Proper Protein Glycosylation Promotes Mitogen-Activated Protein Kinase Signal Fidelity

The ability of cells to sense and respond appropriately to changing environmental conditions is often mediated by signal transduction pathways that employ mitogen-activated protein kinases (MAPKs). In the yeast Saccharomyces cerevisiae, the high osmolarity glycerol (HOG) and the filamentous growth (FG) pathways are activated following hyperosmotic stress and nutrient deprivation, respectively. Whereas the HOG pathway requires the MAPK Hog1, the FG pathway employs the MAPK Kss1. We conducted a comprehensive screen of nearly 5,000 gene deletion strains for mutants that exhibit inappropriate cross-talk between the HOG and FG pathways. We identified two novel mutants, mnn10Δ and mnn11Δ, that allow activation of Kss1 under conditions that normally stimulate Hog1. MNN10 and MNN11 encode mannosyltransferases that are part of the N-glycosylation machinery within the Golgi apparatus; deletion of either gene results in N-glycosylated proteins that have shorter mannan chains. Deletion of the cell surface mucin Msb2 suppressed the mnn11Δ phenotype, while mutation of a single glycosylation site within Msb2 was sufficient to confer inappropriate activation of Kss1 by salt stress. These findings reveal new components of the N-glycosylation machinery needed to ensure MAPK signaling fidelity

Warming threat compounds habitat degradation impacts on a tropical butterfly community in Vietnam

AbstractSpecies are threatened globally by multiple and often synergistic environmental changes including habitat loss, fragmentation and climate change. However, how these changes act in concert is poorly understood, especially in the tropics where the vast majority of biodiversity resides. Here, using a unique dataset covering 10~years of butterfly surveys (2003–2013) at Tam Dao National Park in northern Vietnam, we examined the combined impacts of habitat degradation (following intensive infrastructure development in 2005) and the possible threat of warming (extrapolating upon the relationship between natural climatic variation and community indices) for tropical butterfly communities. We found that both habitat degradation and warmer temperatures led to fewer narrow-range and forest-associated species comprising the sampled communities. Under projected climate change scenarios, the impact of warming was comparable to habitat degradation with respect to community change, and degraded forest communities were projected to shift towards cosmopolitan and non-forest species even more. The tropics have been heavily deforested world-wide and also suffer from heavy impacts of degradation and fragmentation, especially road construction. Warming will compound habitat degradation impacts such that the conservation of tropical biodiversity will require addressing these multiple global changes simultaneously

Probing the extragalactic fast transient sky at minute timescales with DECam

Searches for optical transients are usually performed with a cadence of days to weeks, optimised for supernova discovery. The optical fast transient sky is still largely unexplored, with only a few surveys to date having placed meaningful constraints on the detection of extragalactic transients evolving at sub-hour timescales. Here, we present the results of deep searches for dim, minute-timescale extragalactic fast transients using the Dark Energy Camera, a core facility of our all-wavelength and all-messenger Deeper, Wider, Faster programme. We used continuous 20s exposures to systematically probe timescales down to 1.17 minutes at magnitude limits $g > 23$ (AB), detecting hundreds of transient and variable sources. Nine candidates passed our strict criteria on duration and non-stellarity, all of which could be classified as flare stars based on deep multi-band imaging. Searches for fast radio burst and gamma-ray counterparts during simultaneous multi-facility observations yielded no counterparts to the optical transients. Also, no long-term variability was detected with pre-imaging and follow-up observations using the SkyMapper optical telescope. We place upper limits for minute-timescale fast optical transient rates for a range of depths and timescales. Finally, we demonstrate that optical $g$-band light curve behaviour alone cannot discriminate between confirmed extragalactic fast transients such as prompt GRB flashes and Galactic stellar flares.Comment: Published in MNRA

MSC-Regulated MicroRNAs Converge on the Transcription Factor FOXP2 and Promote Breast Cancer Metastasis

