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Frequency and isostericity of RNA base pairs

Jesse Stombaugh, Craig L. Zirbel, Eric Westhof, Neocles B. Leontis
2009 Nucleic Acids Research  
The 5S rRNA sequence alignments were further refined manually by comparison with the 3D structure (Stombaugh, unpublished results).  ... 
doi:10.1093/nar/gkp011 pmid:19240142 pmcid:PMC2673412 fatcat:hv7y7fmg7rgvxoqdcvpxarkjve

The mind-body-microbial continuum

Antonio Gonzalez, Jesse Stombaugh, Catherine Lozupone, Peter J Turnbaugh, Jeffrey I Gordon, Rob Knight
2011 Dialogues in Clinical Neuroscience  
Our understanding of the vast collection of microbes that live on and inside us (microbiota) and their collective genes (microbiome) has been revolutionized by culture-independent "metagenomic" techniques and DNA sequencing technologies. Most of our microbes live in our gut, where they function as a metabolic organ and provide attributes not encoded in our human genome. Metagenomic studies are revealing shared and distinctive features of microbial communities inhabiting different humans. A
more » ... al question in psychiatry is the relative role of genes and environment in shaping behavior. The human microbiome serves as the interface between our genes and our history of environmental exposures; explorations of our microbiomes thus offer the possibility of providing new insights into our neurodevelopment and our behavioral phenotypes by affecting complex processes such as inter- and intra personal variations in cognition, personality, mood, sleep, and eating behavior, and perhaps even a variety of neuropsychiatric diseases ranging from affective disorders to autism. Better understanding of microbiome-encoded pathways for xenobiotic metabolism also has important implications for improving the efficacy of pharmacologic interventions with neuromodulatory agents.
pmid:21485746 pmcid:PMC3139398 fatcat:l3ygbymmanf5zk6mjytmlflpbm

UniFrac: an effective distance metric for microbial community comparison

Catherine Lozupone, Manuel E Lladser, Dan Knights, Jesse Stombaugh, Rob Knight
2010 The ISME Journal  
doi:10.1038/ismej.2010.133 pmid:20827291 pmcid:PMC3105689 fatcat:xacb7lv4ifgelftcztzzfrewly

Microbial Biogeography of Public Restroom Surfaces

Gilberto E. Flores, Scott T. Bates, Dan Knights, Christian L. Lauber, Jesse Stombaugh, Rob Knight, Noah Fierer, Mark R. Liles
2011 PLoS ONE  
We spend the majority of our lives indoors where we are constantly exposed to bacteria residing on surfaces. However, the diversity of these surface-associated communities is largely unknown. We explored the biogeographical patterns exhibited by bacteria across ten surfaces within each of twelve public restrooms. Using high-throughput barcoded pyrosequencing of the 16 S rRNA gene, we identified 19 bacterial phyla across all surfaces. Most sequences belonged to four phyla: Actinobacteria,
more » ... odetes, Firmicutes and Proteobacteria. The communities clustered into three general categories: those found on surfaces associated with toilets, those on the restroom floor, and those found on surfaces routinely touched with hands. On toilet surfaces, gut-associated taxa were more prevalent, suggesting fecal contamination of these surfaces. Floor surfaces were the most diverse of all communities and contained several taxa commonly found in soils. Skin-associated bacteria, especially the Propionibacteriaceae, dominated surfaces routinely touched with our hands. Certain taxa were more common in female than in male restrooms as vagina-associated Lactobacillaceae were widely distributed in female restrooms, likely from urine contamination. Use of the SourceTracker algorithm confirmed many of our taxonomic observations as human skin was the primary source of bacteria on restroom surfaces. Overall, these results demonstrate that restroom surfaces host relatively diverse microbial communities dominated by human-associated bacteria with clear linkages between communities on or in different body sites and those communities found on restroom surfaces. More generally, this work is relevant to the public health field as we show that human-associated microbes are commonly found on restroom surfaces suggesting that bacterial pathogens could readily be transmitted between individuals by the touching of surfaces. Furthermore, we demonstrate that we can use high-throughput analyses of bacterial communities to determine sources of bacteria on indoor surfaces, an approach which could be used to track pathogen transmission and test the efficacy of hygiene practices.
doi:10.1371/journal.pone.0028132 pmid:22132229 pmcid:PMC3223236 fatcat:yspj3v5lunc25cmcy4qa2xxnqu

