ALBERT

Description: Viruses with single-stranded (ss) DNA genomes infect hosts in all three domains of life and include many medically, ecologically, and economically important pathogens. Recently, a new group of ssDNA viruses with chimeric genomes has been discovered through viral metagenomics. These chimeric viruses combine capsid protein genes and replicative protein genes that, respectively, appear to have been inherited from viruses with positive-strand RNA genomes, such as tombusviruses, and ssDNA genomes, such as circoviruses, nanoviruses or geminiviruses. Here, we describe the genome sequence of a new representative of this virus group and reveal an additional layer of chimerism among ssDNA viruses. We show that not only do these viruses encompass genes for capsid proteins and replicative proteins that have distinct evolutionary histories, but also the replicative genes themselves are chimeras of functional domains inherited from viruses of different families. Our results underscore the importance of horizontal gene transfer in the evolution of ssDNA viruses and the role of genetic recombination in the emergence of novel virus groups.

Description: Accumulation of amyloid-β (Aβ) in synaptic mitochondria is associated with mitochondrial and synaptic injury. The underlying mechanisms and strategies to eliminate Aβ and rescue mitochondrial and synaptic defects remain elusive. Presequence protease (PreP), a mitochondrial peptidasome, is a novel mitochondrial Aβ degrading enzyme. Here, we demonstrate for the first time that increased expression of active human PreP in cortical neurons attenuates Alzheimer disease's (AD)-like mitochondrial amyloid pathology and synaptic mitochondrial dysfunction, and suppresses mitochondrial oxidative stress. Notably, PreP-overexpressed AD mice show significant reduction in the production of proinflammatory mediators. Accordingly, increased neuronal PreP expression improves learning and memory and synaptic function in vivo AD mice, and alleviates Aβ-mediated reduction of long-term potentiation (LTP). Our results provide in vivo evidence that PreP may play an important role in maintaining mitochondrial integrity and function by clearance and degradation of mitochondrial Aβ along with the improvement in synaptic and behavioral function in AD mouse model. Thus, enhancing PreP activity/expression may be a new therapeutic avenue for treatment of AD.

Description: Motivation: Many drugs interact with numerous proteins besides their intended therapeutic targets and a substantial portion of these interactions is yet to be elucidated. Protein–Drug Interaction Database (PDID) addresses incompleteness of these data by providing access to putative protein–drug interactions that cover the entire structural human proteome. Results: PDID covers 9652 structures from 3746 proteins and houses 16 800 putative interactions generated from close to 1.1 million accurate, all-atom structure-based predictions for several dozens of popular drugs. The predictions were generated with three modern methods: ILbind, SMAP and eFindSite. They are accompanied by propensity scores that quantify likelihood of interactions and coordinates of the putative location of the binding drugs in the corresponding protein structures. PDID complements the current databases that focus on the curated interactions and the BioDrugScreen database that relies on docking to find putative interactions. Moreover, we also include experimentally curated interactions which are linked to their sources: DrugBank, BindingDB and Protein Data Bank. Our database can be used to facilitate studies related to polypharmacology of drugs including repurposing and explaining side effects of drugs. Availability and implementation: PDID database is freely available at http://biomine.ece.ualberta.ca/PDID/ . Contact: lkurgan@vcu.edu

Description: The TET family of FE(II) and 2-oxoglutarate-dependent enzymes (Tet1/2/3) promote DNA demethylation by converting 5-methylcytosine to 5-hydroxymethylcytosine (5hmC), which they further oxidize into 5-formylcytosine and 5-carboxylcytosine. Tet1 is robustly expressed in mouse embryonic stem cells (mESCs) and has been implicated in mESC maintenance. Here we demonstrate that, unlike genetic deletion, RNAi-mediated depletion of Tet1 in mESCs led to a significant reduction in 5hmC and loss of mESC identity. The differentiation phenotype due to Tet1 depletion positively correlated with the extent of 5hmC loss. Meta-analyses of genomic data sets suggested interaction between Tet1 and leukemia inhibitory factor (LIF) signaling. LIF signaling is known to promote self-renewal and pluripotency in mESCs partly by opposing MAPK/ERK-mediated differentiation. Withdrawal of LIF leads to differentiation of mESCs. We discovered that Tet1 depletion impaired LIF-dependent Stat3-mediated gene activation by affecting Stat3's ability to bind to its target sites on chromatin. Nanog overexpression or inhibition of MAPK/ERK signaling, both known to maintain mESCs in the absence of LIF, rescued Tet1 depletion, further supporting the dependence of LIF/Stat3 signaling on Tet1 . These data support the conclusion that analysis of mESCs in the hours/days immediately following efficient Tet1 depletion reveals Tet1 's normal physiological role in maintaining the pluripotent state that may be subject to homeostatic compensation in genetic models.

