Chikungunya virus (CHIKV) is a mosquito-borne alphavirus known to cause epidemics resulting in predominantly symptomatic infections, which in rare cases cause long term debilitating arthritis and ...arthralgia. Significant progress has been made in understanding the roles of canonical RNA sensing pathways in the host recognition of CHIKV; however, less is known regarding antagonism of CHIKV by cytosolic DNA sensing pathways like that of cyclic GMP-AMP synthase (cGAS) and Stimulator of Interferon Genes (STING). With the use of cGAS or STING null cells we demonstrate that the pathway restricts CHIKV replication in fibroblasts and immune cells. We show that DNA accumulates in the cytoplasm of infected cells and that CHIKV blocks DNA dependent IFN-β transcription. This antagonism of DNA sensing is via an early autophagy-mediated degradation of cGAS and expression of the CHIKV capsid protein is sufficient to induce cGAS degradation. Furthermore, we identify an interaction of CHIKV nsP1 with STING and map the interaction to 23 residues in the cytosolic loop of the adaptor protein. This interaction stabilizes the viral protein and increases the level of palmitoylated nsP1 in cells. Together, this work supports previous publications highlighting the relevance of the cGAS-STING pathway in the early detection of (+)ssRNA viruses and provides direct evidence that CHIKV interacts with and antagonizes cGAS-STING signaling.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
We assess evidence relevant to Earth's equilibrium climate sensitivity per doubling of atmospheric CO2, characterized by an effective sensitivity S . This evidence includes feedback process ...understanding, the historical climate record, and the paleoclimate record. An S value lower than 2 K is difficult to reconcile with any of the three lines of evidence. The amount of cooling during the Last Glacial Maximum provides strong evidence against values of S greater than 4.5 K. Other lines of evidence in combination also show that this is relatively unlikely. We use a Bayesian approach to produce a probability density (PDF) for S given all the evidence, including tests of robustness to difficult‐to‐quantify uncertainties and different priors. The 66% range is 2.6‐3.9 K for our Baseline calculation, and remains within 2.3‐4.5 K under the robustness tests; corresponding 5‐95% ranges are 2.3‐4.7 K, bounded by 2.0‐5.7 K (although such high‐confidence ranges should be regarded more cautiously). This indicates a stronger constraint on S than reported in past assessments, by lifting the low end of the range. This narrowing occurs because the three lines of evidence agree and are judged to be largely independent, and because of greater confidence in understanding feedback processes and in combining evidence. We identify promising avenues for further narrowing the range in S , in particular using comprehensive models and process understanding to address limitations in the traditional forcing‐feedback paradigm for interpreting past changes.
Contrary to the well known diffraction limit, the fluorescence microscope is in principle capable of unlimited resolution. The necessary elements are spatially structured illumination light and a ...nonlinear dependence of the fluorescence emission rate on the illumination intensity. As an example of this concept, this article experimentally demonstrates saturated structured-illumination microscopy, a recently proposed method in which the nonlinearity arises from saturation of the excited state. This method can be used in a simple, wide-field (nonscanning) microscope, uses only a single, inexpensive laser, and requires no unusual photophysical properties of the fluorophore. The practical resolving power is determined by the signal-to-noise ratio, which in turn is limited by photobleaching. Experimental results show that a 2D point resolution of <50 nm is possible on sufficiently bright and photostable samples.
Primates of several species respond negatively to receiving less preferred rewards than a partner for completing the same task (inequity responses), either rejecting rewards or refusing to ...participate in the task when disadvantaged. This has been linked to cooperation, with species that cooperate frequently refusing to participate in inequity tasks (the ‘cooperation hypothesis’). However, inequity is a social response, and previous research has involved dyads, precluding studying the effects of additional social partners. While dyads allow for tighter control in experimental settings, dyadic interactions in nature do not take place in a social vacuum, so understanding the role of the social context is needed to verify that the pattern of results supports the cooperation hypothesis. Here we focus on Bolivian squirrel monkeys, Saimiri boliviensis, a highly social species that does not generally cooperate and has not responded to inequity in previous dyadic research, although they do respond to receiving a lower reward than they expected. In the current study, we provide a more nuanced test by studying female Bolivian squirrel monkeys, the demographic most likely to cooperate in both field and laboratory contexts, in a more socially relevant group setting. For some reward values, females responded in both the inequity condition, rejecting less preferred rewards when they were disadvantaged relative to their social group, and a contrast condition, wherein all animals received a lower reward than they expected, making it difficult to disentangle contrast from inequity. As in capuchin monkeys, refusals increased when monkeys were to receive low-value rewards compared to medium-value rewards. These results suggest that the relationship between cooperation and inequity responses may be more nuanced than previously suggested, with demographic, social context and reward value potentially influencing outcomes even within species.
•We tested female squirrel monkeys' responses to inequitable payoffs in a group setting.•Females responded to contrast, a response previously documented only in males.•Low-value rewards were rejected more with contrast and inequity than with equity.•Reward value and social context may both influence study outcomes.
