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Background and purpose: Cyclosporine and FK506 are thought to act by targeting the Ca2+‐dependent protein phosphatase, calcineurin. The aim of the present study was to determine whether cyclosporine and FK506 stabilize mast cells and basophils by interacting with calcineurin. Experimental approach: The effects of cyclosporine and FK506 on the IgE‐mediated release of histamine from mast cells and basophils were evaluated. The presence of calcineurin in cells was determined by Western blotting. Ca2+‐dependent protein phosphatase activities were assessed in cell extracts using a synthetic phosphorylated peptide that is known to serve as a substrate for calcineurin. Key results: FK506 was about 100‐fold more potent than cyclosporine as an inhibitor of IgE‐dependent histamine release from mast cells and basophils. Immunoblotting of solubilized preparations of purified cells demonstrated the presence of calcineurin in mast cells and basophils. In enzyme assays, mast cells expressed approximately 7‐fold higher Ca2+‐dependent protein phosphatase activity than basophils. Whereas cyclosporine effectively inhibited Ca2+‐dependent protein phosphatase activity in cell extracts, FK506 was considerably less effective. Conclusions and implications: FK506 and cyclosporine inhibit the stimulated release of histamine from mast cells and basophils. However, the ability of cyclosporine, but not FK506, to inhibit Ca2+‐dependent protein phosphatase activity questions whether FK506 stabilizes mast cells and basophils by interacting with calcineurin. British Journal of Pharmacology (2007) 150, 509–518. doi:10.1038/sj.bjp.0707002

C-reactive protein (CRP), haptoglobin (Hp) and fibrinogen (Fbgn) are acute phase reactants (APRs), the blood levels of which increase during acute inflammation. However, although the levels of these APRs are used to monitor inflammation in man, their usefulness and sensitivity as markers of inflammation in rodents are less clear. We therefore wished to evaluate, in a comparative fashion, a prototype immunoassay for serum CRP, a commercial assay for serum Hp, and an automated assay for Fbgn, using a model of acute inflammation in the rat. Additionally, pro-inflammatory cytokines and serum protein fractions were also measured. The model of inflammation used was the intraperitoneal injection of Freund's complete adjuvant (FCA). In a concluding experiment, findings with Hp in the FCA rat model were validated in a toxicologically relevant study involving the induction of acute hepatic inflammation using the model hepatotoxicant carbon tetrachloride (CCl(4)). Female Wistar Han rats were treated with a single injection of FCA in a dose-response study (1.25-10.0 ml/kg, sampling at 36 h) and two time-course studies (over 40 h and 21 days). In a final experiment, rats were dosed with CCl(4) at 0.8 ml/kg and sampled over a 17-day period. In FCA and CCl(4) experiments, serum/plasma was prepared and tissues taken at autopsy for histological assessment (CCl(4) study only). In the dose-response study, serum CRP, Hp and plasma Fbgn were increased at all FCA dose levels at 36 h post-dosing. Serum alpha(2) and beta(1) globulin fractions were also increased, while albumin levels were decreased. In the 40-h time-course study, CRP levels peaked at 25-40 h post-dosing, to approximately 120% of control (as 100%). Hp levels increased to a maximum at 25 and 40 h post-dosing with values greater than 400% of control, and alpha(2) and beta(1) globulin fractions peaked at 30 and 40 h post-dosing to 221 and 187% of control, respectively. Increased serum interleukin-6 (IL-6) and interleukin-1beta (IL-1beta) levels peaked at 20 h (11-fold) and 25 h (19-fold), respectively. In a 21-day time-course study, no increased CRP levels were measured despite elevated levels of Hp, which peaked at 36 h (approximately 7-fold above control), and remained elevated up to 21 days. IL-6 and IL-1beta levels peaked at 12 h (19-fold) and 24 h (28-fold), respectively. Liver histopathology of animals treated with CCl(4) showed centrilobular hepatocellular degeneration and necrosis (most significant at 36 h) with an inflammatory response (most significant at 48 h). Resolution of the lesion was complete by 4 days post-dosing. Serum alanine aminotransferase, aspartate aminotransferase and glutamate dehydrogenase levels peaked at 36 h post-dosing. Hp levels increased maximally at 48 h (426% of control). We conclude that serum CRP is a poor marker of acute inflammation in the rat in comparison with serum Hp and plasma Fbgn. Between Hp and Fbgn, serum Hp is shown to be the most sensitive and useful marker of acute inflammation.

