A regulatory region on RIPK2 is required for XIAP binding and NOD signaling activity.

Signaling via the intracellular pathogen receptors nucleotide-binding oligomerization domain-containing proteins NOD1 and NOD2 requires receptor interacting kinase 2 (RIPK2), an adaptor kinase that can be targeted for the treatment of various inflammatory diseases. However, the molecular mechanisms of how RIPK2 contributes to NOD signaling are not completely understood. We generated FLAG-tagged RIPK2 knock-in mice using CRISPR/Cas9 technology to study NOD signaling mechanisms at the endogenous level. Using cells from these mice, we were able to generate a detailed map of post-translational modifications on RIPK2. Similar to other reports, we did not detect ubiquitination of RIPK2 lysine 209 during NOD2 signaling. However, using site-directed mutagenesis we identified a new regulatory region on RIPK2, which dictates the crucial interaction with the E3 ligase XIAP and downstream signaling outcomes. © 2020 The Authors

Small molecule sensitization to TRAIL is mediated via nuclear localization, phosphorylation and inhibition of chaperone activity of Hsp27

10.1038/cddis.2013.413Cell Death and Disease410

Sources of skill in lake temperature, discharge and ice-off seasonal forecasting tools

Despite high potential benefits, the development of seasonal forecasting tools in the water sector has been slower than in other sectors. Here we assess the skill of seasonal forecasting tools for lakes and reservoirs set up at four sites in Australia and Europe. These tools consist of coupled hydrological catchment and lake models forced with seasonal meteorological forecast ensembles to provide probabilistic predictions of seasonal anomalies in water discharge, temperature and ice-off. Successful implementation requires a rigorous assessment of the tools' predictive skill and an apportionment of the predictability between legacy effects and input forcing data. To this end, models were forced with two meteorological datasets from the European Centre for Medium-Range Weather Forecasts (ECMWF), the seasonal forecasting system, SEAS5, with 3-month lead times and the ERA5 reanalysis. Historical skill was assessed by comparing both model outputs, i.e. seasonal lake hindcasts (forced with SEAS5), and pseudo-observations (forced with ERA5). The skill of the seasonal lake hindcasts was generally low although higher than the reference hindcasts, i.e. pseudo-observations, at some sites for certain combinations of season and variable. The SEAS5 meteorological predictions showed less skill than the lake hindcasts. In fact, skilful lake hindcasts identified for selected seasons and variables were not always synchronous with skilful SEAS5 meteorological hindcasts, raising questions on the source of the predictability. A set of sensitivity analyses showed that most of the forecasting skill originates from legacy effects, although during winter and spring in Norway some skill was coming from SEAS5 over the 3-month target season. When SEAS5 hindcasts were skilful, additional predictive skill originates from the interaction between legacy and SEAS5 skill. We conclude that lake forecasts forced with an ensemble of boundary conditions resampled from historical meteorology are currently likely to yield higher-quality forecasts in most cases.</p

Anoxia begets anoxia: a positive feedback to the deoxygenation of temperate lakes

Declining oxygen concentrations in the deep waters of lakes worldwide pose a pressing environmental and societal challenge. Existing theory suggests that low deep-water dissolved oxygen (DO) concentrations could trigger a positive feedback through which anoxia (i.e., very low DO) during a given summer begets increasingly severe occurrences of anoxia in following summers. Specifically, anoxic conditions can promote nutrient release from sediments, thereby stimulating phytoplankton growth, and subsequent phytoplankton decomposition can fuel heterotrophic respiration, resulting in increased spatial extent and duration of anoxia. However, while the individual relationships in this feedback are well established, to our knowledge, there has not been a systematic analysis within or across lakes that simultaneously demonstrates all of the mechanisms necessary to produce a positive feedback that reinforces anoxia. Here, we compiled data from 656 widespread temperate lakes and reservoirs to analyze the proposed anoxia begets anoxia feedback. Lakes in the dataset span a broad range of surface area (1–126,909 ha), maximum depth (6–370 m), and morphometry, with a median time-series duration of 30 years at each lake. Using linear mixed models, we found support for each of the positive feedback relationships between anoxia, phosphorus concentrations, chlorophyll a concentrations, and oxygen demand across the 656-lake dataset. Likewise, we found further support for these relationships by analyzing time-series data from individual lakes. Our results indicate that the strength of these feedback relationships may vary with lake-specific characteristics: For example, we found that surface phosphorus concentrations were more positively associated with chlorophyll a in high-phosphorus lakes, and oxygen demand had a stronger influence on the extent of anoxia in deep lakes. Taken together, these results support the existence of a positive feedback that could magnify the effects of climate change and other anthropogenic pressures driving the development of anoxia in lakes around the world

