Domain structure of human complement C4b extends with increasing NaCl concentration: implications for its regulatory mechanism

During the activation of complement C4 to C4b, the exposure of its thioester domain (TED) is crucial for the attachment of C4b to activator surfaces. In the C4b crystal structure, TED forms an Arg(104)-Glu(1032) salt bridge to tether its neighbouring macroglobulin (MG1) domain. Here, we examined the C4b domain structure to test whether this salt bridge affects its conformation. Dual polarisation interferometry of C4b immobilised at a sensor surface showed that the maximum thickness of C4b increased by 0.46 nm with increase in NaCl concentration from 50 mM to 175 mM NaCl. Analytical ultracentrifugation showed that the sedimentation coefficient s20, w of monomeric C4b of 8.41 S in 50 mM NaCl buffer decreased to 7.98 S in 137 mM NaCl buffer, indicating that C4b became more extended. Small angle X-ray scattering reported similar RG values of 4.89-4.90 nm for C4b in 137-250 mM NaCl. Atomistic scattering modelling of the C4b conformation showed that TED and the MG1 domain were separated by 4.7 nm in 137-250 mM NaCl, this being greater than that of 4.0 nm in the C4b crystal structure. Our data reveal that in low NaCl concentrations, both at surfaces and in solution, C4b forms compact TED-MG1 structures. In solution, physiologically-relevant NaCl concentrations lead to the separation of the TED and MG1 domain, making C4b less able to bind to its complement regulators. These conformational changes are similar to those seen previously for complement C3b, confirming the importance of this salt bridge for regulating both C4b and C3b

Silicic acid cycling in the Bering Sea during the Mid‐Pleistocene Transition

This is the final version. Available from Wiley via the DOI in this record. Data Availability Statement: The data presented in this paper are stored in the Pangaea data repository (https://doi.pangaea.de/10.1594/ PANGAEA.933139)The rate of deep-ocean carbon burial is considered important for modulating glacial-interglacial atmospheric CO2 concentrations and global climate during the Quaternary. It has been suggested that glacial iron fertilization and increased efficiency of the biological pump in the Southern Ocean since the Mid-Pleistocene Transition (MPT) was key in lowering atmospheric pCO2 and facilitating rapid land ice accumulation. There is growing evidence that a similar mechanism may have existed in the subarctic Pacific Ocean, although this has not yet been assessed. Here, the silicon isotope composition of diatoms (δ30Sidiatom) from the Bering Sea upwelling region is used to assess the role of nutrient cycling on the subarctic Pacific biological pump during the MPT. Results show that during and after the “900 kyr event,” the high productivity green belt zone was characterized by low silicic acid utilization but high supply, coincident with the dominance of diatom resting spores. We posit that as nutrient upwelling was suppressed following pack ice growth and expansion of glacial North Pacific Intermediate Water (GNPIW), primary productivity became nitrate-limited and enhanced opal remineralization caused a relative increase in silicic acid supply. However, preferential preservation and higher cellular carbon content of diatom resting spores, as well as increased supply of iron from expanded sea ice, likely sustained the net efficiency of the Bering Sea biological pump through the MPT. Remnant iron and silicic acid may also have propagated into the lower subarctic Pacific Ocean through GNPIW, aiding a regionally efficient biological pump at 900 kyr and during post-MPT glacials.Natural Environment Research CouncilBritish Geological SurveyNatural Environment Research CouncilNatural Environment Research Counci

Reduced upwelling of nutrient and carbon-rich water in the subarctic Pacific during the Mid-Pleistocene Transition