SummaryMesenchymal stem/stromal cells (MSCs) are progenitor cells shown to participate in breast tumor stroma formation and to promote metastasis. Despite expanding knowledge of their contributions to breast malignancy, the underlying molecular responses of breast cancer cells (BCCs) to MSC influences remain incompletely understood. Here, we show that MSCs cause aberrant expression of microRNAs, which, led by microRNA-199a, provide BCCs with enhanced cancer stem cell (CSC) properties. We demonstrate that such MSC-deregulated microRNAs constitute a network that converges on and represses the expression of FOXP2, a forkhead transcription factor tightly associated with speech and language development. FOXP2 knockdown in BCCs was sufficient in promoting CSC propagation, tumor initiation, and metastasis. Importantly, elevated microRNA-199a and depressed FOXP2 expression levels are prominent features of malignant clinical breast cancer and are associated significantly with poor survival. Our results identify molecular determinants of cancer progression of potential utility in the prognosis and therapy of breast cancer

Selenoprotein H is an essential regulator of redox homeostasis that cooperates with p53 in development and tumorigenesis

Selenium, an essential micronutrient known for its cancer prevention properties, is incorporated into a class of selenocysteine-containing proteins (selenoproteins). Selenoprotein H (SepH) is a recently identified nucleolar oxidoreductase whose function is not well understood. Here we report that seph is an essential gene regulating organ development in zebrafish. Metabolite profiling by targeted LC-MS/MS demonstrated that SepH deficiency impairs redox balance by reducing the levels of ascorbate and methionine, while increasing methionine sulfoxide. Transcriptome analysis revealed that SepH deficiency induces an inflammatory response and activates the p53 pathway. Consequently, loss of seph renders larvae susceptible to oxidative stress and DNA damage. Finally, we demonstrate that seph interacts with p53 deficiency in adulthood to accelerate gastrointestinal tumor development. Overall, our findings establish that seph regulates redox homeostasis and suppresses DNA damage. We hypothesize that SepH deficiency may contribute to the increased cancer risk observed in cohorts with low selenium levels.National Cancer Institute (U.S.) (Grant R01 DK090311)National Cancer Institute (U.S.) (Grant R24OD017870

Dissecting cell-type-specific metabolism in pancreatic ductal adenocarcinoma.

Tumors are composed of many different cell types including cancer cells, fibroblasts, and immune cells. Dissecting functional metabolic differences between cell types within a mixed population can be challenging due to the rapid turnover of metabolites relative to the time needed to isolate cells. To overcome this challenge, we traced isotope-labeled nutrients into macromolecules that turn over more slowly than metabolites. This approach was used to assess differences between cancer cell and fibroblast metabolism in murine pancreatic cancer organoid-fibroblast co-cultures and tumors. Pancreatic cancer cells exhibited increased pyruvate carboxylation relative to fibroblasts, and this flux depended on both pyruvate carboxylase and malic enzyme 1 activity. Consequently, expression of both enzymes in cancer cells was necessary for organoid and tumor growth, demonstrating that dissecting the metabolism of specific cell populations within heterogeneous systems can identify dependencies that may not be evident from studying isolated cells in culture or bulk tissue

LSST Science Book, Version 2.0

A survey that can cover the sky in optical bands over wide fields to faint magnitudes with a fast cadence will enable many of the exciting science opportunities of the next decade. The Large Synoptic Survey Telescope (LSST) will have an effective aperture of 6.7 meters and an imaging camera with field of view of 9.6 deg^2, and will be devoted to a ten-year imaging survey over 20,000 deg^2 south of +15 deg. Each pointing will be imaged 2000 times with fifteen second exposures in six broad bands from 0.35 to 1.1 microns, to a total point-source depth of r~27.5. The LSST Science Book describes the basic parameters of the LSST hardware, software, and observing plans. The book discusses educational and outreach opportunities, then goes on to describe a broad range of science that LSST will revolutionize: mapping the inner and outer Solar System, stellar populations in the Milky Way and nearby galaxies, the structure of the Milky Way disk and halo and other objects in the Local Volume, transient and variable objects both at low and high redshift, and the properties of normal and active galaxies at low and high redshift. It then turns to far-field cosmological topics, exploring properties of supernovae to z~1, strong and weak lensing, the large-scale distribution of galaxies and baryon oscillations, and how these different probes may be combined to constrain cosmological models and the physics of dark energy.Comment: 596 pages. Also available at full resolution at http://www.lsst.org/lsst/sciboo

