Tumours use various strategies to evade immune surveillance
. Immunotherapies targeting tumour immune evasion such as immune checkpoint blockade have shown considerable efficacy on multiple cancers
...but are ineffective for most patients due to primary or acquired resistance
. Recent studies showed that some epigenetic regulators suppress anti-tumour immunity
, suggesting that epigenetic therapies could boost anti-tumour immune responses and overcome resistance to current immunotherapies. Here we show that, in mouse melanoma models, depletion of KDM5B-an H3K4 demethylase that is critical for melanoma maintenance and drug resistance
-induces robust adaptive immune responses and enhances responses to immune checkpoint blockade. Mechanistically, KDM5B recruits the H3K9 methyltransferase SETDB1 to repress endogenous retroelements such as MMVL30 in a demethylase-independent manner. Derepression of these retroelements activates cytosolic RNA-sensing and DNA-sensing pathways and the subsequent type-I interferon response, leading to tumour rejection and induction of immune memory. Our results demonstrate that KDM5B suppresses anti-tumour immunity by epigenetic silencing of retroelements. We therefore reveal roles of KDM5B in heterochromatin regulation and immune evasion in melanoma, opening new paths for the development of KDM5B-targeting and SETDB1-targeting therapies to enhance tumour immunogenicity and overcome immunotherapy resistance.
Abstract
We present an update of the open-source photochemical kinetics code VULCAN to include C–H–N–O–S networks and photochemistry. The additional new features are advection transport, ...condensation, various boundary conditions, and temperature-dependent UV cross sections. First, we validate our photochemical model for hot Jupiter atmospheres by performing an intercomparison of HD 189733b models between Moses et al., Venot et al., and VULCAN, to diagnose possible sources of discrepancy. Second, we set up a model of Jupiter extending from the deep troposphere to upper stratosphere to verify the kinetics for low temperature. Our model reproduces hydrocarbons consistent with observations, and the condensation scheme successfully predicts the locations of water and ammonia ice clouds. We show that vertical advection can regulate the local ammonia distribution in the deep atmosphere. Third, we validate the model for oxidizing atmospheres by simulating Earth and find agreement with observations. Last, VULCAN is applied to four representative cases of extrasolar giant planets: WASP-33b, HD 189733b, GJ 436b, and 51 Eridani b. We look into the effects of the C/O ratio and chemistry of titanium/vanadium species for WASP-33b, we revisit HD 189733b for the effects of sulfur and carbon condensation, the effects of internal heating and vertical mixing (
K
zz
) are explored for GJ 436b, and we test updated planetary properties for 51 Eridani b with S
8
condensates. We find that sulfur can couple to carbon or nitrogen and impact other species, such as hydrogen, methane, and ammonia. The observable features of the synthetic spectra and trends in the photochemical haze precursors are discussed for each case.
Uncertainty in tropical rainfall projections under increasing radiative forcing is studied by using 26 models from phase 5 of the Coupled Model Intercomparison Project. Intermodel spread in projected ...rainfall change generally increases with interactive sea surface temperature (SST) warming in coupled models compared to atmospheric models with a common pattern of prescribed SST increase. Moisture budget analyses reveal that much of the model uncertainty in tropical rainfall projections originates from intermodel discrepancies in the dynamical contribution due to atmospheric circulation change. Intermodel singular value decomposition (SVD) analyses further show a tight coupling between the intermodel variations in SST warming pattern and circulation change in the tropics. In the zonal mean, the first SVD mode features an anomalous interhemispheric Hadley circulation, while the second mode displays an SST peak near the equator. The asymmetric mode is accompanied by a coupled pattern of wind–evaporation–SST feedback in the tropics and is further tied to interhemispheric asymmetric change in extratropical shortwave radiative flux at the top of the atmosphere. Intermodel variability in the tropical circulation change exerts a strong control on the spread in tropical cloud cover change and cloud radiative effects among models. The results indicate that understanding the coupling between the anthropogenic changes in SST pattern and atmospheric circulation holds the key to reducing uncertainties in projections of future changes in tropical rainfall and clouds.
