Estimation of adjusted rate differences using additive negative binomial regression

Rate differences are an important effect measure in biostatistics and provide an alternative perspective to rate ratios. When the data are event counts observed during an exposure period, adjusted rate differences may be estimated using an identity-link Poisson generalised linear model, also known as additive Poisson regression. A problem with this approach is that the assumption of equality of mean and variance rarely holds in real data, which often show overdispersion. An additive negative binomial model is the natural alternative to account for this, however, standard model-fitting methods are often unable to cope with the constrained parameter space arising from the non-negativity restrictions of the additive model. In this paper, we propose a novel solution to this problem using a variant of the ECME algorithm. Our method provides a reliable way to fit an additive negative binomial regression model and also permits flexible generalisations using semi-parametric regression functions. We illustrate the method using a placebo-controlled clinical trial of fenofibrate treatment in patients with type II diabetes, where the outcome is the number of laser therapy courses administered to treat diabetic retinopathy. An R package is available that implements the proposed method. Copyright c 2015 John Wiley & Sons, Ltd

Context Specificity in Causal Signaling Networks Revealed by Phosphoprotein Profiling.

Signaling networks downstream of receptor tyrosine kinases are among the most extensively studied biological networks, but new approaches are needed to elucidate causal relationships between network components and understand how such relationships are influenced by biological context and disease. Here, we investigate the context specificity of signaling networks within a causal conceptual framework using reverse-phase protein array time-course assays and network analysis approaches. We focus on a well-defined set of signaling proteins profiled under inhibition with five kinase inhibitors in 32 contexts: four breast cancer cell lines (MCF7, UACC812, BT20, and BT549) under eight stimulus conditions. The data, spanning multiple pathways and comprising ∼70,000 phosphoprotein and ∼260,000 protein measurements, provide a wealth of testable, context-specific hypotheses, several of which we experimentally validate. Furthermore, the data provide a unique resource for computational methods development, permitting empirical assessment of causal network learning in a complex, mammalian setting.This work was supported by the National Institutes of Health National Cancer Institute (grant U54 CA112970 to J.W.G., G.B.M., S.M., and P.T.S.). S.M.H. and S.M. were supported by the UK Medical Research Council (unit program numbers MC_UP_1302/1 and MC_UP_1302/3). S.M. was a recipient of a Royal Society Wolfson Research Merit Award. The MD Anderson Cancer Center RPPA Core Facility is funded by the National Institutes of Health National Cancer Institute (Cancer Center Core Grant CA16672)

Branching dendrites with resonant membrane: a “sum-over-trips” approach

Dendrites form the major components of neurons. They are complex branching structures that receive and process thousands of synaptic inputs from other neurons. It is well known that dendritic morphology plays an important role in the function of dendrites. Another important contribution to the response characteristics of a single neuron comes from the intrinsic resonant properties of dendritic membrane. In this paper we combine the effects of dendritic branching and resonant membrane dynamics by generalising the “sum-over-trips” approach (Abbott et al. in Biol Cybernetics 66, 49–60 1991). To illustrate how this formalism can shed light on the role of architecture and resonances in determining neuronal output we consider dual recording and reconstruction data from a rat CA1 hippocampal pyramidal cell. Specifically we explore the way in which an Ih current contributes to a voltage overshoot at the soma

"Practical Knowledge" and Perceptions of Antibiotics and Antibiotic Resistance Among Drugsellers in Tanzanian Private Drugstores.

