The re-emergence of natural products for drug discovery in the genomics era

Natural products have been a rich source of compounds for drug discovery. However, their use has diminished in the past two decades, in part because of technical barriers to screening natural products in high-throughput assays against molecular targets. Here, we review strategies for natural product screening that harness the recent technical advances that have reduced these barriers. We also assess the use of genomic and metabolomic approaches to augment traditional methods of studying natural products, and highlight recent examples of natural products in antimicrobial drug discovery and as inhibitors of protein-protein interactions. The growing appreciation of functional assays and phenotypic screens may further contribute to a revival of interest in natural products for drug discovery

Behavioral and molecular genetics of reading-related AM and FM detection thresholds

Auditory detection thresholds for certain frequencies of both amplitude modulated (AM) and frequency modulated (FM) dynamic auditory stimuli are associated with reading in typically developing and dyslexic readers. We present the first behavioral and molecular genetic characterization of these two auditory traits. Two extant extended family datasets were given reading tasks and psychoacoustic tasks to determine FM 2 Hz and AM 20 Hz sensitivity thresholds. Univariate heritabilities were significant for both AM (h2 = 0.20) and FM (h2 = 0.29). Bayesian posterior probability of linkage (PPL) analysis found loci for AM (12q, PPL = 81 %) and FM (10p, PPL = 32 %; 20q, PPL = 65 %). Bivariate heritability analyses revealed that FM is genetically correlated with reading, while AM was not. Bivariate PPL analysis indicates that FM loci (10p, 20q) are not also associated with reading

The DCDC2 deletion is not a risk factor for dyslexia

Dyslexia is a specific impairment in learning to read and has strong heritability. An intronic deletion within the DCDC2 gene, with ~8% frequency in European populations, is increasingly used as a marker for dyslexia in neuroimaging and behavioral studies. At a mechanistic level, this deletion has been proposed to influence sensory processing capacity, and in particular sensitivity to visual coherent motion. Our re-assessment of the literature, however, did not reveal strong support for a role of this specific deletion in dyslexia. We also analyzed data from five distinct cohorts, enriched for individuals with dyslexia, and did not identify any signal indicative of associations for the DCDC2 deletion with reading-related measures, including in a combined sample analysis (N=526). We believe we conducted the first replication analysis for a proposed deletion effect on visual motion perception and found no association (N=445 siblings). We also report that the DCDC2 deletion has a frequency of 37.6% in a cohort representative of the general population recruited in Hong Kong (N=220). This figure, together with a lack of association between the deletion and reading abilities in this cohort, indicates the low likelihood of a direct deletion effect on reading skills. Therefore, on the basis of multiple strands of evidence, we conclude that the DCDC2 deletion is not a strong risk factor for dyslexia. Our analyses and literature re-evaluation are important for interpreting current developments within multidisciplinary studies of dyslexia and, more generally, contribute to current discussions about the importance of reproducibility in science

Postural control is not systematically related to reading skills:implications for the assessment of balance as a risk factor for developmental dyslexia

Impaired postural control has been associated with poor reading skills, as well as with lower performance on measures of attention and motor control variables that frequently co-occur with reading difficulties. Measures of balance and motor control have been incorporated into several screening batteries for developmental dyslexia, but it is unclear whether the relationship between such skills and reading manifests as a behavioural continuum across the range of abilities or is restricted to groups of individuals with specific disorder phenotypes. Here were obtained measures of postural control alongside measures of reading, attention and general cognitive skills in a large sample of young adults (n = 100). Postural control was assessed using centre of pressure (CoP) measurements, obtained over 5 different task conditions. Our results indicate an absence of strong statistical relationships between balance measures with either reading, cognitive or attention measures across the sample as a whole. © 2014 Loras et al

Further evidence for a parent-of-origin effect at the NOP9 locus on language-related phenotypes

Background - Specific language impairment (SLI) is a common neurodevelopmental disorder, observed in 5–10 % of children. Family and twin studies suggest a strong genetic component, but relatively few candidate genes have been reported to date. A recent genome-wide association study (GWAS) described the first statistically significant association specifically for a SLI cohort between a missense variant (rs4280164) in the NOP9 gene and language-related phenotypes under a parent-of-origin model. Replications of these findings are particularly challenging because the availability of parental DNA is required. Methods - We used two independent family-based cohorts characterised with reading- and language-related traits: a longitudinal cohort (n = 106 informative families) including children with language and reading difficulties and a nuclear family cohort (n = 264 families) selected for dyslexia. Results - We observed association with language-related measures when modelling for parent-of-origin effects at the NOP9 locus in both cohorts: minimum P = 0.001 for phonological awareness with a paternal effect in the first cohort and minimum P = 0.0004 for irregular word reading with a maternal effect in the second cohort. Allelic and parental trends were not consistent when compared to the original study. Conclusions - A parent-of-origin effect at this locus was detected in both cohorts, albeit with different trends. These findings contribute in interpreting the original GWAS report and support further investigations of the NOP9 locus and its role in language-related traits. A systematic evaluation of parent-of-origin effects in genetic association studies has the potential to reveal novel mechanisms underlying complex traits

