A Machine Learning Approach for Identifying Amino Acid Signatures in the HIV Env Gene Predictive of Dementia

The identification of nucleotide sequence variations in viral pathogens linked to disease and clinical outcomes is important for developing vaccines and therapies. However, identifying these genetic variations in rapidly evolving pathogens adapting to selection pressures unique to each host presents several challenges. Machine learning tools provide new opportunities to address these challenges. In HIV infection, virus replicating within the brain causes HIV-associated dementia (HAD) and milder forms of neurocognitive impairment in 20–30% of patients with unsuppressed viremia. HIV neurotropism is primarily determined by the viral envelope (env) gene. To identify amino acid signatures in the HIV env gene predictive of HAD, we developed a machine learning pipeline using the PART rule-learning algorithm and C4.5 decision tree inducer to train a classifier on a meta-dataset (n = 860 env sequences from 78 patients: 40 HAD, 38 non-HAD). To increase the flexibility and biological relevance of our analysis, we included 4 numeric factors describing amino acid hydrophobicity, polarity, bulkiness, and charge, in addition to amino acid identities. The classifier had 75% predictive accuracy in leave-one-out cross-validation, and identified 5 signatures associated with HAD diagnosis (p<0.05, Fisher’s exact test). These HAD signatures were found in the majority of brain sequences from 8 of 10 HAD patients from an independent cohort. Additionally, 2 HAD signatures were validated against env sequences from CSF of a second independent cohort. This analysis provides insight into viral genetic determinants associated with HAD, and develops novel methods for applying machine learning tools to analyze the genetics of rapidly evolving pathogens

HIVBrainSeqDB: a database of annotated HIV envelope sequences from brain and other anatomical sites

<p>Abstract</p> <p>Background</p> <p>The population of HIV replicating within a host consists of independently evolving and interacting sub-populations that can be genetically distinct within anatomical compartments. HIV replicating within the brain causes neurocognitive disorders in up to 20-30% of infected individuals and is a viral sanctuary site for the development of drug resistance. The primary determinant of HIV neurotropism is macrophage tropism, which is primarily determined by the viral envelope (<it>env</it>) gene. However, studies of genetic aspects of HIV replicating in the brain are hindered because existing repositories of HIV sequences are not focused on neurotropic virus nor annotated with neurocognitive and neuropathological status. To address this need, we constructed the HIV Brain Sequence Database.</p> <p>Results</p> <p>The HIV Brain Sequence Database is a public database of HIV envelope sequences, directly sequenced from brain and other tissues from the same patients. Sequences are annotated with clinical data including viral load, CD4 count, antiretroviral status, neurocognitive impairment, and neuropathological diagnosis, all curated from the original publication. Tissue source is coded using an anatomical ontology, the Foundational Model of Anatomy, to capture the maximum level of detail available, while maintaining ontological relationships between tissues and their subparts. 44 tissue types are represented within the database, grouped into 4 categories: (i) brain, brainstem, and spinal cord; (ii) meninges, choroid plexus, and CSF; (iii) blood and lymphoid; and (iv) other (bone marrow, colon, lung, liver, etc). Patient coding is correlated across studies, allowing sequences from the same patient to be grouped to increase statistical power. Using Cytoscape, we visualized relationships between studies, patients and sequences, illustrating interconnections between studies and the varying depth of sequencing, patient number, and tissue representation across studies. Currently, the database contains 2517 envelope sequences from 90 patients, obtained from 22 published studies. 1272 sequences are from brain; the remaining 1245 are from blood, lymph node, spleen, bone marrow, colon, lung and other non-brain tissues. The database interface utilizes a faceted interface, allowing real-time combination of multiple search parameters to assemble a meta-dataset, which can be downloaded for further analysis.</p> <p>Conclusions</p> <p>This online resource, which is publicly available at <url>http://www.HIVBrainSeqDB.org</url>, will greatly facilitate analysis of the genetic aspects of HIV macrophage tropism, HIV compartmentalization and evolution within the brain and other tissue reservoirs, and the relationship of these findings to HIV-associated neurological disorders and other clinical consequences of HIV infection.</p

Computational prediction of essential genes in an unculturable endosymbiotic bacterium, Wolbachia of Brugia malayi