Yap reprograms glutamine metabolism to increase nucleotide biosynthesis and enable liver growth

The Hippo pathway is an important regulator of organ size and tumorigenesis. It is unclear, however, how Hippo signaling provides the cellular building blocks required for rapid growth. Here, we demonstrate that transgenic zebrafish expressing an activated form of the Hippo pathway effector Yap1 (also known as YAP) develop enlarged livers and are prone to liver tumor formation. Transcriptomic and metabolomic profiling identify that Yap1 reprograms glutamine metabolism. Yap1 directly enhances glutamine synthetase (glul) expression and activity, elevating steady-state levels of glutamine and enhancing the relative isotopic enrichment of nitrogen during de novo purine and pyrimidine biosynthesis. Genetic or pharmacological inhibition of GLUL diminishes the isotopic enrichment of nitrogen into nucleotides, suppresses hepatomegaly and the growth of liver cancer cells. Consequently, Yap-driven liver growth is susceptible to nucleotide inhibition. Together, our findings demonstrate that Yap1 integrates the anabolic demands of tissue growth during development and tumorigenesis by reprogramming nitrogen metabolism to stimulate nucleotide biosynthesis

Effects of Anacetrapib in Patients with Atherosclerotic Vascular Disease

BACKGROUND: Patients with atherosclerotic vascular disease remain at high risk for cardiovascular events despite effective statin-based treatment of low-density lipoprotein (LDL) cholesterol levels. The inhibition of cholesteryl ester transfer protein (CETP) by anacetrapib reduces LDL cholesterol levels and increases high-density lipoprotein (HDL) cholesterol levels. However, trials of other CETP inhibitors have shown neutral or adverse effects on cardiovascular outcomes. METHODS: We conducted a randomized, double-blind, placebo-controlled trial involving 30,449 adults with atherosclerotic vascular disease who were receiving intensive atorvastatin therapy and who had a mean LDL cholesterol level of 61 mg per deciliter (1.58 mmol per liter), a mean non-HDL cholesterol level of 92 mg per deciliter (2.38 mmol per liter), and a mean HDL cholesterol level of 40 mg per deciliter (1.03 mmol per liter). The patients were assigned to receive either 100 mg of anacetrapib once daily (15,225 patients) or matching placebo (15,224 patients). The primary outcome was the first major coronary event, a composite of coronary death, myocardial infarction, or coronary revascularization. RESULTS: During the median follow-up period of 4.1 years, the primary outcome occurred in significantly fewer patients in the anacetrapib group than in the placebo group (1640 of 15,225 patients [10.8%] vs. 1803 of 15,224 patients [11.8%]; rate ratio, 0.91; 95% confidence interval, 0.85 to 0.97; P=0.004). The relative difference in risk was similar across multiple prespecified subgroups. At the trial midpoint, the mean level of HDL cholesterol was higher by 43 mg per deciliter (1.12 mmol per liter) in the anacetrapib group than in the placebo group (a relative difference of 104%), and the mean level of non-HDL cholesterol was lower by 17 mg per deciliter (0.44 mmol per liter), a relative difference of -18%. There were no significant between-group differences in the risk of death, cancer, or other serious adverse events. CONCLUSIONS: Among patients with atherosclerotic vascular disease who were receiving intensive statin therapy, the use of anacetrapib resulted in a lower incidence of major coronary events than the use of placebo. (Funded by Merck and others; Current Controlled Trials number, ISRCTN48678192 ; ClinicalTrials.gov number, NCT01252953 ; and EudraCT number, 2010-023467-18 .)

Differential cross-section measurements of the production of four charged leptons in association with two jets using the ATLAS detector

Differential cross-sections are measured for the production of four charged leptons in association with two jets. These measurements are sensitive to final states in which the jets are produced via the strong interaction as well as to the purely-electroweak vector boson scattering process. The analysis is performed using proton-proton collision data collected by ATLAS at √s = 13 TeV and with an integrated luminosity of 140 fb−1. The data are corrected for the effects of detector inefficiency and resolution and are compared to state-of-the-art Monte Carlo event generator predictions. The differential cross-sections are used to search for anomalous weak-boson self-interactions that are induced by dimension-six and dimension-eight operators in Standard Model effective field theory