Diversity, stability and resilience of the human gut microbiota

Catherine A. Lozupone, Jesse I. Stombaugh, Jeffrey I. Gordon, Janet K. Jansson, Rob Knight
2012 Nature  
Lozupone 1 , Jesse I. Stombaugh 1 , Jeffrey I. Gordon 2 , Janet K. Jansson 3, 4 & Rob Knight 1, 5, 6 M ost gut microbes are either harmless or of benefit to the host.  ... 
doi:10.1038/nature11550 pmid:22972295 pmcid:PMC3577372 fatcat:hvok7pp7dbbwzeobphdq6d5jyq

Classification and energetics of the base-phosphate interactions in RNA

Craig L. Zirbel, Judit E. Šponer, Jiri Šponer, Jesse Stombaugh, Neocles B. Leontis
2009 Nucleic Acids Research  
We selected a reduced-redundancy set of PDB files for analysis as previously described (12) and these files are listed in 'Supplemental Materials S4' of Stombaugh et al. (12) .  ... 
doi:10.1093/nar/gkp468 pmid:19528080 pmcid:PMC2731888 fatcat:7syi2neaxrfvzddutvzmukna5u

Combined phylogenetic and genomic approaches for the high-throughput study of microbial habitat adaptation

Jesse R.R. Zaneveld, Laura Wegener Parfrey, Will Van Treuren, Catherine Lozupone, Jose C. Clemente, Dan Knights, Jesse Stombaugh, Justin Kuczynski, Rob Knight
2011 Trends in Microbiology  
High-throughput sequencing technologies provide new opportunities to address longstanding questions about habitat adaptation in microbial organisms. How have microbes managed to adapt to such a wide range of environments, and what genomic features allow for such adaptation? We review recent large-scale studies of habitat adaptation, with emphasis on those that utilize phylogenetic techniques. On the basis of current trends, we summarize methodological challenges faced by investigators, and the
more » ... ools, techniques, and analytical approaches available to overcome them. Phylogenetic approaches and detailed information about each environmental sample will be critical as the ability to collect genome sequences continues to expand.
doi:10.1016/j.tim.2011.07.006 pmid:21872475 pmcid:PMC3184378 fatcat:wu6mcsxe2fcdrceqissib7dp7u

Comprehensive survey and geometric classification of base triples in RNA structures

Amal S. Abu Almakarem, Anton I. Petrov, Jesse Stombaugh, Craig L. Zirbel, Neocles B. Leontis
2011 Nucleic Acids Research  
Base triples are recurrent clusters of three RNA nucleobases interacting edge-to-edge by hydrogen bonding. We find that the central base in almost all triples forms base pairs with the other two bases of the triple, providing a natural way to geometrically classify base triples. Given 12 geometric base pair families defined by the Leontis-Westhof nomenclature, combinatoric enumeration predicts 108 potential geometric base triple families. We searched representative atomic-resolution RNA 3D
more » ... tures and found instances of 68 of the 108 predicted base triple families. Model building suggests that some of the remaining 40 families may be unlikely to form for steric reasons. We developed an on-line resource that provides exemplars of all base triples observed in the structure database and models for unobserved, predicted triples, grouped by triple family, as well as by three-base combination ( The classification helps to identify recurrent triple motifs that can substitute for each other while conserving RNA 3D structure, with applications in RNA 3D structure prediction and analysis of RNA sequence evolution.
doi:10.1093/nar/gkr810 pmid:22053086 pmcid:PMC3287178 fatcat:w5fnteunw5cbvg6cdzm3xdjk64

