Geochemical Analysis of Ironstone Preserved Molluscan Fossils of the Hell Creek Formation (Cretaceous) and Ludlow Member of the Fort Union Formation (Paleogene) of Southwestern North Dakota

The uppermost Cretaceous Hell Creek Formation and Paleocene Ludlow Member of the Fort Union Formation in easternmost Montana and western North Dakota produce ironstone preserved freshwater molluscan fossils. Ironstone preserved mollusks are associated with ironstone nodules, which have been described as composed of iron carbonate, iron oxide, or manganese oxide by various researchers. To date, the exact composition of the ironstone preservation has not been satisfactorily determined to allow agreement between researchers. Freshwater mollusk fossils, preserved as ironstone external casts, molds, and steinkerns, tend to be highly weathered. The poor preservation of the fossils has resulted in little professional interest, with a limited understanding of the geochemical conditions that produced this preservational phenomenon. The intent of this project was to determine the composition of the ironstone, and attempt to constrain the geochemical conditions necessary to produce the ironstone preservation. Ironstone preserved fossils and nodules were collected from five localities in Bowman and Slope Counties in southwestern North Dakota. In order to determine the mineralogical composition, samples of mollusks and nodules were analyzed using x-ray diffraction (XRD). Four fossil and four nodule samples were sent to the University of Arizona for 18O and 13C isotope analyses. The elemental composition of three mollusks and two nodules were analyzed using a scanning electron microscope (SEM) equipped with an energy dispersive spectroscope (EDS). Composition information collected from the XRD analyses were entered into the computer program Geochemist’s Workbench®, in which Eh-pH stability diagrams were created to constrain the geochemical conditions necessary to produce ironstone preservation. XRD analyses have identified the current mineralogical composition of the ironstone nodules and fossils as siderite (FeCO3), quartz (SiO2), and goethite (FeOOH). The original nodule-forming iron mineral was identified as siderite. Analysis of thermodynamic relationships and stability diagrams indicates that siderite formation occurs within a fairly restricted range of ion activities and Eh-pH conditions. Because sulfate will preferentially combine with ferrous iron to form pyrite, the system must have little to no sulfate activity. Similarly, the fugacity of carbon dioxide must be relatively high in order to encourage the precipitation of siderite. The activity of iron must be above 10-6 mol/kg for siderite precipitation; however, increased iron activity beyond 10-6 mol/kg does not appear to increase the overall stability of siderite. From Eh-pH diagrams, it can be determined that siderite is only stable in a neutral to basic and a moderately to severely reducing environment. Ferrous iron ions may have directly replaced the calcium ions in aragonitic shells without the dissolution of aragonite and precipitation of siderite. A replacement scenario allows for the preservation of shell ornamentation observed on many of the ironstone preserved mollusks. SEM and isotope analyses indicate that the siderite was formed in a completely continental environment. The restrictions for siderite precipitation and stability provide a guide for the geochemical pore water conditions that may have existed during early diagenesis of the Hell Creek Formation and Ludlow Member

Combining isotonic regression and EM algorithm to predict genetic risk under monotonicity constraint

In certain genetic studies, clinicians and genetic counselors are interested in estimating the cumulative risk of a disease for individuals with and without a rare deleterious mutation. Estimating the cumulative risk is difficult, however, when the estimates are based on family history data. Often, the genetic mutation status in many family members is unknown; instead, only estimated probabilities of a patient having a certain mutation status are available. Also, ages of disease-onset are subject to right censoring. Existing methods to estimate the cumulative risk using such family-based data only provide estimation at individual time points, and are not guaranteed to be monotonic or nonnegative. In this paper, we develop a novel method that combines Expectation-Maximization and isotonic regression to estimate the cumulative risk across the entire support. Our estimator is monotonic, satisfies self-consistent estimating equations and has high power in detecting differences between the cumulative risks of different populations. Application of our estimator to a Parkinson's disease (PD) study provides the age-at-onset distribution of PD in PARK2 mutation carriers and noncarriers, and reveals a significant difference between the distribution in compound heterozygous carriers compared to noncarriers, but not between heterozygous carriers and noncarriers.Comment: Published in at http://dx.doi.org/10.1214/14-AOAS730 the Annals of Applied Statistics (http://www.imstat.org/aoas/) by the Institute of Mathematical Statistics (http://www.imstat.org

