Medieval property investors, ca. 1300-1500

This paper utilises a dataset of freehold land and property transactions from medieval England to highlight the growing commercialisation of the economy. By drawing on the legal records we are able to demonstrate that the medieval real estate market provided the opportunity for investors to profit. Careful analysis of the data provides evidence of group purchases, multiple transactions and investors buying outside of their own locality. The identification of these ‘investors’ and their buying behaviours, set within the context of the English medieval economy, contributes to the early commercialisation debate

The first real estate bubble? Land prices and rents in medieval England c. 1300-1500

This paper tests for speculative bubbles in the medieval English property market based on a unique hand-collected dataset from the feet of fines spanning the fourteenth and fifteenth centuries. We focus on asset types where there are sufficiently large numbers of transactions each year to make a long and reliable run of information, and we transform this into annual time-series of prices. We employ a regime switching model that allows for boom and crash episodes to characterise and test for bubble dynamics. The results are consistent with the presence of periodic, partially collapsing speculative bubbles in the market for agricultural land, but there is no such evidence in the context of messuages. Our findings demonstrate that the medieval English property market shares important features with its contemporary counterpart, for instance with the recent so-called ‘barn bubble’

The Role of the Iron Transporter ABCB7 in Refractory Anemia with Ring Sideroblasts

Refractory Anemia with Ring Sideroblasts (RARS) is an acquired myelodysplastic syndrome (MDS) characterized by an excess iron accumulation in the mitochondria of erythroblasts. The pathogenesis of RARS and the cause of this unusual pattern of iron deposition remain unknown. We considered that the inherited X-linked sideroblastic anemia with ataxia (XLSA/A) might be informative for the acquired disorder, RARS. XLSA/A is caused by partial inactivating mutations of the ABCB7 ATP-binding cassette transporter gene, which functions to enable transport of iron from the mitochondria to the cytoplasm. Furthermore, ABCB7 gene silencing in HeLa cells causes an accumulation of iron in the mitochondria. We have studied the role of ABCB7 in RARS by DNA sequencing, methylation studies, and gene expression studies in primary CD34+ cells and in cultured erythroblasts. The DNA sequence of the ABCB7 gene is normal in patients with RARS. We have investigated ABCB7 gene expression levels in the CD34+ cells of 122 MDS cases, comprising 35 patients with refractory anemia (RA), 33 patients with RARS and 54 patients with RA with excess blasts (RAEB), and in the CD34+ cells of 16 healthy controls. We found that the expression levels of ABCB7 are significantly lower in the RARS group. RARS is thus characterized by lower levels of ABCB7 gene expression in comparison to other MDS subtypes. Moreover, we find a strong relationship between increasing percentage of bone marrow ring sideroblasts and decreasing ABCB7 gene expression levels. Erythroblast cell cultures confirm the low levels of ABCB7 gene expression levels in RARS. These data provide an important link between inherited and acquired forms of sideroblastic anemia and indicate that ABCB7 is a strong candidate gene for RARS

A reappraisal of the freehold property market in late medieval England

This paper re-examines the late medieval market in freehold land, the extent to which it was governed by market forces as opposed to political or social constraints, and how this contributed to the commercialisation of the late medieval English economy. We employ a valuable new resource for study of this topic in the form of an extensive dataset on late medieval English freehold property transactions. Through analysis of this data, we examine how the level of market activity (the number of sales) and the nature of the properties (the relative proportions of different types of asset) varied across regions and over time. In particular, we consider the impact of exogenous factors and the effects of growing commercialisation. We argue that peaks of activity following periods of crisis (Great Famine and Black Death) indicate that property ownership became open to market speculation. In so doing, we present an important new perspective on the long-term evolution of the medieval English property market

Impact of spliceosome mutations on RNA splicing in myelodysplasia: dysregulated genes/pathways and clinical associations.

