Latent factor analysis to discover pathway-associated putative segmental aneuploidies in human cancers.

Tumor microenvironmental stresses, such as hypoxia and lactic acidosis, play important roles in tumor progression. Although gene signatures reflecting the influence of these stresses are powerful approaches to link expression with phenotypes, they do not fully reflect the complexity of human cancers. Here, we describe the use of latent factor models to further dissect the stress gene signatures in a breast cancer expression dataset. The genes in these latent factors are coordinately expressed in tumors and depict distinct, interacting components of the biological processes. The genes in several latent factors are highly enriched in chromosomal locations. When these factors are analyzed in independent datasets with gene expression and array CGH data, the expression values of these factors are highly correlated with copy number alterations (CNAs) of the corresponding BAC clones in both the cell lines and tumors. Therefore, variation in the expression of these pathway-associated factors is at least partially caused by variation in gene dosage and CNAs among breast cancers. We have also found the expression of two latent factors without any chromosomal enrichment is highly associated with 12q CNA, likely an instance of "trans"-variations in which CNA leads to the variations in gene expression outside of the CNA region. In addition, we have found that factor 26 (1q CNA) is negatively correlated with HIF-1alpha protein and hypoxia pathways in breast tumors and cell lines. This agrees with, and for the first time links, known good prognosis associated with both a low hypoxia signature and the presence of CNA in this region. Taken together, these results suggest the possibility that tumor segmental aneuploidy makes significant contributions to variation in the lactic acidosis/hypoxia gene signatures in human cancers and demonstrate that latent factor analysis is a powerful means to uncover such a linkage.

Genetic signatures in the envelope glycoproteins of HIV-1 that associate with broadly neutralizing antibodies.

A steady increase in knowledge of the molecular and antigenic structure of the gp120 and gp41 HIV-1 envelope glycoproteins (Env) is yielding important new insights for vaccine design, but it has been difficult to translate this information to an immunogen that elicits broadly neutralizing antibodies. To help bridge this gap, we used phylogenetically corrected statistical methods to identify amino acid signature patterns in Envs derived from people who have made potently neutralizing antibodies, with the hypothesis that these Envs may share common features that would be useful for incorporation in a vaccine immunogen. Before attempting this, essentially as a control, we explored the utility of our computational methods for defining signatures of complex neutralization phenotypes by analyzing Env sequences from 251 clonal viruses that were differentially sensitive to neutralization by the well-characterized gp120-specific monoclonal antibody, b12. We identified ten b12-neutralization signatures, including seven either in the b12-binding surface of gp120 or in the V2 region of gp120 that have been previously shown to impact b12 sensitivity. A simple algorithm based on the b12 signature pattern was predictive of b12 sensitivity/resistance in an additional blinded panel of 57 viruses. Upon obtaining these reassuring outcomes, we went on to apply these same computational methods to define signature patterns in Env from HIV-1 infected individuals who had potent, broadly neutralizing responses. We analyzed a checkerboard-style neutralization dataset with sera from 69 HIV-1-infected individuals tested against a panel of 25 different Envs. Distinct clusters of sera with high and low neutralization potencies were identified. Six signature positions in Env sequences obtained from the 69 samples were found to be strongly associated with either the high or low potency responses. Five sites were in the CD4-induced coreceptor binding site of gp120, suggesting an important role for this region in the elicitation of broadly neutralizing antibody responses against HIV-1.

Modeling the evolution of regulatory elements by simultaneous detection and alignment with phylogenetic pair HMMs.

The computational detection of regulatory elements in DNA is a difficult but important problem impacting our progress in understanding the complex nature of eukaryotic gene regulation. Attempts to utilize cross-species conservation for this task have been hampered both by evolutionary changes of functional sites and poor performance of general-purpose alignment programs when applied to non-coding sequence. We describe a new and flexible framework for modeling binding site evolution in multiple related genomes, based on phylogenetic pair hidden Markov models which explicitly model the gain and loss of binding sites along a phylogeny. We demonstrate the value of this framework for both the alignment of regulatory regions and the inference of precise binding-site locations within those regions. As the underlying formalism is a stochastic, generative model, it can also be used to simulate the evolution of regulatory elements. Our implementation is scalable in terms of numbers of species and sequence lengths and can produce alignments and binding-site predictions with accuracy rivaling or exceeding current systems that specialize in only alignment or only binding-site prediction. We demonstrate the validity and power of various model components on extensive simulations of realistic sequence data and apply a specific model to study Drosophila enhancers in as many as ten related genomes and in the presence of gain and loss of binding sites. Different models and modeling assumptions can be easily specified, thus providing an invaluable tool for the exploration of biological hypotheses that can drive improvements in our understanding of the mechanisms and evolution of gene regulation.

