Precipitation extremes have implications for many facets of both the human and natural systems, predominantly through flooding events. Observations have demonstrated increasing trends in extreme ...precipitation in North America, and models and theory consistently suggest continued increases with future warming. Here, we address the question of whether observed changes in annual maximum 1- and 5-d precipitation can be attributed to human influence on the climate. Although attribution has been demonstrated for global and hemispheric scales, there are few results for continental and subcontinental scales. We utilize three large ensembles, including simulations from both a fully coupled Earth system model and a regional climate model. We use two different attribution approaches and find many qualitatively consistent results across different methods, different models, and different regional scales. We conclude that external forcing, dominated by human influence, has contributed to the increase in frequency and intensity of regional precipitation extremes in North America. If human emissions continue to increase, North America will see further increases in these extremes.
Arctic sea ice extent (SIE) has decreased over recent decades, with record-setting minimum events in 2007 and again in 2012. A question of interest across many disciplines concerns the extent to ...which such extreme events can be attributed to anthropogenic influences. First, a detection and attribution analysis is performed for trends in SIE anomalies over the observed period. The main objective of this study is an event attribution analysis for extreme minimum events in Arctic SIE. Although focus is placed on the 2012 event, the results are generalized to extreme events of other magnitudes, including both past and potential future extremes. Several ensembles of model responses are used, including two single-model large ensembles. Using several different metrics to define the events in question, it is shown that an extreme SIE minimum of the magnitude seen in 2012 is consistent with a scenario including anthropogenic influence and is extremely unlikely in a scenario excluding anthropogenic influence. Hence, the 2012 Arctic sea ice minimum provides a counterexample to the often-quoted idea that individual extreme events cannot be attributed to human influence.
Celotno besedilo
Dostopno za:
BFBNIB, DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Although the West Antarctic surface climate has experienced large changes over the past decades with widespread surface warming, an overall increase in snow accumulation and a deepening of the ...Amundsen Sea Low, the exact role of human activities in these changes has not yet been fully investigated, which limits confidence in future projections. Here, we perform a detection and attribution analysis using instrumental and proxy‐based reconstructions, and two large climate model simulation ensembles to quantify the forced response in these observed changes. We show that surface climate changes since the 1950s were driven by anthropogenic forcing, in particular the greenhouse gas forcing and stratospheric ozone depletion. Therefore, our results indicate that the 21st century changes will depend on both the greenhouse gas emissions and the ozone layer recovery.
Plain Language Summary
Since the second half of the 20th century, West Antarctica has experienced large climate changes, such as widespread warming, increased snow accumulation, and a deepening of a low‐pressure system located off the West Antarctic coasts. The observed climate changes in West Antarctica are influenced by both the internal (related to the chaotic nature of climate) and forced (related to changes in forcings) variability but it is still unclear to what extent human activities are responsible for these changes. We used a statistical method to distinguish between changes caused by humans and by natural influences both for instrumental observations and reconstructions of past climate. Our results show that the observed changes since the 1950s are out of the range of natural variability and can be attributed to human activities—that is, the increase of greenhouse gases and stratospheric ozone depletion. Therefore, our findings indicate that the future state of the West Antarctic surface climate will depend on the greenhouse gas emissions as well as the ozone layer recovery.
Key Points
Surface climate changes since the 1950s in West Antarctica are out of the range of internal variability
The increase in greenhouse gas emissions and stratospheric ozone depletion are responsible for these changes
The future changes over the 21st century will depend on both the greenhouse gas emissions and the ozone layer recovery
Pancreatic ductal adenocarcinoma (PDA) is one of the most lethal human malignancies, owing in part to its propensity for metastasis. Here, we used an organoid culture system to investigate how ...transcription and the enhancer landscape become altered during discrete stages of disease progression in a PDA mouse model. This approach revealed that the metastatic transition is accompanied by massive and recurrent alterations in enhancer activity. We implicate the pioneer factor FOXA1 as a driver of enhancer activation in this system, a mechanism that renders PDA cells more invasive and less anchorage-dependent for growth in vitro, as well as more metastatic in vivo. In this context, FOXA1-dependent enhancer reprogramming activates a transcriptional program of embryonic foregut endoderm. Collectively, our study implicates enhancer reprogramming, FOXA1 upregulation, and a retrograde developmental transition in PDA metastasis.