A series of environmental policies have been implemented in the European Union (EU) to decrease nitrogen (N) emissions from agriculture. The Nitrates Directive (ND) is one of the main policies; it ...aims to reduce nitrate leaching from agriculture through a number of measures.
A study was carried out to quantify the effects of the ND in the EU-27 on the leaching and runoff of nitrate (NO3−) to groundwater and surface waters, and on the emissions of ammonia (NH3), nitrous oxide (N2O), nitrogen oxides (NOx) and dinitrogen (N2) to the atmosphere. We formulated a scenario with and a scenario without implementation of the ND. The model MITERRA-Europe was used to calculate N emissions on a regional level in the EU-27 for the period 2000–2008.
The calculated total N loss from agriculture in the EU-27 was 13Mton N in 2008, with 53% as N2, 22% as NO3, 21% as NH3, 3% as N2O, and 1% as NOx. The N emissions and leaching in the EU-27 slightly decreased in the period 2000–2008. Total emissions in the EU in 2008 were smaller with implementation of the ND than without the ND, by 3% for NH3, 6% for N2O, 9% for NOx, and 16% for N leaching and runoff in 2008. However, regional differences were large. The lower emissions with ND were mainly due to the lower N inputs by fertilizers and manures.
In conclusion, implementation of the ND decreased both N leaching losses to ground and surface waters, and gaseous emissions to the atmosphere. It is expected that the ND will result in a further decrease in N emissions in EU-27 in the near future, because the implementation of the measures for the ND is expected to become more strict.
•The Nitrates Directive decreased nitrate leaching in the EU-27 by 16% in 2008.•Measures of the Nitrates Directive also reduced gaseous nitrogen emissions.•Emission of ammonia decreased by 3% and of nitrous oxide by 6% in 2008.•Regional differences in nitrogen emissions in the EU-27 are large.•Balanced nitrogen application is an effective measure to mitigate nitrogen emissions.
Worldwide, fishways are increasingly criticized for failing to meet conservation goals. We argue that this is largely due to the dominance of diadromous species of the Northern Hemisphere (e.g., ...Salmonidae) in the research that underpins the concepts and methods of fishway science and management. With highly diverse life histories, swimming abilities and spatial ecologies, most freshwater fish species do not conform to the stereotype imposed by this framework. This is leading to a global proliferation of fishways that are often unsuitable for native species. The vast majority of fish populations do not undertake extensive migrations between clearly separated critical habitats, yet the movement of individuals and the genetic information they carry is critically important for population viability. We briefly review some of the latest advances in spatial ecological modelling for dendritic networks to better define what it means to achieve effective fish passage at a barrier. Through a combination of critical habitat assessment and the modelling of metapopulations, climate change‐driven habitat shifts, and adaptive gene flow, we recommend a conceptual and methodological framework for fishway target‐setting and monitoring suitable for a wide range of species. In the process, we raise a number of issues that should contribute to the ongoing debate about fish passage research and the design and monitoring of fishways.
Objective: The objective of this study was to find readily ascertainable intraoperative pathologic indicators that would discriminate a subgroup of early corpus cancers that would not require ...lymphadenectomy or adjuvant radiotherapy. Study Design: Between 1984 and 1993, a total of 328 patients with endometrioid corpus cancer, grade 1 or 2 tumor, myometrial invasion ≤50%, and no intraoperative evidence of macroscopic extrauterine spread were treated surgically. Pelvic lymphadenectomy was performed in 187 cases (57%), and nodes were positive in nine cases (5%). Adjuvant radiotherapy was administered to 65 patients (20%). Median follow-up was 88 months. Results: The 5-year overall cancer-related and recurrence-free survivals were 97% and 96%, respectively. Primary tumor diameter and lymphatic or vascular invasion significantly affected longevity. No patient with tumor diameter ≤2 cm had positive lymph nodes or died of disease. Conclusion: Patients who have International Federation of Gynecology and Obstetrics grade 1 or 2 endometrioid corpus cancer with greatest surface dimension ≤2 cm, myometrial invasion ≤50%, and no intraoperative evidence of macroscopic disease can be treated optimally with hysterectomy only. (Am J Obstet Gynecol 2000;182:1506-19.)
The development of computational methods to assess pathogenicity of pre-messenger RNA splicing variants is critical for diagnosis of human disease. We assessed the capability of eight algorithms, and ...a consensus approach, to prioritize 249 variants of uncertain significance (VUSs) that underwent splicing functional analyses. The capability of algorithms to differentiate VUSs away from the immediate splice site as being 'pathogenic' or 'benign' is likely to have substantial impact on diagnostic testing. We show that SpliceAI is the best single strategy in this regard, but that combined usage of tools using a weighted approach can increase accuracy further. We incorporated prioritization strategies alongside diagnostic testing for rare disorders. We show that 15% of 2783 referred individuals carry rare variants expected to impact splicing that were not initially identified as 'pathogenic' or 'likely pathogenic'; one in five of these cases could lead to new or refined diagnoses.
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