Description: Motivation: Off-target interactions of a popular immunosuppressant Cyclosporine A (CSA) with several proteins besides its molecular target, cyclophilin A, are implicated in the activation of signaling pathways that lead to numerous side effects of this drug. Results: Using structural human proteome and a novel algorithm for inverse ligand binding prediction, ILbind, we determined a comprehensive set of 100+ putative partners of CSA. We empirically show that predictive quality of ILbind is better compared with other available predictors for this compound. We linked the putative target proteins, which include many new partners of CSA, with cellular functions, canonical pathways and toxicities that are typical for patients who take this drug. We used complementary approaches (molecular docking, molecular dynamics, surface plasmon resonance binding analysis and enzymatic assays) to validate and characterize three novel CSA targets: calpain 2, caspase 3 and p38 MAP kinase 14. The three targets are involved in the apoptotic pathways, are interconnected and are implicated in nephrotoxicity. Contact: lkurgan@ece.ualberta.ca Supplementary information: Supplementary data are available at Bioinformatics online.

Description: Consider the scattering of time-harmonic electromagnetic plane waves by a doubly periodic surface in R 3 . The medium above the surface is supposed to be homogeneous and isotropic with a constant dielectric coefficient, while the material below is perfectly conducting. This paper is concerned with the existence of quasiperiodic solutions for any frequency. Based on an equivalent variational formulation established by the mortar technique of Nitsche, we verify the existence of solutions for a broad class of incident waves including plane waves. The only assumption is that the grating profile is a Lipschitz biperiodic surface. Note that the solvability result of the present paper covers the resonance case where Rayleigh frequencies are allowed. Finally, non-uniqueness examples are presented in the resonance case and in the case of TE or TM polarization for classical gratings.

Description: Immunodeficiency, centromeric instability and facial anomalies type I (ICF1) syndrome is a rare genetic disease caused by mutations in DNA methyltransferase (DNMT) 3B, a de novo DNA methyltransferase. However, the molecular basis of how DNMT3B deficiency leads to ICF1 pathogenesis is unclear. Induced pluripotent stem cell (iPSC) technology facilitates the study of early human developmental diseases via facile in vitro paradigms. Here, we generate iPSCs from ICF Type 1 syndrome patient fibroblasts followed by directed differentiation of ICF1-iPSCs to mesenchymal stem cells (MSCs). By performing genome-scale bisulfite sequencing, we find that DNMT3B-deficient iPSCs exhibit global loss of non-CG methylation and select CG hypomethylation at gene promoters and enhancers. Further unbiased scanning of ICF1-iPSC methylomes also identifies large megabase regions of CG hypomethylation typically localized in centromeric and subtelomeric regions. RNA sequencing of ICF1 and control iPSCs reveals abnormal gene expression in ICF1-iPSCs relevant to ICF syndrome phenotypes, some directly associated with promoter or enhancer hypomethylation. Upon differentiation of ICF1 iPSCs to MSCs, we find virtually all CG hypomethylated regions remained hypomethylated when compared with either wild-type iPSC-derived MSCs or primary bone-marrow MSCs. Collectively, our results show specific methylome and transcriptome defects in both ICF1-iPSCs and differentiated somatic cell lineages, providing a valuable stem cell system for further in vitro study of the molecular pathogenesis of ICF1 syndrome. GEO accession number : GSE46030.

Description: Aims Spatial distribution patterns of species reflect not only the ecological processes but also the habitat features that are related to species distribution. In karst topography, species distribution patterns provide more specific information about their environments. The objectives of this study are as follows: (i) to analyse and explain the spatial distribution patterns of conspecific trees in an old-growth subtropical karst forest; (ii) to investigate pattern changes at different spatial scales; (iii) to test the spatial pattern similarity (or dissimilarity) between trees at different abundances, diameter at breast height classes, canopy layers and different functional groups (shade tolerance and seed dispersal mode); (iv) to examine whether habitat heterogeneity has an important effect on the species spatial distribution. Methods The spatial distributions of woody species with ≥20 individuals in a 1-ha subtropical karst forest plot at Maolan in southwestern China were quantified using the relative neighbourhood density based on the average density of conspecific species in a circular neighbourhood around each species. Important Findings Aggregated distribution is the dominant pattern in the karst forest, but the ratio of aggregated species in total species number decreases with an increase in spatial scale. Less abundant species are more aggregated than most abundant species. Aggregation is weaker in larger diameter classes, which is consistent with the prediction of self-thinning. Seed dispersal mode influences spatial patterns, with species dispersed by animals being less aggregated than those dispersed by wind and gravity. Other species functional traits (e.g. shade tolerance) also influence the species spatial distributions. Moreover, differences among species habitat associations, e.g. with rocky outcrops, play a significant role in species spatial distributions. These results indicate that habitat heterogeneity, seed dispersal limitation and self-thinning primarily contribute to the species spatial distributions in this subtropical karst forest.