Convergent input from brainstem coincidence detectors onto delay-sensitive neurons in the inferior colliculus.

Responses of low-frequency neurons in the inferior colliculus (IC) of anesthetized guinea pigs were studied with binaural beats to assess their mean best interaural phase (BP) to a range of stimulating frequencies. Phase plots (stimulating frequency vs BP) were produced, from which measures of characteristic delay (CD) and characteristic phase (CP) for each neuron were obtained. The CD provides an estimate of the difference in travel time from each ear to coincidence-detector neurons in the brainstem. The CP indicates the mechanism underpinning the coincidence detector responses. A linear phase plot indicates a single, constant delay between the coincidencedetector inputs from the two ears. In more than half (54 of 90) of the neurons, the phase plot was not linear. We hypothesized that neurons with nonlinear phase plots received convergent input from brainstem coincidence detectors with different CDs. Presentation of a second tone with a fixed, unfavorable delay suppressed the response of one input, linearizing the phase plot and revealing other inputs to be relatively simple coincidence detectors. For some neurons with highly complex phase plots, the suppressor tone altered BP values, but did not resolve the nature of the inputs. For neurons with linear phase plots, the suppressor tone either completely abolished their responses or reduced their discharge rate with no change in BP. By selectively suppressing inputs with a second tone, we are able to reveal the nature of underlying binaural inputs to IC neurons, confirming the hypothesis that the complex phase plots of many IC neurons are a result of convergence from simple brainstem coincidence detectors

Origin of basalts by hybridization in andesite-dominated arcs

Mafic magmas are common in subduction zone settings, yet their high density restricts their ascent to the surface. Once stalled in the crust, these magmas may differentiate, assimilate crust and other melts and mushes to produce hybridised intermediate magmas. The Soufriere Hills Volcano on Montserrat is a ‘type locality’ for these hybridisation processes and yet, just 3 km south of the crater, voluminous basalts have erupted from the South Soufriere Hills volcano within the same time period as the Soufriere Hills Volcano was erupting hybrid andesites (131 - 128 ka). Basaltic South Soufriere Hills magmas have 48 - 53 32 wt% SiO2 and 4 - 6 wt% MgO. They were hot (970 - 1160 °C), volatile-rich (melt inclusions contain up to 6.2 wt% H2O) and were stored at 8 – 13 km prior to eruption (based on olivine and pyroxene-hosted melt inclusion volatile geochemistry). Melt inclusions do not preserve basaltic liquids: they are andesitic to rhyolitic in composition, related to one another by a line of descent controlled by simple closed-system fractionation. Whole rock compositions, however, are best described by a hybridisation model involving “back”-mixing of andesitic to rhyolitic melts with mafic crystal phases such as magnetite, olivine, orthopyroxene and clinopyroxene. Phenocryst zoning illustrates repeated mixing events between evolved melts and mafic phenocrysts, which, when coupled with the heterogeneity of crystal compositions, strongly suggests that although the bulk composition is basalt (containing Fo80 olivine), they were assembled from disparate ingredients, likely derived from mafic crystal mushes and more evolved melt lenses of variable composition. The mixing events occur days to weeks prior to eruption. We propose that the South Soufriere Hills basaltic magmas, with their higher bulk density over andesites from neighbouring volcanoes, ultimately may have been eruptible owing to both the transtensional tectonics imposed by offshore grabens (related to the oblique subduction of the Lesser Antilles) and to surface unloading caused by large scale edifice collapse. Our observations support the idea that compositional changes in arcs might reflect not only changes in source compositions, but also effects caused by patterns in crustal strain and tectonics.MC and SFLW thank NERC for financial support via grant NE/K000403/1.This is the accepted manuscript. The final version is available from OUP at http://dx.doi.org/10.1093/petrology/egv00

