Evaluation of machine-learning methods for ligand-based virtual screening

Machine-learning methods can be used for virtual screening by analysing the structural characteristics of molecules of known (in)activity, and we here discuss the use of kernel discrimination and naive Bayesian classifier (NBC) methods for this purpose. We report a kernel method that allows the processing of molecules represented by binary, integer and real-valued descriptors, and show that it is little different in screening performance from a previously described kernel that had been developed specifically for the analysis of binary fingerprint representations of molecular structure. We then evaluate the performance of an NBC when the training-set contains only a very few active molecules. In such cases, a simpler approach based on group fusion would appear to provide superior screening performance, especially when structurally heterogeneous datasets are to be processed

A Regularized Graph Layout Framework for Dynamic Network Visualization

Many real-world networks, including social and information networks, are dynamic structures that evolve over time. Such dynamic networks are typically visualized using a sequence of static graph layouts. In addition to providing a visual representation of the network structure at each time step, the sequence should preserve the mental map between layouts of consecutive time steps to allow a human to interpret the temporal evolution of the network. In this paper, we propose a framework for dynamic network visualization in the on-line setting where only present and past graph snapshots are available to create the present layout. The proposed framework creates regularized graph layouts by augmenting the cost function of a static graph layout algorithm with a grouping penalty, which discourages nodes from deviating too far from other nodes belonging to the same group, and a temporal penalty, which discourages large node movements between consecutive time steps. The penalties increase the stability of the layout sequence, thus preserving the mental map. We introduce two dynamic layout algorithms within the proposed framework, namely dynamic multidimensional scaling (DMDS) and dynamic graph Laplacian layout (DGLL). We apply these algorithms on several data sets to illustrate the importance of both grouping and temporal regularization for producing interpretable visualizations of dynamic networks.Comment: To appear in Data Mining and Knowledge Discovery, supporting material (animations and MATLAB toolbox) available at http://tbayes.eecs.umich.edu/xukevin/visualization_dmkd_201

Galaxy Harassment and the Evolution of Clusters of Galaxies

Disturbed spiral galaxies with high rates of star formation pervaded clusters of galaxies just a few billion years ago, but nearby clusters exclude spirals in favor of ellipticals. ``Galaxy harassment" (frequent high speed galaxy encounters) drives the morphological transformation of galaxies in clusters, provides fuel for quasars in subluminous hosts and leaves detectable debris arcs. Simulated images of harassed galaxies are strikingly similar to the distorted spirals in clusters at $z \sim 0.4$ observed by the Hubble Space Telescope.Comment: Submitted to Nature. Latex file, 7 pages, 10 photographs in gif and jpeg format included. 10 compressed postscript figures and text available using anonymous ftp from ftp://ftp-hpcc.astro.washington.edu/pub/hpcc/moore/ (mget *) Also available at http://www-hpcc.astro.washington.edu/papers

PT-Symmetric Dimer in a Generalized Model of Coupled Nonlinear Oscillators

Abstract In the present work, we explore the case of a general PT -symmetric dimer in the context of two both linearly and nonlinearly coupled cubic oscillators. To obtain an analytical handle on the system, we first explore the rotating wave approximation converting it into a discrete nonlinear Schrödinger type dimer. In the latter context, the stationary solutions and their stability are identified numerically but also wherever possible analytically. Solutions stemming from both symmetric and anti-symmetric special limits are identified. A number of special cases are explored regarding the ratio of coefficients of nonlinearity between oscillators over the intrinsic one of each oscillator. Finally, the considerations are extended to the original oscillator model, where periodic orbits and their stability are obtained. When the solutions are found to be unstable their dynamics is monitored by means of direct numerical simulations