Moving pictures of the human microbiome

J Gregory Caporaso, Christian L Lauber, Elizabeth K Costello, Donna Berg-Lyons, Antonio Gonzalez, Jesse Stombaugh, Dan Knights, Pawel Gajer, Jacques Ravel, Noah Fierer, Jeffrey I Gordon, Rob Knight
2011 Genome Biology  
Understanding the normal temporal variation in the human microbiome is critical to developing treatments for putative microbiome-related afflictions such as obesity, Crohn's disease, inflammatory bowel disease and malnutrition. Sequencing and computational technologies, however, have been a limiting factor in performing dense time series analysis of the human microbiome. Here, we present the largest human microbiota time series analysis to date, covering two individuals at four body sites over
more » ... 96 timepoints. Results: We find that despite stable differences between body sites and individuals, there is pronounced variability in an individual's microbiota across months, weeks and even days. Additionally, only a small fraction of the total taxa found within a single body site appear to be present across all time points, suggesting that no core temporal microbiome exists at high abundance (although some microbes may be present but drop below the detection threshold). Many more taxa appear to be persistent but non-permanent community members. Conclusions: DNA sequencing and computational advances described here provide the ability to go beyond infrequent snapshots of our human-associated microbial ecology to high-resolution assessments of temporal variations over protracted periods, within and between body habitats and individuals. This capacity will allow us to define normal variation and pathologic states, and assess responses to therapeutic interventions.
doi:10.1186/gb-2011-12-5-r50 pmid:21624126 pmcid:PMC3271711 fatcat:rbrev7hmfnb4ldk7tut6br7kt4

FR3D: finding local and composite recurrent structural motifs in RNA 3D structures

Michael Sarver, Craig L. Zirbel, Jesse Stombaugh, Ali Mokdad, Neocles B. Leontis
2007 Journal of Mathematical Biology  
New methods are described for finding recurrent three-dimensional (3D) motifs in RNA atomic-resolution structures. Recurrent RNA 3D motifs are sets of RNA nucleotides with similar spatial arrangements. They can be local or composite. Local motifs comprise nucleotides that occur in the same hairpin or internal loop. Composite motifs comprise nucleotides belonging to three or more different RNA strand segments or molecules. We use a base-centered approach to construct efficient, yet exhaustive
more » ... rch procedures using geometric, symbolic, or mixed representations of RNA structure that we implement in a suite of MATLAB programs, "Find RNA 3D" (FR3D). The first modules of FR3D preprocess structure files to classify base-pair and -stacking interactions. Each base is represented geometrically by the position of its glycosidic nitrogen in 3D space and by the rotation matrix that describes its orientation with respect to a common frame. Base-pairing and base-stacking interactions are calculated from the base geometries and are represented symbolically according to the Leontis/Westhof basepairing classification, extended to include base-stacking. These data are stored and used to organize motif searches. For geometric searches, the user supplies the 3D structure of a query motif which FR3D uses to find and score geometrically similar candidate motifs, without regard to the sequential position of their nucleotides in the RNA chain or the identity of their bases. To score and rank candidate motifs, FR3D calculates a geometric discrepancy by rigidly rotating candidates to align optimally with the query motif and then comparing the relative orientations of the corresponding bases in the query and candidate motifs. Given the growing size of the RNA structure database, it is impossible to explicitly compute the discrepancy for all conceivable candidate motifs, even for motifs with less than ten nucleotides. The screening algorithm that we describe finds all candidate motifs whose geometric discrepancy with respect to the query motif falls below a user-specified cutoff discrepancy. This technique can be applied to RMSD searches. Candidate motifs identified geometrically may be further screened symbolically to identify those that contain particular basepair types or base-stacking arrangements or that conform to sequence continuity or nucleotide identity constraints. Purely symbolic Introduction The database of atomic-resolution RNA 