Early Cenozoic denudation of central west Britain in response to transient and permanent uplift above a mantle plume

Upwelling mantle plumes beneath continental crust are predicted to produce difficult to quantify, modest uplift and denudation. The contribution of permanent and transient components to the uplift is also difficult to distinguish. A pulse of denudation in Britain in the Early Paleogene has been linked, although with some controversy, with the arrival of the proto-Iceland mantle plume. In this contribution we show that combining apatite and zircon (U-Th-Sm)/He and apatite fission track analyses from central west Britain with numerical modeling clearly identifies a pulse of early Cenozoic denudation. The data indicate that rock uplift and denudation were centered on the northern East Irish Sea Basin and 1.0–2.4 km of rocks were removed during the latest Cretaceous-early Paleogene. Uplift and erosion appears to have started a few million years before the earliest magmatism in the region. The regional denudation pattern mirrors the distribution of low-density magmatic rocks that has been imaged in the deep crust. However, the injection of the underplating melt is not enough to account for the total denudation. An additional regional uplift of at least 300 m is required, which is consistent with a transient thermal effect from the hot mantle plume. The rapid exhumation event ceased by ~40 Ma and the data do not require significant Neogene exhumation

Assessment of a rapid liquid-based cytology method for measuring sputum cell counts

Differential sputum cell counting is not widely available despite proven clinical utility in the management of asthma. We compared eosinophil counts obtained using liquid-based cytology (LBC), a routine histopathological processing method, and the current standard method. Eosinophil counts obtained using LBC were a strong predictor of sputum eosinophilia (≥3%) determined by the standard method suggesting LBC could be used in the management of asthma

Better Together: Expanding Rural Partnerships to Support Families

Chronic shortages of health, social service, and mental health professionals in rural areas necessitate creative partnerships in support of families. Cooperative extension professionals in Family and Consumer Sciences and community health nurses are introduced as trusted professionals in rural communities who can bring critical skills to human services teams. Multidisciplinary prevention programs offer particularly good contexts for county extension educators and community health nurses to work in collaboration with social workers. The case of grandparents raising grandchildren illustrates the critical roles that can be filled by professionals in these two fields to extend the reach of family support programs

The natural history of <i>Chlamydia trachomatis </i>infection in women:a multi-parameter evidence synthesis

Background and objectives: The evidence base supporting the National Chlamydia Screening Programme, initiated in 2003, has been questioned repeatedly, with little consensus on modelling assumptions, parameter values or evidence sources to be used in cost-effectiveness analyses. The purpose of this project was to assemble all available evidence on the prevalence and incidence of Chlamydia trachomatis (CT) in the UK and its sequelae, pelvic inflammatory disease (PID), ectopic pregnancy (EP) and tubal factor infertility (TFI) to review the evidence base in its entirety, assess its consistency and, if possible, arrive at a coherent set of estimates consistent with all the evidence. Methods: Evidence was identified using ‘high-yield’ strategies. Bayesian Multi-Parameter Evidence Synthesis models were constructed for separate subparts of the clinical and population epidemiology of CT. Where possible, different types of data sources were statistically combined to derive coherent estimates. Where evidence was inconsistent, evidence sources were re-interpreted and new estimates derived on a post-hoc basis. Results: An internally coherent set of estimates was generated, consistent with a multifaceted evidence base, fertility surveys and routine UK statistics on PID and EP. Among the key findings were that the risk of PID (symptomatic or asymptomatic) following an untreated CT infection is 17.1% [95% credible interval (CrI) 6% to 29%] and the risk of salpingitis is 7.3% (95% CrI 2.2% to 14.0%). In women aged 16–24 years, screened at annual intervals, at best, 61% (95% CrI 55% to 67%) of CT-related PID and 22% (95% CrI 7% to 43%) of all PID could be directly prevented. For women aged 16–44 years, the proportions of PID, EP and TFI that are attributable to CT are estimated to be 20% (95% CrI 6% to 38%), 4.9% (95% CrI 1.2% to 12%) and 29% (95% CrI 9% to 56%), respectively. The prevalence of TFI in the UK in women at the end of their reproductive lives is 1.1%: this is consistent with all PID carrying a relatively high risk of reproductive damage, whether diagnosed or not. Every 1000 CT infections in women aged 16–44 years, on average, gives rise to approximately 171 episodes of PID and 73 of salpingitis, 2.0 EPs and 5.1 women with TFI at age 44 years. Conclusions and research recommendations: The study establishes a set of interpretations of the major studies and study designs, under which a coherent set of estimates can be generated. CT is a significant cause of PID and TFI. CT screening is of benefit to the individual, but detection and treatment of incident infection may be more beneficial. Women with lower abdominal pain need better advice on when to seek early medical attention to avoid risk of reproductive damage. The study provides new insights into the reproductive risks of PID and the role of CT. Further research is required on the proportions of PID, EP and TFI attributable to CT to confirm predictions made in this report, and to improve the precision of key estimates. The cost-effectiveness of screening should be re-evaluated using the findings of this report. Funding: The Medical Research Council grant G0801947

Inhibition of HER2 enriches for Jagged1-dependent breast cancer stem cells: role for membrane Jagged1