Node Vulnerability under Finite Perturbations in Complex Networks

A measure to quantify vulnerability under perturbations (attacks, failures, large fluctuations) in ensembles (networks) of coupled dynamical systems is proposed. Rather than addressing the issue of how the network properties change upon removal of elements of the graph (the strategy followed by most of the existing methods for studying the vulnerability of a network based on its topology), here a dynamical definition of vulnerability is introduced, referring to the robustness of a collective dynamical state to perturbing events occurring over a fixed topology. In particular, we study how the collective (synchronized) dynamics of a network of chaotic units is disrupted under the action of a finite size perturbation on one of its nodes. Illustrative examples are provided for three systems of identical chaotic oscillators coupled according to three distinct well-known network topologies. A quantitative comparison between the obtained vulnerability rankings and the classical connectivity/centrality rankings is made that yields conclusive results. Possible applications of the proposed strategy and conclusions are also discussed

A review of trisomy X (47,XXX)

Trisomy X is a sex chromosome anomaly with a variable phenotype caused by the presence of an extra X chromosome in females (47,XXX instead of 46,XX). It is the most common female chromosomal abnormality, occurring in approximately 1 in 1,000 female births. As some individuals are only mildly affected or asymptomatic, it is estimated that only 10% of individuals with trisomy X are actually diagnosed. The most common physical features include tall stature, epicanthal folds, hypotonia and clinodactyly. Seizures, renal and genitourinary abnormalities, and premature ovarian failure (POF) can also be associated findings. Children with trisomy X have higher rates of motor and speech delays, with an increased risk of cognitive deficits and learning disabilities in the school-age years. Psychological features including attention deficits, mood disorders (anxiety and depression), and other psychological disorders are also more common than in the general population. Trisomy X most commonly occurs as a result of nondisjunction during meiosis, although postzygotic nondisjunction occurs in approximately 20% of cases. The risk of trisomy X increases with advanced maternal age. The phenotype in trisomy X is hypothesized to result from overexpression of genes that escape X-inactivation, but genotype-phenotype relationships remain to be defined. Diagnosis during the prenatal period by amniocentesis or chorionic villi sampling is common. Indications for postnatal diagnoses most commonly include developmental delays or hypotonia, learning disabilities, emotional or behavioral difficulties, or POF. Differential diagnosis prior to definitive karyotype results includes fragile X, tetrasomy X, pentasomy X, and Turner syndrome mosaicism. Genetic counseling is recommended. Patients diagnosed in the prenatal period should be followed closely for developmental delays so that early intervention therapies can be implemented as needed. School-age children and adolescents benefit from a psychological evaluation with an emphasis on identifying and developing an intervention plan for problems in cognitive/academic skills, language, and/or social-emotional development. Adolescents and adult women presenting with late menarche, menstrual irregularities, or fertility problems should be evaluated for POF. Patients should be referred to support organizations to receive individual and family support. The prognosis is variable, depending on the severity of the manifestations and on the quality and timing of treatment

The roles of herbal remedies in survival and quality of life among long-term breast cancer survivors - results of a prospective study

<p>Abstract</p> <p>Background</p> <p>Few data exist on survival or health-related quality of life (QOL) related to herbal remedy use among long-term breast cancer survivors. The objective of this report is to examine whether herbal remedy use is associated with survival or the health-related QOL of these long-term breast cancer survivors.</p> <p>Methods</p> <p>In 1999-2000, we collected the information of herbal remedy use and QOL during a telephone interview with 371 Los Angeles Non-Hispanic/Hispanic white women who had survived more than 10 years after breast cancer diagnosis. QOL was measured using the Medical Outcomes Study Short Form-36 (SF-36) questionnaire. Patients were followed for mortality from the baseline interview through 2007. 299 surviving patients completed a second telephone interview on QOL in 2002-2004. We used multivariable Cox proportional hazards methods to estimate relative risks (RR) and 95% confidence intervals (CI) for mortality and applied multivariable linear regression models to compare average SF-36 change scores (follow-up - baseline) between herbal remedy users and non-users.</p> <p>Results</p> <p>Fifty-nine percent of participants were herbal remedy users at baseline. The most commonly used herbal remedies were echinacea, herbal teas, and ginko biloba. Herbal remedy use was associated with non-statistically significant increases in the risks for all-cause (44 deaths, RR = 1.28, 95% CI = 0.62-2.64) and breast cancer (33 deaths, RR = 1.78, 95% CI = 0.72-4.40) mortality. Both herbal remedy users' and non-users' mental component summary scores on the SF-36 increased similarly from the first survey to the second survey (<it>P </it>= 0.16), but herbal remedy users' physical component summary scores decreased more than those of non-users (-5.7 vs. -3.2, <it>P </it>= 0.02).</p> <p>Conclusions</p> <p>Our data provide some evidence that herbal remedy use is associated with poorer survival and a poorer physical component score for health-related QOL among women who have survived breast cancer for at least 10 years. These conclusions are based on exploratory analyses of data from a prospective study using two-sided statistical tests with no correction for multiple testing and are limited by few deaths for mortality analysis and lack of information on when herbal remedy use was initiated or duration of or reasons for use.</p