This is the author accepted manuscript. The final version is available from the publisher via the DOI in this recordReduction in atmosphericpCO2has been hypothesised as a causal mechanism for the Mid-Pleistocene Transition(MPT), which saw global cooling and increased duration of glacials between 0.6 and 1.2 Ma. Sea ice-modulatedhigh latitude upwelling and ocean-atmospheric CO2flux is considered a potential mechanism forpCO2decline,although there are no long-term nutrient upwelling records from high latitude regions to test this hypothesis.Using nitrogen isotopes and opal mass accumulation rates from 0 to 1.2 Ma, we calculate a continuous highresolution nutrient upwelling index for the Bering Sea and assess possible changes to regional CO2fluxes and tothe relative control of sea ice, sea level and glacial North Pacific Intermediate Water (GNPIW) on deep mixingand nutrient upwelling in the region. Wefind nutrient upwelling in the Bering Sea correlates with global icevolume and air temperature throughout the study interval. From ~1 Ma, and particularly during the 900 kaevent, suppressed nutrient upwelling would have lowered oceanicfluxes of CO2to the atmosphere supporting areduction in globalpCO2during the MPT. This timing is consistent with a pronounced increase in sea ice duringthe early Pleistocene and restriction offlow through the Bering Strait during glacials after ~900 ka, both ofwhich would have acted to suppress upwelling. We suggest that sea-level modulated GNPIW expansion duringglacials after 900 ka was the dominant control on subarctic Pacific upwelling strength during the mid-latePleistocene, while sea ice variability played a secondary role.Natural Environment Research Council (NERC

Closure of the Bering Strait caused Mid-Pleistocene Transition cooling

This is the final version. Available from Springer Nature via the DOI in this record. Data availability: All data generated during this study supporting its findings are available within the paper and the supplementary information.The Mid-Pleistocene Transition (MPT) is characterised by cooling and lengthening glacial cycles from 600–1200 ka, thought to be driven by reductions in glacial CO2 in particular from ~900 ka onwards. Reduced high latitude upwelling, a process that retains CO2 within the deep ocean over glacials, could have aided drawdown but has so far not been constrained in either hemisphere over the MPT. Here, we find that reduced nutrient upwelling in the Bering Sea, and North Pacific Intermediate Water expansion, coincided with the MPT and became more persistent at ~900 ka. We propose reduced upwelling was controlled by expanding sea ice and North Pacific Intermediate Water formation, which may have been enhanced by closure of the Bering Strait. The regional extent of North Pacific Intermediate Water across the subarctic northwest Pacific would have contributed to lower atmospheric CO2 and global cooling during the MPT.Natural Environment Research Council (NERC)National Research Foundation of Kore

The formation of professional identity in medical students: considerations for educators

<b>Context</b> Medical education is about more than acquiring an appropriate level of knowledge and developing relevant skills. To practice medicine students need to develop a professional identity – ways of being and relating in professional contexts.<p></p> <b>Objectives</b> This article conceptualises the processes underlying the formation and maintenance of medical students’ professional identity drawing on concepts from social psychology.<p></p> <b>Implications</b> A multi-dimensional model of identity and identity formation, along with the concepts of identity capital and multiple identities, are presented. The implications for educators are discussed.<p></p> <b>Conclusions</b> Identity formation is mainly social and relational in nature. Educators, and the wider medical society, need to utilise and maximise the opportunities that exist in the various relational settings students experience. Education in its broadest sense is about the transformation of the self into new ways of thinking and relating. Helping students form, and successfully integrate their professional selves into their multiple identities, is a fundamental of medical education

