Association between DNA Damage Response and Repair Genes and Risk of Invasive Serous Ovarian Cancer

Background

We analyzed the association between 53 genes related to DNA repair and p53-mediated damage response and serous ovarian cancer risk using case-control data from the North Carolina Ovarian Cancer Study (NCOCS), a population-based, case-control study.

Methods/Principal Findings

The analysis was restricted to 364 invasive serous ovarian cancer cases and 761 controls of white, non-Hispanic race. Statistical analysis was two staged: a screen using marginal Bayes factors (BFs) for 484 SNPs and a modeling stage in which we calculated multivariate adjusted posterior probabilities of association for 77 SNPs that passed the screen. These probabilities were conditional on subject age at diagnosis/interview, batch, a DNA quality metric and genotypes of other SNPs and allowed for uncertainty in the genetic parameterizations of the SNPs and number of associated SNPs. Six SNPs had Bayes factors greater than 10 in favor of an association with invasive serous ovarian cancer. These included rs5762746 (median OR(odds ratio)_{per allele} = 0.66; 95% credible interval (CI) = 0.44–1.00) and rs6005835 (median OR_{per allele}  = 0.69; 95% CI  = 0.53–0.91) in CHEK2, rs2078486 (median OR_{per allele}  = 1.65; 95% CI = 1.21–2.25) and rs12951053 (median OR_{per allele}  = 1.65; 95% CI = 1.20–2.26) in TP53, rs411697 (median OR _{rare homozygote}  = 0.53; 95% CI  = 0.35 – 0.79) in BACH1 and rs10131 (median OR _{rare homozygote}  =  not estimable) in LIG4. The six most highly associated SNPs are either predicted to be functionally significant or are in LD with such a variant. The variants in TP53 were confirmed to be associated in a large follow-up study.

Conclusions/Significance

Based on our findings, further follow-up of the DNA repair and response pathways in a larger dataset is warranted to confirm these results.     

Citrus limonoid effects on Colorado potato beetle larval survival and development

The effects of citrus limonoids, applied topically to potato (Solanum tuberosum L. var. Katahdin) foliage, on Colorado potato beetle (Leptinotarsa decemlineata) (Say) (Chrysomelidae) larval development, growth, and survival were quantified in laboratory assays and a small-plot field test. In laboratory assays, survival, development rate, and body weight decreased with increasing limonoid concentration, however these measures of larval response did not significantly differ among varying periods of limonoid exposure (three, six, or nine days). Significant limonoid application concentration and frequency effects on survival, development rate, and defoliation were observed in the field test. These results indicate the potential utility of lethal and non-lethal effects of citrus limonoids for management of the Colorado potato beetle.     

Chemokine receptor CXCR3 desensitization by IL-16/CD4 signaling is dependent on CCR5 and intact membrane cholesterol

Previous work has shown that IL-16/CD4 induces desensitization of both CCR5- and CXCR4-induced migration, with no apparent effect on CCR2b or CCR3. To investigate the functional relationship between CD4 and other chemokine receptors, we determined the effects of IL-16 interaction with CD4 on CXCR3-induced migration. In this study we demonstrate that IL-16/CD4 induced receptor desensitization of CXCR3 on primary human T cells. IL-16/CD4 stimulation does not result in surface modulation of CXCR3 or changes in CXCL10 binding affinity. This effect does require p56(lck) enzymatic activity and the presence of CCR5, because desensitization is not transmitted in the absence of CCR5. Treatment of human T cells with methyl-beta-cyclodextrin, a cholesterol chelator, prevented the desensitization of CXCR3 via IL-16/CD4, which was restored after reloading of cholesterol, indicating a requirement for intact cholesterol. These studies demonstrate an intimate functional relationship among CD4, CCR5, and CXCR3, in which CCR5 can act as an adaptor molecule for CD4 signaling. This process of regulating Th1 cell chemoattraction may represent a mechanism for orchestrating cell recruitment in Th1-mediated diseases.     

A ratiometric fluorescent sensor for Zn2+ based on internal charge transfer (ICT)

A ratiometric fluorescent chemosensor 5 was designed and synthesized based on internal charge transfer (ICT). The indicator absorbs and emits light in the visible wavelength range. In acetonitrile, blue shifts in fluorescent emission upon zinc binding are due to the formation of a 1:2 metal/ligand complex, which induced a fluorescent emission at 616 nm at the expense of the fluorescent emission at 672 nm.     