Gene selection using iterative feature elimination random forests for survival outcomes.

Although many feature selection methods for classification have been developed, there is a need to identify genes in high-dimensional data with censored survival outcomes. Traditional methods for gene selection in classification problems have several drawbacks. First, the majority of the gene selection approaches for classification are single-gene based. Second, many of the gene selection procedures are not embedded within the algorithm itself. The technique of random forests has been found to perform well in high-dimensional data settings with survival outcomes. It also has an embedded feature to identify variables of importance. Therefore, it is an ideal candidate for gene selection in high-dimensional data with survival outcomes. In this paper, we develop a novel method based on the random forests to identify a set of prognostic genes. We compare our method with several machine learning methods and various node split criteria using several real data sets. Our method performed well in both simulations and real data analysis.Additionally, we have shown the advantages of our approach over single-gene-based approaches. Our method incorporates multivariate correlations in microarray data for survival outcomes. The described method allows us to better utilize the information available from microarray data with survival outcomes.

Computational inference of neural information flow networks.

Determining how information flows along anatomical brain pathways is a fundamental requirement for understanding how animals perceive their environments, learn, and behave. Attempts to reveal such neural information flow have been made using linear computational methods, but neural interactions are known to be nonlinear. Here, we demonstrate that a dynamic Bayesian network (DBN) inference algorithm we originally developed to infer nonlinear transcriptional regulatory networks from gene expression data collected with microarrays is also successful at inferring nonlinear neural information flow networks from electrophysiology data collected with microelectrode arrays. The inferred networks we recover from the songbird auditory pathway are correctly restricted to a subset of known anatomical paths, are consistent with timing of the system, and reveal both the importance of reciprocal feedback in auditory processing and greater information flow to higher-order auditory areas when birds hear natural as opposed to synthetic sounds. A linear method applied to the same data incorrectly produces networks with information flow to non-neural tissue and over paths known not to exist. To our knowledge, this study represents the first biologically validated demonstration of an algorithm to successfully infer neural information flow networks.

HPV clearance and the neglected role of stochasticity.

Clearance of anogenital and oropharyngeal HPV infections is attributed primarily to a successful adaptive immune response. To date, little attention has been paid to the potential role of stochastic cell dynamics in the time it takes to clear an HPV infection. In this study, we combine mechanistic mathematical models at the cellular level with epidemiological data at the population level to disentangle the respective roles of immune capacity and cell dynamics in the clearing mechanism. Our results suggest that chance-in form of the stochastic dynamics of basal stem cells-plays a critical role in the elimination of HPV-infected cell clones. In particular, we find that in immunocompetent adolescents with cervical HPV infections, the immune response may contribute less than 20% to virus clearance-the rest is taken care of by the stochastic proliferation dynamics in the basal layer. In HIV-negative individuals, the contribution of the immune response may be negligible.

The Evolution of Rachmaninov's Pianistic Style from 1892 to 1941 as Seen in Selected Original Works and Transcriptions for Piano