3D structures is growing rapidly [6, 7, 11, 21] and now includes ribozymes [1, 14, 25] , ribosomal subunits [3, 16, 44] and intact 70S ribosomes [42] . The number, size, and complexity of these structures make manual analyses to find and classify recurrent RNA 3D motifs difficult and time-consuming. Systematic and exhaustive RNA motif identification and classification is crucial for integration of RNA structural and sequence data. As new experimental structures become available they must be systematically searched for new motifs as well as for new examples of known motifs. Data integration will make possible more powerful RNA sequence searching in genomes, more accurate alignment of homologous RNA sequences and more realistic modeling of RNA 3D structures, and will thus increase knowledge of RNA structure, function and evolution [28] . RNA molecules form compact 3D structures by hierarchical folding of the RNA chain. RNA secondary structure comprises the double helices made of contiguous Watson-Crick basepairs, which contribute most of the free energy of stabilization and serve as structurally well-defined struts connecting the other elements of the 3D structure. These elements appear in RNA secondary structures as single-stranded hairpin, internal, and multi-helix (junction) "loops," but in fact most of their nucleotides form non-Watson-Crick basepairs that stack in characteristic ways to form modular motifs. RNA bases can pair in 12 geometrically distinct ways, depending on which of their three edges interact (Watson-Crick, Hoogsteen, or Sugar) and the relative orientations of their glycosidic bonds (cis or trans) [32] . The Watson-Crick basepairs belong to the cis Watson-Crick/Watson-Crick geometric family. The Watson-Crick edges of bases forming non-Watson-Crick basepairs are available to form tertiary interactions that stabilize the compact folding of the biologically active structures of RNA molecules. In addition, unpaired bases extruded from motifs may intercalate to form tertiary basepairs or stacking interactions that also stabilize tertiary interactions with other RNA regions, distant in the secondary structure. RNA motifs are called recurrent when they occur independently in different, non-homologous places of the same or different RNA molecules while sharing a similar 3D structure. Many of the motifs composing hairpin, internal and junction "loops" and the RNA tertiary interactions they form recur in RNA 3D structure and so a general approach to 3D motif searching must handle all these cases. Recurrent motifs usually share a core of base-paired and -stacked nucleotides arranged in the same way while differing from each other in the identity of the nucleotides forming each basepair and the number of unpaired bases bulged out or extruded from the motif. By comparing all available examples of recurrent motifs, we can better understand the natural variability within each motif family. Recurrent motifs can be local or composite. Local motifs are composed of nucleotides that belong to the same hairpin (terminal) or internal loop. Terminal loops occur at the ends of individual helices while internal loops are flanked by two helices. Composite motifs are composed of nucleotides from disparate and discontinuous stretches of polynucleotide sequence. The same recurrent motif can occur in local and composite versions. For example, composite instances of sarcin motifs [31] and kink-turn motifs [34] have been identified in the structures of the 5S, 16S, and 23S ribosomal RNAs (rRNA). The internal loop in Helix 95 of 23S rRNA is a local example of the sarcin/ricin motif. A composite version of this motif occurs in the multi-helix junction in Domain 2 of 23S rRNA (Helices 35, 37, 39, 40 and 45)[31]. Composite motifs are easy to overlook in visual analyses and are generally missed by computational approaches that analyze the conformations of successive nucleotides in the RNA chain [18, 43] . Thus, none of the composite kink-turn motifs were identified in the original paper [26] . Recurrent motifs play similar roles in different RNA molecules or domains. Some play architectural roles, for example forming bends, kinks or branch points, while others serve as anchors for tertiary interactions that compact and stabilize the folded 3D structure of the molecule [12] . Still others mediate RNA-protein or RNA-ligand inter-molecular interactions.
doi:10.1007/s00285-007-0110-x pmid:17694311 pmcid:PMC2837920 fatcat:hulpfnzgerctba6hee4v3hb5j4

