Synthesis and biological evaluation of indane-based fluorescent probes for detection of amyloid-ß aggregates in Alzheimer's disease.

In this article, the development of fluorescent imaging probes for the detection of Alzheimer's disease (AD)-associated protein aggregates is described. Indane derivatives with a donor-π-acceptor (D-π-A) structure were designed and synthesized. The probes were evaluated for their ability to bind to ß-amyloid (Aß) protein aggregates, which are a key pathological hallmark of AD. The results showed that several probes exhibited significant changes in fluorescence intensity at wavelengths greater than 600 nm when they were bound to Aß aggregates compared to the Aß monomeric form. Among the tested probes, four D-π-A type indane derivatives showed promising binding selectivity to Aß aggregates over non-specific proteins such as bovine serum albumin (BSA). The molecular docking study showed that our compounds were appropriately located along the Aß fibril axis through the hydrophobic tunnel structure. Further analysis revealed that the most active compound having dimethylaminopyridyl group as an election donor and dicyano group as an electron acceptor could effectively stain Aß plaques in brain tissue samples from AD transgenic mice. These findings suggest that our indane-based compounds have the potential to serve as fluorescent probes for the detection and monitoring of Aß aggregation in AD.

Stereoselective Synthesis of Benzo[a]quinolizidines via Aerobic DDQ-Catalyzed Allylation and Reductive Cyclization.

Stereoselective synthesis of C4-substituted benzo[a]quinolizidines via redox-controlled catalytic C-C-bond-forming reactions was carried out. Aerobic DDQ-catalyzed allylation of N-Cbz tetrahydroisoquinolines efficiently provided α-allylated products 5, which were transformed to enones 6 via cross-metathesis reactions using the second-generation Hoveyda-Grubbs catalyst. Palladium-catalyzed hydrogenation of 6 prompted alkene reduction, protecting group removal, and intramolecular reductive amination in one step to afford the desired benzo[a]quinolizidines 7 as single diastereomers.

A new approach for calculating microalgae culture growth based on an inhibitory effect of the surrounding biomass.

Ever since the potential of algae in biotechnology was recognized, models describing the growth of algae inside photobioreactors have been proposed. These models are the basis for the optimization of process conditions and reactor designs. Over the last few decades, models became more and more elaborate with the increase of computational capacity. Thus far, these models have been based on light attenuation due to the absorption and scattering effects of the biomass. This manuscript presents a new way of predicting the apparent growth inside photobioreactors using simple models for enzymatic kinetics to describe the reaction between photons and the photosynthetic unit. The proposed model utilizes an inhibition kinetic formula based on the surrounding biomass to describe the average growth rate of a culture, which is determined by the local light intensities inside the reactor. The result is a mixed-inhibition scheme with multiple inhibition sites. The parameters of the new kinetic equation are replaced by empirical regression functions to correlate their dependency on incident light intensity and reactor size. The calibrations of the parameters and the regression functions are based on the numerical solutions of the growth rate computed with a classical Type II model. As a final verification, we apply the new equation in predicting the growth behavior of three phototrophic organisms in reactors of three different sizes.

Evaluation of Chemical Interactions between Small Molecules in the Gas Phase Using Chemical Force Microscopy.

Chemical force microscopy analyzes the interactions between various chemical/biochemical moieties in situ. In this work we examined force-distance curves and lateral force to measure the interaction between modified AFM tips and differently functionalized molecular monolayers. Especially for the measurements in gas phase, we investigated the effect of humidity on the analysis of force-distance curves and the images in lateral force mode. Flat chemical patterns composed of different functional groups were made through micro-contact printing and lateral force mode provided more resolved analysis of the chemical patterns. From the images of 1-octadecanethiol/11-mercapto-1-undecanoic acid patterns, the amine group functionalized tip brought out higher contrast of the patterns than an intact silicon nitride tip owing to the additional chemical interaction between carboxyl and amine groups. For more complex chemical interactions, relative chemical affinities toward specific peptides were assessed on the pattern of 1-octadecanethiol/phenyl-terminated alkanethiol. The lateral image of chemical force microscopy reflected specific preference of a peptide to phenyl group as well as the hydrophobic interaction.