SF3B1, SRSF2, and U2AF1 are the most frequently mutated splicing factor genes in the myelodysplastic syndromes (MDS). We have performed a comprehensive and systematic analysis to determine the effect of these commonly mutated splicing factors on pre-mRNA splicing in the bone marrow stem/progenitor cells and in the erythroid and myeloid precursors in splicing factor mutant MDS. Using RNA-seq, we determined the aberrantly spliced genes and dysregulated pathways in CD34+ cells of 84 patients with MDS. Splicing factor mutations result in different alterations in splicing and largely affect different genes, but these converge in common dysregulated pathways and cellular processes, focused on RNA splicing, protein synthesis, and mitochondrial dysfunction, suggesting common mechanisms of action in MDS. Many of these dysregulated pathways and cellular processes can be linked to the known disease pathophysiology associated with splicing factor mutations in MDS, whereas several others have not been previously associated with MDS, such as sirtuin signaling. We identified aberrantly spliced events associated with clinical variables, and isoforms that independently predict survival in MDS and implicate dysregulation of focal adhesion and extracellular exosomes as drivers of poor survival. Aberrantly spliced genes and dysregulated pathways were identified in the MDS-affected lineages in splicing factor mutant MDS. Functional studies demonstrated that knockdown of the mitosis regulators SEPT2 and AKAP8, aberrantly spliced target genes of SF3B1 and SRSF2 mutations, respectively, led to impaired erythroid cell growth and differentiation. This study illuminates the effect of the common spliceosome mutations on the MDS phenotype and provides novel insights into disease pathophysiology

