Constraining mantle carbon: CO2-trace element systematics in basalts and the roles of magma mixing and degassing

Our present understanding of the mantle carbon budget is in part built upon measurements of carbon concentrations in olivine hosted melt inclusions. Only a small number of such datasets are thought to have avoided degassing, having been entrapped prior to CO2 vapour saturation, and are therefore able to constrain primary CO2 concentrations. The absence of degassing in melt inclusion datasets has been inferred from the presence of strong correlations between CO2 and trace elements. In this contribution, we demonstrate that partial degassing followed by magma mixing not only retains such positive correlations, but can enhance them. Simple models of magma mixing and degassing are used to characterise how CO2-trace element systematics respond to CO2 vapour saturation in primary mantle melts entering the crust, followed by magma mixing. Positive correlations are expected between CO2 and most trace elements, and the average CO2/Ba and CO2/Nb ratios are controlled by the pressure of magma storage, rather than the CO2 concentration in the mantle. We find that the best estimates of mantle CO2 are the maximum CO2/Ba ratios observed in melt inclusion datasets, though a large number of analyses are required to adequately characterise the maximum of the CO2/Ba distribution. Using the mixing and degassing models we estimate the number of analyses required to obtain a maximum CO2/Ba observation within 10% of the mantle value. In light of our results, we reassess existing melt inclusion datasets, and find they exhibit systematics associated with partial degassing and mixing. We argue that all the data presently available is consistent with a depleted mantle CO2/Ba ratio of ~140, and there is as yet no evidence for heterogeneity in the CO2/Ba ratio of the depleted mantle

Genome-wide association study of behavioural and psychiatric features in human prion disease.

Prion diseases are rare neurodegenerative conditions causing highly variable clinical syndromes, which often include prominent neuropsychiatric symptoms. We have recently carried out a clinical study of behavioural and psychiatric symptoms in a large prospective cohort of patients with prion disease in the United Kingdom, allowing us to operationalise specific behavioural/psychiatric phenotypes as traits in human prion disease. Here, we report exploratory genome-wide association analysis on 170 of these patients and 5200 UK controls, looking for single-nucleotide polymorphisms (SNPs) associated with three behavioural/psychiatric phenotypes in the context of prion disease. We also specifically examined a selection of candidate SNPs that have shown genome-wide association with psychiatric conditions in previously published studies, and the codon 129 polymorphism of the prion protein gene, which is known to modify various aspects of the phenotype of prion disease. No SNPs reached genome-wide significance, and there was no evidence of altered burden of known psychiatric risk alleles in relevant prion cases. SNPs showing suggestive evidence of association (P<10(-5)) included several lying near genes previously implicated in association studies of other psychiatric and neurodegenerative diseases. These include ANK3, SORL1 and a region of chromosome 6p containing several genes implicated in schizophrenia and bipolar disorder. We would encourage others to acquire phenotype data in independent cohorts of patients with prion disease as well as other neurodegenerative and neuropsychiatric conditions, to allow meta-analysis that may shed clearer light on the biological basis of these complex disease manifestations, and the diseases themselves

The global melt inclusion C/Ba array: Mantle variability, melting process, or degassing?

The Earth’s mantle holds more carbon than its oceans, atmosphere and con- tinents combined, yet the distribution of carbon within the mantle remains uncertain. Our best constraints on the distribution of carbon within the up- per mantle are derived from the carbon-trace element systematics of ultra- depleted glasses and melt inclusions from mid-ocean ridge basalts. How- ever, carbon-trace element systematics are susceptible to modification by crustal processes, including concurrent degassing and mixing, and melt in- clusion decrepitation. In this study we explore how the influence of these processes varies systematically with both the mantle source and melting pro- cess, thereby modulating both global and local carbon-trace element trends. We supplement the existing melt inclusion data from Iceland with four new datasets, significantly enhancing the spatial and geochemical coverage of melt inclusion datasets from the island. Within the combined Iceland dataset there is significant variation in melt inclusion C/Ba ratio, which is tightly correlated with trace element enrichment. The trends in C/Ba- Ba space displayed by our new data coincide with the same trends in data compiled from global ocean islands and mid-ocean ridges, forming a global array. The overall structure of the global C/Ba-Ba array is not a property of the source, instead it is controlled by CO2 vapour loss pre- and post-melt inclusion entrapment; i.e., the array is a consequence of degassing creating near-constant maximum melt-inclusion carbon contents over many orders of magnitude of Ba concentration. On Iceland, extremely high C/Ba (>100) and C/Nb (>1000) ratios are found in melt inclusions from the most depleted eruptions. The high C/Ba and C/Nb ratios are unlikely to be either analytical artefacts, or to be the product of extreme fractionation of the most incompatible elements during silicate melting. Whilst high C/Ba and C/Nb ratios could be generated by regassing of melt inclusions by CO2 vapour, or by mantle melting occurring in the presence of residual graphite, we suggest the high values most likely derive from an intrinsically high C/Ba and C/Nb mantle component that makes up a small fraction of the Icelandic mantle

