Fine-mapping of the HNF1B multicancer locus identifies candidate variants that mediate endometrial cancer risk

Common variants in the hepatocyte nuclear factor 1 homeobox B (HNF1B) gene are associated with the risk of Type II diabetes and multiple cancers. Evidence to date indicates that cancer risk may be mediated via genetic or epigenetic effects on HNF1B gene expression. We previously found single-nucleotide polymorphisms (SNPs) at the HNF1B locus to be associated with endometrial cancer, and now report extensive fine-mapping and in silico and laboratory analyses of this locus. Analysis of 1184 genotyped and imputed SNPs in 6608 Caucasian cases and 37 925 controls, and 895 Asian cases and 1968 controls, revealed the best signal of association for SNP rs11263763 (P = 8.4 × 10−14, odds ratio = 0.86, 95% confidence interval = 0.82–0.89), located within HNF1B intron 1. Haplotype analysis and conditional analyses provide no evidence of further independent endometrial cancer risk variants at this locus. SNP rs11263763 genotype was associated with HNF1B mRNA expression but not with HNF1B methylation in endometrial tumor samples from The Cancer Genome Atlas. Genetic analyses prioritized rs11263763 and four other SNPs in high-to-moderate linkage disequilibrium as the most likely causal SNPs. Three of these SNPs map to the extended HNF1B promoter based on chromatin marks extending from the minimal promoter region. Reporter assays demonstrated that this extended region reduces activity in combination with the minimal HNF1B promoter, and that the minor alleles of rs11263763 or rs8064454 are associated with decreased HNF1B promoter activity. Our findings provide evidence for a single signal associated with endometrial cancer risk at the HNF1B locus, and that risk is likely mediated via altered HNF1B gene expression.

BRCA1 deficiency exacerbates estrogen-induced DNA damage and genomic instability

Germline mutations in BRCA1 predispose carriers to a high incidence of breast and ovarian cancers. BRCA1 functions to maintain genomic stability through critical roles in DNA repair, cell cycle arrest and transcriptional control. A major question has been why BRCA1 loss or mutation leads to tumors mainly in estrogen-regulated tissues, given that BRCA1 has essential functions in all cell types. Here we report that estrogen and estrogen metabolites can cause DNA double strand breaks (DSB) in estrogen receptor-α negative breast cells and that BRCA1 is required to repair these DSBs to prevent metabolite-induced genomic instability. We found that BRCA1 also regulates estrogen metabolism and metabolite-mediated DNA damage by repressing the transcription of estrogen-metabolising enzymes, such as CYP1A1, in breast cells. Lastly, we used a knock-in human cell model with a heterozygous BRCA1 pathogenic mutation to show how BRCA1 haploinsufficiency affects these processes. Our findings provide pivotal new insights into why BRCA1 mutation drives the formation of tumours in estrogen-regulated tissues, despite the general role of BRCA1 in DNA repair in all cell types.

Nanosheets Co3O4 interleaved with graphene for highly efficient oxygen reduction

Efficient yet inexpensive electrocatalysts for oxygen reduction reaction (ORR) are an essential component of renewable energy devices, such as fuel cells and metal-air batteries. We herein interleaved novel Co3O4 nanosheets with graphene to develop a first ever sheet-on-sheet heterostructured electrocatalyst for ORR, whose electrocatalytic activity outperformed the state-of-the-art commercial Pt/C with exceptional durability in alkaline solution. The composite demonstrates the highest activity of all the nonprecious metal electrocatalysts, such as those derived from Co3O4 nanoparticle/nitrogen-doped graphene hybrids and carbon nanotube/nanoparticle composites. Density functional theory (DFT) calculations indicated that the outstanding performance originated from the significant charge transfer from graphene to Co3O4 nanosheets promoting the electron transport through the whole structure. Theoretical calculations revealed that the enhanced stability can be ascribed to the strong interaction generated between both types of sheets.

