The Contribution of Diet and Genotype to Iron Status in Women: A Classical Twin Study

This is the first published report examining the combined effect of diet and genotype on body iron content using a classical twin study design. The aim of this study was to determine the relative contribution of genetic and environmental factors in determining iron status. The population was comprised of 200 BMI- and age-matched pairs of MZ and DZ healthy twins, characterised for habitual diet and 15 iron-related candidate genetic markers. Variance components analysis demonstrated that the heritability of serum ferritin (SF) and soluble transferrin receptor was 44% and 54% respectively. Measured single nucleotide polymorphisms explained 5% and selected dietary factors 6% of the variance in iron status; there was a negative association between calcium intake and body iron (p = 0.02) and SF (p = 0.04).     

Bumblebee Venom Serine Protease Increases Fungal Insecticidal Virulence by Inducing Insect Melanization

Insect-killing (entomopathogenic) fungi have high potential for controlling agriculturally harmful pests. However, their pathogenicity is slow, and this is one reason for their poor acceptance as a fungal insecticide. The expression of bumblebee, Bombus ignitus, venom serine protease (VSP) by Beauveria bassiana (ERL1170) induced melanization of yellow spotted longicorn beetles (Psacothea hilaris) as an over-reactive immune response, and caused substantially earlier mortality in beet armyworm (Spodopetra exigua) larvae when compared to the wild type. No fungal outgrowth or sporulation was observed on the melanized insects, thus suggesting a self-restriction of the dispersal of the genetically modified fungus in the environment. The research is the first use of a multi-functional bumblebee VSP to significantly increase the speed of fungal pathogenicity, while minimizing the dispersal of the fungal transformant in the environment.     

Multilocus loss of DNA methylation in individuals with mutations in the histone H3 Lysine 4 Demethylase KDM5C

Background

A number of neurodevelopmental syndromes are caused by mutations in genes encoding proteins that normally function in epigenetic regulation. Identification of epigenetic alterations occurring in these disorders could shed light on molecular pathways relevant to neurodevelopment.

Results

Using a genome-wide approach, we identified genes with significant loss of DNA methylation in blood of males with intellectual disability and mutations in the X-linked KDM5C gene, encoding a histone H3 lysine 4 demethylase, in comparison to age/sex matched controls. Loss of DNA methylation in such individuals is consistent with known interactions between DNA methylation and H3 lysine 4 methylation. Further, loss of DNA methylation at the promoters of the three top candidate genes FBXL5, SCMH1, CACYBP was not observed in more than 900 population controls. We also found that DNA methylation at these three genes in blood correlated with dosage of KDM5C and its Y-linked homologue KDM5D. In addition, parallel sex-specific DNA methylation profiles in brain samples from control males and females were observed at FBXL5 and CACYBP.

Conclusions

We have, for the first time, identified epigenetic alterations in patient samples carrying a mutation in a gene involved in the regulation of histone modifications. These data support the concept that DNA methylation and H3 lysine 4 methylation are functionally interdependent. The data provide new insights into the molecular pathogenesis of intellectual disability. Further, our data suggest that some DNA methylation marks identified in blood can serve as biomarkers of epigenetic status in the brain.     

Evaluating Predictive Pharmacogenetic Signatures of Adverse Events in Colorectal Cancer Patients Treated with Fluoropyrimidines

The potential clinical utility of genetic markers associated with response to fluoropyrimidine treatment in colorectal cancer patients remains controversial despite extensive study. Our aim was to test the clinical validity of both novel and previously identified markers of adverse events in a broad clinical setting. We have conducted an observational pharmacogenetic study of early adverse events in a cohort study of 254 colorectal cancer patients treated with 5-fluorouracil or capecitabine. Sixteen variants of nine key folate (pharmacodynamic) and drug metabolising (pharmacokinetic) enzymes have been analysed as individual markers and/or signatures of markers. We found a significant association between TYMP S471L (rs11479) and early dose modifications and/or severe adverse events (adjusted OR = 2.02 [1.03; 4.00], p = 0.042, adjusted OR = 2.70 [1.23; 5.92], p = 0.01 respectively). There was also a significant association between these phenotypes and a signature of DPYD mutations (Adjusted OR = 3.96 [1.17; 13.33], p = 0.03, adjusted OR = 6.76 [1.99; 22.96], p = 0.002 respectively). We did not identify any significant associations between the individual candidate pharmacodynamic markers and toxicity. If a predictive test for early adverse events analysed the TYMP and DPYD variants as a signature, the sensitivity would be 45.5 %, with a positive predictive value of just 33.9 % and thus poor clinical validity. Most studies to date have been under-powered to consider multiple pharmacokinetic and pharmacodynamic variants simultaneously but this and similar individualised data sets could be pooled in meta-analyses to resolve uncertainties about the potential clinical utility of these markers.     

