Testing significance relative to a fold-change threshold is a TREAT

Motivation: Statistical methods are used to test for the differential expression of genes in microarray experiments. The most widely used methods successfully test whether the true differential expression is different from zero, but give no assurance that the differences found are large enough to be biologically meaningful

A Hindbrain Inhibitory Microcircuit Mediates Vagally-Coordinated Glucose Regulation

Neurons in the brainstem dorsal vagal complex integrate neural and humoral signals to coordinate autonomic output to viscera that regulate a variety of physiological functions, but how this circuitry regulates metabolism is murky. We tested the hypothesis that premotor, GABAergic neurons in the nucleus tractus solitarius (NTS) form a hindbrain micro-circuit with preganglionic parasympathetic motorneurons of the dorsal motor nucleus of the vagus (DMV) that is capable of modulating systemic blood glucose concentration. In vitro, neuronal activation or inhibition using either excitatory or inhibitory designer receptor exclusively activated by designer drugs (DREADDs) constructs expressed in GABAergic NTS neurons increased or decreased, respectively, action potential firing of GABAergic NTS neurons and downstream synaptic inhibition of the DMV. In vivo, DREADD-mediated activation of GABAergic NTS neurons increased systemic blood glucose concentration, whereas DREADD-mediated silencing of these neurons was without effect. The DREADD-induced hyperglycemia was abolished by blocking peripheral muscarinic receptors, consistent with the hypothesis that altered parasympathetic drive mediated the response. This effect was paralleled by elevated serum glucagon and hepatic phosphoenolpyruvate carboxykinase 1 (PEPCK1) expression, without affecting insulin levels or muscle metabolism. Activity in a hindbrain inhibitory microcircuit is sufficient to modulate systemic glucose concentration, independent of insulin secretion or utilization

The Subluminous Supernova 2007qd: A Missing Link in a Family of Low-Luminosity Type Ia Supernovae

We present multi-band photometry and multi-epoch spectroscopy of the peculiar Type Ia supernova (SN Ia) 2007qd, discovered by the SDSS-II Supernova Survey. It possesses physical properties intermediate to those of the peculiar SN 2002cx and the extremely low-luminosity SN 2008ha. Optical photometry indicates that it had an extraordinarily fast rise time of <= 10 days and a peak absolute B magnitude of -15.4 +/- 0.2 at most, making it one of the most subluminous SN Ia ever observed. Follow-up spectroscopy of SN 2007qd near maximum brightness unambiguously shows the presence of intermediate-mass elements which are likely caused by carbon/oxygen nuclear burning. Near maximum brightness, SN 2007qd had a photospheric velocity of only 2800 km/s, similar to that of SN 2008ha but about 4000 and 7000 km/s less than that of SN 2002cx and normal SN Ia, respectively. We show that the peak luminosities of SN 2002cx-like objects are highly correlated with both their light-curve stretch and photospheric velocities. Its strong apparent connection to other SN 2002cx-like events suggests that SN 2007qd is also a pure deflagration of a white dwarf, although other mechanisms cannot be ruled out. It may be a critical link between SN 2008ha and the other members of the SN 2002cx-like class of objects.Comment: To be published in the Astrophysical Journal; 37 pages, 13 figures, 4 table

Finding consensus for hamstring surgery in ambulatory children with cerebral palsy using the Delphi method

PURPOSE There is marked variation in indications and techniques for hamstring surgery in children with cerebral palsy. There is particular uncertainty regarding the indications for hamstring transfer compared to traditional hamstring lengthening. The purpose of this study was for an international panel of experts to use the Delphi method to establish consensus indications for hamstring surgery in ambulatory children with cerebral palsy. METHODS The panel used a five-level Likert-type scale to record agreement or disagreement with statements regarding hamstring surgery, including surgical indications and techniques, post-operative care, and outcome measures. Consensus was defined as at least 80% of responses being in the highest or lowest two of the five Likert-type ratings. General agreement was defined as 60%-79% falling into the highest or lowest two ratings. There was no agreement if neither of these thresholds was reached. RESULTS The panel reached consensus or general agreement for 38 (84%) of 45 statements regarding hamstring surgery. The panel noted the importance of assessing pelvic tilt during gait when considering hamstring surgery, and also that lateral hamstring lengthening is rarely needed, particularly at the index surgery. They noted that repeat hamstring lengthening often has poor outcomes. The panel was divided regarding hamstring transfer surgery, with only half performing such surgery. CONCLUSION The results of this study can help pediatric orthopedic surgeons optimize decision-making in their choice and practice of hamstring surgery for ambulatory children with cerebral palsy. This has the potential to reduce practice variation and significantly improve outcomes for ambulatory children with cerebral palsy. LEVEL OF EVIDENCE level V