<p>Abstract</p> <p>Background</p> <p><it>Wolbachia </it>(<it>w</it>Bm) is an obligate endosymbiotic bacterium of <it>Brugia malayi</it>, a parasitic filarial nematode of humans and one of the causative agents of lymphatic filariasis. There is a pressing need for new drugs against filarial parasites, such as <it>B. malayi</it>. As <it>w</it>Bm is required for <it>B. malayi </it>development and fertility, targeting <it>w</it>Bm is a promising approach. However, the lifecycle of neither <it>B. malayi </it>nor <it>w</it>Bm can be maintained <it>in vitro</it>. To facilitate selection of potential drug targets we computationally ranked the <it>w</it>Bm genome based on confidence that a particular gene is essential for the survival of the bacterium.</p> <p>Results</p> <p><it>w</it>Bm protein sequences were aligned using BLAST to the Database of Essential Genes (DEG) version 5.2, a collection of 5,260 experimentally identified essential genes in 15 bacterial strains. A confidence score, the Multiple Hit Score (MHS), was developed to predict each <it>w</it>Bm gene's essentiality based on the top alignments to essential genes in each bacterial strain. This method was validated using a jackknife methodology to test the ability to recover known essential genes in a control genome. A second estimation of essentiality, the Gene Conservation Score (GCS), was calculated on the basis of phyletic conservation of genes across <it>Wolbachia's </it>parent order <it>Rickettsiales</it>. Clusters of orthologous genes were predicted within the 27 currently available complete genomes. Druggability of <it>w</it>Bm proteins was predicted by alignment to a database of protein targets of known compounds.</p> <p>Conclusion</p> <p>Ranking <it>w</it>Bm genes by either MHS or GCS predicts and prioritizes potentially essential genes. Comparison of the MHS to GCS produces quadrants representing four types of predictions: those with high confidence of essentiality by both methods (245 genes), those highly conserved across <it>Rickettsiales </it>(299 genes), those similar to distant essential genes (8 genes), and those with low confidence of essentiality (253 genes). These data facilitate selection of <it>w</it>Bm genes for entry into drug design pipelines.</p

The anti-fibrotic effect of inhibition of TGFβ-ALK5 signalling in experimental pulmonary fibrosis in mice is attenuated in the presence of concurrent γ-herpesvirus infection.

Journal ArticleTGFβ-ALK5 pro-fibrotic signalling and herpesvirus infections have been implicated in the pathogenesis and exacerbation of pulmonary fibrosis. In this study we addressed the role of TGFβ-ALK5 signalling during the progression of fibrosis in a two-hit mouse model of murine γ-herpesvirus 68 (MHV-68) infection on the background of pre-existing bleomycin-induced pulmonary fibrosis. Assessment of total lung collagen levels in combination with ex vivo micro-computed tomography (µCT) analysis of whole lungs demonstrated that MHV-68 infection did not enhance lung collagen deposition in this two-hit model but led to a persistent and exacerbated inflammatory response. Moreover, µCT reconstruction and analysis of the two-hit model revealed distinguishing features of diffuse ground-glass opacities and consolidation superimposed on pre-existing fibrosis that were reminiscent of those observed in acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF). Virally-infected murine fibrotic lungs further displayed evidence of extensive inflammatory cell infiltration and increased levels of CCL2, TNFα, IL-1β and IL-10. Blockade of TGFβ-ALK5 signalling attenuated lung collagen accumulation in bleomycin-alone injured mice, but this anti-fibrotic effect was reduced in the presence of concomitant viral infection. In contrast, inhibition of TGFβ-ALK5 signalling in virally-infected fibrotic lungs was associated with reduced inflammatory cell aggregates and increased levels of the antiviral cytokine IFNγ. These data reveal newly identified intricacies for the TGFβ-ALK5 signalling axis in experimental lung fibrosis, with different outcomes in response to ALK5 inhibition depending on the presence of viral infection. These findings raise important considerations for the targeting of TGFβ signalling responses in the context of pulmonary fibrosis.MRCNovartis CASE studentshi

Multi-wavelength analysis of high energy electrons in solar flares: a case study of August 20, 2002 flare

A multi-wavelength spatial and temporal analysis of solar high energy electrons is conducted using the August 20, 2002 flare of an unusually flat (gamma=1.8) hard X-ray spectrum. The flare is studied using RHESSI, Halpha, radio, TRACE, and MDI observations with advanced methods and techniques never previously applied in the solar flare context. A new method to account for X-ray Compton backscattering in the photosphere (photospheric albedo) has been used to deduce the primary X-ray flare spectra. The mean electron flux distribution has been analysed using both forward fitting and model independent inversion methods of spectral analysis. We show that the contribution of the photospheric albedo to the photon spectrum modifies the calculated mean electron flux distribution, mainly at energies below 100 keV. The positions of the Halpha emission and hard X-ray sources with respect to the current-free extrapolation of the MDI photospheric magnetic field and the characteristics of the radio emission provide evidence of the closed geometry of the magnetic field structure and the flare process in low altitude magnetic loops. In agreement with the predictions of some solar flare models, the hard X-ray sources are located on the external edges of the Halpha emission and show chromospheric plasma heated by the non-thermal electrons. The fast changes of Halpha intensities are located not only inside the hard X-ray sources, as expected if they are the signatures of the chromospheric response to the electron bombardment, but also away from them.Comment: 26 pages, 9 figures, accepted to Solar Physic

