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Search Results: 1 - 10 of 168 matches for " Gleb Kichaev "
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Integrating Functional Data to Prioritize Causal Variants in Statistical Fine-Mapping Studies
Gleb Kichaev,Wen-Yun Yang,Sara Lindstrom,Farhad Hormozdiari,Eleazar Eskin,Alkes L. Price,Peter Kraft,Bogdan Pasaniuc
PLOS Genetics , 2014, DOI: doi/10.1371/journal.pgen.1004722
Abstract: Standard statistical approaches for prioritization of variants for functional testing in fine-mapping studies either use marginal association statistics or estimate posterior probabilities for variants to be causal under simplifying assumptions. Here, we present a probabilistic framework that integrates association strength with functional genomic annotation data to improve accuracy in selecting plausible causal variants for functional validation. A key feature of our approach is that it empirically estimates the contribution of each functional annotation to the trait of interest directly from summary association statistics while allowing for multiple causal variants at any risk locus. We devise efficient algorithms that estimate the parameters of our model across all risk loci to further increase performance. Using simulations starting from the 1000 Genomes data, we find that our framework consistently outperforms the current state-of-the-art fine-mapping methods, reducing the number of variants that need to be selected to capture 90% of the causal variants from an average of 13.3 to 10.4 SNPs per locus (as compared to the next-best performing strategy). Furthermore, we introduce a cost-to-benefit optimization framework for determining the number of variants to be followed up in functional assays and assess its performance using real and simulation data. We validate our findings using a large scale meta-analysis of four blood lipids traits and find that the relative probability for causality is increased for variants in exons and transcription start sites and decreased in repressed genomic regions at the risk loci of these traits. Using these highly predictive, trait-specific functional annotations, we estimate causality probabilities across all traits and variants, reducing the size of the 90% confidence set from an average of 17.5 to 13.5 variants per locus in this data.
Elucidating the Kinetics of Expression and Immune Cell Infiltration Resulting from Plasmid Gene Delivery Enhanced by Surface Dermal Electroporation
Janess M. Mendoza,Dinah H. Amante,Gleb Kichaev,Christine L. Knott,William B. Kiosses,Trevor R. F. Smith,Niranjan Y. Sardesai,Kate E. Broderick
Vaccines , 2013, DOI: 10.3390/vaccines1030384
Abstract: The skin is an attractive tissue for vaccination in a clinical setting due to the accessibility of the target, the ease of monitoring and most importantly the immune competent nature of the dermal tissue. While skin electroporation offers an exciting and novel future methodology for the delivery of DNA vaccines in the clinic, little is known about the actual mechanism of the approach and the elucidation of the resulting immune responses. To further understand the mechanism of this platform, the expression kinetics and localization of a reporter plasmid delivered via a surface dermal electroporation (SEP) device as well as the effect that this treatment would have on the resident immune cells in that tissue was investigated. Initially a time course (day 0 to day 21) of enhanced gene delivery with electroporation (EP) was performed to observe the localization of green fluorescent protein (GFP) expression and the kinetics of its appearance as well as clearance. Using gross imaging, GFP expression was not detected on the surface of the skin until 8 h post treatment. However, histological analysis by fluorescent microscopy revealed GFP positive cells as early as 1 h after plasmid delivery and electroporation. Peak GFP expression was observed at 24 h and the expression was maintained in skin for up to seven days. Using an antibody specific for a keratinocyte cell surface marker, reporter gene positive keratinocytes in the epidermis were identified. H&E staining of treated skin sections demonstrated an influx of monocytes and granulocytes at the EP site starting at 4 h and persisting up to day 14 post treatment. Immunological staining revealed a significant migration of lymphocytic cells to the EP site, congregating around cells expressing the delivered antigen. In conclusion, this study provides insights into the expression kinetics following EP enhanced DNA delivery targeting the dermal space. These findings may have implications in the future to design efficient DNA vaccination strategies for the clinic.
Enhanced Delivery and Potency of Self-Amplifying mRNA Vaccines by Electroporation in Situ
Yen Cu,Kate E. Broderick,Kaustuv Banerjee,Julie Hickman,Gillis Otten,Susan Barnett,Gleb Kichaev,Niranjan Y. Sardesai,Jeffrey B. Ulmer,Andrew Geall
Vaccines , 2013, DOI: 10.3390/vaccines1030367
Abstract: Nucleic acid-based vaccines such as viral vectors, plasmid DNA (pDNA), and mRNA are being developed as a means to address limitations of both live-attenuated and subunit vaccines. DNA vaccines have been shown to be potent in a wide variety of animal species and several products are now licensed for commercial veterinary but not human use. Electroporation delivery technologies have been shown to improve the generation of T and B cell responses from synthetic DNA vaccines in many animal species and now in humans. However, parallel RNA approaches have lagged due to potential issues of potency and production. Many of the obstacles to mRNA vaccine development have recently been addressed, resulting in a revival in the use of non-amplifying and self-amplifying mRNA for vaccine and gene therapy applications. In this paper, we explore the utility of EP for the in vivo delivery of large, self-amplifying mRNA, as measured by reporter gene expression and immunogenicity of genes encoding HIV envelope protein. These studies demonstrated that EP delivery of self-amplifying mRNA elicited strong and broad immune responses in mice, which were comparable to those induced by EP delivery of pDNA.