Studies indicate that antibiotics are sold against regulation and without prescription in private drugstores in rural Tanzania. The objective of the study was to explore and describe antibiotics sale and dispensing practices and link it to drugseller knowledge and perceptions of antibiotics and antibiotic resistance. Exit customers of private drugstores in eight districts were interviewed about the drugstore encounter and drugs bought. Drugsellers filled in a questionnaire with closed- and open-ended questions about antibiotics and resistance. Data were analyzed using mixed quantitative and qualitative methods. Of 350 interviewed exit customers, 24% had bought antibiotics. Thirty percent had seen a health worker before coming and almost all of these had a prescription. Antibiotics were dispensed mainly for cough, stomachache, genital complaints and diarrhea but not for malaria or headache. Dispensed drugs were assessed as relevant for the symptoms or disease presented in 83% of all cases and 51% for antibiotics specifically. Non-prescribed drugs were assessed as more relevant than the prescribed. The knowledge level of the drugseller was ranked as high or very high by 75% of the respondents. Seventy-five drugsellers from three districts participated. Seventy-nine percent stated that diseases caused by bacteria can be treated with antibiotics but 24% of these also said that antibiotics can be used for treating viral disease. Most (85%) said that STI can be treated with antibiotics while 1% said the same about headache, 4% general weakness and 3% 'all diseases'. Seventy-two percent had heard of antibiotic resistance. When describing what an antibiotic is, the respondents used six different kinds of keywords. Descriptions of what antibiotic resistance is and how it occurs were quite rational from a biomedical point of view with some exceptions. They gave rise to five categories and one theme: Perceiving antibiotic resistance based on practical experience. The drugsellers have considerable "practical knowledge" of antibiotics and a perception of antibiotic resistance based on practical experience. In the process of upgrading private drugstores and formalizing the sale of antibiotics from these outlets in resource-constrained settings, their "practical knowledge" as well as their perceptions must be taken into account in order to attain rational dispensing practices

Do Individual Females Differ Intrinsically in Their Propensity to Engage in Extra-Pair Copulations?

BACKGROUND: While many studies have investigated the occurrence of extra-pair paternity in wild populations of birds, we still know surprisingly little about whether individual females differ intrinsically in their principal readiness to copulate, and to what extent this readiness is affected by male attractiveness. METHODOLOGY/FINDINGS: To address this question I used captive zebra finches (Taeniopygia guttata) as a model system. I first measured female readiness to copulate when courted by a male for the first time in life. Second, I conducted choice-chamber experiments to assess the mating preferences of individual females prior to pair formation. I then paired females socially with a non-desired mate and once they had formed a stable pair bond, I observed the inclination of these females to engage in extra-pair copulations with various males. Females showing a high readiness to copulate when courted by a male for the first time in life were much more likely to engage in extra-pair copulations later in life than others. Male attractiveness, as measured in choice tests, was a useful predictor of whether females engaged in extra-pair copulations with these males, but, surprisingly, the attractiveness of a female's social partner had no effect on her fidelity. However, it remained unclear what made some males more attractive than others. Contrary to a widespread but rarely tested hypothesis, females did not preferentially copulate with males having a redder beak or singing at a higher rate. Rather it seemed that song rate was a confounding factor in choice-chamber experiments: song attracted the female's attention but did not increase the male's attractiveness as a copulation partner. CONCLUSIONS/SIGNIFICANCE: Intrinsic variation in female readiness to copulate as well as variation in the attractiveness of the extra-pair male but not the social partner decided the outcome of extra-pair encounters

A global characterization of the translational and transcriptional programs induced by methionine restriction through ribosome profiling and RNA-seq