The Role of Tephra in Enhancing Organic Carbon Preservation in Marine Sediments

Preservation of organic carbon (Corg) in marine sediments plays a major role in defining ocean-atmosphere CO2 levels, Earth climate, and the generation of hydrocarbons. Important controls over sedimentary Corg preservation include; biological productivity, Corg isolation from oxidants (mainly dissolved O2) in the overlying water column and sediments, and Corg – mineral association in sediments. Deposition of the products of explosive volcanism (tephra) in the oceans directly enhances Corg burial through all these mechanisms, and indirectly through enhanced formation of authigenic carbonate (Cauth) derived from sedimentary Corg. In the modern oceans, it is suggested that tephra deposition may account for 5–10% of the Corg burial flux and 10–40% of the Cauth burial flux. However, during certain periods in Earth's history, extensive explosive volcanism may have led to enhanced Cauth precipitation on a sufficiently large scale to influence the global ocean-atmosphere carbon cycle. Changes in tephra-related Corg preservation may also have played a role in increasing Corg preservation rates in local marine basins, at the oxic-anoxic boundary and enhanced the generation of hydrocarbon deposits in these settings

A Comparison of Three Methods of Mendelian Randomization when the Genetic Instrument, the Risk Factor and the Outcome Are All Binary

The method of instrumental variable (referred to as Mendelian randomization when the instrument is a genetic variant) has been initially developed to infer on a causal effect of a risk factor on some outcome of interest in a linear model. Adapting this method to nonlinear models, however, is known to be problematic. In this paper, we consider the simple case when the genetic instrument, the risk factor, and the outcome are all binary. We compare via simulations the usual two-stages estimate of a causal odds-ratio and its adjusted version with a recently proposed estimate in the context of a clinical trial with noncompliance. In contrast to the former two, we confirm that the latter is (under some conditions) a valid estimate of a causal odds-ratio defined in the subpopulation of compliers, and we propose its use in the context of Mendelian randomization. By analogy with a clinical trial with noncompliance, compliers are those individuals for whom the presence/absence of the risk factor X is determined by the presence/absence of the genetic variant Z (i.e., for whom we would observe X = Z whatever the alleles randomly received at conception). We also recall and illustrate the huge variability of instrumental variable estimates when the instrument is weak (i.e., with a low percentage of compliers, as is typically the case with genetic instruments for which this proportion is frequently smaller than 10%) where the inter-quartile range of our simulated estimates was up to 18 times higher compared to a conventional (e.g., intention-to-treat) approach. We thus conclude that the need to find stronger instruments is probably as important as the need to develop a methodology allowing to consistently estimate a causal odds-ratio

Chlorhexidine Substantivity on Salivary Flora and Plaque-Like Biofilm: An In Situ Model

This work was supported by project FIS PI11/01383 from Carlos III Institute of Health (Ministry of Economy and Competitiveness, Madrid, Spain

Assessment of higher order cognitive skills in undergraduate education: modified essay or multiple choice questions? Research paper

Background: Reliable and valid written tests of higher cognitive function are difficult to produce, particularly for the assessment of clinical problem solving. Modified Essay Questions (MEQs) are often used to assess these higher order abilities in preference to other forms of assessment, including multiple-choice questions (MCQs). MEQs often form a vital component of end-of-course assessments in higher education. It is not clear how effectively these questions assess higher order cognitive skills. This study was designed to assess the effectiveness of the MEQ to measure higher-order cognitive skills in an undergraduate institution. Methods: An analysis of multiple-choice questions and modified essay questions (MEQs) used for summative assessment in a clinical undergraduate curriculum was undertaken. A total of 50 MCQs and 139 stages of MEQs were examined, which came from three exams run over two years. The effectiveness of the questions was determined by two assessors and was defined by the questions ability to measure higher cognitive skills, as determined by a modification of Bloom's taxonomy, and its quality as determined by the presence of item writing flaws. Results: Over 50% of all of the MEQs tested factual recall. This was similar to the percentage of MCQs testing factual recall. The modified essay question failed in its role of consistently assessing higher cognitive skills whereas the MCQ frequently tested more than mere recall of knowledge. Conclusion: Construction of MEQs, which will assess higher order cognitive skills cannot be assumed to be a simple task. Well-constructed MCQs should be considered a satisfactory replacement for MEQs if the MEQs cannot be designed to adequately test higher order skills. Such MCQs are capable of withstanding the intellectual and statistical scrutiny imposed by a high stakes exit examination.Edward J Palmer, Peter G Devit