Unlike some other major composer-pianists (Franz Liszt and Alexander Scriabin being the most notable examples), Sergei Rachmaninov did not experience any dramatic changes in his compositional style; one can, however, notice certain stylistic differences between piano works composed during different periods of his long creative life. This dissertation argues that a clear evolution of Rachmaninov's pianistic style through his three creative periods can be traced by examining a selection of his compositions, from his first significant cycle for piano, 5 Marceaux de fantaisie, Op. 3 (1892), all the way through to his last piano work, a transcription of P.I.Tchakovsky's Lullaby, Op. 16, No. 1 (1941). Rachmaninov's life as a composer can be divided into three periods. His early period was ended abruptly by the disastrous premiere ofhis First Symphony in 1897, which caused a deep psychological crisis in the life of the young composer. Piano works of this period are often characterized by relatively simple homophonic texture, when Rachmaninov was clearly influenced by some of his Russian predecessors, most notably Tchaikovsky. His second and most productive period, also known as the period of"Russian maturity," started in 1900, when he began working on the Second Suite for two pianos, Op. 17, and the Second Concerto, Op. 18; this phase ended with the Russian Bolshevik revolution of 1917. Works of this time exhibit a mature style of piano writing, with rich, virtuosic - often considered excessive by many critics - texture and ever-increasing use of chromatic harmonies. Rachmaninov's works of the third period are limited in number owing to the composer's preoccupation with a career as pianist. Original works for piano now give way to revisions of earlier compositions and transcriptions: Rachmaninov's piano writing becomes more efficient and economical without losing any of its virtuosic brilliance. This dissertation project examines in detail, over the course of three piano recitals, a variety of works composed during the "Russian maturity" period, from several Preludes from Op. 23 (1903), the first major cycle for solo piano of the period, to 9 Etudes-Tableaux, Op.39 (1917), the last one; the early period is represented by 3 of 5 Marceaux defantaisie, Op. 3 (1892), while the late period is shown through several piano transcriptions and revised versions of the remaining 2 pieces from Op. 3.

Bridging the Divide Between the Soloist and the Ensemble Player

In conservatories and music schools, the general practice for an aspiring pianist is to focus on solo performance learning mainly solo repertoire. With the advent of the advanced degree in collaborative piano, pianists could submerge themselves in the study of duo sonatas, larger chamber music ensembles, and art song. The appearance of this degree was an important step in the development of pianists, as this kind of work requires specific training and focus to master the vast repertoire involved. However it also more clearly brought out the invisible divide separating the solo pianist from the collaborative pianist, a.k.a. the accompanist. While geniuses such as Bach, Beethoven and Brahms were known to compose and perform all types of music, the appearance of super stars such as Liszt and Paganini helped bring into being the term accompanist and since then music world has tacitly embraced this divide. The goal of my dissertational study is to show that this divide need not exist. The three recitals which comprise this dissertational project were all performed at the University of Maryland, the first on 12 November 2010 at Gildenhom Recital Hall, the second at Ulrich Recital Hall on 10 September 2011, and the third at Gildenhorn Recital Hall on 11 November 2011. The repertoire included Rachmaninoff Prelude in g# minor op. 32 no. 12 and Etude-Tableaux in Eb minor op. 29 no. 5, Brahms Sonata for Piano and Violin in d minor op. 108, Mendelssohn Piano Trio in d minor op. 49, Chopin Sonata No.2 in Bb minor, Franck Sonata for Piano and Violin, Prokofiev Piano Concerto no. 2 in g minor op. 16 with pianist Elizabeth Brown as orchestra, Beethoven Sonata for Piano and Violin in A op 47 (Kreutzer), and Paul Schoenfield Cafe Music. All works with violin and cello were performed with violinist Rebecca Racusin, and cellist Devree Lewis. The recitals were recorded on compact discs and are archived within the Digital Repository at the University of Maryland(DRUM).

The 2015 Bioinformatics Open Source Conference (BOSC 2015).

The Bioinformatics Open Source Conference (BOSC) is organized by the Open Bioinformatics Foundation (OBF), a nonprofit group dedicated to promoting the practice and philosophy of open source software development and open science within the biological research community. Since its inception in 2000, BOSC has provided bioinformatics developers with a forum for communicating the results of their latest efforts to the wider research community. BOSC offers a focused environment for developers and users to interact and share ideas about standards; software development practices; practical techniques for solving bioinformatics problems; and approaches that promote open science and sharing of data, results, and software. BOSC is run as a two-day special interest group (SIG) before the annual Intelligent Systems in Molecular Biology (ISMB) conference. BOSC 2015 took place in Dublin, Ireland, and was attended by over 125 people, about half of whom were first-time attendees. Session topics included "Data Science;" "Standards and Interoperability;" "Open Science and Reproducibility;" "Translational Bioinformatics;" "Visualization;" and "Bioinformatics Open Source Project Updates". In addition to two keynote talks and dozens of shorter talks chosen from submitted abstracts, BOSC 2015 included a panel, titled "Open Source, Open Door: Increasing Diversity in the Bioinformatics Open Source Community," that provided an opportunity for open discussion about ways to increase the diversity of participants in BOSC in particular, and in open source bioinformatics in general. The complete program of BOSC 2015 is available online at http://www.open-bio.org/wiki/BOSC_2015_Schedule.

