FAK acts as a suppressor of RTK-MAP kinase signalling in Drosophila melanogaster epithelia and human cancer cells

Receptor Tyrosine Kinases (RTKs) and Focal Adhesion Kinase (FAK) regulate multiple signalling pathways, including mitogen-activated protein (MAP) kinase pathway. FAK interacts with several RTKs but little is known about how FAK regulates their downstream signalling. Here we investigated how FAK regulates signalling resulting from the overexpression of the RTKs RET and EGFR. FAK suppressed RTKs signalling in Drosophila melanogaster epithelia by impairing MAPK pathway. This regulation was also observed in MDA-MB-231 human breast cancer cells, suggesting it is a conserved phenomenon in humans. Mechanistically, FAK reduced receptor recycling into the plasma membrane, which resulted in lower MAPK activation. Conversely, increasing the membrane pool of the receptor increased MAPK pathway signalling. FAK is widely considered as a therapeutic target in cancer biology; however, it also has tumour suppressor properties in some contexts. Therefore, the FAK-mediated negative regulation of RTK/MAPK signalling described here may have potential implications in the designing of therapy strategies for RTK-driven tumours

Trade-offs in linking adaptation and mitigation in the forests of the Congo Basin

Recent discussions on forests and climate change have highlighted the potential for conservation of tropical forests to contribute synergistically to both mitigation (reducing emissions of greenhouse gases) and adaptation (increasing capacity to cope with changing climate conditions). Key mechanisms through which adaptive advantages might be gained include the potential for forest resources to support livelihoods in the context of climatic strains on agriculture and the protection that intact forest ecosystems might provide against landslides, flash floods and other hazards related to extreme weather. This paper presents findings from field research with forest communities in three areas of the Congo Basin in Central Africa, in which the adaptive role and potential of forests in these respects is critically analysed. The investigation was carried out through a combination of structured and semi-structured qualitative techniques within six villages in Cameroon, Equatorial Guinea and Rwanda. The findings of the research highlight the need to understand both the limits of synergy, and the constraints and trade-offs for rural livelihoods that may be associated with a forest conservation agenda driven by the additional impetus of carbon sequestration. The search for synergy may be conceptually laudable, but if forest management actions do not take account of on-the-ground contexts of constraints and social trade-offs then the result of those actions risks undermining wider livelihood resilience

Phosphorylated c-Src in the nucleus is associated with improved patient outcome in ER-positive breast cancer

Elevated c-Src protein expression has been shown in breast cancer and <i>in vitro</i> evidence suggests a role in endocrine resistance. To investigate whether c-Src is involved in endocrine resistance, we examined the expression of both total and activated c-Src in human breast cancer specimens from a cohort of oestrogen receptor (ER)-positive tamoxifen-treated breast cancer patients. Tissue microarray technology was employed to analyse 262 tumour specimens taken before tamoxifen treatment. Immunohistochemistry using total c-Src and activated c-Src antibodies was performed. Kaplan–Meier survival curves were constructed and log-rank test were performed. High level of nuclear activated Src was significantly associated with improved overall survival (<i>P</i>=0.047) and lower recurrence rates on tamoxifen (<i>P</i>=0.02). Improved patient outcome was only seen with activated Src in the nucleus. Nuclear activated Src expression was significantly associated with node-negative disease and a lower NPI (<i>P</i><0.05). On subgroup analysis, only ER-positive/progesterone receptor (PgR)-positive tumours were associated with improved survival (<i>P</i>=0.004). This shows that c-Src activity is increased in breast cancer and that activated Src within the nucleus of ER-positive tumours predicts an improved outcome. In ER/PgR-positive disease, activated Src kinase does not appear to be involved in <i>de novo</i> endocrine resistance. Further study is required in ER-negative breast cancer as this may represent a cohort in which it is associated with poor outcome

Investigating event-specific drought attribution using self-organizing maps

Previous studies evaluating anthropogenic influences on the meteorological drivers of drought have found mixed results owing to (1) the complex physical mechanisms which lead to the onset of drought, (2) differences in the characteristics and time scales of drought for different regions of the world, and (3) different approaches to the question of attribution. For a midlatitude, temperate climate like New Zealand, strongly modulated by oceanic influences, summer droughts last on the order of 3 months, and are less strongly linked to persistent temperature anomalies than continental climates. Here we demonstrate the utility of a novel approach for characterizing the meteorological conditions conducive to extreme drought over the North Island of New Zealand, using the January–March 2013 event as a case study. Specifically, we consider the use of self‐organizing map techniques in a multimember coupled climate model ensemble to capture changes in daily circulation, between two 41 year periods (1861–1901 and 1993–2033). Comparisons are made with seasonal pressure and precipitation indices. Our results demonstrate robust (>99% confidence) increases in the likelihood of observing circulation patterns like those of the 2013 drought in the recent‐climate simulations when compared with the early‐climate simulations. Best guess estimates of the fraction of attributable risk range from 0.2 to 0.4, depending on the metric used and threshold considered. Contributions to uncertainty in these attribution statements are discussed