Dynamics of plant populations in Heteropogon contortus(black speargrass) pastures on a granite landscape in southern Queensland. 2. Seed production and soil seed banks of H. contortus

Seed production and soil seed hanks of H. contortus were studied in a subset of treatments within an extensive grazing study conducted in H. contortus pasture in southern Queensland between 1990 and 1996. Seed production of H. contortus in autumn ranged from 260 to 1800 seeds/m2 with much of this variation due to differences in rainfall between years. Seed production was generally higher in the silver-leaved ironbark than in the narrow-leaved ironbark land class and was also influenced by a consistent stocking rate x pasture type interaction. Inflorescence density was the main factor contributing to the variable seed production and was related to the rainfall received during February. The number of seeds per inflorescence was unaffected by seasonal rainfall, landscape position, stocking rate or legume oversowing. Seed viability was related to the rainfall received during March. Soil seed banks in spring varied from 130 to 520 seeds/m2 between 1990 and 1995 with generally more seed present in the silver-leaved ironbark than in the narrow-leaved ironbark land class. There were poor relationships between viable seed production and the size of the soil seed bank, and between the size of the soil seed bank and seedling recruitment. This study indicates that H. contortus has the potential to produce relatively large amounts of seed and showed that the seasonal pattern of rainfall plays a major role in achieving this potential

Dynamics of plant populations in Heteropogon contortus(black speargrass) pastures on a granite landscape in southern Queensland. 1. Dynamics of H. contortus populations

The dynamics of Heteropogon contortus (black speargrass) populations were measured in a subset of treatments contained within an extensive grazing study conducted between 1990 and 1996 in H. contortus pasture in southern Queensland. This subset included 2 landscape positions and 3 stocking rates in both native pasture and legume-oversown native pasture. Severe drought conditions throughout much of the study necessitated ongoing adjustments to the original stocking rates and, as a result, drought was the major influence on the dynamics of H. contortus populations. Plant density and basal area in the silver-leaved ironbark landscape were consistently higher than those in the narrow-leaved ironbark landscape. There was limited evidence of any impact by either light or moderate stocking rate but there was evidence of an impact at the heaviest stocking rate. There was minimal impact of legume oversowing. Relatively large fluctuations in plant density occurred during this study resulting from the death of existing plants, due mainly to drought, and seedling recruitment. Similarly, there were relatively large fluctuations in basal area caused mainly by changes in plant size. Rates for turnover of plant numbers were relatively high whereas plant turnover rates of basal areas were relatively low. Regular seedling recruitment appeared necessary to ensure the persistence of this species. Despite the high turnover, populations were maintained at reasonable levels indicating the overall resilience of H. contortus.

Dynamics of plant populations in Heteropogon contortus (black speargrass) pastures on a granite landscape in southern Queensland. 3. Dynamics of Aristida spp. populations

The dynamics of the unpalatable Aristida spp. (wiregrasses) were measured in a subset of treatments contained within an extensive grazing study conducted between 1990 and 1996 in H. contortus pasture in southern Queensland. This paper reports the results from these treatments which included 2 land classes (silver-leaved and narrowleaved ironbark), 3 stocking rates (0.3, 0.6 and 0.9 beasts/ha) in both native pasture and legumeoversown native pasture, all in the absence of fire. Changes in plant density and basal area of Aristida spp. reflected differences in both the survival and size of existing plants together with a large seedling recruitment in 1991. Two different taxa of Aristida spp. were distinguished; however, there were no clear differences in the response of these 2 taxa to the treatments. Grazing had the greatest impact on population dynamics through reducing basal area as stocking rate increased. Neither landscape position nor legume oversowing had a major impact on Aristida spp. The results suggest that populations of Aristida spp. will be highest under light grazing and that seedling recruitment may be episodic

Dynamics of plant populations in Heteropogon contortus (black speargrass) pastures on a granite landscape in southern Queensland. 4. The effects of burning on H.contortus and Aristida spp. populations

This paper reports an experiment undertaken to examine the impact of burning in spring together with reduced grazing pressure on the dynamics of H. contortus and Aristida spp. In H. contortus pasture in south-eastern Queensland. The overall results indicate that spring burning in combination with reduced grazing pressure had no marked effect on the density of either grass species. This was attributed to 2 factors. Firstly, extreme drought conditions restricted any increase in H. contortus seedling establishment despite the presence of an adequate soil seed bank prior to summer; and secondly, some differences occurred in the response to fire of the diverse taxonomic groupings in the species of Aristida spp. present at the study site. This study concluded that it is necessary to identify appropriate taxonomic units within the Aristida genus and that, where appropriate, burning in spring to manage pasture composition should be conducted under favorable rainfall conditions using seasonal forecasting indicators such as the Southern Oscillation Index