Consistent deformations of [p,p]-type gauge field theories

Using BRST-cohomological techniques, we analyze the consistent deformations of theories describing free tensor gauge fields whose symmetries are represented by Young tableaux made of two columns of equal length p, p > 1. Under the assumptions of locality and Poincaré invariance, we find that there is no consistent deformation of these theories that non-trivially modifies the gauge algebra and/or the gauge transformations. Adding the requirement that the deformation contains no more than two derivatives, the only possible deformation is a cosmological-constant-like term. © SISSA/ISAS 2004.

Discrete-time modelling of woodwind instrument bores using wave variables

A method for simulation of acoustical bores, useful in the context of sound synthesis by physical modeling of woodwind instruments, is presented. As with previously developed methods, such as digital waveguide modeling (DWM) [Smith, Comput. Music J. 16, pp 74-91 (1992)] and the multi convolution algorithm (MCA) [Martinez et al., J. Acoust. Soc. Am. 84, pp 1620-1627 (1988)], the approach is based on a one-dimensional model of wave propagation in the bore. Both the DWM method and the MCA explicitly compute the transmission and reflection of wave variables that represent actual traveling pressure waves. The method presented in this report, the wave digital modeling (WDM) method, avoids the typical limitations associated with these methods by using a more general definition of the wave variables. An efficient and spatially modular discrete-time model is constructed from the digital representations of elemental bore units such as cylindrical sections, conical sections, and toneholes. Frequency-dependent phenomena, such as boundary losses, are approximated with digital filters. The stability of a simulation of a complete acoustic bore is investigated empirically. Results of the simulation of a full clarinet show that a very good concordance with classic transmission-line theory is obtained.

Electron impact excitation of Ar XVII

Energies for the lowest 49 levels among the 1s(2) and 1snl (n = 2-5) configurations of Ar XVII have been calculated using the GRASP code of Dyall et al. (1989, Comput. Phys. Comm., 55, 424). Additionally, radiative rates, oscillator strengths, and line strengths are calculated for all electric dipole (E1), magnetic dipole (M1), electric quadrupole (E2), and magnetic quadrupole (M2) transitions among these levels. Furthermore, collision strengths have also been calculated for all the 1176 transitions among the above 49 levels using the Dirac Atomic R-matrix Code (DARC) of Norrington & Grant (2005, Comput. Phys. Commun., in preparation), over a wide energy range up to 580 Ryd. Resonances have been resolved in the threshold region, and effective collision strengths have been obtained over a wide temperature range up to log T-e = 7.2 K. Comparisons are made with the limited results available in the literature, and the accuracy of the data is assessed. Our energy levels are estimated to be accurate to better than 0.1%, whereas results for other parameters are probably accurate to better than 20%.

Ion-Atom/Argon - Calculation of ionization cross sections by fast ion impact for neutral target atoms ranging from hydrogen to argon

