Reply to discussion on 'A high-precision U-Pb age constraint on the Rhynie Chert Konservat-Lagerstatte: time scale and other implications': Journal, 168, 863-872

We welcome the opportunity to address the points raised by Mark et al. in their discussion of the chemical abrasion isotope dilution thermal ionization mass spectrometry (CA–ID–TIMS) U–Pb age constraint on the Rhynie Chert Konservat-Lagerstätte presented by Parry et al. (2011) and also to make some further observations of our own. We begin by briefly providing some context for the benefit of the wider readership. Two radio-isotopic age constraints on the Rhynie Chert Konservat-Lagerstätte and, by corollary, its parental hydrothermal (hot-spring) system have recently been published. The first of these is a weighted mean 40Ar/39Ar plateau age of 403.9 ± 2.1 Ma (2σ) derived from the analysis of two samples of vein-hosted hydrothermal K-feldspar and a single sample of hydrothermally altered andesite (Mark et al. 2011). In order to account for systematic uncertainties associated with the 40Ar/39Ar geochronometer, Mark et al. (2011) recalculated their individual sample ages with reference to the Fish Canyon Tuff sanidine (FCs) age of 28.201 Ma (Kuiper et al. 2008), thereby producing a ‘U–Pb comparable’ mean age of 407.1 ± 2.2 Ma (2σ). An alternative ‘preferred age’ for the Rhynie hot-spring activity (407.6 ± 2.2 Ma (2σ)) has now been produced from the ‘raw’ data using the optimization model of Renne et al. (2010, 2011) (this discussion). The 40Ar/39Ar system calibrations on which these various ages are based are summarized in Table 1. The second radio-isotopic age constraint in question is a weighted mean 206Pb/238U zircon age of 411.5 ± 1.3 Ma (2σ, including decay constant- and tracer calibration-related uncertainties; MSWD = 0.12, n = 4) yielded by the Milton of Noth Andesite, a moderately altered basaltic andesite lava flow (cum near-surface sill?) that lies along the northwestern margin of the Rhynie Outlier (Parry et al. 2011). U–Pb titanite data corroborate the zircon data, and c. 411.5 Ma is interpreted as the crystallization-eruption age of the Milton of Noth Andesite. Lavas and tuffs of andesitic composition occur elsewhere within the northern half of the Rhynie Outlier (Rice & Ashcroft 2004) and a holistic view of the available evidence would suggest that these volcanic rocks represent the surficial expression of the thermal drive for the Rhynie hot-spring system. Parry et al. (2011) therefore concluded that that the U–Pb zircon age yielded by the Milton of Noth Andesite dates the Rhynie hydrothermal activity within error [our italics]

Compartmentalized megakaryocyte death generates functional platelets committed to caspase-independent death

Caspase-directed apoptosis usually fragments cells, releasing nonfunctional, prothrombogenic, membrane-bound apoptotic bodies marked for rapid engulfment by macrophages. Blood platelets are functional anucleate cells generated by specialized fragmentation of their progenitors, megakaryocytes (MKs), but committed to a constitutive caspase-independent death. Constitutive formation of the proplatelet-bearing MK was recently reported to be caspase-dependent, apparently involving mitochondrial release of cytochrome c, a known pro-apoptogenic factor. We extend those studies and report that activation of caspases in MKs, either constitutively or after Fas ligation, yields platelets that are functionally responsive and evade immediate phagocytic clearance, and retain mitochondrial transmembrane potential until constitutive platelet death ensues. Furthermore, the exclusion from the platelet progeny of caspase-9 present in the progenitor accounts for failure of mitochondrial release of cytochrome c to activate caspase-3 during platelet death. Thus, progenitor cell death by apoptosis can result in birth of multiple functional anucleate daughter cells

The Strategic Exploitation of Limited Information and Opportunity in Networked Markets

This paper studies the effect of constraining interactions within a market. A model is analysed in which boundedly rational agents trade with and gather information from their neighbours within a trade network. It is demonstrated that a trader’s ability to profit and to identify the equilibrium price is positively correlated with its degree of connectivity within the market. Where traders differ in their number of potential trading partners, well-connected traders are found to benefit from aggressive trading behaviour.Where information propagation is constrained by the topology of the trade network, connectedness affects the nature of the strategies employed

High-protein-low-carbohydrate diet: deleterious metabolic and cardiovascular effects depend on age

High-protein-low-carbohydrate (HP-LC) diets have become widespread. Yet their deleterious consequences, especially on glucose metabolism and arteries, have already been underlined. Our previous study (2) has already shown glucose intolerance with major arterial dysfunction in very old mice subjected to an HP-LC diet. The hypothesis of this work was that this diet had an age-dependent deleterious metabolic and cardiovascular outcome. Two groups of mice, young and adult (3 and 6 mo old), were subjected for 12 wk to a standard or to an HP-LC diet. Glucose and lipid metabolism was studied. The cardiovascular system was explored from the functional stage with Doppler-echography to the molecular stage (arterial reactivity, mRNA, immunohistochemistry). Young mice did not exhibit any significant metabolic modification, whereas adult mice presented marked glucose intolerance associated with an increase in resistin and triglyceride levels. These metabolic disturbances were responsible for cardiovascular damages only in adult mice, with decreased aortic distensibility and left ventricle dysfunction. These seemed to be the consequence of arterial dysfunctions. Mesenteric arteries were the worst affected with a major oxidative stress, whereas aorta function seemed to be maintained with an appreciable role of cyclooxygenase-2 to preserve endothelial function. This study highlights for the first time the age-dependent deleterious effects of an HP-LC diet on metabolism, with glucose intolerance and lipid disorders and vascular (especially microvessels) and cardiac functions. This work shows that HP-LC lead to equivalent cardiovascular alterations, as observed in very old age, and underlines the danger of such diet