High-Resolution Physical Map of the X-linked Retinoschisis Interval in Xp22

X-linked retinoschisis (RS) is the leading cause of macular degeneration in young males and has been mapped to Xp22 between DXS418 and DXS999. To facilitate identification of the RS gene, we have constructed a yeast artificial chromosome (YAC) contig across this region comprising 28 YACs and 32 sequence-tagged sites including seven novel end clone markers. To establish the definitive marker order, a PAC contig containing 50 clones was also constructed, and all clones were fingerprinted. The marker order is: Xpter–DXS1317–(AFM205yd12–DXS7175–DXS7992)–60N8T7–DXS1195–DXS7993–DXS7174–60N8-SP6–DXS418–DXS7994–DXS7995–DXS7996–HYAT2–25HA10R–HYAT1–DXS7997–DXS7998–DXS257–434E8R–3542R–DXS6762–DXS7999–DXS6763–434E8L–DXS8000–DXS6760–DXS7176–DXS8001–DXS999–3176R–PHKA2–Xcen. A long-range restriction map was constructed, and the RS region is estimated to be 1300 kb, containing three putative CpG islands. An unstable region was identified between DXS6763 and 434E8L. These data will facilitate positional cloning of RS and other disease genes in Xp22.     

Leaf manganese concentrations as a tool to assess belowground plant functioning in phosphorus-impoverished environments

Plant and Soil - Root-released carboxylates enhance the availability of manganese (Mn), which enters roots through transporters with low substrate specificity. Leaf Mn concentration ([Mn]) has been...     

Lack of gonadotrophin-releasing hormone (GnRH) neuron response to decreasing photoperiod in thyroidectomized male starlings (Sturnus vulgaris)

Exposure of starlings to long days initially causes reproductive maturation, but eventually leads to photorefractoriness. During photorefractoriness, gonadotrophin-releasing hormone (GnRH) decreases in the GnRH cell bodies and fibers emanating from these to the median eminence, circulating gonadotrophin concentrations decrease to a minimum, and the gonads regress. Thyroidectomy profoundly affects these photoperiodic responses. In chronically thyroidectomized starlings, gonadal responses to changes in day length are attenuated. This investigation was conducted to determine whether, in the absence of gonadal responsiveness, the GnRH system of chronically thyroidectomized starlings responds to changes in day length. Two groups of thyroidectomized male starlings were transferred from short days (8L:16D) to long days (18L:6D) for four weeks, and testicular volume increased. One group was kept on long days (TxLD) and the other was returned to short days (TxSD). Testicular volume did not decrease in the TxSD group. The GnRH neurons of the two thyroidectomized groups were compared to those of two groups of intact starlings, one of them on long days and photorefractory (ILD), the other on short days and photosensitive (ISD). Group ILD had lower numbers of GnRH-stained cells than groups TxLD, TxSD and ISD, which did not differ in this respect. Similar differences were observed for GnRH cell size in the pre-optic area (POA) and for density of staining of GnRH fibers in the median eminence. The results confirm that thyroidectomy attenuates gonadal responses to change in day length and suggest that this results from an effect upon the central nervous system rather than a peripheral effect.     

Relative photorefractoriness, prolactin, and reproductive regression in a flexibly breeding sonoran desert passerine, the rufous-winged sparrow, Aimophila carpalis

We tested the hypothesis that adult male rufous-winged sparrows, Aimophila carpalis, exhibit relative photorefractoriness. This condition results in partial loss of sensitivity to photoperiod as a reproductive stimulus after prolonged exposure to long photoperiods and is similar to the mammalian condition called photoperiodic memory. Captive birds were exposed either to 8 h of light/16 h of dark per day (8L) or to 16L for 11 weeks and were then exposed either to 8L, 13L, 14L, or 16L. Testicular diameter, plasma luteinizing hormone (LH), and plasma prolactin (PRL) were measured to assess reproductive system activity in response to photostimulation. In free-living birds, testicular diameter, plasma LH, and PRL were compared in birds caught in September in a year when birds were breeding and in a year when birds were not breeding to further evaluate the role of PRL in the termination of seasonal breeding. Testes completely developed after transfer from 8L to 14L or to 16L and partially developed after transfer from 8L to 13L. However, after 11 weeks of 16L exposure, transfer to 14L caused partial regression and transfer to 13L caused complete regression of the testes. Plasma LH increased in all birds that were transferred from 8L to a longer photoperiod. PRL showed a weak response to longer photoperiod treatment and was elevated in birds after chronic 16L exposure in comparison to birds exposed to chronic 8L. These data indicate that male rufous-winged sparrows lose sensitivity to photoperiod after long photoperiod exposure consistent with the relative photorefractoriness and photoperiodic memory models. Lower PRL in birds that developed testes on 13L and 14L compared to birds that regressed testes on 13L and 14L are consistent with the hypothesis that PRL regulates relative photorefractoriness. However, PRL does not appear to regulate interannual differences in the timing of testicular regression.     