Anterior distal femoral hemiepiphysiodesis in children with cerebral palsy: Establishing surgical indications and techniques using the modified Delphi method and literature review

PURPOSE The purpose of this study was to develop consensus for the surgical indications of anterior distal femur hemiepiphysiodesis in children with cerebral palsy using expert surgeon opinion through a modified Delphi technique. METHODS The panel used a 5-level Likert-type scale to record agreement or disagreement with 27 statements regarding anterior distal femur hemiepiphysiodesis. Consensus was defined as at least 80% of responses being in the highest or lowest 2 of the Likert-type ratings. General agreement was defined as 60%-79% falling into the highest or lowest 2 ratings. RESULTS For anterior distal femur hemiepiphysiodesis, 27 statements were surveyed: consensus or general agreement among the panelists was achieved for 22 of 27 statements (22/27, 82%) and 5 statements had no agreement (5/27, 18%). There was general consensus that anterior distal femur hemiepiphysiodesis is indicated for ambulatory children with cerebral palsy, with at least 2 years growth remaining, and smaller (<30 degrees) knee flexion contractures and for minimally ambulatory children to aid in standing/transfers. Consensus was achieved regarding the importance of close radiographic follow-up after screw insertion to identify or prevent secondary deformity. There was general agreement that percutaneous screws are preferred over anterior plates due to the pain and irritation associated with plates. Finally, it was agreed that anterior distal femur hemiepiphysiodesis was not indicated in the absence of a knee flexion contracture. CONCLUSION Anterior distal femur hemiepiphysiodesis can be used to treat fixed knee flexion contractures in the setting of crouch gait, but other associated lever arm dysfunctions must be addressed by single-event multilevel surgery. LEVEL OF EVIDENCE V

The Exceptionally Luminous Type II-L SN 2008es

We report on our early photometric and spectroscopic observations of the extremely luminous Type II supernova (SN) 2008es. With an observed peak optical magnitude of m_V = 17.8 and at a redshift z = 0.213, SN 2008es had a peak absolute magnitude of M_V = -22.3, making it the second most luminous SN ever observed. The photometric evolution of SN 2008es exhibits a fast decline rate (~0.042 mag d^-1), similar to the extremely luminous Type II-L SN 2005ap. We show that SN 2008es spectroscopically resembles the luminous Type II-L SN 1979C. Although the spectra of SN 2008es lack the narrow and intermediate-width line emission typically associated with the interaction of a SN with the circumstellar medium of its progenitor star, we argue that the extreme luminosity of SN 2008es is powered via strong interaction with a dense, optically thick circumstellar medium. The integrated bolometric luminosity of SN 2008es yields a total radiated energy at ultraviolet and optical wavelengths of >10^51 ergs. Finally, we examine the apparently anomalous rate at which the Texas Supernova Search has discovered rare kinds of supernovae, including the five most luminous supernovae observed to date, and find that their results are consistent with those of other modern SN searches.Comment: accepted to ApJ, 10 pages, 7 figures, 6 tables. Minor revisions, conclusions remain unchange

Structure of Chimpanzee Gut Microbiomes across Tropical Africa

Understanding variation in host-associated microbial communities is important given the relevance of microbiomes to host physiology and health. Using 560 fecal samples collected from wild chimpanzees (Pan troglodytes) across their range, we assessed how geography, genetics, climate, vegetation, and diet relate to gut microbial community structure (prokaryotes, eukaryotic parasites) at multiple spatial scales. We observed a high degree of regional specificity in the microbiome composition, which was associated with host genetics, available plant foods, and potentially with cultural differences in tool use, which affect diet. Genetic differences drove community composition at large scales, while vegetation and potentially tool use drove within-region differences, likely due to their influence on diet. Unlike industrialized human populations in the United States, where regional differences in the gut microbiome are undetectable, chimpanzee gut microbiomes are far more variable across space, suggesting that technological developments have decoupled humans from their local environments, obscuring regional differences that could have been important during human evolution.Additional co-authors: Heather Cohen, Charlotte Coupland, Tobias Deschner, Villard Ebot Egbe, Annemarie Goedmakers, Anne-Céline Granjon, Cyril C. Grueter, Josephine Head, R. Adriana Hernandez-Aguilar, Sorrel Jones, Parag Kadam, Michael Kaiser, Juan Lapuente, Bradley Larson, Sergio Marrocoli, David Morgan, Badru Mugerwa, Felix Mulindahabi, Emily Neil, Protais Niyigaba, Liliana Pacheco, Alex K. Piel, Martha M. Robbins, Aaron Rundus, Crickette M. Sanz, Lilah Sciaky, Douglas Sheil, Volker Sommer, Fiona A. Stewart, Els Ton, Joost van Schijndel, Virginie Vergnes, Erin G. Wessling, Roman M. Wittig, Yisa Ginath Yuh, Kyle Yurkiw, Klaus Zuberbühler, Jan F. Gogarten, Anna Heintz-Buschart, Alexandra N. Muellner-Riehl, Christophe Boesch, Hjalmar S. Kühl, Noah Fierer, Mimi Arandjelovic, Robert R. Dun

