ALBERT

Description: Motivation: To address ‘missing heritability’ issue, many statistical methods for pathway-based analyses using rare variants have been proposed to analyze pathways individually. However, neglecting correlations between multiple pathways can result in misleading solutions, and pathway-based analyses of large-scale genetic datasets require massive computational burden. We propose a Pathway-based approach using HierArchical components of collapsed RAre variants Of High-throughput sequencing data (PHARAOH) for the analysis of rare variants by constructing a single hierarchical model that consists of collapsed gene-level summaries and pathways and analyzes entire pathways simultaneously by imposing ridge-type penalties on both gene and pathway coefficient estimates; hence our method considers the correlation of pathways without constraint by a multiple testing problem. Results: Through simulation studies, the proposed method was shown to have higher statistical power than the existing pathway-based methods. In addition, our method was applied to the large-scale whole-exome sequencing data with levels of a liver enzyme using two well-known pathway databases Biocarta and KEGG. This application demonstrated that our method not only identified associated pathways but also successfully detected biologically plausible pathways for a phenotype of interest. These findings were successfully replicated by an independent large-scale exome chip study. Availability and Implementation: An implementation of PHARAOH is available at http://statgen.snu.ac.kr/software/pharaoh/ . Contact: tspark@stats.snu.ac.kr Supplementary information: Supplementary data are available at Bioinformatics online.

Description: We compute the natural frequencies for the oscillation of the free boundary of a perfect incompressible fluid in the presence of capillary forces and partially in contact with a solid container. First, we study the case when the fluid occupies the domain { ( x , y ): y ≤ h ( x , t )} with h ( x , t )=0 for | x | 〉 a and h ( x , t ) the free boundary for | x | ≤ a . We deduce an integrodifferential evolutionary equation for the linearized free boundary and impose two different boundary conditions: the condition that the contact line between free boundary and the solid is pinned and the condition that the contact line can move vertically with a contact angle /2. For both cases, we compute the natural oscillation frequencies for the free surface and compare the results with the frequencies of oscillation in the absence of solid walls. Secondly, we study the effect of having two parallel solid walls at | x | = b + a on the natural frequencies of oscillation of the free boundary.

Description: We investigate the star formation rate and its location in the major merger cluster Abell 2465 at z  = 0.245. Optical properties of the cluster are described in Paper I . Measurements of the Hα and infrared dust emission of galaxies in the cluster were made with an interference filter centred on the redshifted line at a wavelength of 817 nm and utilized data from the Wide-field Infrared Survey Explorer satellite 12 μm band. Imaging in the Johnson U and B bands was obtained, and along with Sloan Digital Sky Survey u and r was used to study the blue fraction, which appears enhanced, as a further signature of star formation in the cluster. Star formation rates were calculated using standard calibrations. The total star formation rate normalized by the cluster mass, SFR/ M cl compared to compilations for other clusters indicate that the components of Abell 2465 lie above the mean z and M cl relations, suggestive that interacting galaxy clusters have enhanced star formation. The projected radial distribution of the star-forming galaxies does not follow an NFW profile and is relatively flat indicating that fewer star-forming galaxies are in the cluster centre. The morphologies of the Hα sources within R 200 for the cluster as a whole indicate that many are disturbed or merging, suggesting that a combination of merging or harassment is working.