Grazing management influences the dynamics of populations of Stylosanthes hippocampoides (Oxley fine stem stylo)

This paper describes a study to identify those factors which control the persistence of the Subtropical legume Stylosanthes hippocampoides, formerly S. guianensis cv. Oxley (fine stem stylo). The dynamics of S. hippocampoides populations was recorded in permanent quadrats at 2 stocking rates in a grazing study conducted between 1987 and 1992 in south-eastern Queensland. Density of mature plants fluctuated between 10 and 60 plants/m(2) during the 5 years with the major contributing factors being variations in seedling recruitment and survival, which, in turn, reflected the size of the soil seed bank and seasonal rainfall. Plant density was consistently higher at the lower stocking rate of 1 beast/1.5 ha compared with 1 beast/1 ha; however, the effect of stocking rate was minor compared with fluctuation due to seasonal variation in rainfall. The maximum life span of the original plants exceeded 5 years, while the survival of seedling cohorts was strongly impacted by seasonal rainfall. Total exclosure from grazing during summer increased the size of the soil seed bank although a precise time period during summer was not identified, while grazing at the lower stocking pressure produced the same outcome. It was concluded that the large seasonal variation that occurs in S. hippocampoides density is driven by large seasonal variation in seedling recruitment, which, in turn, is influenced by the size of the soil seed bank.

Impacts of grazing management options on pasture and animal productivity in a Heteropogon contortus (black speargrass) pasture in central Queensland. 4. Animal production.

Steer liveweight gains were measured in an extensive grazing study conducted in a Heteropogon contortus (black speargrass) pasture in central Queensland between 1988 and 2001. Treatments included a range of stocking rates in native pastures, legume-oversown native pasture and animal diet supplement/spring-burning pastures. Seasonal rainfall throughout this study was below the long-term mean. Mean annual pasture utilisation ranged from 13 to 61%. Annual liveweight gains per head in native pasture were highly variable among years and ranged from a low of 43 kg/steer at 2 ha/steer to a high of 182 kg/steer at 8 ha/steer. Annual liveweight gains were consistently highest at light stocking and decreased with increasing stocking rate. Annual liveweight gain per hectare increased linearly with stocking rate. These stocking rate trends were also evident in legume-oversown pastures although both the intercept and slope of the regressions for legume-oversown pastures were higher than that for native pasture. The highest annual liveweight gain for legume-oversown pasture was 221 kg/steer at 4 ha/steer. After 13 years, annual liveweight gain per unit area occurred at the heaviest stocking rate despite deleterious changes in the pasture. Across all years, the annual liveweight advantage for legume-oversown pastures was 37 kg/steer. Compared with native pasture, changes in annual liveweight gain with burning were variable. It was concluded that cattle productivity is sustainable when stocking rates are maintained at 4 ha/steer or lighter (equivalent to a utilisation rate around 30%). Although steer liveweight gain occurred at all stocking rates and economic returns were highest at heaviest stocking rates, stocking rates heavier than 4 ha/steer are unsustainable because of their long-term impact on pasture productivity.

Demography of three perennial grasses in a central Queensland eucalypt woodland.

The population dynamics of the palatable, perennial grasses Bothriochloa ewartiana (Domin) C.E.Hubb. (desert Mitchell grass), Chrysopogon fallax S.T.Blake (golden beard grass) and Heteropogon contortus (L.) P.Beauv. ex Roem. & Schult. (black speargrass), were studied in an extensive grazing study conducted in a eucalypt woodland within the Aristida-Bothriochloa pasture community in central Queensland between 1994 and 2000. Treatments were three grazing pressures based on light, medium and heavy utilisation of forage available at the end of summer and two timber treatments (trees intact and trees killed). Seasonal rainfall throughout this study was generally favourable for plant growth with no severe drought periods. Grazing pressure had a greater overall impact on plant dynamics than timber treatment, which had minimal impact. Grazing pressure had a large impact on H. contortus dynamics, an intermediate impact on B. ewartiana and no impact on C. fallax. Fluctuations in plant density of both B. ewartiana and C. fallax were small because both species were long lived with low levels of seedling recruitment and plant death, whereas fluctuations in H. contortus density were relatively high because of its relatively short life span and higher levels of both recruitment and death. Heavy grazing pressure increased the recruitment of B. ewartiana and H. contortus in some years but had no impact on that of C. fallax. Heavy grazing pressure reduced the survival of the original plants of both B. ewartiana and H.contortus but not of C. fallax. For H. contortus, the size of the original plants was larger where trees were killed than where trees were left intact and plants of the 1995 seedling cohort were larger in 1998 at heavy compared with those at light and medium grazing pressure. Grazing had a minor negative impact on the soil seed bank of H. contortus. Populations of all three species remained stable throughout this study, although the favourable seasonal rainfall experienced and the short duration of this study relative to the life span of these species may have masked longer term, deleterious impacts of heavy grazing pressure.

