A di-arginine ER retention signal regulates trafficking of HCN1 channels from the early secretory pathway to the plasma membrane

Hyperpolarization-activated cyclic nucleotide-gated 1 (HCN1) channels carry I_h, which contributes to neuronal excitability and signal transmission in the nervous system. Controlling the trafficking of HCN1 is an important aspect of its regulation, yet the details of this process are poorly understood. Here, we investigated how the C-terminus of HCN1 regulates trafficking by testing for its ability to redirect the localization of a non-targeted reporter in transgenic Xenopus laevis photoreceptors. We found that HCN1 contains an ER localization signal and through a series of deletion constructs, identified the responsible di-arginine ER retention signal. This signal is located in the intrinsically disordered region of the C-terminus of HCN1. To test the function of the ER retention signal in intact channels, we expressed wild type and mutant HCN1 in HEK293 cells and found this signal negatively regulates surface expression of HCN1. In summary, we report a new mode of regulating HCN1 trafficking: through the use of a di-arginine ER retention signal that monitors processing of the channel in the early secretory pathway.     

CpG island methylator phenotype underlies sporadic microsatellite instability and is tightly associated with BRAF mutation in colorectal cancer

Aberrant DNA methylation of CpG islands has been widely observed in human colorectal tumors and is associated with gene silencing when it occurs in promoter areas. A subset of colorectal tumors has an exceptionally high frequency of methylation of some CpG islands, leading to the suggestion of a distinct trait referred to as 'CpG island methylator phenotype', or 'CIMP'. However, the existence of CIMP has been challenged. To resolve this continuing controversy, we conducted a systematic, stepwise screen of 195 CpG island methylation markers using MethyLight technology, involving 295 primary human colorectal tumors and 16,785 separate quantitative analyses. We found that CIMP-positive (CIMP+) tumors convincingly represent a distinct subset, encompassing almost all cases of tumors with BRAF mutation (odds ratio = 203). Sporadic cases of mismatch repair deficiency occur almost exclusively as a consequence of CIMP-associated methylation of MLH1 . We propose a robust new marker panel to classify CIMP+ tumors.     

A dynamical calibration of the mass-luminosity relation at very low stellar masses and young ages

Mass is the most fundamental parameter of a star, yet it is also one of the most difficult to measure directly. In general, astronomers estimate stellar masses by determining the luminosity and using the 'mass-luminosity' relationship, but this relationship has never been accurately calibrated for young, low-mass stars and brown dwarfs. Masses for these low-mass objects are therefore constrained only by theoretical models. A new high-contrast adaptive optics camera enabled the discovery of a young (50 million years) companion only 0.156 arcseconds (2.3 au) from the more luminous (> 120 times brighter) star AB Doradus A. Here we report a dynamical determination of the mass of the newly resolved low-mass companion AB Dor C, whose mass is 0.090 +/- 0.005 solar masses. Given its measured 1-2-micrometre luminosity, we have found that the standard mass-luminosity relations overestimate the near-infrared luminosity of such objects by about a factor of approximately 2.5 at young ages. The young, cool objects hitherto thought to be substellar in mass are therefore about twice as massive, which means that the frequency of brown dwarfs and planetary mass objects in young stellar clusters has been overestimated.     

Genomic screening and replication using the same data set in family-based association testing

The Human Genome Project and its spin-offs are making it increasingly feasible to determine the genetic basis of complex traits using genome-wide association studies. The statistical challenge of analyzing such studies stems from the severe multiple-comparison problem resulting from the analysis of thousands of SNPs. Our methodology for genome-wide family-based association studies, using single SNPs or haplotypes, can identify associations that achieve genome-wide significance. In relation to developing guidelines for our screening tools, we determined lower bounds for the estimated power to detect the gene underlying the disease-susceptibility locus, which hold regardless of the linkage disequilibrium structure present in the data. We also assessed the power of our approach in the presence of multiple disease-susceptibility loci. Our screening tools accommodate genomic control and use the concept of haplotype-tagging SNPs. Our methods use the entire sample and do not require separate screening and validation samples to establish genome-wide significance, as population-based designs do.     

Epigenetic stem cell signature in cancer

Embryonic stem cells rely on Polycomb group proteins to reversibly repress genes required for differentiation. We report that stem cell Polycomb group targets are up to 12-fold more likely to have cancer-specific promoter DNA hypermethylation than non-targets, supporting a stem cell origin of cancer in which reversible gene repression is replaced by permanent silencing, locking the cell into a perpetual state of self-renewal and thereby predisposing to subsequent malignant transformation.     

Rainfall and drought in equatorial east Africa during the past 1,100 years

Knowledge of natural long-term rainfall variability is essential for water-resource and land-use management in sub-humid regions of the world. In tropical Africa, data relevant to determining this variability are scarce because of the lack of long instrumental climate records and the limited potential of standard high-resolution proxy records such as tree rings and ice cores. Here we present a decade-scale reconstruction of rainfall and drought in equatorial east Africa over the past 1,100 years, based on lake-level and salinity fluctuations of Lake Naivasha (Kenya) inferred from three different palaeolimnological proxies: sediment stratigraphy and the species compositions of fossil diatom and midge assemblages. Our data indicate that, over the past millennium, equatorial east Africa has alternated between contrasting climate conditions, with significantly drier climate than today during the 'Medieval Warm Period' (approximately AD 1000-1270) and a relatively wet climate during the 'Little Ice Age' (approximately AD 1270-1850) which was interrupted by three prolonged dry episodes. We also find strong chronological links between the reconstructed history of natural long-term rainfall variation and the pre-colonial cultural history of east Africa, highlighting the importance of a detailed knowledge of natural long-term rainfall fluctuations for sustainable socio-economic development.