The effects of a graduated aerobic exercise programme on cardiovascular disease risk factors in the NHS workplace: a randomised controlled trial

BACKGROUND: Sufficient levels of physical activity provide cardio-protective benefit. However within developed society sedentary work and inflexible working hours promotes physical inactivity. Consequently to ensure a healthy workforce there is a requirement for exercise strategies adaptable to occupational time constraint. This study examined the effect of a 12 week aerobic exercise training intervention programme implemented during working hours on the cardiovascular profile of a sedentary hospital workforce. METHODS: Twenty healthy, sedentary full-time staff members of the North West London Hospital Trust cytology unit were randomly assigned to an exercise (n = 12; mean +/- SD age 41 +/- 8 years, body mass 69 +/- 12 kg) or control (n = 8; mean +/- SD age 42 +/- 8 years, body mass 69 +/- 12 kg) group. The exercise group was prescribed a progressive aerobic exercise-training programme to be performed 4 times a week for 8 weeks (initial intensity 65% peak oxygen consumption (VO2 peak)) and to be conducted without further advice for another 4 weeks. The control was instructed to maintain their current physical activity level. Oxygen economy at 2 minutes (2minVO2), 4 minutes (4minVO2), VO2 peak, systolic blood pressure (SBP), diastolic blood pressure (DBP), BMI, C-reactive protein (CRP), fasting glucose (GLU) and total cholesterol (TC) were determined in both groups pre-intervention and at 4 week intervals. Both groups completed a weekly Leisure Time Questionnaire to quantify additional exercise load. RESULTS: The exercise group demonstrated an increase from baseline for VO2 peak at week 4 (5.8 +/- 6.3 %) and 8 (5.0 +/- 8.7 %) (P < 0.05). 2minVO2 was reduced from baseline at week 4 (-10.2 +/- 10.3 %), 8 (-16.8 +/- 10.6 %) and 12 (-15.1 +/- 8.7 %), and 4minVO2 at week 8 (-10.7 +/- 7.9 %) and 12 (-6.8 +/- 9.2) (P < 0.05). There was also a reduction from baseline in CRP at week 4 (-0.4 +/- 0.6 mg.L-1) and 8 (-0.9 +/- 0.8 mg.L-1) (P < 0.05). The control group showed no such improvements. CONCLUSION: This is the first objectively monitored RCT to show that moderate exercise can be successfully incorporated into working hours, to significantly improve physical capacity and cardiovascular health

Extrapolation before imputation reduces bias when imputing censored covariates

Modeling symptom progression to identify informative subjects for a new Huntington's disease clinical trial is problematic since time to diagnosis, a key covariate, can be heavily censored. Imputation is an appealing strategy where censored covariates are replaced with their conditional means, but existing methods saw over 200% bias under heavy censoring. Calculating these conditional means well requires estimating and then integrating over the survival function of the censored covariate from the censored value to infinity. To estimate the survival function flexibly, existing methods use the semiparametric Cox model with Breslow's estimator, leaving the integrand for the conditional means (the estimated survival function) undefined beyond the observed data. The integral is then estimated up to the largest observed covariate value, and this approximation can cut off the tail of the survival function and lead to severe bias, particularly under heavy censoring. We propose a hybrid approach that splices together the semiparametric survival estimator with a parametric extension, making it possible to approximate the integral up to infinity. In simulation studies, our proposed approach of extrapolation then imputation substantially reduces the bias seen with existing imputation methods, even when the parametric extension was misspecified. We further demonstrate how imputing with corrected conditional means helps to prioritize patients for future clinical trials.Comment: 16 pages main text (incl. 2 tables and 3 figures); Supplemental Materials, R code, and R package available on GitHub (linked in main text

Exploring the validity of the complete case analysis for regression models with a right-censored covariate

