energy increased, vertical and adiabatic energies of deprotonation tended to decrease. Thus, extrapolating to carvedilol and the proton transfer mechanism involved in oxidative phosphorylation uncoupling, events of deprotonation will favour molecular conformations with minimal intramolecular stabilization and with higher relative energies

The Schistosoma mansoni genome encodes thousands of long non-coding RNAs predicted to be functional at different parasite life-cycle stages

Next Generation Sequencing (NGS) strategies, like RNA-Seq, have revealed the transcription of a wide variety of long non-coding RNAs (lncRNAs) in the genomes of several organisms. In the present work we assessed the lncRNAs complement of Schistosoma mansoni, the blood fluke that causes schistosomiasis, ranked among the most prevalent parasitic diseases worldwide. We focused on the long intergenic/intervening ncRNAs (lincRNAs), hidden within the large amount of information obtained through RNA-Seq in S. mansoni (88 libraries). Our computational pipeline identified 7029 canonically-spliced putative lincRNA genes on 2596 genomic loci (at an average 2.7 isoforms per lincRNA locus), as well as 402 spliced lncRNAs that are antisense to protein-coding (PC) genes. Hundreds of lincRNAs showed traits for being functional, such as the presence of epigenetic marks at their transcription start sites, evolutionary conservation among other schistosome species and differential expression across five different life-cycle stages of the parasite. Real-time qPCR has confirmed the differential life-cycle stage expression of a set of selected lincRNAs. We have built PC gene and lincRNA co-expression networks, unraveling key biological processes where lincRNAs might be involved during parasite development. This is the first report of a large-scale identification and structural annotation of lncRNAs in the S. mansoni genome

Antinociceptive properties and acute toxicity of ethanol extract of Bromelia laciniosa Mart. ex Schult. f. (Bromeliaceae)

Purpose: To investigate the antinociceptive activity and acute toxicity of the ethanol extract of Bromelia laciniosa leaf.Methods: A high performance liquid chromatography HPLC fingerprint of phenolic compounds was developed. The antinociceptive effect of ethanol extract (Bl-EtOH) in mice was carried out using chemical (writhing and formalin) and thermal (hot plate) models of nociception. The acute toxicity of the extract was performed in mice using doses of 2.0 g/kg intraperitoneally and 5.0 g/kg orally. Blood was removed for laboratory analysis of hematological and biochemical parameters.Results: Bl-EtOH (100, 200 and 400 mg/kg, i.p.) reduced the number of writhing (91.80, 93.44 and 78.68 %, respectively) and the number of paw licks during the first (60.86, 62.84 and 66.79 %) and second phase (91.93, 82.18 and 88.73 %) of the formalin test. Naloxone (1.5 mg/kg, i.p.) antagonized the antinociceptive action of Bl-EtOH (100 mg/kg), and this finding suggests involvement of opioid mechanism. The effect of Bl-EtOH on hot plate response provides a confirmation of its central effect.Conclusion: B. laciniosa leaf extract has antinociceptive properties. Peripheral, and at least in part, central mechanisms, may be involved in this antinociceptive effect. The ethanol leaf extract apparently presents no significant toxicity.Keywords: Bromelia laciniosa, Nociception, Pain, Writhing, Acute toxicit

Highly Dynamic Host Actin Reorganization around Developing Plasmodium Inside Hepatocytes

Plasmodium sporozoites are transmitted by Anopheles mosquitoes and infect hepatocytes, where a single sporozoite replicates into thousands of merozoites inside a parasitophorous vacuole. The nature of the Plasmodium-host cell interface, as well as the interactions occurring between these two organisms, remains largely unknown. Here we show that highly dynamic hepatocyte actin reorganization events occur around developing Plasmodium berghei parasites inside human hepatoma cells. Actin reorganization is most prominent between 10 to 16 hours post infection and depends on the actin severing and capping protein, gelsolin. Live cell imaging studies also suggest that the hepatocyte cytoskeleton may contribute to parasite elimination during Plasmodium development in the liver

Probing ultrafast carrier dynamics and nonlinear absorption and refraction in core-shell silicon nanowires

We investigate the relaxation dynamics of photogenerated carriers in silicon nanowires consisting of a crystalline core and a surrounding amorphous shell, using femtosecond time-resolved differential reflectivity and transmission spectroscopy at photon energies of 3.15 eV and 1.57 eV. The complex behavior of the differential transmission and reflectivity transients is the mixed contributions from the crystalline core and the amorphous silicon on the nanowire surface and the substrate where competing effects of state filling and photoinduced absorption govern the carrier dynamics. Faster relaxation rates are observed on increasing the photo-generated carrier density. Independent experimental results on crystalline silicon-on-sapphire help us in separating the contributions from the carrier dynamics in crystalline core and the amorphous regions in the nanowire samples. Further, single beam z-scan nonlinear transmission experiments at 1.57 eV in both open and close aperture configurations yield two-photon absorption coefficient \$beta$ (~3 cm/GW) and nonlinear refraction coefficient \$gamma$ (-2.5x10^-4 cm2/GW).Comment: 6 pages, 6 figure