Purpose: Human Epidermal Growth Factor Receptor 2 (HER2) positive breast cancer is driven by cells possessing stem-like properties of self-renewal and differentiation, referred to as Cancer Stem Cells (CSCs). CSCs are implicated in radiotherapy, chemotherapy resistance, and tumor recurrence. Notch promotes breast CSCs survival and self-renewal, and overexpression of Notch1 and the Notch ligand Jagged1 predict poor outcome. Resistance to anti-HER2 therapy in HER2+ breast cancer requires Notch1, and that combination of trastuzumab and a Gamma Secretase Inhibitor (GSI) prevents tumor relapse in xenograft models. Experimental Design: The current study investigates mechanisms by which HER2 tyrosine kinase activity regulates Notch-dependent CSC survival and tumor initiation. Results: Lapatinib-mediated HER2 inhibition shifts the population of HER2+ breast cancer cells from low membrane Jagged1 expressing to higher levels, independent of sensitivity to anti-HER2 treatment within the bulk cell population. This increase in membrane Jagged1 is associated with higher Notch receptor expression, activation, and enrichment of CSCs in vitro and in vivo. Importantly, lapatinib treatment results in growth arrest and cell death of Jagged1 low-expressing cells while the Jagged1 high-expressing cells continue to cycle. High membrane Jagged1 protein expression predicts poor overall cumulative survival in women with HER2+ breast cancer. Conclusions: These results indicate that higher membrane Jagged1 expression may be used to either predict response to anti-HER2 therapy or for detection of Notch sensitive CSCs post therapy. Sequential blockade of HER2 followed by Jagged1 or Notch could be more effective than simultaneous blockade to prevent drug resistance and tumor progression

Setting a national consensus for managing mild and blast traumatic brain injury: post-meeting consensus report

A meeting was held on Wednesday 15 January 2020 to examine the current evidence for non-routine imaging and for neuroendocrine screening in the management of military personnel with brain injury and overlapping symptom domains. The Summit aimed to specifically address the relative utility of magnetoencephalography (MEG), diffusion tensor imaging (DTI) and susceptibility weighted imaging (SWI) in the UK context. This Consensus Report discusses points of consensus, points for further discussion/points of equipoise and recommendations that arose during, and following, the meeting

How did we do that? Histories and political economies of rapid and just transitions

It is becoming increasingly clear that deep and rapid transitions in technologies, infrastructures and ways of organising the economy are imperative if we are to live safely within planetary boundaries. But what historical precedents are there for such profound shifts within short spaces of time, and what were the enabling conditions? When have transitions in sectors such as energy, food, finance and transport come about before, and how would they be brought about again? Do these episodes shed any analogous light on our current collective predicament? This paper develops an account of the politics and prospects of deeper transitions towards sustainability based on a critical empirical, but theoretically informed, reading of previous socio-technical transitions. The scale and urgency of our current ecological predicament is daunting and can be disempowering in the absence of strategic thinking about when analogous challenges have been encountered before and how societies have sought to overcome them. Providing a combination of concrete empirical examples drawn both from academic literature and a series of public workshops reflecting on these themes, this paper seeks to provide a basis for understanding as well as engaging with the scope for accelerated transitions within and beyond capitalism

Deposition and provenance of the Early Pleistocene Siliceous Member in Westbury Cave, Somerset, England

The Early Pleistocene is an important interval in the Quaternary period as a time not only of climatic and environmental change, but also of key events in human evolution. However, knowledge of this period in northwest Europe is hampered by the limited extent of deposits of this age. Westbury Cave in the Mendip Hills of Somerset preserves an understudied example of fossil-bearing Early Pleistocene sediments, with rare potential to inform our understanding of British Early Pleistocene stratigraphy and landscape evolution outside the East Anglian Crag Basin. This study identifies the processes responsible for deposition of the Early Pleistocene Siliceous Member in Westbury Cave, thereby aiding taphonomic and palaeoenvironmental interpretations of associated fossil assemblages. New excavations revealed over ten metres of Siliceous Member stratigraphy, dominated by fine-grained silts/clays with interbedded sands and gravels, interpreted as being deposited within a subterranean lake or flooded conduit with fluvial input. All sediments sampled were reversely magnetised and are assigned to the Matuyama Reversed Chron. Lithological analysis of gravel clasts revealed variable components of durable non-local and non-durable local clasts. Gravels containing the latter are interpreted as distal talus slope deposits, and those lacking non-durable lithologies as stream or flood deposits. However, it remains unclear from available data whether apparently non-local clasts were sourced from long distance or stem from a more local, now denuded catchment. Siliceous Member bio- and magnetostratigraphy suggest that deposition occurred late in the Early Pleistocene, a period apparently otherwise unrepresented in the UK.</p

Sp1-regulated expression of p11 contributes to motor neuron degeneration by membrane insertion of TASK1

Disruption in membrane excitability contributes to malfunction and differential vulnerability of specific neuronal subpopulations in a number of neurological diseases. The adaptor protein p11, and background potassium channel TASK1, have overlapping distributions in the CNS. Here, we report that the transcription factor Sp1 controls p11 expression, which impacts on excitability by hampering functional expression of TASK1. In the SOD1-G93A mouse model of ALS, Sp1-p11-TASK1 dysregulation contributes to increased excitability and vulnerability of motor neurons. Interference with either Sp1 or p11 is neuroprotective, delaying neuron loss and prolonging lifespan in this model. Nitrosative stress, a potential factor in human neurodegeneration, stimulated Sp1 expression and human p11 promoter activity, at least in part, through a Sp1-binding site. Disruption of Sp1 or p11 also has neuroprotective effects in a traumatic model of motor neuron degeneration. Together our work suggests the Sp1-p11- TASK1 pathway is a potential target for treatment of degeneration of motor neurons