ABSTRACT We present novel, analytical, equilibrium-chemistry formulae for the abundances of molecules in hot exoplanetary atmospheres that include the carbon, oxygen, and nitrogen networks. Our ...hydrogen-dominated solutions involve acetylene (C2H2), ammonia (NH3), carbon dioxide (CO2), carbon monoxide (CO), ethylene (C2H4), hydrogen cyanide (HCN), methane (CH4), molecular nitrogen (N2), and water (H2O). By considering only the gas phase, we prove that the mixing ratio of carbon monoxide is governed by a decic equation (polynomial equation of 10 degrees). We validate our solutions against numerical calculations of equilibrium chemistry that perform Gibbs free energy minimization and demonstrate that they are accurate at the level for temperatures from 500 to 3000 K. In hydrogen-dominated atmospheres, the ratio of abundances of HCN to CH4 is nearly constant across a wide range of carbon-to-oxygen ratios, which makes it a robust diagnostic of the metallicity in the gas phase. Our validated formulae allow for the convenient benchmarking of chemical kinetics codes and provide an efficient way of enforcing chemical equilibrium in atmospheric retrieval calculations.
Objective:The authors sought to determine whether cannabis use is associated with a change in the risk of incident nonmedical prescription opioid use and opioid use disorder at 3-year ...follow-up.Method:The authors used logistic regression models to assess prospective associations between cannabis use at wave 1 (2001–2002) and nonmedical prescription opioid use and prescription opioid use disorder at wave 2 (2004–2005) of the National Epidemiologic Survey on Alcohol and Related Conditions. Corresponding analyses were performed among adults with moderate or more severe pain and with nonmedical opioid use at wave 1. Cannabis and prescription opioid use were measured with a structured interview (the Alcohol Use Disorder and Associated Disabilities Interview Schedule–DSM-IV version). Other covariates included age, sex, race/ethnicity, anxiety or mood disorders, family history of drug, alcohol, and behavioral problems, and, in opioid use disorder analyses, nonmedical opioid use.Results:In logistic regression models, cannabis use at wave 1 was associated with increased incident nonmedical prescription opioid use (odds ratio=5.78, 95% CI=4.23–7.90) and opioid use disorder (odds ratio=7.76, 95% CI=4.95–12.16) at wave 2. These associations remained significant after adjustment for background characteristics (nonmedical opioid use: adjusted odds ratio=2.62, 95% CI=1.86–3.69; opioid use disorder: adjusted odds ratio=2.18, 95% CI=1.14–4.14). Among adults with pain at wave 1, cannabis use was also associated with increased incident nonmedical opioid use (adjusted odds ratio=2.99, 95% CI=1.63–5.47) at wave 2; it was also associated with increased incident prescription opioid use disorder, although the association fell short of significance (adjusted odds ratio=2.14, 95% CI=0.95–4.83). Among adults with nonmedical opioid use at wave 1, cannabis use was also associated with an increase in nonmedical opioid use (adjusted odds ratio=3.13, 95% CI=1.19–8.23).Conclusions:Cannabis use appears to increase rather than decrease the risk of developing nonmedical prescription opioid use and opioid use disorder.
A large-scale anomalous anticyclone (AAC) is a recurrent pattern in post-El Niño summers, extending from the tropical Northwest Pacific (NWP) to the North Indian Ocean. In boreal summer, there is a ...strongly confluent lower-level flow between the monsoonal westerlies and easterly trades over the Indo-Northwest Pacific. The effect of this basic state confluent flow on the AAC is investigated with energetics analysis and numerical modeling. The results show that the lower-level mean flow over the Indo-Northwest Pacific aids the AAC development. Specifically, the conversion of kinetic energy from the mean confluent flow to perturbations helps amplify easterly anomalies over the Indo-Northwest Pacific in post-El Niño summers. The enhanced easterly wind anomalies provide a positive feedback onto the AAC by inducing surface Ekman divergence to suppress convection over the NWP. Moreover, the structure of the optimal diabatic heating for the AAC pattern is determined using a method similar to the Green’s function approach. The optimal forcing features heating in the tropical Indian Ocean and cooling in the NWP. This suggests that barotropic energy conversion in the confluence zone and the El Niño-induced positive (negative) sea surface temperature anomalies over the TIO (NWP) together lead to the AAC development over the Indo-Northwest Pacific in post-El Niño summers.
Abstract
Planets smaller than Neptune and larger than Earth make up the majority of the discovered exoplanets. Those with H
2
-rich atmospheres are prime targets for atmospheric characterization. The ...transition between the two main classes, super-Earths and sub-Neptunes, is not clearly understood as the rocky surface is likely not accessible to observations. Tracking several trace gases (specifically the loss of ammonia (NH
3
) and hydrogen cyanide (HCN)) has been proposed as a proxy for the presence of a shallow surface. In this work, we revisit the proposed mechanism of nitrogen conversion in detail and find its timescale on the order of a million years. NH
3
exhibits dual paths converting to N
2
or HCN, depending on the UV radiation of the star and the stage of the system. In addition, methanol (CH
3
OH) is identified as a robust and complementary proxy for a shallow surface. We follow the fiducial example of K2-18b with a 2D photochemical model on an equatorial plane. We find a fairly uniform composition distribution below 0.1 mbar controlled by the dayside, as a result of slow chemical evolution. NH
3
and CH
3
OH are concluded to be the most unambiguous proxies to infer surfaces on sub-Neptunes in the era of the James Webb Space Telescope.
