Defining the clinical and cognitive phenotype of child savants with autism spectrum disorder

Objective: Whilst savant syndrome is most commonly observed in individuals with Autism Spectrum Disorder (ASD), it has historically been associated with intellectual impairment, and little is known about the clinical and cognitive characteristics of intellectually able individuals with ASD and savant skills. Methods: Participants with ASD and validated savant skills were compared with age and intelligence matched non-savants with ASD using a range of diagnostic and standardised tests. Results: Although the analysis of the clinical data revealed few differences between the groups, striking differences emerged during cognitive testing. Children with savant skills exhibited highly superior working memory and their scores on tests of analytic skills were also superior to those of non-savants. Conclusion: We propose that obsessionality, focused attention, superior working memory and analytic skills facilitate veridical mapping and pattern perception abilities characteristic in savant syndrome

Fe(III) Protoporphyrin IX Encapsulated in a Zinc Metal–Organic Framework Shows Dramatically Enhanced Peroxidatic Activity

Two MOFs, [H₂N­(CH₃)₂]­[Zn₃(TATB)₂­(HCOO)]·HN­(CH₃)₂·DMF·6H₂O (<b>1</b>) and Zn-HKUST-1 (<b>2</b>), were investigated as potential hosts to encapsulate Fe­(III) heme (Fe­(III) protoporphyrin IX = Fe­(III)­PPIX). Methyl orange (MO) adsorption was used as an initial model for substrate uptake. MOF <b>1</b> showed good adsorption of MO (10.3 ± 0.8 mg g^–1) which could undergo <i>in situ</i> protonation upon exposure to aqueous HCl vapor. By contrast, MO uptake by <b>2</b> was much lower (2 ± 1 mg g^–1), and PXRD indicated that structural instability on exposure to water was the likely cause. Two methods for Fe­(III)­PPIX-<b>1</b> preparation were investigated: soaking and encapsulation. Encapsulation was verified by SEM-EDS and showed comparable concentrations of Fe­(III)­PPIX on exposed interior surfaces and on the original surface of fractured crystals. SEM-EDS results were consistent with ICP-OES data on bulk material (1.2 ± 0.1 mass % Fe). PXRD data showed that the framework in <b>1</b> was unchanged after encapsulation of Fe­(III)­PPIX. MO adsorption (5.8 ± 1.2 mg g^–1) by Fe­(III)­PPIX-<b>1</b> confirmed there is space for substrate diffusion into the framework, while the UV–vis spectrum of solubilized crystals confirmed that Fe­(III)­PPIX retained its integrity. A solid-state UV–vis spectrum of Fe­(III)­PPIX-<b>1</b> indicated that Fe­(III)­PPIX was not in a μ-oxo dimeric form. Although single-crystal XRD data did not allow for full refinement of the encapsulated Fe­(III)­PPIX molecule owing to disorder of the metalloporphyrin, the Fe atom and pyrrole N atoms were located, enabling rigid-body modeling of the porphine core. Reaction of 2,2′-azino-bis­(3-ethylbenzothiazoline)-6-sulfonic acid (ABTS) with H₂O₂, catalyzed by Fe­(III)­PPIX-<b>1</b> and -<b>2</b>, showed that Fe­(III)­PPIX-<b>1</b> is significantly more efficient than Fe­(III)­PPIX-<b>2</b> and is superior to solid Fe­(III)­PPIX-Cl. Fe­(III)­PPIX-<b>1</b> was used to catalyze the oxidation of hydroquinone, thymol, benzyl alcohol, and phenyl ethanol by <i>tert</i>-butyl-hydroperoxide with <i>t</i>_1/2 values that increase with increasing substrate molecular volume

The Single Crystal X‑ray Structure of β‑Hematin DMSO Solvate Grown in the Presence of Chloroquine, a β‑Hematin Growth-Rate Inhibitor