Assessing the materiality of nature-related financial risks for the UK

•At least half of global GDP is moderately or highly directly dependent on nature, and ultimately there is no economy without its critical services, including clean and abundant water, clean air and food. Nature across most of the globe has now been significantly altered by multiple human drivers, such as land-use change, pollution, extraction of minerals, abstraction of water and climate change. Statistics on the current state of biodiversity loss and environmental degradation are alarming: the extent and condition of ecosystems has declined in 50% of natural ecosystems, including more than 85% of wetland area lost, and 25% of species are at risk of extinction (IPBES, 2019). The 2019 Global Assessment Report of the Intergovernmental Science-Policy Platform on Biodiversity and Ecosystem Services (IPBES) concluded that fourteen of the eighteen ecosystem services that were assessed had declined since the 1970s. The United Kingdom is no exception. The percentage of UK habitats ‘in favourable or improving conservation status’ has been deteriorating since 2007, exacerbating impacts on our soils, pollinators, air and environmental pollution, water and flood protection. Our analyses show that 75% of the United Kingdom is covered by at least one hotspot of natural capital depletion, and 25% is covered by two or more hotspots of natural capital depletion. The UK, with its globally interconnected economy, is also exposed to significant global emerging risks. •The erosion of UK and global natural capital generates significant and long-term risks to society and the UK economy and financial sector. Studies by Central Banks around the world have highlighted the high degree of dependence on nature and the exposure of financial portfolios to nature-related risks. What is not yet clear, is the extent to which this is a material risk to financial stability, on a par with other risks on the radar of Central Banks, and if so, on what timescales this risk could emerge and where it might ‘fall through the cracks’ of current supervision and regulation. •The objective of this project was to assess the materiality of nature-related risks to the UK financial sector both in the near-term and the longer-term. To address this, we develop six innovations: 1.The first Nature-Related Risk Inventory for the UK (UK-NRRI), equivalent in format to the National Risk Register or Climate Change Risk Assessment (CCRA). 2.Dependency analysis with spatial information to track dependencies on international supply and the nature risks therein, alongside transition risk exposures for the seven largest banks. 3.Development of sector-specific nature-related Value at Risk (nVaR) scores. 4.Co-development of three benchmark scenarios of nature-related risks, following the approach outlined by the Taskforce on Nature-Related Financial Disclosures (TNFD 2023). 5.Macroeconomic modelling to gauge the potential impacts on UK prosperity and resilience. 6.Preliminary financial ‘stress test’ for the domestic lending of the UK’s seven largest banks. The analyses focus on physical nature-related risks, with exposure analysis or transition risks. The findings demonstrate that biodiversity loss and environmental degradation create material risks for the UK economy and financial sector, in addition to their wider social and biodiversity impacts. These impacts are near and present. We find that the deterioration of our natural environment could slow economic growth and result in UK Gross Domestic Product (GDP) being 6% lower than it would have been otherwise by the 2030s under two scenarios (domestic and international) and 12% lower under an AMR-pandemic scenario. These are greater than the impact on GDP experienced in the Global Financial Crisis, in which UK GDP fell by around 4% to 6%, and - for the AMR-pandemic scenario – greater than the GDP impact of the COVID-19 pandemic when GDP fell 11% over 2020. While these findings are preliminary, all the evidence points to them being conservative. This study focussed on quantifying near- to medium-term risks, but the evidence clearly demonstrates these risks will increase over time with the potential for crossing tipping points. •The compounding impacts of climate and nature loss would have a very material impact on UK GDP; equivalent to several lost years of growth. It is not realistic to consider nature in isolation as climate change and environmental degradation are occurring in parallel and are interconnected. Environmental degradation increases the likelihood and severity of an acute climate or health shock, and the combined effect would have a very material impact on the economy. For this reason, we also draw upon the NGFS climate scenarios to explore the compounding impacts of climate and nature. We find that in our acute shock scenarios, these compounding impacts can lead to a UK GDP that is 8% lower than it would be otherwise, with a peak shock that wipes out around £200 billion from UK GDP and persists for several quarters, equivalent to 4 – 7 years of lost growth over the period. •The gradual impacts of environmental degradation on the economy are as detrimental or more so than climate change in the near-term - and the chronic year-to-year changes lead to losses that are as important as more sudden shocks. We find that the impact to GDP of chronic year-on-year environmental degradation is at least on par with that from physical climate change risks in the coming decade and for acute shocks, can be far greater than climate impacts alone. In effect, the impacts of environmental degradation are doubling or more the impact of climate change. Antimicrobial resistance (AMR) and zoonotic diseases are closely linked with deforestation and habitat destruction which can bring humans and wild animals into closer contact and have been shown to lead to greater abundance of antibiotic resistance genes in soil. Chronic nature-related risks associated with soil degradation, water provisioning, pollution and pollination services have material impacts on agriculture, manufacturing, construction, utilities and key supply chains. •Around half of UK nature-related risks come from overseas, through supply chains and financial exposures, pointing toward the importance of working internationally to close the gaps in disclosures and risk management. The four trillion GBP of financial assets assessed are dependent upon many trillions more of assets globally. Analyses of UK financial exposures suggest that 56% of the total upstream financial exposures have a High or Very High dependence on ecosystem services. Exposures to overseas risks are most material (in financial terms) for the services and manufacturing sectors, with highest risks related to water. The agricultural sector is most at risk in percentage terms, but the largest risks in monetary terms are to the services and manufacturing sectors. Agriculture can be impacted by disruption to several ecosystem services, with potential reductions in output (the nature-related value at risk – or nVaR) up to 15% of total annual production for disruption of any one service, albeit multiple ecosystem services at risk and impacts occur simultaneously, with risks to related to pollination services, soil quality and invasive species. Looking across the UK economy, we find that the nVaR associated with disruption to ecosystem services is in the hundreds of billions and equivalent to several percentage points of GDP; water risks alone are equivalent to around 13% UK GDP (for an extreme 1-in-100 year risk). The agricultural sector is also the most exposed to transition risks and opportunities. •Looking across the portfolios of the seven largest UK banks, the analyses indicate possible adjustments in the valuations of domestic holdings (excluding finance) of up to 4 – 5% over the coming decade from physical nature-related risks. Depending on the bank, the most at-risk sectors include agriculture, utilities, real-estate and manufacturing. Preliminary analyses suggest that between 8% and 53% of the portfolios of the seven largest banks are exposed also to transition risks. Firms could also derive opportunities from the nature-positive transition; including new demand for nature-positive products and services. The findings of this study take us further than previous studies to-date by clearly demonstrating the materiality of nature-related risks and the potential for compounding risks with climate change. Further work is needed to assess the implications for regulation, policy and supervision. Based upon the findings presented here and elsewhere, we believe there is a case for action by Central Banks, regulators and governments to assess if and where nature may be falling through the cracks of current frameworks and where this could lead to financial stability risks that justify explicit changes to those frameworks. We make a series of arguments based on the evidence for why nature may present new challenges that necessitate action. It is clear, for example, from other work (e.g. GARP 2024 and TNFD 2023), that there are sizeable information asymmetries created by the lack of disclosures of nature-related risks and impacts that mean that risks are currently under-priced. This may lead to an accumulation of systemic risk that goes undetected. We also lay out how nature-related risks suffer from the same ‘tragedy of the horizon’ issue identified by Mark Carney in 2015, but also additional challenges of a ‘tragedy of scale’ and unique drivers and risk transmission channels that are not captured within current climate-related risk assessments. •This study adds further evidence to support the conclusion from the Dasgupta Review and others that an early orderly transition toward a nature-positive economy brings significant benefits for UK prosperity and financial stability, through reducing both transition and physical risks, as well as for people and planet. Actions that could be considered by regulators and supervisors to mitigate risks to financial stability include advancing disclosures, broadening supervisory statements on climate to explicitly include environmental risks and introducing a simple nature-risk scenario within exploratory scenario exercises. There are many low-regrets measures that could be taken now, including supporting capability building through fora such as the Climate Financial Risk Forum and working with the scientific community to advance a set of benchmark scenarios, building upon those developed here. Regulators should also take timely opportunities to incorporate nature alongside climate into emerging frameworks, for example on transition plans, ISSB standards and taxonomies. •For financial institutions, the findings should motivate action to assess and manage nature-related financial risks, build capability, and begin to incorporate nature into emerging transition plans. These preliminary results suggest that even in the short-term nature-related risk is not negligible, especially if the losses are considered in relative terms to specific fractions of a lending portfolio. Financial institutions can manage risks to their own portfolios through working with their clients to reduce risks through supporting their transition and resilience. Importantly the transition toward a nature-positive economy presents opportunities as well as risks. With early action, UK firms – both financial and real-economy – can capture these opportunities. •For government, the materiality of nature-related risks demonstrated in this study add additional urgency to put in place the mechanisms, domestically and globally, to meet the goals and targets of the Kunming-Montreal Global Biodiversity Framework (GBF), as well as domestic policies such as the Environmental Improvement Plan (2023). This includes engaging internationally to ensure that emerging sustainable finance frameworks incorporate nature and nature related, including the IFRS Foundation’s ISSB. There is also an urgent rationale for investment and closer working with the scientific community to improve data and analytics as a public good to underpin the UK's transition to a resilient, nature-positive economy. •To continue to advance this area, strengthening collaboration between financial institutions and the scientific community is essential. Nature-related financial risk assessment is in its infancy, but risks are significant. This study has revealed several gaps in knowledge and approaches that require further study. It has also produced a series of tools that can be advanced today: •A Nature-Related Risk Inventory (UK-NRRI) that includes 29 key risks to the UK, with zoonotic diseases and antimicrobial resistance, soil health decline and global repercussions of food insecurity emerging as highest risks in terms of likelihood and impacts. •A set of benchmark narrative and quantitative scenarios that could form the basis for the further co-development of a set of scenarios for financial institutions, through fora such as the Climate Financial Risk Forum and UK Integrating Finance and Biodiversity network. There is a need to build platforms for collaboration and an opportunity to build upon existing fora such as the Climate Financial Risk Forum. The new £7m UKRI Integrating Finance and Biodiversity network, bringing together 17 research institutions, provides a ready venue to deepen collaborations. •Finally, while our focus has been on nature-related risks, the findings have implications for climate change given the strong interconnections between climate and nature The findings suggest that incorporating nature-related risk amplifications in climate scenarios would double the estimated impact of climate change on the UK economy, beyond what is currently predicted by the NGFS