Lentiviral-based reporter constructs for profiling chondrogenic activity in primary equine cell populations

Successful clinical translation of mesenchymal stem cell (MSC)-based therapies for cartilage repair will likely require the implementation of standardised protocols and broadly applicable tools to facilitate the comparisons among cell types and chondroinduction methods. The present study investigated the utility of recombinant lentiviral reporter vectors as reliable tools for comparing chondrogenic potential among primary cell populations and distinguishing cellular-level variations of chondrogenic activity in widely used three-dimensional (3D) culture systems. Primary equine MSCs and chondrocytes were transduced with vectors containing combinations of fluorescent and luciferase reporter genes under constitutive cytomeglavirus (CMV) or chondrocyte-lineage (Col2) promoters. Reporter activity was measured by fluorescence imaging and luciferase assay. In 3D cultures of MSC aggregates and polyethylene glycol-hyaluronic acid (PEG-HA) hydrogels, transforming growth factor beta 3 (TGF-β3)-mediated chondroinduction increased Col2 reporter activity, demonstrating close correlation with histology and mRNA expression levels of COL2A1 and SOX9. Comparison of chondrogenic activities among MSC populations using a secretable luciferase reporter revealed enhanced chondrogenesis in bone-marrow-derived MSCs relative to MSC populations from synovium and adipose tissues. A dual fluorescence reporter – enabling discrimination of highly chondrogenic (Col2-GFP) cells within an MSC population (CMV-tdTomato) – revealed marked heterogeneity in differentiating aggregate cultures and identified chondrogenic cells in chondrocyte-seeded PEG-HA hydrogels after 6 weeks in a subcutaneous implant model – indicating stable, long-term reporter expression in vivo. These results suggested that lentiviral reporter vectors may be used to address fundamental questions regarding chondrogenic activity in chondroprogenitor cell populations and accelerate clinical translation of cell-based cartilage repair strategies

Discovery of a small molecule agonist of phosphatidylinositol 3-kinase p110α that reactivates latent HIV-1

Combination antiretroviral therapy (cART) can effectively suppress HIV-1 replication, but the latent viral reservoir in resting memory CD4+ T cells is impervious to cART and represents a major barrier to curing HIV-1 infection. Reactivation of latent HIV-1 represents a possible strategy for elimination of this reservoir. In this study we describe the discovery of 1,2,9,10-tetramethoxy-7H-dibenzo[de,g]quinolin-7-one (57704) which reactivates latent HIV-1 in several cell-line models of latency (J89GFP, U1 and ACH-2). 57704 also increased HIV-1 expression in 3 of 4 CD8+-depleted blood mononuclear cell preparations isolated from HIV-1-infected individuals on suppressive cART. In contrast, vorinostat increased HIV-1 expression in only 1 of the 4 donors tested. Importantly, 57704 does not induce global T cell activation. Mechanistic studies revealed that 57704 reactivates latent HIV-1 via the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) signaling pathway. 57704 was found to be an agonist of PI3K with specificity to the p110a isoform, but not the p110β, δ or γ isoforms. Taken together, our work suggests that 57704 could serve as a scaffold for the development of more potent activators of latent HIV-1. Furthermore, it highlights the involvement of the PI3K/Akt pathway in the maintenance of HIV-1 latency. © 2014 Doyon et al

Recognizing speculative language in biomedical research articles: a linguistically motivated perspective

We explore a linguistically motivated approach to the problem of recognizing speculative language (“hedging”) in biomedical research articles. We describe a method, which draws on prior linguistic work as well as existing lexical resources and extends them by introducing syntactic patterns and a simple weighting scheme to estimate the speculation level of the sentences. We show that speculative language can be recognized successfully with such an approach, discuss some shortcomings of the method and point out future research possibilities.