Teaching Young Children with Special Needs and Their Peers to Play Board Games: Effects of a Least to Most Prompting Procedure to Increase Independent Performance.

We investigated the effects of a least to most prompting procedure on the performance of board game steps and game-related on-task behavior of young children with special needs and their typically developing peers. This study was conducted employing a concurrent multiple baseline design across participants. After teaching the board game steps using a systematic prompting strategy, the participants demonstrated increases in the performance of board game steps and game-related on-task behavior. In addition, the participants maintained high levels of performance and game-related on-task behavior during post-game training. The effects of teaching board games using prompting strategies, implications for practice, and areas for future study are presented.

Teaching play skills to young children with autism.

BACKGROUND: Play is critical for the development of young children and is an important part of their daily routine. However, children with autism often exhibit deficits in play skills and engage in stereotypic behaviour. We reviewed studies to identify effective instructional strategies for teaching play skills to young children with autism. METHOD: Empirical studies on teaching play skills to young children with autism published from 1990 to 2011 were located. These studies included single subject and group designs. RESULTS: Twenty-six studies were reviewed. The majority of studies on teaching play skills used combined interventions. Children with autism improved their play skills, with direct intervention embedding their interests during play. Improvements in play skills increased positive social interactions and decreased inappropriate behaviour as collateral effects. CONCLUSIONS: Further research is needed to develop more effective play skill interventions that assess the functional use of play and are implemented in the natural environment.

Glucosylation of the flavonoid, astragalin by Leuconostoc mesenteroides B-512FMCM dextransucrase acceptor reactions and characterization of the products.

Astragalin (kaempferol-3-O-ß-D-glucopyranoside, Ast) glucosides were synthesized by the acceptor reaction of a dextransucrase produced by Leuconostoc mesenteroides B-512FMCM with astragalin and sucrose. Each glucoside was purified and their structures were assigned as kaempferol-3-O-ß-D-glucopyranosyl-(1→3)-O-α-D-glucopyranoside (or kaempferol-3-O-ß-D-nigeroside, Ast-G1') and kaempferol-3-O-ß-D-glucopyranosyl-(1→6)-O-α-D-glucopyranoside (or kaempferol-3-O-ß-D-isomaltoside, Ast-G1) for one glucose transferred, and kaempferol-3-O-ß-D-isomaltooligosacharide (Ast-IMO or Ast-Gn; n=2-8). The astragalin glucosides exhibited 8.3-60.6% higher inhibitory effects on matrix metalloproteinase-1 expression, 18.8-20.3% increased antioxidant effects, and 3.8-18.8% increased inhibition activity of melanin synthesis compared to control (without the addition of compound), depending on the number of glucosyl residues linked to astragalin. These novel compounds could be used to further expand the industrial applications of astragalin glucosides, in particular in the cosmetics industry.

Inhibitory effects of epigallocatechin gallate and its glucoside on the human intestinal maltase inhibition.

Human intestinal maltase (HMA) is an α-glucosidase responsible for the hydrolysis of α-1,4-linkages from the non-reducing end of malto-oligosaccharides. HMA has become an important target in the treatment of type-2 diabetes. In this study, epigallocatechin gallate (EGCG) and EGCG glucoside (EGCG-G1) were identified as inhibitors of HMA by an in vitro assay with IC50 of 20 ± 1.0 and 31.5 ± 1.0 µM, respectively. A Lineweaver-Burk plot confirmed that EGCG and EGCG-G1 were competitive inhibitors of maltose substrate against HMA and inhibition kinetic constants (K i ) calculated from a Dixon plot were 5.93 ± 0.26 and 7.88 ± 0.57 µM, respectively. Both EGCG and EGCG-G1 bound to the active site of HMA with numerous hydrophobic and hydrogen bond interactions.