Climate change is leading to shifts in species geographical distributions, but populations are also probably adapting to environmental change at different rates across their range. Owing to a lack of natural and empirical data on the influence of phenotypic adaptation on range shifts of marine species, we provide a general conceptual model for understanding population responses to climate change that incorporates plasticity and adaptation to environmental change in marine ecosystems. We use this conceptual model to help inform where within the geographical range each mechanism will probably operate most strongly and explore the supporting evidence in species. We then expand the discussion from a single-species perspective to community-level responses and use the conceptual model to visualize and guide research into the important yet poorly understood processes of plasticity and adaptation. This article is part of the theme issue ‘The role of plasticity in phenotypic adaptation to rapid environmental change’.

Declining atmospheric CO 2 concentrations are considered the primary driver for the Cenozoic Greenhouse-Icehouse transition, ~34 million years ago. A role for tectonically opening Southern Ocean gateways, initiating the onset of a thermally isolating Antarctic Circumpolar Current, has been disputed as ocean models have not reproduced expected heat transport to the Antarctic coast. Here we use high-resolution ocean simulations with detailed paleobathymetry to demonstrate that tectonics did play a fundamental role in reorganising Southern Ocean circulation patterns and heat transport, consistent with available proxy data. When at least one gateway (Tasmanian or Drake) is shallow (300 m), gyres transport warm waters towards Antarctica. When the second gateway subsides below 300 m, these gyres weaken and cause a dramatic cooling (average of 2–4 °C, up to 5 °C) of Antarctic surface waters whilst the ACC remains weak. Our results demonstrate that tectonic changes are crucial for Southern Ocean climate change and should be carefully considered in constraining long-term climate sensitivity to CO 2 . The role of Southern Ocean gateways contributing to the Eocene-Oligocene climate transition is still debated. Here, the authors present high-resolution ocean simulations to show that gateways opening led to a reorganization of ocean circulation, heat transport and Antarctic surface water cooling.

Case isolation and contact tracing can contribute to the control of COVID-19 outbreaks 1 , 2 . However, it remains unclear how real-world social networks could influence the effectiveness and efficiency of such approaches. To address this issue, we simulated control strategies for SARS-CoV-2 transmission in a real-world social network generated from high-resolution GPS data that were gathered in the course of a citizen-science experiment 3 , 4 . We found that tracing the contacts of contacts reduced the size of simulated outbreaks more than tracing of only contacts, but this strategy also resulted in almost half of the local population being quarantined at a single point in time. Testing and releasing non-infectious individuals from quarantine led to increases in outbreak size, suggesting that contact tracing and quarantine might be most effective as a ‘local lockdown’ strategy when contact rates are high. Finally, we estimated that combining physical distancing with contact tracing could enable epidemic control while reducing the number of quarantined individuals. Our findings suggest that targeted tracing and quarantine strategies would be most efficient when combined with other control measures such as physical distancing. Combining fine-scale social contact data with epidemic modeling reveals interactions among contact tracing, quarantine, testing and physical distancing for controlling COVID-19.

Pivotal to projecting the fate of coral reefs is the capacity of reef-building corals to acclimatize and adapt to climate change. Transgenerational plasticity may enable some marine organisms to acclimatize over several generations and it has been hypothesized that epigenetic processes and microbial associations might facilitate adaptive responses. However, current evidence is equivocal and understanding of the underlying processes is limited. Here, we discuss prospects for observing transgenerational plasticity in corals and the mechanisms that could enable adaptive plasticity in the coral holobiont, including the potential role of epigenetics and coral-associated microbes. Well-designed and strictly controlled experiments are needed to distinguish transgenerational plasticity from other forms of plasticity, and to elucidate the underlying mechanisms and their relative importance compared with genetic adaptation.