Impacts of grazing management options on pasture and animal productivity in a Heteropogon contortus (black speargrass) pasture in central Queensland. 3. Diet composition in autumn

The diet selected in autumn by steers fistulated at the oesophageous was studied in a subset of treatments in an extensive grazing study conducted in a Heteropogon contortus pasture in central Queensland between 1988 and 2001. These treatments were a factorial array of three stocking rates (4, 3 and 2 ha/steer) and three pasture types (native pasture, legume-oversown native pasture and animal diet supplement/spring-burning native pasture). Seasonal rainfall throughout this study was below the long-term mean and mean annual pasture utilisation ranged from 30 to 61%. Steers consistently selected H. contortus with levels decreasing from 47 to 18% of the diet as stocking rate increased from 4 ha/steer to 2 ha/steer. Stylosanthes scabra cv. Seca was always selected in legume-oversown pastures with diet composition varying from 35 to 66% despite its plant density increasing from 7 to 65 plants/m(2) and pasture composition from 20 to 50%. Steers also selected a diet containing Chrysopogon fallax, forbs and sedges in higher proportions than they were present in the pasture. Greater availability of the intermediate grasses Chloris divaricata and Eragrostis spp. was associated with increased stocking rates. Bothriochloa bladhii was seldom selected in the diet, especially when other palatable species were present in the pasture, despite B. bladhii often being the major contributor to total pasture yield. It was concluded that a stocking rate of 4 ha/steer will maintain the availability of H. contortus in the pasture.

Impacts of grazing management options on pasture and animal productivity in a Heteropogon contortus (black speargrass) pasture in central Queensland. 2. Population dynamics of Heteropogon contortus and Stylosanthes scabra cv. Seca.

The dynamics of Heteropogon contortus and Stylosanthes scabra cv. Seca populations were studied in a subset of treatments in an extensive grazing study conducted in central Queensland between 1988 and 2001. These treatments were 4 stocking rates in native pasture and 2 of these stocking rates in legume oversown and supplement/spring burning treatments. For the 1999-2000 summer, population data for H. contortus in 5 of these native pasture and supplement/burning treatments were compared with those for an additional burnt treatment. Seasonal rainfall throughout this study was below the long-term mean and mean annual pasture utilisation ranged from 24 to 61%. Increasing stocking rate from 5 to 2 ha/steer in native pasture reduced H. contortus plant density. Increasing stocking rate reduced seedling recruitment as a result of its effect on soil seedbanks. Seedling recruitment was the major determinant of change in plant density, although some individual H. contortus plants did survive throughout the study. Burning in spring 1999, particularly at light stocking rate, promoted seedling recruitment above that in both unburnt native and legume oversown pasture and resulted in increased H. contortus plant density. In the legume oversown treatments, S. scabra cv. Seca density increased rapidly from 15 plants/m2 in 1988 to 140 plants/m2 in 2001 following a lag phase between 1988 and 1993. This increased S. scabra density was associated with an eventual decline in H. contortus plant density through reduced seedling recruitment. It was concluded that H. contortus population density is sustainable at stocking rates of 4 and 5 ha/steer (30% pasture utilisation) and that spring burning at light stocking rate can promote H. contortus populations. Increasing densities of S. scabra need to be managed to prevent its dominance.