Integrating attribution with adaptation for unprecedented future heatwaves

Citizens in many countries are now experiencing record-smashing heatwaves that were intensified due to anthropogenic climate change. Whether today’s most impactful heatwaves could have occurred in a pre-industrial climate, traditionally a central focus of attribution research, is fast becoming an obsolete question. The next frontier for attribution science is to inform adaptation decision-making in the face of unprecedented future heat

Initial experience of a large, self-expanding, and fully recapturable transcatheter aortic valve: The UK & Ireland Implanters' registry.

OBJECTIVES: The UK & Ireland Implanters' registry is a multicenter registry which reports on real-world experience with novel transcatheter heart valves. BACKGROUND: The 34 mm Evolut R transcatheter aortic valve is a self-expanding and fully recapturable transcatheter aortic valve, designed to treat patients with a large aortic annulus. METHODS: Between January 2017 and April 2018, clinical, procedural and 30-day outcome data were prospectively collected from all patients receiving the 34 mm Evolut R valve across 17 participating centers in the United Kingdom and Ireland. The primary efficacy outcome was the Valve Academic Research Consortium-2(VARC-2)-defined endpoint of device success. The primary safety outcome was the VARC-2-defined composite endpoint of early safety at 30 days. RESULTS: A total of 217 patients underwent attempted implant. Mean age was 79.5 ± 8.8 years and Society of Thoracic Surgeons Predicted Risk of Mortality Score 5.2% ± 3.4%. Iliofemoral access was used in 91.2% of patients. Device success was 79.7%. Mean gradient was 7.0 ± 4.6 mmHg and effective orifice area 2.0 ± 0.6 cm2 . Paravalvular regurgitation was more than mild in 7.2%. A new permanent pacemaker was implanted in 15.7%. Early safety was demonstrated in 91.2%. At 30 days, all-cause mortality was 3.2%, stroke 3.7%, and major vascular complication 2.3%. CONCLUSIONS: Real-world experience of the 34 mm Evolut R transcatheter aortic valve demonstrated acceptable procedural success, safety, valve function, and incidence of new permanent pacemaker implantation

IPEM code of practice for high-energy photon therapy dosimetry based on the NPL absorbed dose calibration service

The 1990 code of practice (COP), produced by the IPSM (now the Institute of Physics and Engineering in Medicine, IPEM) and the UK National Physical Laboratory (NPL), gave instructions for determining absorbed dose to water for megavoltage photon (MV) radiotherapy beams (Lillicrap et al 1990). The simplicity and clarity of the 1990 COP led to widespread uptake and high levels of consistency in external dosimetry audits. An addendum was published in 2014 to include the non-conventional conditions in Tomotherapy units. However, the 1990 COP lacked detailed recommendations for calibration conditions, and the corresponding nomenclature, to account for modern treatment units with different reference fields, including small fields as described in IAEA TRS483 (International Atomic Energy Agency (IAEA) 2017, Vienna). This updated COP recommends the irradiation geometries, the choice of ionisation chambers, appropriate correction factors and the derivation of absorbed dose to water calibration coefficients, for carrying out reference dosimetry measurements on MV external beam radiotherapy machines. It also includes worked examples of application to different conditions. The strengths of the 1990 COP are retained: recommending the NPL2611 chamber type as secondary standard; the use of tissue phantom ratio (TPR) as the beam quality specifier; and NPL-provided direct calibration coefficients for the user's chamber in a range of beam qualities similar to those in clinical use. In addition, the formalism is now extended to units that cannot achieve the standard reference field size of 10 cm × 10 cm, and recommendations are given for measuring dose in non-reference conditions. This COP is designed around the service that NPL provides and thus it does not require the range of different options presented in TRS483, such as generic correction factors for beam quality. This approach results in a significantly simpler, more concise and easier to follow protocol

Attribution: how is it relevant for loss and damage policy and practice?