Parasitoids in low-level populations ofLymantria dispar [Lep.: Lymantriidae] in different forest physiographic zones

A 2-year study was conducted on the distribution of parasitoids of gypsy moth,Lymantria dispar (L.) (Lep.: Lymantriidae), in mesic and adjacent higher elevation transition and xeric forest habitats in Vermont (U.S.A.). In both years, overall parasitism ranged from 12–18% in each habitat. When analyzed according to the life stage at which the host was collected, parasitism rates of greater than 40% were obtained among the late instars.Parasetigena silvestris (Robineau-Desvoidy) andPhobocampe disparis (Viereck) were recovered most commonly from the mesic habitat, andCotesia melanoscelus (Ratzeburg) andBlepharipa pratensis (= Sturmia scutellata) (Meigen) were most common in collections from the xeric area. Parasitism byCompsilura concinnata (Meigen) occurred at similar levels in all three habitats, and this species was responsible for the highest parasitism rates on the site, reaching 40% among the late instars in 1985. Percent parasitism byC. concinnata increased three-four-fold from 1984 to 1985, while parasitism by other species declined.     

Histopathogenesis of the Galls Induced by Nothanguina phyllobia in Solanum elaeagnifolium

The histopathogenesis of the foliar galls induced by Nothanguina phyllobia Thorne in Solanum elaeagnilolium Cav. was examined via serial sections prepared from plant shoots at 11 time intervals (0.5-30 days) following inoculation. Nematodes infected the blades and petioles of young leaves surrounding the shoot apex. Hypertrophy and hyperplasia of the palisade, pith, cortical, and vascular parenchyma resulted in the formation of confluent leaf, petiole, and stem galls up to 25 cm³ in volume. Externally, leaf galls were irregular, light-green, convoluted spheroid bulges distending the abaxial surface. Mature galls contained a cavity lined with parenchymogenous nutritive tissue comprising intercellular spaces and actively dividing hypertrophied cells. These cells contained granular cytoplasm, hypertrophied nuclei, and brightly stained large nucleoli. Vascular tissues were not discernibly affected during the early stages of gall development. As gall development progressed, however, vascular elements were often displaced and disoriented. The histopathology of this nematode indicates that N. phyllobia is a highly specialized parasite and, for that reason, is suitable as a biological control agent.     

Analysis of microquantities of choline and its esters utilizing gas chromatography-chemical ionization mass spectrometry.

Gas chromatography-chemical ionization mass spectrometry has been applied successfully in the analysis of choline and its esters. This approach serves to extend further the potential of existing gas chromatographic procedures which are capable of the microestimation of choline esters following their N-demethylation by either chemical or physical means. Typical fragmentation patterns with ions at $\text{m}\text{e}\text{= 72}$ and $\text{m}\text{e}\text{= (M + 1)}$ were obtained for each choline ester derivative. When methane was used as the reactant gas, the above fragments were approximately of equal abundance for each ester. Use of isobutane as reactant gas yielded almost 80% of the (M + 1) fragment, and only approximately 5% of the fragment ion at $\text{m}\text{e}\text{= 72}$. Recovery of all fragments was linear for nondeuterated as well as deuterated analogs of choline ester derivatives. Recovery, as evident from the analysis of records of relative ratios of injected isotopic variants of these esters, indicated that this analysis of choline esters using chemical ionization mass spectrometry coupled with gas chromatography is quantitative and highly reproducible.     

The North American «Hipparion Datum and implications for the Neogene of the Old World

A large sample of skulls and associated dentitions of Cormohipparion sphenodus (Cope, 1889). new combination, is described from Miocene deposits of Nebraska, Colorado, New Mexico, and California. This species is morphologically more advanced than the most primitive species of the genus, C. goorisiMacFadden & Skinner, 1981, and more primitive than a third and more advanced species of this genus. C. occidentale (Leidy, 1856). In several characters such as configuration of the preobrital fossa, size, hypsodonty, shape of protocone, and complexity of enamel plication, C. sphenodus is morphologically similar, and potentially related to, some Old World Vallesian «Hipparion. In addition, based on radiometric calibration of stratigraphic sequences in Nebraska and California, C. sphenodus spans an interval of time from about 13.6 to 11 Ma. Inasmuch as the Old World «Hipparion Datum is calibrated at about 12 Ma, we conclude that C. sphenodus exhibits the morphological and chronological prerequisites to have been directly ancestral to some of these Old World forms.The hipparion horses apparently were a polyphyletic assemblage of several genera, and their biogeographic and biochronologic history is more complex than classically thought. Several dispersal events involving these horses may have occurred between the New and Old Worlds during the late Miocene.