In response to the COVID-19 pandemic, the UK first adopted physical distancing measures in March, 2020. Vaccines against SARS-CoV-2 became available in December, 2020. We explored the health and economic value of introducing SARS-CoV-2 immunisation alongside physical distancing in the UK to gain insights about possible future scenarios in a post-vaccination era. We used an age-structured dynamic transmission and economic model to explore different scenarios of UK mass immunisation programmes over 10 years. We compared vaccinating 75% of individuals aged 20 years or older (and annually revaccinating 50% of individuals aged 20–64 years and 75% of individuals aged 65 years or older) to no vaccination. We assumed either 50% vaccine efficacy against disease and 45-week protection (worst-case scenario) or 95% vaccine efficacy against infection and 3-year protection (best-case scenario). Natural immunity was assumed to wane within 45 weeks. We also explored the additional impact of physical distancing on vaccination by assuming either an initial lockdown followed by voluntary physical distancing, or an initial lockdown followed by increased physical distancing mandated above a certain threshold of incident daily infections. We considered benefits in terms of quality-adjusted life-years (QALYs) and costs, both to the health-care payer and the national economy. We discounted future costs and QALYs at 3·5% annually and assumed a monetary value per QALY of £20 000 and a conservative long-run cost per vaccine dose of £15. We explored and varied these parameters in sensitivity analyses. We expressed the health and economic benefits of each scenario with the net monetary value: QALYs × (monetary value per QALY) – costs. Without the initial lockdown, vaccination, and increased physical distancing, we estimated 148·0 million (95% uncertainty interval 48·5–198·8) COVID-19 cases and 3·1 million (0·84–4·5) deaths would occur in the UK over 10 years. In the best-case scenario, vaccination minimises community transmission without future periods of increased physical distancing, whereas SARS-CoV-2 becomes endemic with biannual epidemics in the worst-case scenario. Ongoing transmission is also expected in intermediate scenarios with vaccine efficacy similar to published clinical trial data. From a health-care perspective, introducing vaccination leads to incremental net monetary values ranging from £12·0 billion to £334·7 billion in the best-case scenario and from –£1·1 billion to £56·9 billion in the worst-case scenario. Incremental net monetary values of increased physical distancing might be negative from a societal perspective if national economy losses are persistent and large. Our model findings highlight the substantial health and economic value of introducing SARS-CoV-2 vaccination. Smaller outbreaks could continue even with vaccines, but population-wide implementation of increased physical distancing might no longer be justifiable. Our study provides early insights about possible future post-vaccination scenarios from an economic and epidemiological perspective. National Institute for Health Research, European Commission, Bill & Melinda Gates Foundation.

SARS-CoV-2 lineage B.1.1.7, a variant that was first detected in the UK in September 2020 1 , has spread to multiple countries worldwide. Several studies have established that B.1.1.7 is more transmissible than pre-existing variants, but have not identified whether it leads to any change in disease severity 2 . Here we analyse a dataset that links 2,245,263 positive SARS-CoV-2 community tests and 17,452 deaths associated with COVID-19 in England from 1 November 2020 to 14 February 2021. For 1,146,534 (51%) of these tests, the presence or absence of B.1.1.7 can be identified because mutations in this lineage prevent PCR amplification of the spike ( S ) gene target (known as S gene target failure (SGTF) 1 ). On the basis of 4,945 deaths with known SGTF status, we estimate that the hazard of death associated with SGTF is 55% (95% confidence interval, 39–72%) higher than in cases without SGTF after adjustment for age, sex, ethnicity, deprivation, residence in a care home, the local authority of residence and test date. This corresponds to the absolute risk of death for a 55–69-year-old man increasing from 0.6% to 0.9% (95% confidence interval, 0.8–1.0%) within 28 days of a positive test in the community. Correcting for misclassification of SGTF and missingness in SGTF status, we estimate that the hazard of death associated with B.1.1.7 is 61% (42–82%) higher than with pre-existing variants. Our analysis suggests that B.1.1.7 is not only more transmissible than pre-existing SARS-CoV-2 variants, but may also cause more severe illness. Analysis of community-tested cases of SARS-CoV-2 indicates that the B.1.1.7 variant is not only more transmissible than pre-existing variants, but may also cause more severe illness, and is associated with a higher risk of death.

Recent studies have shown that the behaviour and development of coral reef fish larvae is hampered by projected future CO 2 levels. However, it is uncertain to what extent this effect also occurs in temperate species. The effects that elevated p CO 2 (~2000 µatm) levels, which are expected to occur in coastal upwelling regions in the future, have on shoaling behaviour and lateralization (turning preference) of fish, were tested in temperate sand smelt Atherina presbyter larvae. The hypothesis that behavioural changes are caused by interference of high CO 2 with GABA-A receptor function was tested by treating larvae with a receptor antagonist (gabazine). Routine swimming speed did not differ between control and high p CO 2 , but exposure to high p CO 2 for 7 days affected group cohesion, which presented a more random distribution when compared to control fish. However, this random distribution was reversed after 21 days of exposure to high CO 2 conditions. Lateralization at the individual level decreased in fish exposed to high p CO 2 for 7 and 21 days, but gabazine reversed this decline. This adds to the growing body of evidence that the effects of a more acidified environment on fish larvae behaviour are likely due to altered function of GABA-A receptors. Overall, our results suggest that future p CO 2 levels likely to occur in temperate coastal ecosystems could have an adverse effect on temperate larval fish behaviour.