Psychophysics with children: Investigating the effects of attentional lapses on threshold estimates

When assessing the perceptual abilities of children, researchers tend to use psychophysical techniques designed for use with adults. However, children’s poorer attentiveness might bias the threshold estimates obtained by these methods. Here, we obtained speed discrimination threshold estimates in 6- to 7-year-old children in UK Key Stage 1 (KS1), 7- to 9-year-old children in Key Stage 2 (KS2), and adults using three psychophysical procedures: QUEST, a 1-up 2-down Levitt staircase, and Method of Constant Stimuli (MCS). We estimated inattentiveness using responses to “easy” catch trials. As expected, children had higher threshold estimates and made more errors on catch trials than adults. Lower threshold estimates were obtained from psychometric functions fit to the data in the QUEST condition than the MCS and Levitt staircases, and the threshold estimates obtained when fitting a psychometric function to the QUEST data were also lower than when using the QUEST mode. This suggests that threshold estimates cannot be compared directly across methods. Differences between the procedures did not vary significantly with age group. Simulations indicated that inattentiveness biased threshold estimates particularly when threshold estimates were computed as the QUEST mode or the average of staircase reversals. In contrast, thresholds estimated by post-hoc psychometric function fitting were less biased by attentional lapses. Our results suggest that some psychophysical methods are more robust to attentiveness, which has important implications for assessing the perception of children and clinical groups

Identification of Candidate Genes for Dyslexia Susceptibility on Chromosome 18

Background: Six independent studies have identified linkage to chromosome 18 for developmental dyslexia or general reading ability. Until now, no candidate genes have been identified to explain this linkage. Here, we set out to identify the gene(s) conferring susceptibility by a two stage strategy of linkage and association analysis. Methodology/Principal Findings: Linkage analysis: 264 UK families and 155 US families each containing at least one child diagnosed with dyslexia were genotyped with a dense set of microsatellite markers on chromosome 18. Association analysis: Using a discovery sample of 187 UK families, nearly 3000 SNPs were genotyped across the chromosome 18 dyslexia susceptibility candidate region. Following association analysis, the top ranking SNPs were then genotyped in the remaining samples. The linkage analysis revealed a broad signal that spans approximately 40 Mb from 18p11.2 to 18q12.2. Following the association analysis and subsequent replication attempts, we observed consistent association with the same SNPs in three genes; melanocortin 5 receptor (MC5R), dymeclin (DYM) and neural precursor cell expressed, developmentally down-regulated 4-like (NEDD4L). Conclusions: Along with already published biological evidence, MC5R, DYM and NEDD4L make attractive candidates for dyslexia susceptibility genes. However, further replication and functional studies are still required.Publisher PDFPeer reviewe

INFOGEST static in vitro simulation of gastrointestinal food digestion

peer-reviewedSupplementary information is available at http://dx.doi.org/10.1038/s41596-018-0119-1 or https://www.nature.com/articles/s41596-018-0119-1#Sec45.Developing a mechanistic understanding of the impact of food structure and composition on human health has increasingly involved simulating digestion in the upper gastrointestinal tract. These simulations have used a wide range of different conditions that often have very little physiological relevance, and this impedes the meaningful comparison of results. The standardized protocol presented here is based on an international consensus developed by the COST INFOGEST network. The method is designed to be used with standard laboratory equipment and requires limited experience to encourage a wide range of researchers to adopt it. It is a static digestion method that uses constant ratios of meal to digestive fluids and a constant pH for each step of digestion. This makes the method simple to use but not suitable for simulating digestion kinetics. Using this method, food samples are subjected to sequential oral, gastric and intestinal digestion while parameters such as electrolytes, enzymes, bile, dilution, pH and time of digestion are based on available physiological data. This amended and improved digestion method (INFOGEST 2.0) avoids challenges associated with the original method, such as the inclusion of the oral phase and the use of gastric lipase. The method can be used to assess the endpoints resulting from digestion of foods by analyzing the digestion products (e.g., peptides/amino acids, fatty acids, simple sugars) and evaluating the release of micronutrients from the food matrix. The whole protocol can be completed in ~7 d, including ~5 d required for the determination of enzyme activities.COST action FA1005 INFOGEST (http://www.cost-infogest.eu/ ) is acknowledged for providing funding for travel, meetings and conferences (2011-2015). The French National Institute for Agricultural Research (INRA, www.inra.fr) is acknowledged for their continuous support of the INFOGEST network by organising and co-funding the International Conference on Food Digestion and workgroup meeting