The Southern Ocean is a key region for global carbon uptake and is characterized by a strong seasonality with the annual CO2 uptake being mediated by biological carbon drawdown in summer. Here we ...show that the contribution of biology to CO2 uptake will become even more important until 2100. This is the case even if biological production remains unaltered and can be explained by the decreasing buffer capacity of the ocean as its carbon content increases. The same amount of biological carbon drawdown leads to a more than twice as large reduction in CO2(aq) concentration and hence to a larger CO2 gradient between ocean and atmosphere that drives the gas exchange. While the winter uptake south of 44°S changes little, the summer uptake increases largely and is responsible for the annual mean response. The combination of decreasing buffer capacity and strong seasonality of biological carbon drawdown introduces a strong and increasing seasonality in the anthropogenic carbon uptake.
Key Points
Decrease of buffer capacity leads to stronger summer CO2 uptake in the future
Biology will contribute more to future CO2 uptake in Southern Ocean
Seasonality affects anthropogenic carbon uptake strongly
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Advanced and aggressive prostate cancer (PCa) depends on glutamine for survival and proliferation. We have previously shown that inhibition of glutaminase 1, which catalyzes the rate-limiting step of ...glutamine catabolism, achieves significant therapeutic effect; however, therapy resistance is inevitable. Here we report that while the glutamine carbon is critical to PCa survival, a parallel pathway of glutamine nitrogen catabolism that actively contributes to pyrimidine assembly is equally important for PCa cells. Importantly, we demonstrate a reciprocal feedback mechanism between glutamine carbon and nitrogen pathways which leads to therapy resistance when one of the two pathways is inhibited. Combination treatment to inhibit both pathways simultaneously yields better clinical outcome for advanced PCa patients.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Past model studies have projected a global decrease in marine net primary production (NPP) over the 21st century, but these studies focused on the multi-model mean rather than on the large ...inter-model differences. Here, we analyze model-simulated changes in NPP for the 21st century under IPCC's high-emission scenario RCP8.5. We use a suite of nine coupled carbon–climate Earth system models with embedded marine ecosystem models and focus on the spread between the different models and the underlying reasons. Globally, NPP decreases in five out of the nine models over the course of the 21st century, while three show no significant trend and one even simulates an increase. The largest model spread occurs in the low latitudes (between 30° S and 30° N), with individual models simulating relative changes between −25 and +40 %. Of the seven models diagnosing a net decrease in NPP in the low latitudes, only three simulate this to be a consequence of the classical interpretation, i.e., a stronger nutrient limitation due to increased stratification leading to reduced phytoplankton growth. In the other four, warming-induced increases in phytoplankton growth outbalance the stronger nutrient limitation. However, temperature-driven increases in grazing and other loss processes cause a net decrease in phytoplankton biomass and reduce NPP despite higher growth rates. One model projects a strong increase in NPP in the low latitudes, caused by an intensification of the microbial loop, while NPP in the remaining model changes by less than 0.5 %. While models consistently project increases NPP in the Southern Ocean, the regional inter-model range is also very substantial. In most models, this increase in NPP is driven by temperature, but it is also modulated by changes in light, macronutrients and iron as well as grazing. Overall, current projections of future changes in global marine NPP are subject to large uncertainties and necessitate a dedicated and sustained effort to improve the models and the concepts and data that guide their development.
Heat shock factor 1 (HSF1) is a cellular stress-protective transcription factor exploited by a wide range of cancers to drive proliferation, survival, invasion, and metastasis. Nuclear HSF1 abundance ...is a prognostic indicator for cancer severity, therapy resistance, and shortened patient survival. The
gene was amplified, and nuclear HSF1 abundance was markedly increased in prostate cancers and particularly in neuroendocrine prostate cancer (NEPC), for which there are no available treatment options. Despite genetic validation of HSF1 as a therapeutic target in a range of cancers, a direct and selective small-molecule HSF1 inhibitor has not been validated or developed for use in the clinic. We described the identification of a direct HSF1 inhibitor, Direct Targeted HSF1 InhiBitor (DTHIB), which physically engages HSF1 and selectively stimulates degradation of nuclear HSF1. DTHIB robustly inhibited the HSF1 cancer gene signature and prostate cancer cell proliferation. In addition, it potently attenuated tumor progression in four therapy-resistant prostate cancer animal models, including an NEPC model, where it caused profound tumor regression. This study reports the identification and validation of a direct HSF1 inhibitor and provides a path for the development of a small-molecule HSF1-targeted therapy for prostate cancers and other therapy-resistant cancers.