Neutrophil GM-CSF receptor dynamics in acute lung injury.

GM-CSF is important in regulating acute, persistent neutrophilic inflammation in certain settings, including lung injury. Ligand binding induces rapid internalization of the GM-CSF receptor (GM-CSFRα) complex, a process essential for signaling. Whereas GM-CSF controls many aspects of neutrophil biology, regulation of GM-CSFRα expression is poorly understood, particularly the role of GM-CSFRα in ligand clearance and whether signaling is sustained despite major down-regulation of GM-CSFRα surface expression. We established a quantitative assay of GM-CSFRα surface expression and used this, together with selective anti-GM-CSFR antibodies, to define GM-CSFRα kinetics in human neutrophils, and in murine blood and alveolar neutrophils in a lung injury model. Despite rapid sustained ligand-induced GM-CSFRα loss from the neutrophil surface, which persisted even following ligand removal, pro-survival effects of GM-CSF required ongoing ligand-receptor interaction. Neutrophils recruited to the lungs following LPS challenge showed initially high mGM-CSFRα expression, which along with mGM-CSFRβ declined over 24 hr; this was associated with a transient increase in bronchoalveolar lavage fluid (BALF) mGM-CSF concentration. Treating mice in an LPS challenge model with CAM-3003, an anti-mGM-CSFRα mAb, inhibited inflammatory cell influx into the lung and maintained the level of BALF mGM-CSF. Consistent with neutrophil consumption of GM-CSF, human neutrophils depleted exogenous GM-CSF, independent of protease activity. These data show that loss of membrane GM-CSFRα following GM-CSF exposure does not preclude sustained GM-CSF/GM-CSFRα signaling and that this receptor plays a key role in ligand clearance. Hence neutrophilic activation via GM-CSFR may play an important role in neutrophilic lung inflammation even in the absence of high GM-CSF levels or GM-CSFRα expression