An equilibrium model for ribosome competition

The number of ribosomes in a cell is considered as limiting, and gene expression is thus largely determined by their cellular concentration. In this work we develop a toy model to study the trade-off between the ribosomal supply and the demand of the translation machinery, dictated by the composition of the transcript pool. Our equilibrium framework is useful to highlight qualitative behaviours and new means of gene expression regulation determined by the fine balance of this trade-off. We also speculate on the possible impact of these mechanisms on cellular physiology

Imaging and CSF analyses effectively distinguish CJD from its mimics

OBJECTIVE: To review clinical and investigation findings in patients referred to a specialist prion clinic who were suspected to have sporadic Creutzfeldt-Jakob disease (sCJD) and yet were found to have an alternative final diagnosis. METHODS: Review the clinical findings and investigations in 214 patients enrolled into the UK National Prion Monitoring Cohort Study between October 2008 and November 2015 who had postmortem confirmed sCJD and compare these features with 50 patients referred over the same period who had an alternative final diagnosis (CJD mimics). RESULTS: Patients with an alternative diagnosis and those with sCJD were of similar age, sex and frequency of dementia but CJD mimics had a longer clinical history. Myoclonus, rigidity and hallucinations were more frequent in patients with sCJD but these features were not helpful in classifying individual patients. Alzheimer's disease, dementia with Lewy bodies and genetic neurodegenerative disorders were alternative diagnoses in more than half of the CJD mimic cases, and 10% had an immune-mediated encephalopathy; lymphoma, hepatic encephalopathy and progressive multifocal leukoencephalopathy were seen more than once. Diffusion-weighted MRI was the most useful readily available test to classify cases correctly (92% CJD, 2% CJD mimics). The CSF cell count, 14-3-3 protein detection and S100B were of limited value. A positive CSF RT-QuIC test, introduced during the course of the study, was found in 89% of tested CJD cases and 0% CJD mimics. CONCLUSION: The combination of diffusion-weighted MRI analysis and CSF RT-QuIC allowed a perfect classification of sCJD versus its mimics in this study

Cognitive decline heralds onset of symptomatic inherited prion disease

The clinical effectiveness of any disease-modifying treatment for prion disease, as for other neurodegenerative disorders, will depend on early treatment before damage to neural tissue is irrevocable. Thus, there is a need to identify markers that predict disease onset in healthy at-risk individuals. Whilst imaging and neurophysiological biomarkers have shown limited use in this regard, we recently reported progressive neurophysiological changes in individuals with the inherited prion disease mutation P102L. We have also previously demonstrated a signature pattern of fronto-parietal dysfunction in mild prion disease. Here we address whether these cognitive features anticipate the onset of symptoms in a unique sample of patients with inherited prion disease. In the cross-sectional analysis, we analysed the performance of patients at three time points in the course of disease onset: prior to symptoms (n = 27), onset of subjective symptoms without positive clinical findings (n = 8) and symptomatic with positive clinical findings (n = 24). In the longitudinal analysis, we analysed data from 24 patients who were presymptomatic at the time of recruitment and were followed up over a period of up to 17 years, of whom 16 remained healthy and eight converted to become symptomatic. In the cross-sectional analysis, the key finding was that, relative to a group of 25 healthy non-gene carrier controls, patients with subjective symptoms but without positive clinical findings were impaired on a smaller but similar set of tests (Trail Making Test part A, Stroop test, Performance IQ, gesture repetition, figure recall) to those previously found to be impaired in mild prion disease. In the longitudinal analysis, Trail Making Test parts A and B, Stroop test and Performance IQ scores significantly discriminated between patients who remained presymptomatic and those who converted, even before the converters reached criteria for formal diagnosis. Notably, performance on the Stroop test significantly discriminated between presymptomatic patients and converters before the onset of clinical symptoms [area under the curve = 0.83 (95% confidence interval, 0.62–1.00), P = 0.009]. Thus, we report here, for the first time, neuropsychological abnormalities in healthy patients prior to either symptom onset or clinical diagnosis of inherited prion disease. This constitutes an important component of an evolving profile of clinical and biomarker abnormalities in this crucial group for preventive medicine

