First Steps towards Underdominant Genetic Transformation of Insect Populations

The idea of introducing genetic modifications into wild populations of insects to stop them from spreading diseases is more than 40 years old. Synthetic disease refractory genes have been successfully generated for mosquito vectors of dengue fever and human malaria. Equally important is the development of population transformation systems to drive and maintain disease refractory genes at high frequency in populations. We demonstrate an underdominant population transformation system in Drosophila melanogaster that has the property of being both spatially self-limiting and reversible to the original genetic state. Both population transformation and its reversal can be largely achieved within as few as 5 generations. The described genetic construct {Ud} is composed of two genes; (1) a UAS-RpL14.dsRNA targeting RNAi to a haploinsufficient gene RpL14 and (2) an RNAi insensitive RpL14 rescue. In this proof-of-principle system the UAS-RpL14.dsRNA knock-down gene is placed under the control of an Actin5c-GAL4 driver located on a different chromosome to the {Ud} insert. This configuration would not be effective in wild populations without incorporating the Actin5c-GAL4 driver as part of the {Ud} construct (or replacing the UAS promoter with an appropriate direct promoter). It is however anticipated that the approach that underlies this underdominant system could potentially be applied to a number of species. Figure

Setting limits on Effective Field Theories: the case of Dark Matter

The usage of Effective Field Theories (EFT) for LHC new physics searches is receiving increasing attention. It is thus important to clarify all the aspects related with the applicability of the EFT formalism in the LHC environment, where the large available energy can produce reactions that overcome the maximal range of validity, i.e. the cutoff, of the theory. We show that this does forbid to set rigorous limits on the EFT parameter space through a modified version of the ordinary binned likelihood hypothesis test, which we design and validate. Our limit-setting strategy can be carried on in its full-fledged form by the LHC experimental collaborations, or performed externally to the collaborations, through the Simplified Likelihood approach, by relying on certain approximations. We apply it to the recent CMS mono-jet analysis and derive limits on a Dark Matter (DM) EFT model. DM is selected as a case study because the limited reach on the DM production EFT Wilson coefficient and the structure of the theory suggests that the cutoff might be dangerously low, well within the LHC reach. However our strategy can also be applied to EFT's parametrising the indirect effects of heavy new physics in the Electroweak and Higgs sectors

Challenges of Profile Likelihood Evaluation in Multi-Dimensional SUSY Scans

Statistical inference of the fundamental parameters of supersymmetric theories is a challenging and active endeavor. Several sophisticated algorithms have been employed to this end. While Markov-Chain Monte Carlo (MCMC) and nested sampling techniques are geared towards Bayesian inference, they have also been used to estimate frequentist confidence intervals based on the profile likelihood ratio. We investigate the performance and appropriate configuration of MultiNest, a nested sampling based algorithm, when used for profile likelihood-based analyses both on toy models and on the parameter space of the Constrained MSSM. We find that while the standard configuration is appropriate for an accurate reconstruction of the Bayesian posterior, the profile likelihood is poorly approximated. We identify a more appropriate MultiNest configuration for profile likelihood analyses, which gives an excellent exploration of the profile likelihood (albeit at a larger computational cost), including the identification of the global maximum likelihood value. We conclude that with the appropriate configuration MultiNest is a suitable tool for profile likelihood studies, indicating previous claims to the contrary are not well founded.Comment: 21 pages, 9 figures, 1 table; minor changes following referee report. Matches version accepted by JHE

Very high energy particle acceleration powered by the jets of the microquasar SS 433

SS 433 is a binary system containing a supergiant star that is overflowing its Roche lobe with matter accreting onto a compact object (either a black hole or neutron star). Two jets of ionized matter with a bulk velocity of $\sim0.26c$ extend from the binary, perpendicular to the line of sight, and terminate inside W50, a supernova remnant that is being distorted by the jets. SS 433 differs from other microquasars in that the accretion is believed to be super-Eddington, and the luminosity of the system is $\sim10^{40}$ erg s$^{-1}$. The lobes of W50 in which the jets terminate, about 40 pc from the central source, are expected to accelerate charged particles, and indeed radio and X-ray emission consistent with electron synchrotron emission in a magnetic field have been observed. At higher energies (>100 GeV), the particle fluxes of $\gamma$ rays from X-ray hotspots around SS 433 have been reported as flux upper limits. In this energy regime, it has been unclear whether the emission is dominated by electrons that are interacting with photons from the cosmic microwave background through inverse-Compton scattering or by protons interacting with the ambient gas. Here we report TeV $\gamma$-ray observations of the SS 433/W50 system where the lobes are spatially resolved. The TeV emission is localized to structures in the lobes, far from the center of the system where the jets are formed. We have measured photon energies of at least 25 TeV, and these are certainly not Doppler boosted, because of the viewing geometry. We conclude that the emission from radio to TeV energies is consistent with a single population of electrons with energies extending to at least hundreds of TeV in a magnetic field of $\sim16$~micro-Gauss.Comment: Preprint version of Nature paper. Contacts: S. BenZvi, B. Dingus, K. Fang, C.D. Rho , H. Zhang, H. Zho

Metabolic labeling of RNA uncovers principles of RNA production and degradation dynamics in mammalian cells

available in PMC 2011 November 01.Cellular RNA levels are determined by the interplay of RNA production, processing and degradation. However, because most studies of RNA regulation do not distinguish the separate contributions of these processes, little is known about how they are temporally integrated. Here we combine metabolic labeling of RNA at high temporal resolution with advanced RNA quantification and computational modeling to estimate RNA transcription and degradation rates during the response of mouse dendritic cells to lipopolysaccharide. We find that changes in transcription rates determine the majority of temporal changes in RNA levels, but that changes in degradation rates are important for shaping sharp 'peaked' responses. We used sequencing of the newly transcribed RNA population to estimate temporally constant RNA processing and degradation rates genome wide. Degradation rates vary significantly between genes and contribute to the observed differences in the dynamic response. Certain transcripts, including those encoding cytokines and transcription factors, mature faster. Our study provides a quantitative approach to study the integrative process of RNA regulation.Human Frontier Science Program (Strasbourg, France)Howard Hughes Medical InstituteBurroughs Wellcome Fund (Career Award at the Scientific Interface

NUDT2 Disruption Elevates Diadenosine Tetraphosphate (Ap4A) and Down-Regulates Immune Response and Cancer Promotion Genes.