Background: Among twenty amino acids, methionine has a special role as it is coded by the translation initiation codon and methionyl-tRNAi (Met-tRNAi) is required for the assembly of the translation initiation complex. Thus methionine may play a special role in global gene regulation. Methionine has also been known to play important roles in cell growth, development, cancer, and aging. In this work, we characterize the translational and transcriptional programs induced by methionine restriction (MetR) and investigate the potential mechanisms through which methionine regulates gene expression, using the budding yeast S. cerevisiae as the model organism. Results: Using ribosomal profiling and RNA-seq, we observed a broad spectrum of gene expression changes in response to MetR and identified hundreds of genes whose transcript level and/or translational efficiency changed significantly. These genes show clear functional themes, suggesting that cell slows down its growth and cell cycle progression and increases its stress resistance and maintenance in response to MetR. Interestingly, under MetR cell also decreases glycolysis and increases respiration, and increased respiration was linked to lifespan extension caused by caloric restriction. Analysis of genes whose translational efficiency changed significantly under MetR revealed different modes of translational regulation: 1) Ribosome loading patterns in the 5'UTR and coding regions of genes with increased translational efficiency suggested mechanisms both similar and different from that for the translational regulation of Gcn4 under general amino acid starvation condition; 2) Genes with decreased translational efficiency showed strong enrichment of lysine, glutamine, and glutamate codons, supporting the model that methionine can regulate translation by controlling tRNA thiolation. Conclusions: MetR induced a broad spectrum of gene expression changes at both the transcriptional and translational levels, with clear functional themes indicative of the physiological state of the cell under MetR. Different modes of translational regulation were induced by MetR, including the regulation of the ribosome loading at 5'UTR and regulation by tRNA thiolation. Since MetR extends the lifespan of many species, the list of genes we identified in this study can be good candidates for studying the mechanisms of lifespan extension.National Institutes of Health [AG043080]SCI(E)ARTICLE1

Design and function of superfast muscles : new insights into the physiology of skeletal muscle

First published online as a Review in Advance on October 24, 2005. (Some corrections may occur before final publication online and in print)Author Posting. © Annual Reviews, 2005. This article is posted here by permission of Annual Reviews for personal use, not for redistribution. The definitive version was published in Annual Review of Physiology 68 (2006): 22.1-22.29, doi:10.1146/annurev.physiol.68.040104.105418.Superfast muscles of vertebrates power sound production. The fastest, the swimbladder muscle of toadfish, generates mechanical power at frequencies in excess of 200 Hz. To operate at these frequencies, the speed of relaxation has had to increase approximately 50-fold. This increase is accomplished by modifications of three kinetic traits: (a) a fast calcium transient due to extremely high concentration of sarcoplasmic reticulum (SR)-Ca2+ pumps and parvalbumin, (b) fast off-rate of Ca2+ from troponin C due to an alteration in troponin, and (c) fast cross-bridge detachment rate constant (g, 50 times faster than that in rabbit fast-twitch muscle) due to an alteration in myosin. Although these three modifications permit swimbladder muscle to generate mechanical work at high frequencies (where locomotor muscles cannot), it comes with a cost: The high g causes a large reduction in attached force-generating cross-bridges, making the swimbladder incapable of powering low-frequency locomotory movements. Hence the locomotory and sound-producing muscles have mutually exclusive designs.This work was made possible by support from NIH grants AR38404 and AR46125 as well as the University of Pennsylvania Research Foundation

Plasmonically Enhanced Reflectance of Heat Radiation from Low-Bandgap Semiconductor Microinclusions

Increased reflectance from the inclusion of highly scattering particles at low volume fractions in an insulating dielectric offers a promising way to reduce radiative thermal losses at high temperatures. Here, we investigate plasmonic resonance driven enhanced scattering from microinclusions of low-bandgap semiconductors (InP, Si, Ge, PbS, InAs and Te) in an insulating composite to tailor its infrared reflectance for minimizing thermal losses from radiative transfer. To this end, we compute the spectral properties of the microcomposites using Monte Carlo modeling and compare them with results from Fresnel equations. The role of particle size-dependent Mie scattering and absorption efficiencies, and, scattering anisotropy are studied to identify the optimal microinclusion size and material parameters for maximizing the reflectance of the thermal radiation. For composites with Si and Ge microinclusions we obtain reflectance efficiencies of 57 - 65% for the incident blackbody radiation from sources at temperatures in the range 400 - 1600 {\deg}C. Furthermore, we observe a broadbanding of the reflectance spectra from the plasmonic resonances due to charge carriers generated from defect states within the semiconductor bandgap. Our results thus open up the possibility of developing efficient high-temperature thermal insulators through use of the low-bandgap semiconductor microinclusions in insulating dielectrics.Comment: Main article (8 Figures and 2 Tables) + Supporting Information (8 Figures