Expression of tumour-specific antigens underlies cancer immunoediting

Cancer immunoediting is a process by which immune cells, particularly lymphocytes of the adaptive immune system, protect the host from the development of cancer and alter tumour progression by driving the outgrowth of tumour cells with decreased sensitivity to immune attack1, 2. Carcinogen-induced mouse models of cancer have shown that primary tumour susceptibility is thereby enhanced in immune-compromised mice, whereas the capacity for such tumours to grow after transplantation into wild-type mice is reduced2, 3. However, many questions about the process of cancer immunoediting remain unanswered, in part because of the known antigenic complexity and heterogeneity of carcinogen-induced tumours4. Here we adapted a genetically engineered, autochthonous mouse model of sarcomagenesis to investigate the process of cancer immunoediting. This system allows us to monitor the onset and growth of immunogenic and non-immunogenic tumours induced in situ that harbour identical genetic and histopathological characteristics. By comparing the development of such tumours in immune-competent mice with their development in mice with broad immunodeficiency or specific antigenic tolerance, we show that recognition of tumour-specific antigens by lymphocytes is critical for immunoediting against sarcomas. Furthermore, primary sarcomas were edited to become less immunogenic through the selective outgrowth of cells that were able to escape T lymphocyte attack. Loss of tumour antigen expression or presentation on major histocompatibility complex I was necessary and sufficient for this immunoediting process to occur. These results highlight the importance of tumour-specific-antigen expression in immune surveillance, and potentially, immunotherapy.National Institutes of Health (U.S.) (Grant 1 U54 CA126515-01)National Cancer Institute (U.S.) (Cancer Center Support Grant P30-CA14051)Margaret A. Cunningham Immune Mechanisms in Cancer Research Fellowship AwardJohnD. Proctor FoundationDaniel K. Ludwig Schola

A global compilation of diatom silica oxygen isotope records from lake sediment - trends and implications for climate reconstruction

\ua9 Copyright: Oxygen isotopes in biogenic silica (δ18OBSi) from lake sediments allow for quantitative reconstruction of past hydroclimate and proxy-model comparison in terrestrial environments. The signals of individual records have been attributed to different factors, such as air temperature (Tair), atmospheric circulation patterns, hydrological changes, and lake evaporation. While every lake has its own local set of drivers of δ18O variability, here we explore the extent to which regional or even global signals emerge from a series of paleoenvironmental records. This study provides a comprehensive compilation and combined statistical evaluation of the existing lake sediment δ18OBSi records, largely missing in other summary publications (i.e. PAGES network). For this purpose, we have identified and compiled 71 down-core records published to date and complemented these datasets with additional lake basin parameters (e.g. lake water residence time and catchment size) to best characterize the signal properties. Records feature widely different temporal coverage and resolution, ranging from decadal-scale records covering the past 150 years to records with multi-millennial-scale resolution spanning glacial-interglacial cycles. The best coverage in number of records (NCombining double low line37) and data points (NCombining double low line2112) is available for Northern Hemispheric (NH) extratropical regions throughout the Holocene (roughly corresponding to Marine Isotope Stage 1; MIS 1). To address the different variabilities and temporal offsets, records were brought to a common temporal resolution by binning and subsequently filtered for hydrologically open lakes with lake water residence times <100 years. For mid- to high-latitude (>45\ub0N) lakes, we find common δ18OBSi patterns among the lake records during both the Holocene and Common Era (CE). These include maxima and minima corresponding to known climate episodes, such as the Holocene Thermal Maximum (HTM), Neoglacial Cooling, Medieval Climate Anomaly (MCA) and the Little Ice Age (LIA). These patterns are in line with long-term air temperature changes supported by previously published climate reconstructions from other archives, as well as Holocene summer insolation changes. In conclusion, oxygen isotope records from NH extratropical lake sediments feature a common climate signal at centennial (for CE) and millennial (for Holocene) timescales despite stemming from different lakes in different geographic locations and hence constitute a valuable proxy for past climate reconstructions

Involving Citizen Scientists in Biodiversity Observation

The involvement of non-professionals in scientific research and environmental monitoring, termed Citizen Science (CS), has now become a mainstream approach for collecting data on earth processes, ecosystems and biodiversity. This chapter examines how CS might contribute to ongoing efforts in biodiversity monitoring, enhancing observation and recording of key species and systems in a standardised manner, thereby supporting data relevant to the Essential Biodiversity Variables (EBVs), as well as reaching key constituencies who would benefit Biodiversity Observation Networks (BONs). The design of successful monitoring or observation networks that rely on citizen observers requires a careful balancing of the two primary user groups, namely data users and data contributors (i.e., citizen scientists). To this end, this chapter identifies examples of successful CS programs as well as considering practical issues such as the reliability of the data, participant recruitment and motivation, and the use of emerging technologies