Single crystals of solvated β-hematin were grown from a DMSO solution containing the antimalarial drug chloroquine, a known inhibitor of β-hematin formation. In addition, a kinetics study employing biomimetic lipid–water emulsion conditions was undertaken to further investigate the effect of chloroquine and quinidine on the formation of β-hematin. Scanning electron microscopy shows that the external morphology of the β-hematin DMSO solvate crystals is almost indistinguishable from that of malaria pigment (hemozoin), and single crystal X-ray diffraction confirms the presence of μ-propionato coordination dimers of iron­(III) protoporphyrin IX. The free propionic acid functional groups of adjacent dimers hydrogen bond to included DMSO molecules, rather than forming carboxylic acid dimers. The observed exponential kinetics were modeled using the Avrami equation, with an Avrami constant equal to 1. The decreased rate of β-hematin formation observed at low concentrations of both drugs could be accounted for by assuming a mechanism of drug adsorption to sites on the fastest growing face of β-hematin. This behavior was modeled using the Langmuir isotherm. Higher concentrations of drug resulted in decreased final yields of β-hematin, and an irreversible drug-induced precipitation of iron­(III) protoporphyrin IX was postulated to account for this. The model permits determination of the equilibrium adsorption constant (<i>K</i>_ads). The values for chloroquine (log <i>K</i>_ads = 5.55 ± 0.03) and quinidine (log <i>K</i>_ads = 4.92 ± 0.01) suggest that the approach may be useful as a relative probe of the mechanism of action of novel antimalarial compounds

Synthesis, Antiplasmodial Activity, and β‑Hematin Inhibition of Hydroxypyridone–Chloroquine Hybrids

A series of noncytotoxic 4-aminoquinoline-3-hydroxypyridin-4-one hybrids were synthesized on the basis of a synergistic in vitro combination of a precursor <i>N</i>-alkyl-3-hydroxypyridin-4-one with chloroquine (CQ) and tested in vitro against CQ resistant (K1 and W2) and sensitive (3D7) strains of <i>Plasmodium falciparum</i>. In vitro antiplasmodial activity of the precursors was negated by blocking the chelator moiety via complexation with gallium­(III) or benzyl protection. None of the precursors inhibited β-hematin formation. Most hybrids were more potent inhibitors of β-hematin formation than CQ, and a correlation between antiplasmodial activity and inhibition of β-hematin formation was observed. Potent hybrids against K1, 3D7, and W2, respectively, were <b>8c</b> (0.13, 0.004, and 0.1 μM); <b>8d</b> (0.08, 0.01, and 0.02 μM); and <b>7g</b> (0.07, 0.03, and 0.08 μM)

Identification and Mechanistic Evaluation of Hemozoin-Inhibiting Triarylimidazoles Active against <i>Plasmodium falciparum</i>

In a previous study, target based screening was carried out for inhibitors of β-hematin (synthetic hemozoin) formation, and a series of triarylimidazoles were identified as active against <i>Plasmodium falciparum</i>. Here, we report the subsequent synthesis and testing of derivatives with varying substituents on the three phenyl rings for this series. The results indicated that a 2-hydroxy-1,3-dimethoxy substitution pattern on ring A is required for submicromolar parasite activity. In addition, cell-fractionation studies revealed uncommonly large, dose-dependent increases of <i>P. falciparum</i> intracellular exchangeable (free) heme, correlating with decreased parasite survival for β-hematin inhibiting derivatives

Identification and SAR Evaluation of Hemozoin-Inhibiting Benzamides Active against <i>Plasmodium falciparum</i>