Privacy concerns are widely discussed in research and society in general. For the public infrastructure of financial blockchains, this discussion encompasses the privacy of the originator of a ...transaction broadcasted on the underlying peer-to-peer network. Adaptive diffusion is an approach to expose an alternative source of a message to attackers. However, this approach assumes an unsuitable attacker model and a non-realistic network model for current peer-to-peer networks on the Internet. We transform adaptive diffusion into a new statistical privacy-preserving broadcast protocol for realistic current networks. We model a class of unstructured peer-to-peer networks as organically growing graphs and provide models for other classes of such networks. We show that the distribution of shortest paths can be modelled using a normal distribution Formula: see text. We determine statistical estimators for μ, σ via multivariate models. The model behaves logarithmic over the number of nodes n and proportional to an inverse exponential over the number of added edges per node k. These results facilitate the computation of optimal forwarding probabilities during the dissemination phase for maximum privacy, with participants having only limited information about network topology.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background
Prostate cancer (PCa) continues to be one of the leading causes of cancer deaths in men. While androgen deprivation therapy is initially effective, castration‐resistant PCa (CRPC) often ...recurs and has limited treatment options. Our previous study identified glutamine metabolism to be critical for CRPC growth. The glutamine antagonist 6‐diazo‐5‐oxo‐l‐norleucine (DON) blocks both carbon and nitrogen pathways but has dose‐limiting toxicity. The prodrug DRP‐104 is expected to be preferentially converted to DON in tumor cells to inhibit glutamine utilization with minimal toxicity. However, CRPC cells' susceptibility to DRP‐104 remains unclear.
Methods
Human PCa cell lines (LNCaP, LAPC4, C4‐2/MDVR, PC‐3, 22RV1, NCI‐H660) were treated with DRP‐104, and effects on proliferation and cell death were assessed. Unbiased metabolic profiling and isotope tracing evaluated the effects of DRP‐104 on glutamine pathways. Efficacy of DRP‐104 in vivo was evaluated in a mouse xenograft model of neuroendocrine PCa, NCI‐H660.
Results
DRP‐104 inhibited proliferation and induced apoptosis in CRPC cell lines. Metabolite profiling showed decreases in the tricarboxylic acid cycle and nucleotide synthesis metabolites. Glutamine isotope tracing confirmed the blockade of both carbon pathway and nitrogen pathways. DRP‐104 treated CRPC cells were rescued by the addition of nucleosides. DRP‐104 inhibited neuroendocrine PCa xenograft growth without detectable toxicity.
Conclusions
The prodrug DRP‐104 blocks glutamine carbon and nitrogen utilization, thereby inhibiting CRPC growth and inducing apoptosis. Targeting glutamine metabolism pathways with DRP‐104 represents a promising therapeutic strategy for CRPC.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Stratospheric ozone depletion and emission of greenhouse gases lead to a trend of the southern annular mode (SAM) toward its high‐index polarity. The positive phase of the SAM is characterized by ...stronger than usual westerly winds that induce changes in the physical carbon transport. Changes in the natural carbon budget of the upper 100 m of the Southern Ocean in response to a positive SAM phase are explored with a coupled ecosystem‐general circulation model and regression analysis. Previously overlooked processes that are important for the upper ocean carbon budget during a positive SAM period are identified, namely, export production and downward transport of carbon north of the polar front (PF) as large as the upwelling in the south. The limiting micronutrient iron is brought into the surface layer by upwelling and stimulates phytoplankton growth and export production but only in summer. This leads to a drawdown of carbon and less summertime outgassing (or more uptake) of natural CO2. In winter, biological mechanisms are inactive, and the surface ocean equilibrates with the atmosphere by releasing CO2. In the annual mean, the upper ocean region south of the PF loses more carbon by additional export production than by the release of CO2 into the atmosphere, highlighting the role of the biological carbon pump in response to a positive SAM event.
Key Points
The response of carbon fluxes varies between seasons
More biological production at positive SAM south of 55S
Uptake of natural CO2 in summer in contrast to mean response due to biology
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Ring resonator modulators (RRM) combine extreme compactness, low power consumption and wavelength division multiplexing functionality, making them a frontrunner for addressing the scalability ...requirements of short distance optical links. To extend data rates beyond the classically assumed bandwidth capability, we derive and experimentally verify closed form equations of the electro-optic response and asymmetric side band generation resulting from inherent transient time dynamics and leverage these to significantly improve device performance. An equivalent circuit description with a commonly used peaking amplifier model allows straightforward assessment of the effect on existing communication system architectures. A small signal analytical expression of peaking in the electro-optic response of RRMs is derived and used to extend the electro-optic bandwidth of the device above 40 GHz as well as to open eye diagrams penalized by intersymbol interference at 32, 40 and 44 Gbps. Predicted peaking and asymmetric side band generation are in excellent agreement with experiments.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Abstract
The field of quantum simulations in ultra-cold atomic gases has been remarkably successful. In principle it allows for an exact treatment of a variety of highly relevant lattice models and ...their emergent phases of matter. But so far there is a lack in the theoretical literature concerning the systematic study of the effects of the trap potential as well as the finite size of the systems, as numerical studies of such non periodic, correlated fermionic lattices models are numerically demanding beyond one dimension. We use the recently introduced real-space truncated unity functional renormalization group to study these boundary and trap effects with a focus on their impact on the superconducting phase of the 2D Hubbard model. We find that in the experiments not only lower temperatures need to be reached compared to current capabilities, but also system size and trap potential shape play a crucial role to simulate emergent phases of matter.
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