Microbial Functional Capacity Is Preserved Within Engineered Soil Formulations Used In Mine Site Restoration

Mining of mineral resources produces substantial volumes of crushed rock based wastes that are characterised by poor physical structure and hydrology, unstable geochemistry and potentially toxic chemical conditions. Recycling of these substrates is desirable and can be achieved by blending waste with native soil to form a 'novel substrate' which may be used in future landscape restoration. However, these post-mining substrate based 'soils' are likely to contain significant abiotic constraints for both plant and microbial growth. Effective use of these novel substrates for ecosystem restoration will depend on the efficacy of stored topsoil as a potential microbial inoculum as well as the subsequent generation of key microbial soil functions originally apparent in local pristine sites. Here, using both marker gene and shotgun metagenome sequencing, we show that topsoil storage and the blending of soil and waste substrates to form planting substrates gives rise to variable bacterial and archaeal phylogenetic composition but a high degree of metabolic conservation at the community metagenome level. Our data indicates that whilst low phylogenetic conservation is apparent across substrate blends we observe high functional redundancy in relation to key soil microbial pathways, allowing the potential for functional recovery of key belowground pathways under targeted management

Multisite Phosphorylation of the Guanine Nucleotide Exchange Factor Cdc24 during Yeast Cell Polarization

BACKGROUND:Cell polarization is essential for processes such as cell migration and asymmetric cell division. A common regulator of cell polarization in most eukaryotic cells is the conserved Rho GTPase, Cdc42. In budding yeast, Cdc42 is activated by a single guanine nucleotide exchange factor, Cdc24. The mechanistic details of Cdc24 activation at the onset of yeast cell polarization are unclear. Previous studies have suggested an important role for phosphorylation of Cdc24, which may regulate activity or function of the protein, representing a key step in the symmetry breaking process. METHODOLOGY/PRINCIPAL FINDINGS:Here, we directly ask whether multisite phosphorylation of Cdc24 plays a role in its regulation. We identify through mass spectrometry analysis over thirty putative in vivo phosphorylation sites. We first focus on sites matching consensus sequences for cyclin-dependent and p21-activated kinases, two kinase families that have been previously shown to phosphorylate Cdc24. Through site-directed mutagenesis, yeast genetics, and light and fluorescence microscopy, we show that nonphosphorylatable mutations of these consensus sites do not lead to any detectable consequences on growth rate, morphology, kinetics of polarization, or localization of the mutant protein. We do, however, observe a change in the mobility shift of mutant Cdc24 proteins on SDS-PAGE, suggesting that we have indeed perturbed its phosphorylation. Finally, we show that mutation of all identified phosphorylation sites does not cause observable defects in growth rate or morphology. CONCLUSIONS/SIGNIFICANCE:We conclude that lack of phosphorylation on Cdc24 has no overt functional consequences in budding yeast. Yeast cell polarization may be more tightly regulated by inactivation of Cdc42 by GTPase activating proteins or by alternative methods of Cdc24 regulation, such as conformational changes or oligomerization