Quinoline antimalarials target hemozoin formation causing a cytotoxic accumulation of ferriprotoporphyrin IX (Fe­(III)­PPIX). Well-developed SAR models exist for β-hematin inhibition, parasite activity, and cellular mechanisms for this compound class, but no comparably detailed investigations exist for other hemozoin inhibiting chemotypes. Here, benzamide analogues based on previous HTS hits have been purchased or synthesized. Only derivatives containing an electron deficient aromatic ring and capable of adopting flat conformations, optimal for π–π interactions with Fe­(III)­PPIX, inhibited β-hematin formation. The two most potent analogues showed nanomolar parasite activity, with little CQ cross-resistance, low cytotoxicity, and high in vitro microsomal stability. Selected analogues inhibited hemozoin formation in <i>Plasmodium falciparum</i> causing high levels of free heme. In contrast to quinolines, introduction of amine side chains did not lead to benzamide accumulation in the parasite. These data reveal complex relationships between heme binding, free heme levels, cellular accumulation, and in vitro activity of potential novel antimalarials

Synthetic Hemozoin (β-Hematin) Crystals Nucleate at the Surface of Neutral Lipid Droplets that Control Their Sizes

Emulsions of monopalmitoylglycerol (MPG) and of a neutral lipid blend (NLB), consisting of MPG, monostearoylglycerol, dipalmitoylglycerol, dioleoylglycerol, and dilineoylglycerol (4:2:1:1:1), the composition associated with hemozoin from the malaria parasite Plasmodium falciparum, have been used to mediate the formation of β-hematin microcrystals. Transmission electron microscopy (TEM), electron diffraction, and electron spectroscopic imaging/electron energy loss spectroscopy (ESI/EELS) have been used to characterize both the lipid emulsion and β-hematin crystals. The latter have been compared with β-hematin formed at a pentanol/aqueous interface and with hemozoin both within P. falciparum parasites and extracted from the parasites. When lipid and ferriprotoporphyrin IX solutions in 1:9 v/v acetone/methanol were thoroughly premixed either using an extruder or an ultrasound bath, β-hematin crystals were found formed in intimate association with the lipid droplets. These crystals resembled hemozoin crystals, with prominent {100} faces. Lattice fringes in TEM indicated that these faces made contact with the lipid surface. The average length of these crystals was 0.62 times the average diameter of NLB droplets, and their size distributions were statistically equivalent after 10 min incubation, suggesting that the lipid droplets also controlled the sizes of the crystals. This most closely resembles hemozoin formation in the helminth worm Schistosoma mansoni, while in P. falciparum, crystal formation appears to be associated with the much more gently curved digestive vacuole membrane, which apparently leads to formation of much larger hemozoin crystals, similar to those formed at the flat pentanol–water interface

PEGs are able to induce βH formation in acid conditions.

<p>Spontaneous heme crystallization was performed in the presence of 4.7% of different PEGs at 100 µM, in 0.5 M sodium acetate buffer pH 4.8, over 5 days at 28°C with a final volume of 1.0 mL. Samples were centrifuged and the pellet washed in 0.1 M sodium bicarbonate buffer and 2.5% SDS, pH 9.1, until the solution was almost clear. (A) Pellets were then characterized by FTIR spectroscopy. The large Nujol peaks in the region between 1300 cm⁻¹ and 1600 cm⁻¹ are obscured by the labels, but the key βH peaks are clearly seen at 1664 cm⁻¹ and 1210 cm⁻¹. (B) X-ray powder diffraction (XRD) confirms the identity of βH.</p

Values of r² for different values of n and rate constants for β-hematin formation in the presence of PEGs.

a<p>n = 4 for PEG 3.350 and n = 2 for other PEGs.</p

Reduction in water activity drives both heme solubility and βH formation under acidic conditions.

<p>Values of heme in solution were obtained from <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0012694#pone-0012694-g001" target="_blank">Figure 1B</a> and values of βH produced was obtained from <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0012694#pone-0012694-g002" target="_blank">Figure 2A</a>. Black square: nmols heme in solution; open circle: βH. Water activity was calculed based on values obtained in Dupont and Pougeois, 1983 <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0012694#pone.0012694-Dupont1" target="_blank">[43]</a>.</p