Validation of differential gene expression algorithms: Application comparing fold-change estimation to hypothesis testing

<p>Abstract</p> <p>Background</p> <p>Sustained research on the problem of determining which genes are differentially expressed on the basis of microarray data has yielded a plethora of statistical algorithms, each justified by theory, simulation, or ad hoc validation and yet differing in practical results from equally justified algorithms. Recently, a concordance method that measures agreement among gene lists have been introduced to assess various aspects of differential gene expression detection. This method has the advantage of basing its assessment solely on the results of real data analyses, but as it requires examining gene lists of given sizes, it may be unstable.</p> <p>Results</p> <p>Two methodologies for assessing predictive error are described: a cross-validation method and a posterior predictive method. As a nonparametric method of estimating prediction error from observed expression levels, cross validation provides an empirical approach to assessing algorithms for detecting differential gene expression that is fully justified for large numbers of biological replicates. Because it leverages the knowledge that only a small portion of genes are differentially expressed, the posterior predictive method is expected to provide more reliable estimates of algorithm performance, allaying concerns about limited biological replication. In practice, the posterior predictive method can assess when its approximations are valid and when they are inaccurate. Under conditions in which its approximations are valid, it corroborates the results of cross validation. Both comparison methodologies are applicable to both single-channel and dual-channel microarrays. For the data sets considered, estimating prediction error by cross validation demonstrates that empirical Bayes methods based on hierarchical models tend to outperform algorithms based on selecting genes by their fold changes or by non-hierarchical model-selection criteria. (The latter two approaches have comparable performance.) The posterior predictive assessment corroborates these findings.</p> <p>Conclusions</p> <p>Algorithms for detecting differential gene expression may be compared by estimating each algorithm's error in predicting expression ratios, whether such ratios are defined across microarray channels or between two independent groups.</p> <p>According to two distinct estimators of prediction error, algorithms using hierarchical models outperform the other algorithms of the study. The fact that fold-change shrinkage performed as well as conventional model selection criteria calls for investigating algorithms that combine the strengths of significance testing and fold-change estimation.</p

Structure of Chimpanzee Gut Microbiomes across Tropical Africa

Understanding variation in host-associated microbial communities is important given the relevance of microbiomes to host physiology and health. Using 560 fecal samples collected from wild chimpanzees (Pan troglodytes) across their range, we assessed how geography, genetics, climate, vegetation, and diet relate to gut microbial community structure (prokaryotes, eukaryotic parasites) at multiple spatial scales. We observed a high degree of regional specificity in the microbiome composition, which was associated with host genetics, available plant foods, and potentially with cultural differences in tool use, which affect diet. Genetic differences drove community composition at large scales, while vegetation and potentially tool use drove within-region differences, likely due to their influence on diet. Unlike industrialized human populations in the United States, where regional differences in the gut microbiome are undetectable, chimpanzee gut microbiomes are far more variable across space, suggesting that technological developments have decoupled humans from their local environments, obscuring regional differences that could have been important during human evolution. IMPORTANCE Gut microbial communities are drivers of primate physiology and health, but the factors that influence the gut microbiome in wild primate populations remain largely undetermined. We report data from a continent-wide survey of wild chimpanzee gut microbiota and highlight the effects of genetics, vegetation, and potentially even tool use at different spatial scales on the chimpanzee gut microbiome, including bacteria, archaea, and eukaryotic parasites. Microbial community dissimilarity was strongly correlated with chimpanzee population genetic dissimilarity, and vegetation composition and consumption of algae, honey, nuts, and termites were potentially associated with additional divergence in microbial communities between sampling sites. Our results suggest that host genetics, geography, and climate play a far stronger role in structuring the gut microbiome in chimpanzees than in humans