Mutations in the chromatin modifier gene KANSL1 cause the 17q21.31 microdeletion syndrome

We show that haploinsufficiency of KANSL1 is sufficient to cause the 17q21.31 microdeletion syndrome, a multisystem disorder characterized by intellectual disability, hypotonia and distinctive facial features. The KANSL1 protein is an evolutionarily conserved regulator of the chromatin modifier KAT8, which influences gene expression through histone H4 lysine 16 (H4K16) acetylation. RNA sequencing studies in cell lines derived from affected individuals and the presence of learning deficits in Drosophila melanogaster mutants suggest a role for KANSL1 in neuronal processes.     

Oxidative stress induces angiogenesis by activating TLR2 with novel endogenous ligands

Reciprocity of inflammation, oxidative stress and neovascularization is emerging as an important mechanism underlying numerous processes from tissue healing and remodelling to cancer progression. Whereas the mechanism of hypoxia-driven angiogenesis is well understood, the link between inflammation-induced oxidation and de novo blood vessel growth remains obscure. Here we show that the end products of lipid oxidation, ω-(2-carboxyethyl)pyrrole (CEP) and other related pyrroles, are generated during inflammation and wound healing and accumulate at high levels in ageing tissues in mice and in highly vascularized tumours in both murine and human melanoma. The molecular patterns of carboxyalkylpyrroles are recognized by Toll-like receptor 2 (TLR2), but not TLR4 or scavenger receptors on endothelial cells, leading to an angiogenic response that is independent of vascular endothelial growth factor. CEP promoted angiogenesis in hindlimb ischaemia and wound healing models through MyD88-dependent TLR2 signalling. Neutralization of endogenous carboxyalkylpyrroles impaired wound healing and tissue revascularization and diminished tumour angiogenesis. Both TLR2 and MyD88 are required for CEP-induced stimulation of Rac1 and endothelial migration. Taken together, these findings establish a new function of TLR2 as a sensor of oxidation-associated molecular patterns, providing a key link connecting inflammation, oxidative stress, innate immunity and angiogenesis.     

A germline variant in the TP53 polyadenylation signal confers cancer susceptibility

To identify new risk variants for cutaneous basal cell carcinoma, we performed a genome-wide association study of 16 million SNPs identified through whole-genome sequencing of 457 Icelanders. We imputed genotypes for 41,675 Illumina SNP chip-typed Icelanders and their relatives. In the discovery phase, the strongest signal came from rs78378222[C] (odds ratio (OR) = 2.36, P = 5.2 × 10(-17)), which has a frequency of 0.0192 in the Icelandic population. We then confirmed this association in non-Icelandic samples (OR = 1.75, P = 0.0060; overall OR = 2.16, P = 2.2 × 10(-20)). rs78378222 is in the 3' untranslated region of TP53 and changes the AATAAA polyadenylation signal to AATACA, resulting in impaired 3'-end processing of TP53 mRNA. Investigation of other tumor types identified associations of this SNP with prostate cancer (OR = 1.44, P = 2.4 × 10(-6)), glioma (OR = 2.35, P = 1.0 × 10(-5)) and colorectal adenoma (OR = 1.39, P = 1.6 × 10(-4)). However, we observed no effect for breast cancer, a common Li-Fraumeni syndrome tumor (OR = 1.06, P = 0.57, 95% confidence interval 0.88-1.27).     

Sequence variant on 8q24 confers susceptibility to urinary bladder cancer

We conducted a genome-wide SNP association study on 1,803 urinary bladder cancer (UBC) cases and 34,336 controls from Iceland and The Netherlands and follow up studies in seven additional case-control groups (2,165 cases and 3,800 controls). The strongest association was observed with allele T of rs9642880 on chromosome 8q24, 30 kb upstream of MYC (allele-specific odds ratio (OR) = 1.22; P = 9.34 x 10(-12)). Approximately 20% of individuals of European ancestry are homozygous for rs9642880[T], and their estimated risk of developing UBC is 1.49 times that of noncarriers. No association was observed between UBC and the four 8q24 variants previously associated with prostate, colorectal and breast cancers, nor did rs9642880 associate with any of these three cancers. A weaker signal, but nonetheless of genome-wide significance, was captured by rs710521[A] located near TP63 on chromosome 3q28 (allele-specific OR = 1.19; P = 1. 15 x 10(-7)).     

ASIP and TYR pigmentation variants associate with cutaneous melanoma and basal cell carcinoma

Fair color increases risk of cutaneous melanoma (CM) and basal cell carcinoma (BCC). Recent genome-wide association studies have identified variants affecting hair, eye and skin pigmentation in Europeans. Here, we assess the effect of these variants on risk of CM and BCC in European populations comprising 2,121 individuals with CM, 2,163 individuals with BCC and over 40,000 controls. A haplotype near ASIP, known to affect a similar spectrum of pigmentation traits as MC1R variants, conferred significant risk of CM (odds ratio (OR) = 1.45, P = 1.2 x 10(-9)) and BCC (OR = 1.33, P = 1.2 x 10(-6)). The variant in TYR encoding the R402Q amino acid substitution, previously shown to affect eye color and tanning response, conferred risk of CM (OR = 1.21, P = 2.8 x 10(-7)) and BCC (OR = 1.14, P = 6.1 x 10(-4)). An eye color variant in TYRP1 was associated with risk of CM (OR = 1.15, P = 4.6 x 10(-4)). The association of all three variants is robust with respect to adjustment for the effect of pigmentation.     

Estimating and Predicting the General Random Effects Model

This paper extends the ‘remarkable property’ of Breusch (Journal of Econometrics 1987; 36 : 383–389) and Baltagi and Li (Journal of Econometrics 1992; 53 : 45–51) to the three‐way random components framework. Indeed, like its one‐way and two‐way counterparts, the three‐way random effects model maximum likelihood estimation can be obtained as an iterated generalized least squares procedure through an appropriate algorithm of monotonic sequences of some variance components ratios, θ_i (i = 2, 3, 4). More specifically, a search over θ_iwhile iterating on the regression coefficients estimates β and the other θ_jwill guard against the possibility of multiple local maxima of the likelihood function. In addition, the derivations of related prediction functions are obtained based on complete as well as incomplete panels. Finally, an application to international trade issues modeling is presented. Copyright © 2014 John Wiley & Sons, Ltd.     

Anthropogenically enhanced fluxes of water and carbon from the Mississippi River

The water and dissolved inorganic carbon exported by rivers are important net fluxes that connect terrestrial and oceanic water and carbon reservoirs. For most rivers, the majority of dissolved inorganic carbon is in the form of bicarbonate. The riverine bicarbonate flux originates mainly from the dissolution of rock minerals by soil water carbon dioxide, a process called chemical weathering, which controls the buffering capacity and mineral content of receiving streams and rivers. Here we introduce an unprecedented high-temporal-resolution, 100-year data set from the Mississippi River and couple it with sub-watershed and precipitation data to reveal that the large increase in bicarbonate flux that has occurred over the past 50 years (ref. 3) is clearly anthropogenically driven. We show that the increase in bicarbonate and water fluxes is caused mainly by an increase in discharge from agricultural watersheds that has not been balanced by a rise in precipitation, which is also relevant to nutrient and pesticide fluxes to the Gulf of Mexico. These findings demonstrate that alterations in chemical weathering are relevant to improving contemporary biogeochemical budgets. Furthermore, land use change and management were arguably more important than changes in climate and plant CO2 fertilization to increases in riverine water and carbon export from this large region over the past 50 years.