Enzymatic synthesis and characterization of hydroquinone galactoside using Kluyveromyces lactis lactase.

Hydroquinone galactoside (HQ-Gal) as a potential skin whitening agent was synthesized by the reaction of lactase (beta-galactosidase) from Kluyveromyces lactis, Aspergillus oryzae, Bacillus circulans, and Thermus sp. with lactose as a donor and HQ as an acceptor. Among these lactases, the acceptor reaction involving HQ and lactose with K. lactis lactase showed a higher conversion ratio to HQ-Gal (60.27%). HQ-Gal was purified using butanol partitioning and silica gel column chromatography. The structure of the purified HQ-Gal was determined by nuclear magnetic resonance, and the ionic product was observed at m/z 295 (C12H16O7Na)+ using matrix assisted laser desorption ionization time-of-flight mass spectrometry. HQ-Gal was identified as 4-hydroxyphenyl-beta-d-galactopyranoside. The optimum conditions for HQ-Gal synthesis by K. lactis determined using response surface methodology were 50 mM HQ, 60 mM lactose, and 20 U mL(-1) lactase. These conditions produced a yield of 2.01 g L(-1) HQ-Gal. The half maximal inhibitory concentration (IC50) of diphenylpicrylhydrazyl scavenging activity was 3.31 mM, indicating a similar antioxidant activity compared to beta-arbutin (IC50=3.95 mM). The Ki value of HQ-Gal (0.75 mM) against tyrosinase was smaller than that of beta-arbutin (Ki=1.97 mM), indicating its superiority as an inhibitor. HQ-Gal inhibited (23%) melanin synthesis without being significantly toxic to the cells, while beta-arbutin exhibited only 8% reduction of melanin synthesis in B16 melanoma cells compared with the control. These results indicate that HQ-Gal may be a suitable functional component in the cosmetics industry.

Synthesis and evaluation of N-nicotinoyl-2-{2-(2-methyl-5-nitroimidazol-1-yl)ethyloxy}-D,L-glycine as a colon-specific prodrug of metronidazole.

Metronidazole (MTZ) is a drug of choice for protozoal infections such as luminal amoebiasis. We designed and synthesized N-nicotinoyl-2-{2-(2-methyl-5-nitroimidazol-1-yl)ethyloxy}-D,L-glycine (NMG) as a colon-specific prodrug of MTZ. The synthetic yield of NMG was about 34%. The apparent partition coefficient of MTZ was greatly reduced by the chemical modification. While (bio)chemically stable in the contents of the upper intestine, NMG was rapidly cleaved to liberate MTZ on incubation with the cecal contents of rats. MTZ metabolized quickly in the cecal contents at least partly by a microbial nitroreductase, suggesting that the metabolism of MTZ is relevant to its bioactivation leading to amoebicidal action. The systemic absorption, analyzed by the blood concentration and urinary recovery of NMG, was very low after oral administration of NMG. In parallel with this, whereas MTZ disappeared mostly during the transit of the proximal small intestine, a substantial amount of NMG remained in the small intestine moving down to the large intestine where it metabolized rapidly. Moreover, comparing systemic absorption of MTZ after oral administration of NMG or MTZ, NMG markedly reduced the systemic absorption. These results suggest that NMG is a potential colon-specific prodrug of MTZ which improves therapeutic and toxicological properties.

Dexamethasone 21-sulfate improves the therapeutic properties of dexamethasone against experimental rat colitis by specifically delivering the steroid to the large intestine.

PURPOSE: We investigated in vivo-colon targetability and therapeutic properties of DS against experimental rat colitis. METHODS: The systemic absorption and colonic delivery of D after oral administration of DS was analyzed by examining the concentration of drugs in the GI tract, plasma, urine and feces. Therapeutic activity of DS was determined using a TNBS-induced rat colitis model. Adrenal suppression by DS administration was evaluated by monitoring the concentration of ACTH and corticosterone in the plasma. RESULTS: DS administered orally was delivered efficiently to the large intestine resulting in D accumulation at the target site. In addition, DS was not detectable in the plasma and was detected very low in the urine after DS administration. The fecal and urinary recovery of D (after DS administration) was much greater and less than that after D administration, suggesting that DS should exhibit enhanced therapeutic activity and reduced systemic side effects. Consistent with this notion, DS was more effective than D in healing rat colitis. Moreover, oral administration of either D or DS reduced the plasma corticosterone and ACTH levels from the normal levels, which is significantly greater for D. CONCLUSION: DS is a promising colon specific prodrug that improves therapeutic properties of D.