Description: We use velocity dispersion measurements of 21 individual cluster members in the core of Abell 383, obtained with Multiple Mirror Telescope Hectospec, to separate the galaxy and the smooth dark halo (DH) lensing contributions. While lensing usually constrains the overall, projected mass density, the innovative use of velocity dispersion measurements as a proxy for masses of individual cluster members breaks inherent degeneracies and allows us to (a) refine the constraints on single galaxy masses and on the galaxy mass-to-light scaling relation and, as a result, (b) refine the constraints on the DM-only map, a high-end goal of lens modelling. The knowledge of cluster member velocity dispersions improves the fit by 17 per cent in terms of the image reproduction 2 , or 20 per cent in terms of the rms. The constraints on the mass parameters improve by ~10 per cent for the DH, while for the galaxy component, they are refined correspondingly by ~50 per cent, including the galaxy halo truncation radius. For an L * galaxy with $M^{*}_{B}=-20.96$ , for example, we obtain best-fitting truncation radius $r_{\rm tr}^{*}=20.5^{+9.6}_{-6.7}$  kpc and velocity dispersion *  = 324 ± 17 km s –1 . Moreover, by performing the surface brightness reconstruction of the southern giant arc, we improve the constraints on r tr of two nearby cluster members, which have measured velocity dispersions, by more than ~30 per cent. We estimate the stripped mass for these two galaxies, getting results that are consistent with numerical simulations. In the future, we plan to apply this analysis to other galaxy clusters for which velocity dispersions of member galaxies are available.

Description: Double-stranded ribonucleic acid-activated protein kinase (PKR) downregulates translation as a defense mechanism against viral infection. In fish species, PKZ, a PKR-like protein kinase containing left-handed deoxyribonucleic acid (Z-DNA) binding domains, performs a similar role in the antiviral response. To understand the role of PKZ in Z-DNA recognition and innate immune response, we performed structural and functional studies of the Z-DNA binding domain (Zα) of PKZ from Carassius auratus (caZα PKZ ). The 1.7-Å resolution crystal structure of caZα PKZ :Z-DNA revealed that caZα PKZ shares the overall fold with other Zα, but has discrete structural features that differentiate its DNA binding mode from others. Functional analyses of caZα PKZ and its mutants revealed that caZα PKZ mediates the fastest B-to-Z transition of DNA among Zα, and the minimal interaction for Z-DNA recognition is mediated by three backbone phosphates and six residues of caZα PKZ . Structure-based mutagenesis and B-to-Z transition assays confirmed that Lys56 located in the β-wing contributes to its fast B-to-Z transition kinetics. Investigation of the DNA binding kinetics of caZα PKZ further revealed that the B-to-Z transition rate is positively correlated with the association rate constant. Taking these results together, we conclude that the positive charge in the β-wing largely affects fast B-to-Z transition activity by enhancing the DNA binding rate.

Description: We compared the performance of template-free (docking) and template-based methods for the prediction of protein–protein complex structures. We found similar performance for a template-based method based on threading (COTH) and another template-based method based on structural alignment (PRISM). The template-based methods showed similar performance to a docking method (ZDOCK) when the latter was allowed one prediction for each complex, but when the same number of predictions was allowed for each method, the docking approach outperformed template-based approaches. We identified strengths and weaknesses in each method. Template-based approaches were better able to handle complexes that involved conformational changes upon binding. Furthermore, the threading-based and docking methods were better than the structural-alignment-based method for enzyme–inhibitor complex prediction. Finally, we show that the near-native (correct) predictions were generally not shared by the various approaches, suggesting that integrating their results could be the superior strategy.

Description: We investigate the star formation rate and its location in the major merger cluster Abell 2465 at z  = 0.245. Optical properties of the cluster are described in Paper I . Measurements of the Hα and infrared dust emission of galaxies in the cluster were made with an interference filter centred on the redshifted line at a wavelength of 817 nm and utilized data from the Wide-field Infrared Survey Explorer satellite 12 μm band. Imaging in the Johnson U and B bands was obtained, and along with Sloan Digital Sky Survey u and r was used to study the blue fraction, which appears enhanced, as a further signature of star formation in the cluster. Star formation rates were calculated using standard calibrations. The total star formation rate normalized by the cluster mass, SFR/ M cl compared to compilations for other clusters indicate that the components of Abell 2465 lie above the mean z and M cl relations, suggestive that interacting galaxy clusters have enhanced star formation. The projected radial distribution of the star-forming galaxies does not follow an NFW profile and is relatively flat indicating that fewer star-forming galaxies are in the cluster centre. The morphologies of the Hα sources within R 200 for the cluster as a whole indicate that many are disturbed or merging, suggesting that a combination of merging or harassment is working.