Regulation of gene expression is one of several roles proposed for the stress-induced nucleotide diadenosine tetraphosphate (Ap4A). We have examined this directly by a comparative RNA-Seq analysis of KBM-7 chronic myelogenous leukemia cells and KBM-7 cells in which the NUDT2 Ap4A hydrolase gene had been disrupted (NuKO cells), causing a 175-fold increase in intracellular Ap4A. 6,288 differentially expressed genes were identified with P < 0.05. Of these, 980 were up-regulated and 705 down-regulated in NuKO cells with a fold-change ≥ 2. Ingenuity® Pathway Analysis (IPA®) was used to assign these genes to known canonical pathways and functional networks. Pathways associated with interferon responses, pattern recognition receptors and inflammation scored highly in the down-regulated set of genes while functions associated with MHC class II antigens were prominent among the up-regulated genes, which otherwise showed little organization into major functional gene sets. Tryptophan catabolism was also strongly down-regulated as were numerous genes known to be involved in tumor promotion in other systems, with roles in the epithelial-mesenchymal transition, proliferation, invasion and metastasis. Conversely, some pro-apoptotic genes were up-regulated. Major upstream factors predicted by IPA® for gene down-regulation included NFκB, STAT1/2, IRF3/4 and SP1 but no major factors controlling gene up-regulation were identified. Potential mechanisms for gene regulation mediated by Ap4A and/or NUDT2 disruption include binding of Ap4A to the HINT1 co-repressor, autocrine activation of purinoceptors by Ap4A, chromatin remodeling, effects of NUDT2 loss on transcript stability, and inhibition of ATP-dependent regulatory factors such as protein kinases by Ap4A. Existing evidence favors the last of these as the most probable mechanism. Regardless, our results suggest that the NUDT2 protein could be a novel cancer chemotherapeutic target, with its inhibition potentially exerting strong anti-tumor effects via multiple pathways involving metastasis, invasion, immunosuppression and apoptosis

A922 Sequential measurement of 1 hour creatinine clearance (1-CRCL) in critically ill patients at risk of acute kidney injury (AKI)

Meeting abstrac

Eliciting Dirichlet and Gaussian copula prior distributions for multinomial models

In this paper, we propose novel methods of quantifying expert opinion about prior distributions for multinomial models. Two different multivariate priors are elicited using median and quartile assessments of the multinomial probabilities. First, we start by eliciting a univariate beta distribution for the probability of each category. Then we elicit the hyperparameters of the Dirichlet distribution, as a tractable conjugate prior, from those of the univariate betas through various forms of reconciliation using least-squares techniques. However, a multivariate copula function will give a more flexible correlation structure between multinomial parameters if it is used as their multivariate prior distribution. So, second, we use beta marginal distributions to construct a Gaussian copula as a multivariate normal distribution function that binds these marginals and expresses the dependence structure between them. The proposed method elicits a positive-definite correlation matrix of this Gaussian copula. The two proposed methods are designed to be used through interactive graphical software written in Java

Supervised multivariate analysis of sequence groups to identify specificity determining residues

<p>Abstract</p> <p>Background</p> <p>Proteins that evolve from a common ancestor can change functionality over time, and it is important to be able identify residues that cause this change. In this paper we show how a supervised multivariate statistical method, Between Group Analysis (BGA), can be used to identify these residues from families of proteins with different substrate specifities using multiple sequence alignments.</p> <p>Results</p> <p>We demonstrate the usefulness of this method on three different test cases. Two of these test cases, the Lactate/Malate dehydrogenase family and Nucleotidyl Cyclases, consist of two functional groups. The other family, Serine Proteases consists of three groups. BGA was used to analyse and visualise these three families using two different encoding schemes for the amino acids.</p> <p>Conclusion</p> <p>This overall combination of methods in this paper is powerful and flexible while being computationally very fast and simple. BGA is especially useful because it can be used to analyse any number of functional classes. In the examples we used in this paper, we have only used 2 or 3 classes for demonstration purposes but any number can be used and visualised.</p

The Stem Species of Our Species: A Place for the Archaic Human Cranium from Ceprano, Italy

One of the present challenges in the study of human evolution is to recognize the hominin taxon that was ancestral to Homo sapiens. Some researchers regard H. heidelbergensis as the stem species involved in the evolutionary divergence leading to the emergence of H. sapiens in Africa, and to the evolution of the Neandertals in Europe. Nevertheless, the diagnosis and hypodigm of H. heidelbergensis still remain to be clarified. Here we evaluate the morphology of the incomplete cranium (calvarium) known as Ceprano whose age has been recently revised to the mid of the Middle Pleistocene, so as to test whether this specimen may be included in H. heidelbergensis. The analyses were performed according to a phenetic routine including geometric morphometrics and the evaluation of diagnostic discrete traits. The results strongly support the uniqueness of H. heidelbergensis on a wide geographical horizon, including both Eurasia and Africa. In this framework, the Ceprano calvarium – with its peculiar combination of archaic and derived traits – may represent, better than other penecontemporaneous specimens, an appropriate ancestral stock of this species, preceding the appearance of regional autapomorphic features