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•Recurrent changes in enhancer activity are associated with PDA metastasis•FOXA1 drives enhancer reprograming during PDA progression•Manipulation of FOXA1 in PDA cells alters enhancer activity and disease aggressiveness•FOXA1 drives an aberrant developmental transition in PDA toward embryonic endoderm
Large-scale enhancer reprogramming directed by transcription factors such as FOXA1 drives metastasis in the organoid model of pancreatic cancer.
Despite the remarkable success of immune checkpoint blockade (ICB) therapy, most cancer patients still do not respond. We now find that immunotherapy can induce stem-like properties in tumors. Using ...mouse models of breast cancer, we observe that cancer stem cells (CSCs) show not only enhanced resistance to T cell cytotoxicity, but that interferon gamma (IFNγ) produced by activated T cells directly converts non-CSCs to CSCs. IFNγ enhances several CSC phenotypes, such as resistance to chemo- and radiotherapy and metastasis formation. We identified the branched-chain amino acid aminotransaminase 1 (BCAT1) as a downstream mediator of IFNγ-induced CSC plasticity. Targeting BCAT1 in vivo improved cancer vaccination and ICB therapy by preventing IFNγ-induced metastasis formation. Breast cancer patients treated with ICB exhibited a similar increase in CSC markers expression indicating comparable responses to immune activation in humans. Collectively, we discover an unexpected, pro-tumoral role for IFNγ that may contribute to cancer immunotherapy failure.
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•IFNγ increases CSC content by converting non-CSCs to CSCs•BCAT1 is a downstream mediator of IFNγ-mediated CSC plasticity•Targeting BCAT1 improves cancer immunotherapy•CSCs have enhanced resistance to T cell cytotoxicity
Beziaud and colleagues report that IFNγ produced by T cells enhances cancer cell plasticity, which promotes metastasis formation in pre-clinical models and correlates with a cancer stem cell signature in cancer patients treated with immunotherapy. Inhibiting BCAT1 blocks this cancer plasticity without affecting the IFNγ pro-inflammatory effects essential for immunotherapy success.
Abstract
Understanding the mechanisms that enable cancer cells to metastasize is essential in preventing cancer progression. Here we examine the metabolic adaptations of metastasis-initiating cells ...(MICs) in female breast cancer and how those shape their metastatic phenotype. We find that endogenous MICs depend on the oxidative tricarboxylic acid cycle and fatty acid usage. Sorting tumor cells based upon solely mitochondrial membrane potential or lipid storage is sufficient at identifying MICs. We further identify that mitochondrially-generated citrate is exported to the cytoplasm to yield acetyl-CoA, and this is crucial to maintaining heightened levels of H3K27ac in MICs. Blocking acetyl-CoA generating pathways or H3K27ac-specific epigenetic writers and readers reduces expression of epithelial-to-mesenchymal related genes, MIC frequency, and metastatic potential. Exogenous supplementation of a short chain carboxylic acid, acetate, increases MIC frequency and metastasis. In patient cohorts, we observe that higher expression of oxidative phosphorylation related genes is associated with reduced distant relapse-free survival. These data demonstrate that MICs specifically and precisely alter their metabolism to efficiently colonize distant organs.
ABSTRACT We present high-resolution rotation curves and mass models of 26 dwarf galaxies from "Local Irregulars That Trace Luminosity Extremes, The H i Nearby Galaxy Survey" (LITTLE THINGS). LITTLE ...THINGS is a high-resolution (∼6″ angular; <2.6 km s−1 velocity resolution) Very Large Array H i survey for nearby dwarf galaxies in the local volume within 11 Mpc. The high-resolution H i observations enable us to derive reliable rotation curves of the sample galaxies in a homogeneous and consistent manner. The rotation curves are then combined with Spitzer archival 3.6 m and ancillary optical U, B, and V images to construct mass models of the galaxies. This high quality multi-wavelength data set significantly reduces observational uncertainties and thus allows us to examine the mass distribution in the galaxies in detail. We decompose the rotation curves in terms of the dynamical contributions by baryons and dark matter (DM) halos, and compare the latter with those of dwarf galaxies from THINGS as well as ΛCDM Smoothed Particle Hydrodynamic (SPH) simulations in which the effect of baryonic feedback processes is included. Being generally consistent with THINGS and simulated dwarf galaxies, most of the LITTLE THINGS sample galaxies show a linear increase of the rotation curve in their inner regions, which gives shallower logarithmic inner slopes of their DM density profiles. The mean value of the slopes of the 26 LITTLE THINGS dwarf galaxies is which is in accordance with the previous results found for low surface brightness galaxies ( ) as well as the seven THINGS dwarf galaxies ( ). However, this significantly deviates from the cusp-like DM distribution predicted by DM-only ΛCDM simulations. Instead our results are more in line with the shallower slopes found in the ΛCDM SPH simulations of dwarf galaxies in which the effect of baryonic feedback processes is included. In addition, we discuss the central DM distribution of DDO 210 whose stellar mass is relatively low in our sample to examine the scenario of inefficient supernova feedback in low mass dwarf galaxies predicted from recent ΛCDM SPH simulations of dwarf galaxies where central cusps still remain.