High Energy Particles from Monopoles Connected by Strings

Monopole-antimonopole pairs connected by strings and monopole-string networks with $N>2$ strings attached to each monopole can be formed at phase transitions in the early universe. In such hybrid defects, monopoles accelerate under the string tension and can reach ultrarelativistic Lorentz factors, $\gamma\gg 1$. We study the radiation of gauge quanta by accelerating monopoles. For monopoles with a chromomagnetic charge, we also discuss the high-energy hadron production through emission of virtual gluons and their subsequent fragmentation into hadrons. The relevant parameter for gauge boson radiation is $M/a$, where $M$ is the boson mass and $a$ is the proper acceleration of the monopole. For $M\ll a$, the gauge bosons can be considered as massless and the typical energy of the emitted quanta is $E\sim\gamma a$. In the opposite limit, $M\gg a$, the radiation power is exponentially suppressed and gauge quanta are emitted with a typical energy $E\sim\gamma M$ in a narrow range $\Delta E/E\sim (a/M)^{1/2}$. Cosmological monopole-string networks can produce photons and hadrons of extremely high energies. For a wide range of parameters these energies can be much greater than the Planck scale.Comment: 28 pages, ReVTex, 5 postscript figures. Minor changes, some references added. Submitted to Phys. Rev.

Structure and Evolution of Nearby Stars with Planets. I. Short-Period Systems

Using the Yale stellar evolution code, we have calculated theoretical models for nearby stars with planetary-mass companions in short-period nearly circular orbits: 51 Pegasi, Tau Bootis, Upsilon Andromedae, Rho Cancri, and Rho Coronae Borealis. We present tables listing key stellar parameters such as mass, radius, age, and size of the convective envelope as a function of the observable parameters (luminosity, effective temperature, and metallicity), as well as the unknown helium fraction. For each star we construct best models based on recently published spectroscopic data and the present understanding of galactic chemical evolution. We discuss our results in the context of planet formation theory, and, in particular, tidal dissipation effects and stellar metallicity enhancements.Comment: 48 pages including 13 tables and 5 figures, to appear in Ap

Regularized energy-dependent solar flare hard x-ray spectral index

The deduction from solar flare X-ray photon spectroscopic data of the energy dependent model-independent spectral index is considered as an inverse problem. Using the well developed regularization approach we analyze the energy dependency of spectral index for a high resolution energy spectrum provided by Ramaty High Energy Solar Spectroscopic Imager (RHESSI). The regularization technique produces much smoother derivatives while avoiding additional errors typical of finite differences. It is shown that observations imply a spectral index varying significantly with energy, in a way that also varies with time as the flare progresses. The implications of these findings are discussed in the solar flare context.Comment: 13 pages; 5 figures, Solar Physics in pres

de Sitter String Vacua from Kahler Uplifting

We present a new way to construct de Sitter vacua in type IIB flux compactifications, in which the interplay of the leading perturbative and non-perturbative effects stabilize all moduli in dS vacua at parametrically large volume. Here, the closed string fluxes fix the dilaton and the complex structure moduli while the universal leading perturbative quantum correction to the Kahler potential together with non-perturbative effects stabilize the volume Kahler modulus in a dS_4-vacuum. Since the quantum correction is known exactly and can be kept parametrically small, this construction leads to calculable and explicitly realized de Sitter vacua of string theory with spontaneously broken supersymmetry.Comment: 1+21 pages, 5 figures, LaTeX, uses JHEP3 class, v3: conforms with published versio

Gravitational wave background from hybrid topological defects

We investigate the spectrum of stochastic gravitational wave background generated by hybrid topological defects: domain walls bounded by strings and monopoles connected by strings. Such defects typically decay early in the history of the universe, and their mass scale is not subject to the constraints imposed by microwave background and millisecond pulsar observations. Nonetheless, the intensity of the gravitational wave background from hybrid defects can be quite high at frequencies above $10^{-8} Hz$, and in particular in the frequency range of LIGO, VIRGO and LISA detectors.Comment: 11 pages, uses ReVTeX, 2 postscript figures. Detection of a gravitational background by first generation detectors is only marginally possible, BUT detection by second generation detectors is almost certai