4-Alkoxy-2,6-diaminopyrimidine derivatives: inhibitors of cyclin dependent kinases 1 and 2

The cyclin dependent kinase (cdk) inhibitor NU6027, 4-cyclohexylmethoxy-5-nitroso-pyrimidine-2,6-diamine (IC(50) vs cdk1/cyclinB1=2.9+/-0.1 microM and IC(50) vs cdk2/cyclinA3=2.2+/-0.6 microM), was used as the basis for the design of a series of 4-alkoxy-2,6-diamino-5-nitrosopyrimidine derivatives. The synthesis and evaluation of 21 compounds as potential inhibitors of cyclin-dependent kinases 1 and 2 is described and the structure-activity relationships relating to NU6027 have been probed. Simple alkoxy- or cycloalkoxy-groups at the O(4)-position were tolerated, with the 4-(2-methylbutoxy)-derivative (IC(50) vs cdk1/cyclinB1=12+/-2 microM and cdk2/cyclinA3=13+/-4 microM) retaining significant activity. Substitutions at the N(6) position were not tolerated. Replacement of the 5-nitroso substituent with ketone, oxime and semicarbazone groups essentially abolished activity. However, the derivative bearing an isosteric 5-formyl group, 2,6-diamino-4-cyclohexylmethoxy-pyrimidine-5-carbaldehyde, showed modest activity (IC(50) vs cdk1/cyclinB1=35+/-3 microM and cdk2/cyclinA3=43+/-3 microM). The X-ray crystal structure of the 5-formyl compound bound to cdk2 has been determined to 2.3A resolution. The intramolecular H-bond deduced from the structure with NU6027 bound to cdk2 is not evident in the structure with the corresponding formyl compound. Thus the parent compound, 4-cyclohexylmethoxy-5-nitrosopyrimidine-2,6-diamine (NU6027), remains the optimal basis for future structure-activity studies for cyclin-dependent kinase inhibitors in this series.     

Prediction of near-term climate change impacts on UK wheat quality and the potential for adaptation through plant breeding

Wheat is a major crop worldwide, mainly cultivated for human consumption and animal feed. Grain quality is paramount in determining its value and downstream use. While we know that climate change threatens global crop yields, a better understanding of impacts on wheat end-use quality is also critical. Combining quantitative genetics with climate model outputs, we investigated UK-wide trends in genotypic adaptation for wheat quality traits. In our approach, we augmented genomic prediction models with environmental characterisation of field trials to predict trait values and climate effects in historical field trial data between 2001 and 2020. Addition of environmental covariates, such as temperature and rainfall, successfully enabled prediction of genotype by environment interactions (G × E), and increased prediction accuracy of most traits for new genotypes in new year cross validation. We then extended predictions from these models to much larger numbers of simulated environments using climate scenarios projected under Representative Concentration Pathways 8.5 for 2050–2069. We found geographically varying climate change impacts on wheat quality due to contrasting associations between specific weather covariables and quality traits across the UK. Notably, negative impacts on quality traits were predicted in the East of the UK due to increased summer temperatures while the climate in the North and South-west may become more favourable with increased summer temperatures. Furthermore, by projecting 167,040 simulated future genotype–environment combinations, we found only limited potential for breeding to exploit predictable G × E to mitigate year-to-year environmental variability for most traits except Hagberg falling number. This suggests low adaptability of current UK wheat germplasm across future UK climates. More generally, approaches demonstrated here will be critical to enable adaptation of global crops to near-term climate change.