Despite its drawbacks, the complete case analysis is commonly used in regression models with missing covariates. Understanding when implementing complete cases will lead to consistent parameter estimation is vital before use. Here, our aim is to demonstrate when a complete case analysis is appropriate for a nuanced type of missing covariate, the randomly right-censored covariate. Across the censored covariate literature, different assumptions are made to ensure a complete case analysis produces a consistent estimator, which leads to confusion in practice. We make several contributions to dispel this confusion. First, we summarize the language surrounding the assumptions that lead to a consistent complete case estimator. Then, we show a unidirectional hierarchical relationship between these assumptions, which leads us to one sufficient assumption to consider before using a complete case analysis. Lastly, we conduct a simulation study to illustrate the performance of a complete case analysis with a right-censored covariate under different censoring mechanism assumptions, and we demonstrate its use with a Huntington disease data example

STIM1, PKC-δ and RasGRP set a threshold for proapoptotic Erk signaling during B cell development.

Clonal deletion of autoreactive B cells is crucial for the prevention of autoimmunity, but the signaling mechanisms that regulate this checkpoint remain undefined. Here we characterize a previously unrecognized Ca(2+)-driven pathway for activation of the kinase Erk, which was proapoptotic and biochemically distinct from Erk activation induced by diacylglycerol (DAG). This pathway required protein kinase C-δ (PKC-δ) and the guanine nucleotide-exchange factor RasGRP and depended on the concentration of the Ca(2+) sensor STIM1, which controls the magnitude of Ca(2+) entry. Developmental regulation of these proteins was associated with selective activation of the pathway in B cells prone to negative selection. This checkpoint was impaired in PKC-δ-deficient mice, which developed B cell autoimmunity. Conversely, overexpression of STIM1 conferred a competitive disadvantage to developing B cells. Our findings establish Ca(2+)-dependent Erk signaling as a critical proapoptotic pathway that mediates the negative selection of B cells

Cobimetinib and trametinib inhibit platelet MEK but do not cause platelet dysfunction

The MEK inhibitors cobimetinib and trametinib are used in combination with BRAF inhibitors to treat metastatic melanoma but increase rates of hemorrhage relative to BRAF inhibitors alone. Platelets express several members of the MAPK signalling cascade including MEK1 and MEK2 and ERK1 and ERK2 but their role in platelet function and haemostasis is ambiguous as previous reports have been contradictory. It is therefore unclear if MEK inhibitors might be causing platelet dysfunction and contributing to increased hemorrhage. In the present study we performed pharmacological characterisation of cobimetinib and trametinib in vitro to investigate potential for MEK inhibitors to cause platelet dysfunction. We report that whilst both cobimetinib and trametinib are potent inhibitors of platelet MEK activity, treatment with trametinib did not alter platelet function. Treatment with cobimetinib results in inhibition of platelet aggregation, integrin activation, alpha-granule secretion and adhesion but only at suprapharmacological concentrations. We identified that the inhibitory effects of high concentrations of cobimetinib are associated with off-target inhibition on Akt and PKC. Neither inhibitor caused any alteration in thrombus formation on collagen under flow conditions in vitro. Our findings demonstrate that platelets are able to function normally when MEK activity is fully inhibited, indicating MEK activity is dispensable for normal platelet function. We conclude that the MEK inhibitors cobimetinib and trametinib do not induce platelet dysfunction and are therefore unlikely to contribute to increased incidence of bleeding reported during MEK inhibitor therapy

Challenges of the Migration and Integration of Ethiopian Entrepreneurs to South Africa

The various routes of migration-resources, networks, formal and less formal agents and the capacity of individuals undertaking the migration journey-as well as their motivation for migrating from Ethiopia to South Africa are not well understood. Yet, this inquiry couldoffer important insights into the base factors of migration within this ethnic entrepreneurial community. This study, undertaken under the auspices of the Migrating Out of Poverty Research Consortium (MOOP) at the African Centre for Migration & Society (ACMS) explored the migration industry that attends the migration of Ethiopians to South Africa. The study explored these issues through qualitative research that included long form interviews with 40 Ethiopian migrant entrepreneurs in Johannesburg and Durban. This was supplemented with desktop research and key informant interviews.DFIDMigrating out of Povert