Spectral Dependence of the Degree of Localization in a 1D Disordered System with a Complex Structural Unit  [PDF]
Gleb G. Kozlov
Applied Mathematics (AM) , 2011, DOI: 10.4236/am.2011.28133
Abstract: We analyze the spectral distribution of localisation in a 1D diagonally disordered chain of fragments each of which consist of m coupled two-level systems. The calculations performed by means of developed perturbation theory for joint statistics of advanced and retarded Green’s functions. We show that this distribution is rather inhomogeneous and reveals spectral regions of weakly localized states with sharp peaks of the localization degree in the centers of these regions.
Mammalian Auditory Cortex Structure as the Basis of Cortical Sound Processing  [PDF]
Gleb Khorunzhii, Marina Egorova
Journal of Behavioral and Brain Science (JBBS) , 2018, DOI: 10.4236/jbbs.2018.812040
Abstract: The basic morphological aspects of auditory cortex organization in different orders of eutherian mammals are considered in the present review. The modern data describing a partitioning of mammalian auditory cortex into subfields are presented. A detailed observation of the structural organization of primary auditory cortex is given, as well as a review of recent morphological data about secondary auditory areas. Another section describes the system of auditory cortical projections. The data are considered from the perspective of possible homologies existing between the auditory cortices in different mammalian species.
NoN analyticity of Hanle effect at zero magnetic field in a quantum dot
Kozlov Gleb
Physics , 2013,
Abstract: Non analytic behaviour of Hanle effect in InGaAs quantum dots is described in terms of a simple 4-level model. Despite simplicity the model makes it possible to explain the observed fracture of Hanle curve at zero magnetic field and obtain quantitative agreement with the experiment.
Monodromy zeta-function of a polynomial on a complete intersection and Newton polyhedra
Gleb Gusev
Mathematics , 2012,
Abstract: For a generic (polynomial) one-parameter deformation of a complete intersection, there is defined its monodromy zeta-function. We provide explicit formulae for this zeta-function in terms of the corresponding Newton polyhedra in the case the deformation is non-degenerate with respect to its Newton polyhedra. Using this result we obtain the formula for the monodromy zeta-function at the origin of a polynomial on a complete intersection, which is an analog of the Libgober--Sperber theorem.
Prime differential nilalgebra exists
Gleb Pogudin
Mathematics , 2013, DOI: 10.3103/S0027132214010069
Abstract: We construct a monomorphism from the differential algebra $k\{x\} / [x^m]$ to a Grassmann algebra endowed with a structure of differential algebra. Using this monomorphism we prove primality of $k\{x\} / [x^m]$ and its algebra of differential polynomials, solve one of Ritt's problems and give a new proof of integrality of the ideal $[x^m]$.
Focus-focus singularities in classical mechanics
Gleb Smirnov
Mathematics , 2013,
Abstract: In this paper the local singularities of integrable Hamiltonian systems with two degrees of freedom are studied. The topological obstruction to the existence of focus-focus singularity with given complexity was found. It has been showed that only simple focus-focus singularities can appear in a typical mechanical system. The model examples of mechanical systems with complex focus-focus singularity are given.
On Postnikov-Shapiro Algebras and their generalizations
Gleb Nenashev
Mathematics , 2015,
Abstract: In this paper we consider the original and different generalizations of Postnikov-Shapiro algebra, see~\cite{PSh}. Firstly, for a given graph $G$ and a positive integer $t$, we generalize the notion of Postnikov-Shapiro algebras counting forests in $G$ to an algebra counting $t$-labelled forests. We also prove that for large $t$ we can restore the Tutte polynomial of $G$ from the Hilbert series of such algebra. Secondly, we prove that the original Postnikov-Shapiro algebra counting forests depends only on the matroid of $G$. And conversely, we can reconstruct this matroid from the latter algebra. Similar facts hold for analogous algebras counting trees in connected graphs. Thirdly, we present a generalization of such algebras for hypergraphs. Namely, we construct a certain family of algebras for a given hypergraph, such that for almost algebras from this family, their Hilbert series is the same. Finally, we present the definition of a hypergraphical matroid, whose Tutte polynomial allows us to calculate this generic Hilbert series.
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