Cognitive decline heralds onset of symptomatic inherited prion disease

The clinical effectiveness of any disease-modifying treatment for prion disease, as for other neurodegenerative disorders, will depend on early treatment before damage to neural tissue is irrevocable. Thus, there is a need to identify markers which predict disease onset in healthy at-risk individuals. Whilst imaging and neurophysiological biomarkers have shown limited use in this regard, we recently reported progressive neurophysiological changes in healthy people with the inherited prion disease mutation P102L (Rudge et al, Brain 2019). We have also previously demonstrated a signature pattern of fronto-parietal dysfunction in mild prion disease (Caine et al., 2015; 2018). Here we address whether these cognitive features anticipate the onset of symptoms in a unique sample of patients with inherited prion disease. In the cross-sectional analysis, we analysed the performance of patients at three time points in the course of disease onset: prior to symptoms (n = 27), onset of subjective symptoms without positive clinical findings (n = 8) and symptomatic with positive clinical findings (n = 24). In the longitudinal analysis, we analysed data from twenty four patients who were presymptomatic at the time of recruitment and were followed up over a period of up to seventeen years, of whom sixteen remained healthy and eight converted to become symptomatic. In the cross-sectional analysis, the key finding was that, relative to a group of 25 healthy non-gene carrier controls, patients with subjective symptoms but without positive clinical findings were impaired on a smaller but very similar set of tests (Trail Making Test part A, Stroop Test, Performance IQ, gesture repetition, figure recall) to those previously found to be impaired in mild prion disease (Caine et al., 2015; 2018). In the longitudinal analysis, Trail Making Test parts A and B, Stroop test and Performance IQ scores significantly discriminated between patients who remained presymptomatic and those who converted, even before the converters reached criteria for formal diagnosis. Notably, performance on the Stroop test significantly discriminated between presymptomatic patients and converters before the onset of clinical symptoms (AUC = .83 (95% CI, 0.62-1.00), p =.009). Thus, we report here, for the first time, neuropsychological abnormalities in healthy patients prior to either symptom onset or clinical diagnosis of IPD. This constitutes an important component of an evolving profile of clinical and biomarker abnormalities in this crucial group for preventive medicine

Mechanisms of change in dialectical behaviour therapy and cognitive behaviour therapy for borderline personality disorder: A critical review of the literature

Background: Little is known about the ‘active ingredients’ of psychological therapy for Borderline Personality Disorder (BPD) despite a growing evidence base documenting its clinical effectiveness. This information can be used by clinicians to inform service planning and care pathways. Aims: To review published empirical research investigating the potential mechanisms underlying therapeutic change in Dialectical Behaviour Therapy (DBT) and Cognitive Behaviour Therapy (CBT) for BPD. Method: A thorough search of the PsychInfo, CINAHL Plus, PubMed, MEDLINE and EMBASE databases revealed research into potential mechanisms of change. Results: A total of 52 abstracts were reviewed. After a full text screen of the most relevant studies, 14 met inclusion criteria. Twelve examined DBT and two CBT. Mechanisms of change identified broadly fell into three categories: emotion regulation/self-control, skills use and therapeutic alliance/investment in treatment. Outcomes measured included general mental health diagnoses (e.g. anxiety, depression) and BPD-specific symptoms (e.g. self-harm/suicidality, impulsivity, substance misuse, anger). Conclusion: Further empirically-robust research is required to test hypotheses about the influence of the proposed mechanisms on therapeutic change in psychological therapies for BPD

Operation of Faddeev-Kernel in Configuration Space

We present a practical method to solve Faddeev three-body equations at energies above three-body breakup threshold as integral equations in coordinate space. This is an extension of previously used method for bound states and scattering states below three-body breakup threshold energy. We show that breakup components in three-body reactions produce long-range effects on Faddeev integral kernels in coordinate space, and propose numerical procedures to treat these effects. Using these techniques, we solve Faddeev equations for neutron-deuteron scattering to compare with benchmark solutions.Comment: 20 pages, 8 figures, to be published in Few-Body System

Quantitative EEG parameters correlate with the progression of human prion diseases

BACKGROUND: Prion diseases are universally fatal and often rapidly progressive neurodegenerative diseases. EEG has long been used in the diagnosis of sporadic Creutzfeldt-Jakob disease; however, the characteristic waveforms do not occur in all types of prion diseases. Here, we re-evaluate the utility of EEG by focusing on the development of biomarkers. We test whether abnormal quantitative EEG parameters can be used to measure disease progression in prion diseases or predict disease onset in healthy individuals at risk of disease. METHODS: In the National Prion Monitoring Cohort study, we did quantitative encephalography on 301 occasions in 29 healthy controls and 67 patients with prion disease. The patients had either inherited prion disease or sporadic Creutzfeldt-Jakob disease. We computed the main background frequency, the α and θ power and the α/θ power ratio, then averaged these within 5 electrode groups. These measurements were then compared among participant groups and correlated with functional and cognitive scores cross-sectionally and longitudinally. RESULTS: We found lower main background frequency, α power and α/θ power ratio and higher θ power in patients compared to control participants. The main background frequency, the power in the α band and the α/θ power ratio also differed in a consistent way among the patient groups. Moreover, the main background frequency and the α/θ power ratio correlated significantly with functional and cognitive scores. Longitudinally, change in these parameters also showed significant correlation with the change in clinical and cognitive scores. CONCLUSIONS: Our findings support the use of quantitative EEG to follow the progression of prion disease, with potential to help evaluate the treatment effects in future clinical-trials