Sulfate-conjugated methylprednisolone: evaluation as a colon-specific methylprednisolone prodrug and comparison with sulfate-conjugated prednisolone and dexamethasone.

Methylprednisolone 21-sulfate sodium (MPS) was prepared and evaluated as a colon-specific methylprednisolone prodrug and its colon-specific property was compared with prednisolone 21-sulfate sodium (PDS) and dexamethasone 21-sulfate sodium (DS), reported previously as colon-specific prodrugs of the glucocorticoids. The synthetic process and yield of MPS was simple and high. The apparent partition coefficient of methylprednisolone (MP) was greatly reduced by sulfate conjugation. The sulfate conjugates MPS, PDS, and DS were (bio)chemically stable in the homogenates of the upper intestine. In marked contrast, the sulfate conjugates were deconjugated to liberate the corresponding glucocorticoids in the cecal contents. Although the rates of deconjugation were not significantly different, the corresponding glucocorticoids were accumulated with distinct profiles depending on the metabolic susceptibility of the unconjugated glucocorticoids to microbial reductase(s). Upon oral administration of the sulfate conjugates to rats, the plasma concentrations of the conjugates were extremely low and the urinary recoveries were less than 5% of the doses. These results suggest that, like PDS and DS, MPS administered orally is delivered efficiently to the large intestine followed by deconjugation to liberate MP and the metabolic susceptibility of the unconjugated glucocorticoids may affect therapeutic availability of the sulfate conjugates.

Behavioral assessment of impulsivity: a comparison of children with and without attention deficit hyperactivity disorder.

We conducted a brief computer-based assessment involving choices of concurrently presented arithmetic problems associated with competing reinforcer dimensions to assess impulsivity (choices controlled primarily by reinforcer immediacy) as well as the relative influence of other dimensions (reinforcer rate, quality, and response effort), with 58 children. Results were compared for children with attention deficit hyperactivity disorder (ADHD) who were and were not receiving medication, and with typically developing children without ADHD. Within-subject and between-groups analyses of the ordinal influence of each of the reinforcer dimensions were conducted using both time- and response-allocation measures. In general, the choices of children with ADHD were most influenced by reinforcer immediacy and quality and least by rate and effort, suggesting impulsivity. The choices of children in the non-ADHD group were most influenced by reinforcer quality, and the influence of immediacy relative to the other dimensions was not statistically significant. Results are discussed with respect to the implications for assessment and treatment of ADHD.

Effects of modeling versus instructions on sensitivity to reinforcement schedules.

This study examined the effects of modeling versus instructions on the choices of 3 typically developing children and 3 children with attention deficit hyperactivity disorder (ADHD) whose academic responding showed insensitivity to reinforcement schedules. During baseline, students chose between successively presented pairs of mathematics problems associated with different variable-interval schedules of reinforcement. After responding proved insensitive to the schedules, sessions were preceded by either instructions or modeling, counterbalanced across students in a multiple baseline design across subjects. During the instruction condition, students were told how to distribute responding to earn the most reinforcers. During the modeling condition, students observed the experimenter performing the task while describing her distribution of responding to obtain the most reinforcers. Once responding approximated obtained reinforcement under either condition, the schedules of reinforcement were changed, and neither instruction nor modeling was provided. Both instruction and modeling interventions quickly produced patterns of response allocation that approximated obtained rates of reinforcement, but responding established with modeling was more sensitive to subsequent changes in the reinforcement schedules than responding established with instructions. Results were similar for students with and without ADHD.