Widespread drying of European peatlands in recent centuries

This is the author accepted manuscript. The final version is available from Nature Research via the DOI in this record Climate warming and human impacts are thought to be causing peatlands to dry,potentially converting them from sinks to sources of carbon. However, it is unclear whether the hydrological status of peatlands has moved beyond their natural envelope. Here we show that European peatlands have undergone substantial, widespread drying during the last ~300 years. We analyse testate amoeba-derived hydrological reconstructions from 31 peatlands across Britain, Ireland, Scandinavia and continental Europe to examine changes in peatland surface wetness during the last 2000 years. 60% of our study sites were drier during the period CE 1800-2000 than they have been for the last 600 years; 40% of sites were drier than they have been for 1000 years; and 24% of sites were drier than they have been for 2000 years. This marked recent transition in the hydrology of European peatlands is concurrent with compound pressures including climatic drying, warming and direct human impacts on peatlands, although these factors vary between regions and individual sites. Our results suggest that the wetness of many European peatlands may now be moving away from natural baselines. Our findings highlight the need for effective management and restoration of European peatlands.Natural Environment Research Council (NERC

Identification of a BRCA2-Specific modifier locus at 6p24 related to breast cancer risk

Common genetic variants contribute to the observed variation in breast cancer risk for BRCA2 mutation carriers; those known to date have all been found through population-based genome-wide association studies (GWAS). To comprehensively identify breast cancer risk modifying loci for BRCA2 mutation carriers, we conducted a deep replication of an ongoing GWAS discovery study. Using the ranked P-values of the breast cancer associations with the imputed genotype of 1.4 M SNPs, 19,029 SNPs were selected and designed for inclusion on a custom Illumina array that included a total of 211,155 SNPs as part of a multi-consortial project. DNA samples from 3,881 breast cancer affected and 4,330 unaffected BRCA2 mutation carriers from 47 studies belonging to the Consortium of Investigators of Modifiers of BRCA1/2 were genotyped and available for analysis. We replicated previously reported breast cancer susceptibility alleles in these BRCA2 mutation carriers and for several regions (including FGFR2, MAP3K1, CDKN2A/B, and PTHLH) identified SNPs that have stronger evidence of association than those previously published. We also identified a novel susceptibility allele at 6p24 that was inversely associated with risk in BRCA2 mutation carriers (rs9348512; per allele HR = 0.85, 95% CI 0.80-0.90, P = 3.9×10−8). This SNP was not associated with breast cancer risk either in the general population or in BRCA1 mutation carriers. The locus lies within a region containing TFAP2A, which encodes a transcriptional activation protein that interacts with several tumor suppressor genes. This report identifies the first breast cancer risk locus specific to a BRCA2 mutation background. This comprehensive update of novel and previously reported breast cancer susceptibility loci contributes to the establishment of a panel of SNPs that modify breast cancer risk in BRCA2 mutation carriers. This panel may have clinical utility for women with BRCA2 mutations weighing options for medical prevention of breast cancer

An original phylogenetic approach identified mitochondrial haplogroup T1a1 as inversely associated with breast cancer risk in BRCA2 mutation carriers

Introduction: Individuals carrying pathogenic mutations in the BRCA1 and BRCA2 genes have a high lifetime risk of breast cancer. BRCA1 and BRCA2 are involved in DNA double-strand break repair, DNA alterations that can be caused by exposure to reactive oxygen species, a main source of which are mitochondria. Mitochondrial genome variations affect electron transport chain efficiency and reactive oxygen species production. Individuals with different mitochondrial haplogroups differ in their metabolism and sensitivity to oxidative stress. Variability in mitochondrial genetic background can alter reactive oxygen species production, leading to cancer risk. In the present study, we tested the hypothesis that mitochondrial haplogroups modify breast cancer risk in BRCA1/2 mutation carriers. Methods: We genotyped 22,214 (11,421 affected, 10,793 unaffected) mutation carriers belonging to the Consortium of Investigators of Modifiers of BRCA1/2 for 129 mitochondrial polymorphisms using the iCOGS array. Haplogroup inference and association detection were performed using a phylogenetic approach. ALTree was applied to explore the reference mitochondrial evolutionary tree and detect subclades enriched in affected or unaffected individuals. Results: We discovered that subclade T1a1 was depleted in affected BRCA2 mutation carriers compared with the rest of clade T (hazard ratio (HR) = 0.55; 95% confidence interval (CI), 0.34 to 0.88; P = 0.01). Compared with the most frequent haplogroup in the general population (that is, H and T clades), the T1a1 haplogroup has a HR of 0.62 (95% CI, 0.40 to 0.95; P = 0.03). We also identified three potential susceptibility loci, including G13708A/rs28359178, which has demonstrated an inverse association with familial breast cancer risk. Conclusions: This study illustrates how original approaches such as the phylogeny-based method we used can empower classical molecular epidemiological studies aimed at identifying association or risk modification effects.Peer reviewe