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Galaxies observed at redshift z > 6, when the Universe was less than a billion years old, thus far very rarely show evidence (1-3) of the cold dust that accompanies [...]

The under-abundance of very massive galaxies (1,2) in the Universe is frequently attributed to the effect of galactic winds (3-6). Although ionized galactic winds are readily observable, most of the [...]

People with pale skin, red hair, freckles and an inability to tan--the 'red hair/fair skin' phenotype--are at highest risk of developing melanoma, compared to all other pigmentation types (1). Genetically, [...]

Sea ice cover in the Arctic has been steadily decreasing over recent decades, with record losses in recent years (1,2). The late-summer ice cover, mainly composed of thick multi-year ice, [...], Arctic sea ice extent is now more than two million square kilometres less than it was in the late twentieth century, with important consequences for the climate, the ocean and traditional lifestyles in the Arctic (1,2). Although observations show a more or less continuous decline for the past four or five decades (3,4), there are few long-term records with which to assess natural sea ice variability. Until now, the question of whether or not current trends are potentially anomalous (5) has therefore remained unanswerable. Here we use a network of high-resolution terrestrial proxies from the circum-Arctic region to reconstruct past extents of summer sea ice, and show that--although extensive uncertainties remain, especially before the sixteenth century--both the duration and magnitude of the current decline in sea ice seem to be unprecedented for the past 1,450 years. Enhanced advection of warm Atlantic water to the Arctic (6) seems to be the main factor driving the decline of sea ice extent on multidecadal timescales, and may result from nonlinear feedbacks between sea ice and the Atlantic meridional overturning circulation. These results reinforce the assertion that sea ice is an active component of Arctic climate variability and that the recent decrease in summer Arctic sea ice is consistent with anthropogenically forced warming.

Cellular growth, proliferation and survival are regulated by a complex network of intracellular and extracellular signal transduction cascades. The growth-factor-responsive receptor tyrosine kinase (RTK)-phosphatidylinositol-3-kinase (PI3K) pathway has an important role [...], Genome-wide copy number analyses of human cancers identified a frequent 5p13 amplification in several solid tumour types, including lung (56%), ovarian (38%), breast (32%), prostate (37%) and melanoma (32%). Here, using integrative analysis of a genomic profile of the region, we identify a Golgi protein, GOLPH3, as a candidate targeted for amplification. Gain- and loss-of-function studies in vitro and in vivo validated GOLPH3 as a potent oncogene. Physically, GOLPH3 localizes to the trans-Golgi network and interacts with components of the retromer complex, which in yeast has been linked to target of rapamycin (TOR) signalling. Mechanistically, GOLPH3 regulates cell size, enhances growth-factor-induced mTOR (also known as FRAP1) signalling in human cancer cells, and alters the response to an mTOR inhibitor in vivo. Thus, genomic and genetic, biological, functional and biochemical data in yeast and humans establishes GOLPH3 as a new oncogene that is commonly targeted for amplification in human cancer, and is capable of modulating the response to rapamycin, a cancer drug in clinical use.

Author(s): Robert T. Manguso [1, 2, 3]; Hans W. Pope [1, 3]; Margaret D. Zimmer [1, 3]; Flavian D. Brown [1, 2]; Kathleen B. Yates [1, 3]; Brian C. Miller [...], Immunotherapy with PD-1 checkpoint blockade is effective in only a minority of patients with cancer, suggesting that additional treatment strategies are needed. Here we use a pooled in vivo genetic screening approach using CRISPRCas9 genome editing in transplantable tumours in mice treated with immunotherapy to discover previously undescribed immunotherapy targets. We tested 2,368 genes expressed by melanoma cells to identify those that synergize with or cause resistance to checkpoint blockade. We recovered the known immune evasion molecules PD-L1 and CD47, and confirmed that defects in interferon- signalling caused resistance to immunotherapy. Tumours were sensitized to immunotherapy by deletion of genes involved in several diverse pathways, including NF-B signalling, antigen presentation and the unfolded protein response. In addition, deletion of the protein tyrosine phosphatase PTPN2 in tumour cells increased the efficacy of immunotherapy by enhancing interferon--mediated effects on antigen presentation and growth suppression. In vivo genetic screens in tumour models can identify new immunotherapy targets in unanticipated pathways.

Author(s): Jennifer Y. Lin [1, 2]; David E. Fisher [2] Melanocytes can absorb ultraviolet radiation (UVR) and survive considerable genotoxic stress. The skin is the main barrier to the external [...]

Author(s): John A. D'Orazio [1, 2, 3]; Tetsuji Nobuhisa [1, 2]; Rutao Cui [1, 2]; Michelle Arya [1, 2]; Malinda Spry [3]; Kazumasa Wakamatsu [4]; Vivien Igras [1, 2]; Takahiro [...]

Author(s): Levi A. Garraway [1, 3]; Hans R. Widlund [1]; Mark A. Rubin [2, 3]; Gad Getz [5]; Aaron J. Berger [6]; Sridhar Ramaswamy [5, 7]; Rameen Beroukhim [1, 3]; [...]

Microphthalmia (Mi) is a transcription factor of the basic, helix-loop-helix, leucine-zipper (bHLHzip) type, mutations of which can lead to Waardenburg Syndrome type II. It is suggested that Sl, c-Kit and Mi function with a common growth or differentiation pathway. A human melanoma cell line was studied using Western blot analysis, revealing two Mi species having mobilities corresponding to molecular masses of 54K and 60K.