Description: Using Herschel data from the deepest SPIRE and PACS surveys (HerMES and PEP) in COSMOS, GOODS-S and GOODS-N, we examine the dust properties of infrared (IR)-luminous ( L IR  〉 10 10  L ) galaxies at 0.1 〈 z  〈 2 and determine how these evolve with cosmic time. The unique angle of this work is the rigorous analysis of survey selection effects, making this the first study of the star-formation-dominated, IR-luminous population within a framework almost entirely free of selection biases. We find that IR-luminous galaxies have spectral energy distributions (SEDs) with broad far-IR peaks characterized by cool/extended dust emission and average dust temperatures in the 25–45 K range. Hot ( T  〉 45 K) SEDs and cold ( T  〈 25 K), cirrus-dominated SEDs are rare, with most sources being within the range occupied by warm starbursts such as M82 and cool spirals such as M51. We observe a luminosity–temperature ( L - T ) relation, where the average dust temperature of log [ L IR /L ] ~ 12.5 galaxies is about 10 K higher than that of their log [ L IR /L ] ~ 10.5 counterparts. However, although the increased dust heating in more luminous systems is the driving factor behind the L - T relation, the increase in dust mass and/or starburst size with luminosity plays a dominant role in shaping it. Our results show that the dust conditions in IR-luminous sources evolve with cosmic time: at high redshift, dust temperatures are on average up to 10 K lower than what is measured locally ( z 0.1). This is manifested as a flattening of the L - T relation, suggesting that (ultra)luminous infrared galaxies [(U)LIRGs] in the early Universe are typically characterized by a more extended dust distribution and/or higher dust masses than local equivalent sources. Interestingly, the evolution in dust temperature is luminosity dependent, with the fraction of LIRGs with T  〈 35 K showing a two-fold increase from z  ~ 0 to z  ~ 2, whereas that of ULIRGs with T  〈 35 K shows a six-fold increase. Our results suggest a greater diversity in the IR-luminous population at high redshift, particularly for ULIRGs.

Description: We investigate the mass content of galaxies in the core of the galaxy cluster Abell 611. We perform a strong lensing analysis of the cluster core and use velocity dispersion measurements for individual cluster members as additional constraints. Despite the small number of multiply-imaged systems and cluster members with central velocity dispersions available in the core of A611, the addition of velocity dispersion measurements leads to tighter constraints on the mass associated with the galaxy component, and as a result, on the mass associated with the dark matter halo. Without the spectroscopic velocity dispersions, we would overestimate the mass of the galaxy component by a factor of ~1.5, or, equivalently, we would underestimate the mass of the cluster dark halo by ~5 per cent. We perform an additional lensing analysis using surface brightness (SB) reconstruction of the tangential giant arc. This approach improves the constraints on the mass parameters of the five galaxies close to the arc by a factor up to ~10. The resulting parameters are in good agreement with the -r tr scaling relation derived in the pointlike analysis. The galaxy velocity dispersions resulting from the SB analysis are consistent at the 1 confidence level with the spectroscopic measurements. In contrast, the truncation radii for 2–3 galaxies depart significantly from the galaxy scaling relation and suggest differences in the stripping history from galaxy to galaxy.

Description: : Protein–protein interactions are essential to cellular and immune function, and in many cases, because of the absence of an experimentally determined structure of the complex, these interactions must be modeled to obtain an understanding of their molecular basis. We present a user-friendly protein docking server, based on the rigid-body docking programs ZDOCK and M-ZDOCK, to predict structures of protein–protein complexes and symmetric multimers. With a goal of providing an accessible and intuitive interface, we provide options for users to guide the scoring and the selection of output models, in addition to dynamic visualization of input structures and output docking models. This server enables the research community to easily and quickly produce structural models of protein–protein complexes and symmetric multimers for their own analysis. Availability: The ZDOCK server is freely available to all academic and non-profit users at: http://zdock.umassmed.edu . No registration is required. Contact: brian.pierce@umassmed.edu or zhiping.weng@umassmed.edu