Development and validation of an improved algorithm for overlaying flexible molecules

A program for overlaying multiple flexible molecules has been developed. Candidate overlays are generated by a novel fingerprint algorithm, scored on three objective functions (union volume, hydrogen-bond match, and hydrophobic match), and ranked by constrained Pareto ranking. A diverse subset of the best ranked solutions is chosen using an overlay-dissimilarity metric. If necessary, the solutions can be optimised. A multi-objective genetic algorithm can be used to find additional overlays with a given mapping of chemical features but different ligand conformations. The fingerprint algorithm may also be used to produce constrained overlays, in which user-specified chemical groups are forced to be superimposed. The program has been tested on several sets of ligands, for each of which the true overlay is known from protein–ligand crystal structures. Both objective and subjective success criteria indicate that good results are obtained on the majority of these sets

Introduction of Solid Food to Young Infants

Timing of the first introduction of solid food during infancy may have potential effects on life-long health. To understand the characteristics that are associated with the timing of infants’ initial exposure to solid foods. The 2000 National Survey of Early Childhood Health (NSECH) was a nationally representative telephone survey of 2,068 parents of children aged 4–35 months, which profiled content and quality of health care for young children. African-American and Latino families were over-sampled. Analyses in this report include bivariate tests and logistic regressions. 62% of parents reported introducing solids to their child between 4–6 months of age. African-American mothers (OR = 0.5 [0.3, 0.9]), English-speaking Latino mothers (OR = 0.4 [0.2, 0.7]), White mothers with more than high school education (OR = 0.5 [0.2, 1.0]), and mothers who breastfed for 4 months or longer (OR = 0.4 [0.3, 0.7]) were less likely to introduce solids early. Most parents (92%) of children 4–9 months of age reported that their pediatric provider had discussed introduction of solids with them since the child’s birth, and provider discussion of feeding was not associated with the timing of introduction of solids. Although most parents recall discussing the introduction of solid foods with their child’s physician, several subgroups of mothers introduce solid foods earlier than the AAP recommendation of 4–6 months. More effective discussion of solid food introduction linked to counseling and support of breastfeeding by the primary health care provider may reduce early introduction of solids

Peripheral neural cell sensitivity to mTHPC-mediated photodynamic therapy in a 3D in vitro model

Background: The effect of photodynamic therapy (PDT) on neural cells is important when tumours are within or adjacent to the nervous system. The purpose of this study was to investigate PDT using the photosensitiser, meta tetrahydroxyphenyl chlorin (mTHPC), on rat neurons and satellite glia, compared with human adenocarcinoma cell (MCF-7).Methods: Fluorescence microscopy confirmed that mTHPC was incorporated into all three cell types. Sensitivity of cells exposed to mTHPC-PDT (0–10 µg ml–1) was determined in a novel 3-dimensional collagen gel culture system. Cell death was quantified using propidium iodide and cell types were distinguished using immunocytochemistry. In some cases, neuron survival was confirmed by measuring subsequent neurite growth in monolayer culture.Results: MCF-7s and satellite glia were significantly more sensitive to PDT than neurons. Importantly, 4 µg ml–1 mTHPC PDT caused no significant neuron death compared with untreated controls but was sufficient to elicit substantial cell death in the other cell types. Initially, treatment reduced neurite length; neurons then extended neurites equivalent to those of untreated controls. The protocol was validated using hypericin (0–3 µg ml–1), which caused neuron death equivalent to other cell types.Conclusion: Neurons in culture can survive mTHPC-PDT under conditions sufficient to kill tumour cells and other nervous system cells

Quantitative principles of cis-translational control by general mRNA sequence features in eukaryotes.

BackgroundGeneral translational cis-elements are present in the mRNAs of all genes and affect the recruitment, assembly, and progress of preinitiation complexes and the ribosome under many physiological states. These elements include mRNA folding, upstream open reading frames, specific nucleotides flanking the initiating AUG codon, protein coding sequence length, and codon usage. The quantitative contributions of these sequence features and how and why they coordinate to control translation rates are not well understood.ResultsHere, we show that these sequence features specify 42-81% of the variance in translation rates in Saccharomyces cerevisiae, Schizosaccharomyces pombe, Arabidopsis thaliana, Mus musculus, and Homo sapiens. We establish that control by RNA secondary structure is chiefly mediated by highly folded 25-60 nucleotide segments within mRNA 5' regions, that changes in tri-nucleotide frequencies between highly and poorly translated 5' regions are correlated between all species, and that control by distinct biochemical processes is extensively correlated as is regulation by a single process acting in different parts of the same mRNA.ConclusionsOur work shows that general features control a much larger fraction of the variance in translation rates than previously realized. We provide a more detailed and accurate understanding of the aspects of RNA structure that directs translation in diverse eukaryotes. In addition, we note that the strongly correlated regulation between and within cis-control features will cause more even densities of translational complexes along each mRNA and therefore more efficient use of the translation machinery by the cell

