Identification and characterization of novel marine oxasqualenoid yucatecone against Naegleria fowleri.

Naegleria fowleri is an opportunistic protozoan, belonging to the free-living amoeba group, that can be found in warm water bodies. It is causative agent the primary amoebic meningoencephalitis, a fulminant disease with a rapid progression that affects the central nervous system. However, no 100% effective treatments are available and those that are currently used involve the appearance of severe side effects, therefore, there is an urgent need to find novel antiamoebic compounds with low toxicity.

Cyclolauranes as plausible chemical scaffold against Naegleria fowleri.

Primary amoebic meningoencephalitis (PAM) is a central nervous system (CNS) disease caused by Naegleria fowleri that mainly affects children and young adults with fatal consequences in most of the cases. Treatment protocols are based on the combination of different antimicrobial agents, nonetheless there is the need to develop new anti-Naegleria compounds with low toxicity and full effects compared to the currently used drug combination. The marine environment is a well-established source of bioactive natural products.

Synthesis and conformational analysis of cyclic homooligomers from pyranoid ε-sugar amino acids.

New pyranoid ε-sugar amino acids were designed as building blocks, in which the carboxylic acid and the amine groups were placed in positions C2 and C3 with respect to the tetrahydropyran oxygen atom. By using standard solution-phase coupling procedures, cyclic homooligomers containing pyranoid ε-sugar amino acids were synthesized. Conformation analysis was performed by using NMR spectroscopic experiments, FTIR spectroscopic studies, X-ray analysis, and a theoretical conformation search.

Correlation between conformational equilibria of free host and guest binding affinity in non-preorganized receptors.

Positive cooperativity between host conformational equilibria and guest binding has been widely reported in protein receptors. However, reported examples of this kind of cooperativity in synthetic hosts are scarce and largely serendipitous, among other things because it is hard to envision systems which display this kind of cooperativity. In order to shed some light on the correlation between conformational equilibria of free host and guest binding, selected structural modifications have been performed over a family of nonpreorganized hosts in order to induce conformational changes and to analyze their effect on the binding affinity.

A novel approach for the evaluation of positive cooperative guest binding: kinetic consequences of structural tightening.

Cooperativity is one of the most relevant features displayed by biomolecules. Thus, one of the challenges in the field of supramolecular chemistry is to understand the mechanisms underlying cooperative binding effects. Traditionally, cooperativity has been related to multivalent receptors, but Williams et al.

Inward rectifier K(+) currents and Kir2.1 expression in renal afferent and efferent arterioles.

The afferent and efferent arterioles regulate the inflow and outflow resistance of the glomerulus, acting in concert to control the glomerular capillary pressure and glomerular filtration rate. The myocytes of these two vessels are remarkably different, especially regarding electromechanical coupling. This study investigated the expression and function of inward rectifier K(+) channels in these two vessels using perfused hydronephrotic rat kidneys and arterioles and myocytes isolated from normal rat kidneys.

Organocatalysis "on water". Regioselective [3 + 2]-cycloaddition of nitrones and allenolates.

The first example of a regioselective and organocatalyzed 1,3-dipolar cycloaddition reaction between conjugated alkynoates and nitrones "on water" is described.

Distinct dynamic behaviors of water molecules in hydrated pores.

Water molecules confined inside narrow pores are of great importance in understanding the structure, stability, and function of water channels. Here we report that besides the H-bonding water that structures the pore, the permanent presence of a significant, fast-moving fraction of incompletely H-bonded water molecules inside the pore should control the free entry and exit of water. This is achieved by means of complementary DSC and solid-state NMR studies.

Design and synthesis of inositolphosphoglycan putative insulin mediators.

The binding modes of a series of molecules, containing the glucosamine (1-->6) myo-inositol structural motif, into the ATP binding site of the catalytic subunit of cAMP-dependent protein kinase (PKA) have been analysed using molecular docking. These calculations predict that the presence of a phosphate group at the non-reducing end in pseudodisaccharide and pseudotrisaccharide structures properly orientate the molecule into the binding site and that pseudotrisaccharide structures present the best shape complementarity. Therefore, pseudodisaccharides and pseudotrisaccharides have been synthesised from common intermediates using effective synthetic strategies.

Water molecules in hydroxy/acid networks as a competition between dynamics and bonding. Synthesis of a wet hydrophobic pore.

In a model formed by hydroxy acids with a general structure (+/-)-1, we found that solid-state structures depend on steric interactions. Thus, with the exception of molecules 1b and 1e, compounds (+/-)-1a-(+/-)-1m, which possess bulky and conformationally rigid substituents, aggregate by forming tapes and sheets by alternating (+) and (-) subunits held together via carboxylic acid to alcohol hydrogen bonds. Homologue (+/-)-1n with conformationally flexible substituents, which allow conformational deformation gives, by way of the incorporation of water molecules, an efficient hexagonal assembly, which extends to the third-dimension to form tubular H-bonding networks.

Cause of hydration/dehydration in condensed organic materials: synthesis of hydrophobic pores.

[reaction: see text] The unique solid-state hydration/dehydration properties of the diacid (+/-)-1e in comparison with other homologues of the same family are studied. Hydrophobic enhancement, which is a consequence of the loss of water molecules from (+/-)-1e chains, is a property that can be exploited to achieve organic condensed systems for nonpolar molecules by interstitial van der Waals confinement.

Releasing the peri-neuronal net to patch-clamp neurons in adult CNS.

The extracellular matrix of adult neural tissue contains chondroitin sulphated proteogylcans that form a dense peri-neuronal net surrounding the cell body and proximal dendrites of many neuronal classes. Development of the peri-neuronal net beyond approximately postnatal day 17 obscures visualization and often access by patch electrodes to neuronal membranes with the result that patch clamp recordings are most readily obtained from early postnatal animals. We describe a technique in which the surface tension of a sucrose-based medium promotes partial dissociation of thin tissue slices from adult tissue.

Self-association of okadaic acid upon complexation with potassium ion.

Okadaic acid (OA) is a toxin responsible for diarrhetic shellfish poisoning and is an extremely useful tool for studying processes that are regulated by phosphorylation, although the exact mechanism of action is still undetermined. We report on a study that proved the existence of OA in an unusual dimeric form when complexed with potassium ion. The proposed structure of this dimer is based on spectroscopic and conformational studies.

Oscillatory burst discharge generated through conditional backpropagation of dendritic spikes.

Gamma frequencies of burst discharge (>40 Hz) have become recognized in select cortical and non-cortical regions as being important in feature extraction, neural synchrony and oscillatory discharge. Pyramidal cells of the electrosensory lateral line lobe (ELL) of Apteronotus leptorhynchus generate burst discharge in relation to specific features of sensory input in vivo that resemble those recognized as gamma frequency discharge when examined in vitro. We have shown that these bursts are generated by an entirely novel mechanism termed conditional backpropagation that involves an intermittent failure of dendritic Na+ spike conduction.

Inactivation of Kv3.3 potassium channels in heterologous expression systems.

Kv3.3 K+ channels are believed to incorporate an NH2-terminal domain to produce an intermediate rate of inactivation relative to the fast inactivating K+ channels Kv3.4 and Kv1.