Attribution has become a recurring issue in discussions about Loss and Damage (L&D). In this highly-politicised context, attribution is often associated with responsibility and blame; and linked to debates about liability and compensation. The aim of attribution science, however, is not to establish responsibility, but to further scientific understanding of causal links between elements of the Earth System and society. This research into causality could inform the management of climate-related risks through improved understanding of drivers of relevant hazards, or, more widely, vulnerability and exposure; with potential benefits regardless of political positions on L&D. Experience shows that it is nevertheless difficult to have open discussions about the science in the policy sphere. This is not only a missed opportunity, but also problematic in that it could inhibit understanding of scientific results and uncertainties, potentially leading to policy planning which does not have sufficient scientific evidence to support it. In this chapter, we first explore this dilemma for science-policy dialogue, summarising several years of research into stakeholder perspectives of attribution in the context of L&D. We then aim to provide clarity about the scientific research available, through an overview of research which might contribute evidence about the causal connections between anthropogenic climate change and losses and damages, including climate science, but also other fields which examine other drivers of hazard, exposure, and vulnerability. Finally, we explore potential applications of attribution research, suggesting that an integrated and nuanced approach has potential to inform planning to avert, minimise and address losses and damages. The key messages are In the political context of climate negotiations, questions about whether losses and damages can be attributed to anthropogenic climate change are often linked to issues of responsibility, blame, and liability. Attribution science does not aim to establish responsibility or blame, but rather to investigate drivers of change. Attribution science is advancing rapidly, and has potential to increase understanding of how climate variability and change is influencing slow onset and extreme weather events, and how this interacts with other drivers of risk, including socio-economic drivers, to influence losses and damages. Over time, some uncertainties in the science will be reduced, as the anthropogenic climate change signal becomes stronger, and understanding of climate variability and change develops. However, some uncertainties will not be eliminated. Uncertainty is common in science, and does not prevent useful applications in policy, but might determine which applications are appropriate. It is important to highlight that in attribution studies, the strength of evidence varies substantially between different kinds of slow onset and extreme weather events, and between regions. Policy-makers should not expect the later emergence of conclusive evidence about the influence of climate variability and change on specific incidences of losses and damages; and, in particular, should not expect the strength of evidence to be equal between events, and between countries. Rather than waiting for further confidence in attribution studies, there is potential to start working now to integrate science into policy and practice, to help understand and tackle drivers of losses and damages, informing prevention, recovery, rehabilitation, and transformation

Changes to population-based emergence of climate change from CMIP5 to CMIP6

Abstract The Coupled Model Intercomparison Project Phase 6 (CMIP6) model ensemble projects climate change emerging soonest and most strongly at low latitudes, regardless of the emissions pathway taken. In terms of signal-to-noise (S/N) ratios of average annual temperatures, these models project earlier and stronger emergence under the Shared Socio-economic Pathways than the previous generation did under corresponding Representative Concentration Pathways. Spatial patterns of emergence also change between generations of models; under a high emissions scenario, mid-century S/N is lower than previous studies indicated in Central Africa, South Asia, and parts of South America, West Africa, East Asia, and Western Europe, but higher in most other populated areas. We show that these global and regional changes are caused by a combination of higher effective climate sensitivity in the CMIP6 ensemble, as well as changes to emissions pathways, component-wise effective radiative forcing, and region-scale climate responses between model generations. We also present the first population-weighted calculation of climate change emergence for the CMIP6 ensemble, quantifying the number of people exposed to increasing degrees of abnormal temperatures now and into the future. Our results confirm the expected inequity of climate change-related impacts in the decades between now and the 2050 target for net-zero emissions held by many countries. These findings underscore the importance of concurrent investments in both mitigation and adaptation.</jats:p

Lifetime climate impacts of diet transitions: a novel climate change accounting perspective

Dietary transitions, such as eliminating meat consumption, have been proposed as one way to reduce the climate impact of the global and regional food systems. However, it should be ensured that replacement diets are indeed nutritious and that climate benefits are accurately accounted for. This study uses New Zealand food consumption as a case study for exploring the cumulative climate impact of adopting the national dietary guidelines and the substitution of meat from hypothetical diets. The new GWP* metric is used as it was designed to better reflect the climate impacts of the release of methane than the de facto standard 100-year Global Warming Potential metric (GWP100). A transition at age 25 to the hypothetical dietary guideline diet reduces cumulative warming associated with diet by 7 to 9% at the 100th year compared with consuming the average New Zealand diet. The reduction in diet-related cumulative warming from the transition to a hypothetical meat-substituted diet varied between 12 and 15%. This is equivalent to reducing an average individual's lifetime warming contribution by 2 to 4%. General improvements are achieved for nutrient intakes by adopting the dietary guidelines compared with the average New Zealand diet; however, the substitution of meat items results in characteristic nutrient differences, and these differences must be considered alongside changes in emission profiles.fals