Progress in Understanding and Treating SCN2A-Mediated Disorders

Advances in gene discovery for neurodevelopmental disorders have identified SCN2A dysfunction as a leading cause of infantile seizures, autism spectrum disorder, and intellectual disability. SCN2A encodes the neuronal sodium channel NaV1.2. Functional assays demonstrate strong correlation between genotype and phenotype. This insight can help guide therapeutic decisions and raises the possibility that ligands that selectively enhance or diminish channel function may improve symptoms. The well-defined function of sodium channels makes SCN2A an important test case for investigating the neurobiology of neurodevelopmental disorders more generally. Here, we discuss the progress made, through the concerted efforts of a diverse group of academic and industry scientists as well as policy advocates, in understanding and treating SCN2A-related disorders

QTL analysis and genomic selection using RADseq derived markers in Sitka spruce: the potential utility of within family data

Sitka spruce (Picea sitchensis (Bong.) Carr) is the most common commercial plantation species in Britain and a breeding programme based on traditional lines has been in operation since the early 1960s. Rotation lengths of 40-years have led breeders to adopt a process of indirect selection at younger ages based on traits well correlated with final selection, but still the generation interval is unlikely to reduce much below twenty years. Recent successful developments with genomic selection in animal breeding have led tree breeders to consider the application of this technology. In this study a RAD sequence assay was developed as a means of investigating the potential of molecular breeding in a non-model species. DNA was extracted from nearly 500 clonally replicated trees growing in a single full-sibling family at one site in Britain. The technique proved successful in identifying 132 QTLs for 5-year bud-burst and 2 QTLs for 6-year height. In addition, the accuracy of predicting phenotypes by genomic selection was strikingly high at 0.62 and 0.59 respectively. Sensitivity analysis with 200 offspring found only a slight fall in correlation values (0.54 and 0.38) although when the training population reduced to 50 offspring predictive values fell further (0.33 and 0.25). This proved an encouraging first investigation into the potential use of genomic selection in the breeding of Sitka spruce. The authors investigate how problems associated with effective population size and linkage disequilibrium can be avoided and suggest a practical way of incorporating genomic selection into a dynamic breeding programme

Malaria and Fetal Growth Alterations in the 3(rd) Trimester of Pregnancy: A Longitudinal Ultrasound Study.

Pregnancy associated malaria is associated with decreased birth weight, but in-utero evaluation of fetal growth alterations is rarely performed. The objective of this study was to investigate malaria induced changes in fetal growth during the 3(rd) trimester using trans-abdominal ultrasound. An observational study of 876 pregnant women (398 primi- and secundigravidae and 478 multigravidae) was conducted in Tanzania. Fetal growth was monitored with ultrasound and screening for malaria was performed regularly. Birth weight and fetal weight were converted to z-scores, and fetal growth evaluated as fetal weight gain from the 26th week of pregnancy. Malaria infection only affected birth weight and fetal growth among primi- and secundigravid women. Forty-eight of the 398 primi- and secundigravid women had malaria during pregnancy causing a reduction in the newborns z-score of -0.50 (95% CI: -0.86, -0.13, P = 0.008, multiple linear regression). Fifty-eight percent (28/48) of the primi- and secundigravidae had malaria in the first half of pregnancy, but an effect on fetal growth was observed in the 3(rd) trimester with an OR of 4.89 for the fetal growth rate belonging to the lowest 25% in the population (95%CI: 2.03-11.79, P<0.001, multiple logistic regression). At an individual level, among the primi- and secundigravidae, 27% experienced alterations of fetal growth immediately after exposure but only for a short interval, 27% only late in pregnancy, 16.2% persistently from exposure until the end of pregnancy, and 29.7% had no alterations of fetal growth. The effect of malaria infections was observed during the 3(rd) trimester, despite infections occurring much earlier in pregnancy, and different mechanisms might operate leading to different patterns of growth alterations. This study highlights the need for protection against malaria throughout pregnancy and the recognition that observed changes in fetal growth might be a consequence of an infection much earlier in pregnancy.\u