A FORTRAN 90 program is presented which calculates the total cross sections, and the electron energy spectra of the singly and doubly differential cross sections for the single target ionization of neutral atoms ranging from hydrogen up to and including argon. The code is applicable for the case of both high and low Z projectile impact in fast ion-atom collisions. The theoretical models provided for the program user are based on two quantum mechanical approximations which have proved to be very successful in the study of ionization in ion-atom collisions. These are the continuum-distorted-wave (CDW) and continuum-distorted-wave eikonal-initial-state (CDW-EIS) approximations. The codes presented here extend previously published. codes for single ionization of. target hydrogen [Crothers and McCartney, Comput. Phys. Commun. 72 (1992) 288], target helium [Nesbitt, O'Rourke and Crothers, Comput. Phys. Commun. 114 (1998) 385] and target atoms ranging from lithium to neon [O'Rourke, McSherry and Crothers, Comput. Phys. Commun. 131 (2000) 129]. Cross sections for all of these target atoms may be obtained as limiting cases from the present code. Title of program: ARGON Catalogue identifier: ADSE Program summary URL: http://cpc.cs.qub.ac.uk/cpc/summaries/ADSE Program obtainable from: CPC Program Library Queen's University of Belfast, N. Ireland Licensing provisions: none Computer for which the program is designed and others on which it is operable: Computers: Four by 200 MHz Pro Pentium Linux server, DEC Alpha 21164; Four by 400 MHz Pentium 2 Xeon 450 Linux server, IBM SP2 and SUN Enterprise 3500 Installations: Queen's University, Belfast Operating systems under which the program has been tested: Red-hat Linux 5.2, Digital UNIX Version 4.0d, AIX, Solaris SunOS 5.7 Compilers: PGI workstations, DEC CAMPUS Programming language used: FORTRAN 90 with MPI directives No. of bits in a word: 64, except on Linux servers 32 Number of processors used: any number Has the code been vectorized or parallelized? Parallelized using MPI No. of bytes in distributed program, including test data, etc.: 32 189 Distribution format: tar gzip file Keywords: Single ionization, cross sections, continuum-distorted-wave model, continuum- distorted-wave eikonal-initial-state model, target atoms, wave treatment Nature of physical problem: The code calculates total, and differential cross sections for the single ionization of target atoms ranging from hydrogen up to and including argon by both light and heavy ion impact. Method of solution: ARGON allows the user to calculate the cross sections using either the CDW or CDW-EIS [J. Phys. B 16 (1983) 3229] models within the wave treatment. Restrictions on the complexity of the program: Both the CDW and CDW-EIS models are two-state perturbative approximations. Typical running time: Times vary according to input data and number of processors. For one processor the test input data for double differential cross sections (40 points) took less than one second, whereas the test input for total cross sections (20 points) took 32 minutes. Unusual features of the program: none (C) 2003 Elsevier B.V All rights reserved.

PLUMED 2: New feathers for an old bird

Enhancing sampling and analyzing simulations are central issues in molecular simulation. Recently, we introduced PLUMED, an open-source plug-in that provides some of the most popular molecular dynamics (MD) codes with implementations of a variety of different enhanced sampling algorithms and collective variables (CVs). The rapid changes in this field, in particular new directions in enhanced sampling and dimensionality reduction together with new hardware, require a code that is more flexible and more efficient. We therefore present PLUMED 2 here a,complete rewrite of the code in an object-oriented programming language (C++). This new version introduces greater flexibility and greater modularity, which both extends its core capabilities and makes it far easier to add new methods and CVs. It also has a simpler interface with the MD engines and provides a single software library containing both tools and core facilities. Ultimately, the new code better serves the ever-growing community of users and contributors in coping with the new challenges arising in the field.

Program summary

Program title: PLUMED 2

Catalogue identifier: AEEE_v2_0

Program summary URL: http://cpc.cs.qub.ac.uk/summaries/AEEE_v2_0.html

Program obtainable from: CPC Program Library, Queen's University, Belfast, N. Ireland

Licensing provisions: Yes

No. of lines in distributed program, including test data, etc.: 700646

No. of bytes in distributed program, including test data, etc.: 6618136

Distribution format: tar.gz

Programming language: ANSI-C++.

Computer: Any computer capable of running an executable produced by a C++ compiler.

Operating system: Linux operating system, Unix OSs.

Has the code been vectorized or parallelized?: Yes, parallelized using MPI.

RAM: Depends on the number of atoms, the method chosen and the collective variables used.

Classification: 3, 7.7, 23. Catalogue identifier of previous version: AEEE_v1_0.

Journal reference of previous version: Comput. Phys. Comm. 180 (2009) 1961.

External routines: GNU libmatheval, Lapack, Bias, MPI. (C) 2013 Elsevier B.V. All rights reserved.

A generalization of fiedler's lemma and some applications

In a previous paper [M. Robbiano, E.A. Martins, and I. Gutman, Extending a theorem by Fiedler and applications to graph energy, MATCH Commun. Math. Comput. Chem. 64 (2010), pp. 145-156], a lemma by Fiedler was used to obtain eigenspaces of graphs, and applied to graph energy. In this article Fiedler's lemma is generalized and this generalization is applied to graph spectra and graph energy. © 2011 Taylor & Francis.