Abstract
The reorganization of the Atlantic meridional overturning circulation (AMOC) is often associated with changes in Earth’s climate. These AMOC changes are communicated to the Indo-Pacific ...basins via wave processes and induce an overturning circulation anomaly that opposes the Atlantic changes on decadal to centennial time scales. We examine the role of this transient, interbasin overturning response, driven by an AMOC weakening, both in an ocean-only model with idealized geometry and in a coupled CO
2
quadrupling experiment, in which the ocean warms on two distinct time scales: a fast decadal surface warming and a slow centennial subsurface warming. We show that the transient interbasin overturning produces a zonal heat redistribution between the Atlantic and Indo-Pacific basins. Following a weakened AMOC, an anomalous northward heat transport emerges in the Indo-Pacific, which substantially compensates for the Atlantic southward heat transport anomaly. This zonal heat redistribution manifests as a thermal interbasin seesaw between the high-latitude North Atlantic and the subsurface Indo-Pacific and helps to explain why Antarctic temperature records generally show more gradual changes than the Northern Hemisphere during the last glacial period. In the coupled CO
2
quadrupling experiment, we find that the interbasin heat transport due to a weakened AMOC contributes substantially to the slow centennial subsurface warming in the Indo-Pacific, accounting for more than half of the heat content increase and sea level rise. Thus, our results suggest that the transient interbasin overturning circulation is a key component of the global ocean heat budget in a changing climate.
We present an open-source and validated chemical kinetics code for studying hot exoplanetary atmospheres, which we name VULCAN. It is constructed for gaseous chemistry from 500 to 2500 K, using a ...reduced C-H-O chemical network with about 300 reactions. It uses eddy diffusion to mimic atmospheric dynamics and excludes photochemistry. We have provided a full description of the rate coefficients and thermodynamic data used. We validate VULCAN by reproducing chemical equilibrium and by comparing its output versus the disequilibrium-chemistry calculations of Moses et al. and Rimmer & Helling. It reproduces the models of HD 189733b and HD 209458b by Moses et al., which employ a network with nearly 1600 reactions. We also use VULCAN to examine the theoretical trends produced when the temperature-pressure profile and carbon-to-oxygen ratio are varied. Assisted by a sensitivity test designed to identify the key reactions responsible for producing a specific molecule, we revisit the quenching approximation and find that it is accurate for methane but breaks down for acetylene, because the disequilibrium abundance of acetylene is not directly determined by transport-induced quenching, but is rather indirectly controlled by the disequilibrium abundance of methane. Therefore we suggest that the quenching approximation should be used with caution and must always be checked against a chemical kinetics calculation. A one-dimensional model atmosphere with 100 layers, computed using VULCAN, typically takes several minutes to complete. VULCAN is part of the Exoclimes Simulation Platform (ESP; exoclime.net) and publicly available at https://github.com/exoclime/VULCAN.
Spectral features in the observed spectra of exoplanets depend on the composition of their atmospheres. A good knowledge of the main atmospheric processes that drive the chemical distribution is ...therefore essential to interpret exoplanetary spectra. An atmosphere reaches chemical equilibrium if the rates of the forward and backward chemical reactions converge to the same value. However, there are atmospheric processes, such as atmospheric transport, that destabilize this equilibrium. In this work we study the changes in composition driven by a 3D wind field in WASP-43b using our Global Circulation Model, THOR. Our model uses validated temperature- and pressure-dependent chemical timescales that allow us to explore the disequilibrium chemistry of CO, CO2, H2O, and CH4. In WASP-43b the formation of the equatorial jet has an important impact on the chemical distribution of the different species across the atmosphere. At low latitudes the chemistry is longitudinally quenched, except for CO2 at solar abundances. The polar vortexes have a distinct chemical distribution since these are regions with lower temperature and atmospheric mixing. Vertical and latitudinal mixing have a secondary impact on the chemical transport. We determine graphically the effect of disequilibrium on the observed emission spectra. Our results do not show any significant differences in the emission spectra between the equilibrium and disequilibrium solutions for C/O = 0.5. However, if C/O is increased to 2.0, differences in the spectra due to the disequilibrium chemistry of CH4 become non-negligible. In some spectral ranges the emission spectra can have more than 15% departure from the equilibrium solution.
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