Canada is expected to see an increase in fire risk under future climate projections. Large fires, such as that near Fort McMurray, Alberta in 2016, can be devastating to the communities affected. ...Understanding the role of human emissions in the occurrence of such extreme fire events can lend insight into how these events might change in the future. An event attribution framework is used to quantify the influence of anthropogenic forcings on extreme fire risk in the current climate of a western Canada region. Fourteen metrics from the Canadian Forest Fire Danger Rating System are used to define the extreme fire seasons. For the majority of these metrics and during the current decade, the combined effect of anthropogenic and natural forcing is estimated to have made extreme fire risk events in the region 1.5 to 6 times as likely compared to a climate that would have been with natural forcings alone.
A broad range of animals use visual signals to assess potential mates, and the theory of sensory exploitation suggests variation in visual systems drives mate preference variation due to sensory ...bias. Trinidadian guppies (Poecilia reticulata), a classic system for studies of the evolution of female mate choice, provide a unique opportunity to test this theory by looking for covariation in visual tuning, light environment and mate preferences. Female preference co‐evolves with male coloration, such that guppy females from ‘low‐predation’ environments have stronger preferences for males with more orange/red coloration than do females from ‘high‐predation’ environments. Here, we show that colour vision also varies across populations, with ‘low’‐predation guppies investing more of their colour vision to detect red/orange coloration. In independently colonized watersheds, guppies expressed higher levels of both LWS‐1 and LWS‐3 (the most abundant LWS opsins) in ‘low‐predation’ populations than ‘high‐predation’ populations at a time that corresponds to differences in cone cell abundance. We also observed that the frequency of a coding polymorphism differed between high‐ and low‐predation populations. Together, this shows that the variation underlying preference could be explained by simple changes in expression and coding of opsins, providing important candidate genes to investigate the genetic basis of female preference variation in this model system.
The spatial presentation of immobilized extracellular matrix (ECM) cues and matrix mechanical properties play an important role in directed and guided cell behavior and neovascularization. The goal ...of this work was to explore whether gradients of elastic modulus, immobilized matrix metalloproteinase (MMP)-sensitivity, and YRGDS cell adhesion ligands are capable of directing 3D vascular sprout formation in tissue engineered scaffolds. PEGDA hydrogels were engineered with mechanical and biofunctional gradients using perfusion-based frontal photopolymerization (PBFP). Bulk photopolymerized hydrogels with uniform mechanical properties, degradation, and immobilized biofunctionality served as controls. Gradient hydrogels exhibited an 80.4% decrease in elastic modulus and a 56.2% decrease in immobilized YRGDS. PBFP hydrogels also demonstrated gradients in hydrogel degradation with degradation times ranging from 10-12 hours in the more crosslinked regions to 4-6 hours in less crosslinked regions. An in vitro model of neovascularization, composed of co-culture aggregates of endothelial and smooth muscle cells, was used to evaluate the effect of these gradients on vascular sprout formation. Aggregate invasion in gradient hydrogels occurred bi-directionally with sprout alignment observed in the direction parallel to the gradient while control hydrogels with homogeneous properties resulted in uniform invasion. In PBFP gradient hydrogels, aggregate sprout length was found to be twice as long in the direction parallel to the gradient as compared to the perpendicular direction after three weeks in culture. This directionality was found to be more prominent in gradient regions of increased stiffness, crosslinked MMP-sensitive peptide presentation, and immobilized YRGDS concentration.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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