Severe Impairment of TNF Post-transcriptional Regulation Leads to Embryonic Death

Post-transcriptional regulation mechanisms control mRNA stability or translational efficiency via ribosomes, and recent evidence indicates that it is a major determinant of the accurate levels of cytokine mRNAs. Transcriptional regulation of Tnf has been well studied and found to be important for the rapid induction of Tnf mRNA and regulation of the acute phase of inflammation, whereas study of its post-transcriptional regulation has been largely limited to the role of the AU-rich element (ARE), and to a lesser extent, to that of the constitutive decay element (CDE). We have identified another regulatory element (NRE) in the 3' UTR of Tnf and demonstrate that ARE, CDE, and NRE cooperate in vivo to efficiently downregulate Tnf expression and prevent autoimmune inflammatory diseases. We also show that excessive TNF may lead to embryonic death

Technical note: Preventing CO₂ overestimation from mercuric or copper(II) chloride preservation of dissolved greenhouse gases in freshwater samples

The determination of dissolved gases (O2, CO2, CH4, N2O, N2) in surface waters allows the estimation of biological processes and greenhouse gas fluxes in aquatic ecosystems. Mercuric chloride (HgCl2) has been widely used to preserve water samples prior to gas analysis. However, alternates are needed because of the environmental impacts and prohibition of mercury. HgCl2 is a weak acid and interferes with dissolved organic carbon (DOC). Hence, we tested the effect of HgCl2 and two substitutes (copper(II) chloride – CuCl2 – and silver nitrate – AgNO3), as well as storage time (24 h to 3 months) on the determination of dissolved gases in low-ionic-strength and high-DOC water from a typical boreal lake. Furthermore, we investigated and predicted the effect of HgCl2 on CO2 concentrations in periodic samples from another lake experiencing pH variations (5.4–7.3) related to in situ photosynthesis. Samples fixed with inhibitors generally showed negligible O2 consumption. However, effective preservation of dissolved CO2, CH4 and N2O for up to 3 months prior to dissolved gas analysis was only achieved with AgNO3. In contrast, HgCl2 and CuCl2 caused an initial increase in CO2 and N2O from 24 h to 3 weeks followed by a decrease from 3 weeks to 3 months. The CO2 overestimation, caused by HgCl2 acidification and a shift in the carbonate equilibrium, can be calculated from predictions of chemical speciation. Errors due to CO2 overestimation in HgCl2-preserved water, sampled from low-ionic-strength and high-DOC freshwater, which is common in the Northern Hemisphere, could lead to an overestimation of the CO2 diffusion efflux by a factor of &gt; 20 over a month or a factor of 2 over the ice-free season. The use of HgCl2 and CuCl2 for freshwater preservation should therefore be discontinued. Further testing of AgNO3 preservation should be performed under a large range of freshwater chemical conditions.</p

ZC3H12C expression in DCs is necessary to prevent lymphadenopathy of skin-draining lymph nodes.

The role of RNA-binding proteins of the CCCH-containing family in regulating pro-inflammatory cytokine production and inflammation is increasingly recognized. We have identified ZC3H12C (Regnase-3) as a potential post-transcriptional regulator of Tumor necrosis factor expression and have investigated its role in vivo by generating Zc3h12c-deficient mice that express GFP instead of ZC3H12C. Zc3h12c-deficient mice develop hypertrophic lymph nodes. In the immune system, ZC3H12C expression is mostly restricted to the dendritic cell (DC) populations, and we show that DC-restricted ZC3H12C depletion is sufficient to cause lymphadenopathy. ZC3H12C can regulate Tnf mRNA stability via its RNAse activity in vitro, and we confirmed the role of Tnf in the development of lymphadenopathy. Finally, we found that loss of ZC3H12C did not impact the outcome of skin inflammation in the imiquimod-induced murine model of psoriasis, despite Zc3h12c being identified as a risk factor for psoriasis susceptibility in several GWAS studies. Our data suggest a role for ZC3H12C in DC-driven skin homeostasis