On the origin of the inflectional instability of a laminar separation bubble

This is an experimental and theoretical Study of a laminar separation bubble and the associated linear stability mechanisms. Experiments were performed over a flat plate kept in a wind tunnel, with an imposed pressure gradient typical of an aerofoil that would involve a laminar separation bubble. The separation bubble was characterized by measurement of surface-pressure distribution and streamwise velocity using hot-wire anemometry. Single component hot-wire anemometry was also used for a detailed study of the transition dynamics. It was foundthat the so-called dead-air region in the front portion of the bubble corresponded to a region of small disturbance amplitudes, with the amplitude reaching a maximum value close to the reattachment point. An exponential growth rate of the disturbance was seen in the region upstream of the mean maximum height of the bubble, and this was indicative of a linear instability mechanism at work. An infinitesimal disturbance was impulsively introduced into the boundary layer upstream of separation location, and the wave packet was tracked (in an ensemble-averaged sense) while it was getting advected downstream. The disturbance was found to be convective in nature. Linear stability analyses (both the Orr-Sommerfeld and Rayleigh calculations) were performed for mean velocity profiles, starting from an attached adverse-pressure-gradient boundary layer all the way up to the front portion of the separation-bubble region (i.e. up to the end of the dead-air region in which linear evolution of the disturbance could be expected). The conclusion from the present work is that the primary instability mechanism in a separation bubble is inflectional in nature, and its origin can be traced back to upstream of the separation location. In other words, the inviscid inflectional instability of the separated shear layer should be logically seen as an extension of the instability of the upstream attached adverse-pressure-gradient boundary layer. This modifies the traditional view that pegs the origin of the instability in a separation bubble to the detached shear layer Outside the bubble, with its associated Kelvin-Helmholtz mechanism. We contendthat only when the separated shear layer has moved considerably away from the wall (and this happens near the maximum-height location of the mean bubble), a description by the Kelvin-Helmholtz instability paradigm, with its associated scaling principles, Could become relevant. We also propose a new scaling for the most amplified frequency for a wall-bounded shear layer in terms of the inflection-point height and the vorticity thickness and show it to be universal.

Genome-wide meta-analysis identifies five new susceptibility loci for cutaneous malignant melanoma

Thirteen common susceptibility loci have been reproducibly associated with cutaneous malignant melanoma (CMM). We report the results of an international 2-stage meta-analysis of CMM genome-wide association studies (GWAS). This meta-analysis combines 11 GWAS (5 previously unpublished) and a further three stage 2 data sets, totaling 15,990 CMM cases and 26,409 controls. Five loci not previously associated with CMM risk reached genome-wide significance (P < 5 × 10−8), as did 2 previously reported but unreplicated loci and all 13 established loci. Newly associated SNPs fall within putative melanocyte regulatory elements, and bioinformatic and expression quantitative trait locus (eQTL) data highlight candidate genes in the associated regions, including one involved in telomere biology.

Managing the grass-legume balance in Stylosanthes scabra cv. Seca pastures in central Queensland

The impacts of 4 grazing strategies (year-long grazing, summer grazing, winter grazing and winter grazing plus spring burning) on the grass:legume balance were studied between 2000 and 2006 in a pasture oversown with Stylosanthes scabra cv. Seca (Seca stylo) in central Queensland. Seasonal rainfall throughout the study was generally below average. Total pasture yields in autumn were higher in the 2 winter grazing than the 2 summer grazing treatments, largely reflecting the sampling time relative to when grazing occurred. There were few differences in Seca composition in autumn, although there was a clear trend for Seca composition to be reduced by winter grazing plus burning. Both the frequency of occurrence and plant density of Seca were higher under the 2 summer grazing treatments and there was also a trend for the density of juvenile plants (<5 cm height) to be higher in the 2 summer grazing treatments. Seca soil seed banks were generally low and were reduced in the winter grazing plus burning treatment in spring 2002. The frequency of the palatable perennial grass Pennisetum ciliaris (Biloela buffel grass) was reduced while that of the 'increaser' species Bothriochloa pertusa (Indian couch grass) and Stachytarpheta jamaicensis (snake weed) increased in the 2 summer grazing treatments compared with the 2 winter grazing treatments. Burning in spring increased soil loss in treatments grazed in winter. Differences in Seca frequency and density but not composition were explained by the 2 summer grazing treatments promoting 'gaps' in the pasture which were then colonised by Seca plants and other 'increaser' species. It was reasoned that, with time, mature Seca plants in the 2 winter grazing treatments would die so that Seca composition would eventually become higher under summer grazing regimes than under winter grazing. It was concluded that limiting grazing to particular seasons can alter legume:grass balance and that a time-frame of 5-8 years with average to good rainfall would be necessary to achieve large shifts in composition.