An Integrated TCGA Pan-Cancer Clinical Data Resource to Drive High-Quality Survival Outcome Analytics

For a decade, The Cancer Genome Atlas (TCGA) program collected clinicopathologic annotation data along with multi-platform molecular profiles of more than 11,000 human tumors across 33 different cancer types. TCGA clinical data contain key features representing the democratized nature of the data collection process. To ensure proper use of this large clinical dataset associated with genomic features, we developed a standardized dataset named the TCGA Pan-Cancer Clinical Data Resource (TCGA-CDR), which includes four major clinical outcome endpoints. In addition to detailing major challenges and statistical limitations encountered during the effort of integrating the acquired clinical data, we present a summary that includes endpoint usage recommendations for each cancer type. These TCGA-CDR findings appear to be consistent with cancer genomics studies independent of the TCGA effort and provide opportunities for investigating cancer biology using clinical correlates at an unprecedented scale. Analysis of clinicopathologic annotations for over 11,000 cancer patients in the TCGA program leads to the generation of TCGA Clinical Data Resource, which provides recommendations of clinical outcome endpoint usage for 33 cancer types

Approximate Bisimulations for Sodium Channel Dynamics

Abstract. This paper shows that, in the context of the Iyer et al. 67-variable cardiac myocycte model (IMW), it is possible to replace the detailed 13-state continuous-time MDP model of the sodium-channel dy-namics, with a much simpler Hodgkin-Huxley (HH)-like two-state sodium-channel model, while only incurring a bounded approximation error. The technical basis for this result is the construction of an approximate bisim-ulation between the HH and IMW channel models, both of which are input-controlled (voltage in this case) continuous-time Markov chains. The construction of the appropriate approximate bisimulation, as well as the overall result regarding the behavior of this modified IMW model, in-volves: (1) The identification of the voltage-dependent parameters of the m and h gates in the HH-type channel, based on the observations of the IMW channel. (2) Proving that the distance between observations of the two channels never exceeds a given error. (3) Exploring the sensitivity of the overall IMW model to the HH-type sodium-channel approximation. Our extensive simulation results experimentally validate our findings, for varying IMW-type input stimuli

Driver Fusions and Their Implications in the Development and Treatment of Human Cancers.

Gene fusions represent an important class of somatic alterations in cancer. We systematically investigated fusions in 9,624 tumors across 33 cancer types using multiple fusion calling tools. We identified a total of 25,664 fusions, with a 63% validation rate. Integration of gene expression, copy number, and fusion annotation data revealed that fusions involving oncogenes tend to exhibit increased expression, whereas fusions involving tumor suppressors have the opposite effect. For fusions involving kinases, we found 1,275 with an intact kinase domain, the proportion of which varied significantly across cancer types. Our study suggests that fusions drive the development of 16.5% of cancer cases and function as the sole driver in more than 1% of them. Finally, we identified druggable fusions involving genes such as TMPRSS2, RET, FGFR3, ALK, and ESR1 in 6.0% of cases, and we predicted immunogenic peptides, suggesting that fusions may provide leads for targeted drug and immune therapy

The Cholecystectomy As A Day Case (CAAD) Score: A Validated Score of Preoperative Predictors of Successful Day-Case Cholecystectomy Using the CholeS Data Set

Background Day-case surgery is associated with significant patient and cost benefits. However, only 43% of cholecystectomy patients are discharged home the same day. One hypothesis is day-case cholecystectomy rates, defined as patients discharged the same day as their operation, may be improved by better assessment of patients using standard preoperative variables. Methods Data were extracted from a prospectively collected data set of cholecystectomy patients from 166 UK and Irish hospitals (CholeS). Cholecystectomies performed as elective procedures were divided into main (75%) and validation (25%) data sets. Preoperative predictors were identified, and a risk score of failed day case was devised using multivariate logistic regression. Receiver operating curve analysis was used to validate the score in the validation data set. Results Of the 7426 elective cholecystectomies performed, 49% of these were discharged home the same day. Same-day discharge following cholecystectomy was less likely with older patients (OR 0.18, 95% CI 0.15–0.23), higher ASA scores (OR 0.19, 95% CI 0.15–0.23), complicated cholelithiasis (OR 0.38, 95% CI 0.31 to 0.48), male gender (OR 0.66, 95% CI 0.58–0.74), previous acute gallstone-related admissions (OR 0.54, 95% CI 0.48–0.60) and preoperative endoscopic intervention (OR 0.40, 95% CI 0.34–0.47). The CAAD score was developed using these variables. When applied to the validation subgroup, a CAAD score of ≤5 was associated with 80.8% successful day-case cholecystectomy compared with 19.2% associated with a CAAD score >5 (p < 0.001). Conclusions The CAAD score which utilises data readily available from clinic letters and electronic sources can predict same-day discharges following cholecystectomy