The RNA Ontology (RNAO): An ontology for integrating RNA sequence and structure data

Colin Batchelor, Thomas Bittner, Karen Eilbeck, Chris Mungall, Jane Richardson, Rob Knight, Jesse Stombaugh, Craig Zirbel, Eric Westhof, Neocles Leontis
2009 Nature Precedings  
Biomedical Ontologies are intended to integrate diverse biomedical data to enable intelligent datamining and facilitate translation of basic research into useful clinical knowledge. We present the first version of RNAO, an ontology for integrating RNA 3D structural, biochemical and sequence data. While each 3D data file depicts the structure of a specific molecule, such data have broader significance as representatives of classes of homologous molecules, which, while differing in sequence,
more » ... ally share core structural features of functional importance. Thus, 3D structure data gain value by being linked to homologous sequences in genomic data and databases of sequence alignments. Likewise genomic data can increase in value by annotation of shared structural features, especially when these can be linked to specific functions. The RNAO is being developed in line with the developing standards of the Open Biomedical Ontologies (OBO) Consortium.
doi:10.1038/npre.2009.3561.1 fatcat:2ufub5f3sjf6xfwsf6ihl57pca

Tertiary structure and function of an RNA motif required for plant vascular entry to initiate systemic trafficking

Xuehua Zhong, Xiaorong Tao, Jesse Stombaugh, Neocles Leontis, Biao Ding
2007 EMBO Journal  
Jesse Stombaugh is funded by NBL's RCE grant, which is supported by Bowling Green State University's 'Research Capacity Expansion Program' with funds provided by the Ohio Board of Regents Research Incentive  ... 
doi:10.1038/sj.emboj.7601812 pmid:17660743 pmcid:PMC1952227 fatcat:qjddgh3qrbgr3hqhwdns7zqwhy

Responses of Gut Microbiota to Diet Composition and Weight Loss in Lean and Obese Mice

Yann Ravussin, Omry Koren, Ayme Spor, Charles LeDuc, Roee Gutman, Jesse Stombaugh, Rob Knight, Ruth E. Ley, Rudolph L. Leibel
2011 Obesity  
Maintenance of a reduced body weight is accompanied by a decrease in energy expenditure beyond that accounted for by reduced body mass and composition, as well as by an increased drive to eat. These effects appear to be duein part-to reductions in circulating leptin concentrations due to loss of body fat. Gut microbiota have been implicated in the regulation of body weight. The effects of weight loss on qualitative aspects of gut microbiota have been studied in humans and mice, but these
more » ... have been confounded by concurrent changes in diet composition, which influence microbial community composition. We studied the impact of 20% weight loss on the microbiota of dietinduced obese (DIO: 60% calories fat) mice on a high-fat diet (HFD). Weight-reduced DIO (DIO-WR) mice had the same body weight and composition as control (CON) ad-libitum (AL) fed mice being fed a control diet (10% calories fat), allowing a direct comparison of diet and weight-perturbation effects. Microbial community composition was assessed by pyrosequencing 16S rRNA genes derived from the ceca of sacrificed animals. There was a strong effect of diet composition on the diversity and composition of the microbiota. The relative abundance of specific members of the microbiota was correlated with circulating leptin concentrations and gene expression levels of inflammation markers in subcutaneous white adipose tissue in all mice. Together, these results suggest that both host adiposity and diet composition impact microbiota composition, possibly through leptin-mediated regulation of mucus production and/or inflammatory processes that alter the gut habitat.
doi:10.1038/oby.2011.111 pmid:21593810 pmcid:PMC3871199 fatcat:qjxrytbk2fab7l5cwy5rrgyk3y

The Power Decoder Simulator for the Evaluation of Pooled shRNA Screen Performance

Jesse Stombaugh, Abel Licon, Žaklina Strezoska, Joshua Stahl, Sarah Bael Anderson, Michael Banos, Anja van Brabant Smith, Amanda Birmingham, Annaleen Vermeulen
2015 Journal of Biomolecular Screening  
RNA interference screening using pooled, short hairpin RNA (shRNA) is a powerful, high-throughput tool for determining the biological relevance of genes for a phenotype. Assessing an shRNA pooled screen's performance is difficult in practice; one can estimate the performance only by using reproducibility as a proxy for power or by employing a large number of validated positive and negative controls. Here, we develop an open-source software tool, the Power Decoder simulator, for generating shRNA
more » ... pooled screening experiments in silico that can be used to estimate a screen's statistical power. Using the negative binomial distribution, it models both the relative abundance of multiple shRNAs within a single screening replicate and the biological noise between replicates for each individual shRNA. We demonstrate that this simulator can successfully model the data from an actual laboratory experiment. We then use it to evaluate the effects of biological replicates and sequencing counts on the performance of a pooled screen, without the necessity of gathering additional data. The Power Decoder simulator is written in R and Python and is available for download under the GNU General Public License v3.0.
doi:10.1177/1087057115576715 pmid:25777298 pmcid:PMC4543901 fatcat:l35noq6hxjb2vm2p6meoy7gqiq

Technology and Data-Intensive Science in the Beginning of the 21st Century

Philip A. Bernstein, Dave Wecker, Ashok Krishnamurthy, Dinesh Manocha, Jeffrey Gardner, Natali Kolker, Chance Reschke, Jesse Stombaugh, Pamela Vagata, Elizabeth Stewart, Dean Welch, Eugene Kolker
2011 Omics  
This article is a summary of the technology issues and challenges of data-intensive science and cloud computing as discussed in the Data-Intensive Science (DIS) workshop in Seattle,
doi:10.1089/omi.2011.0013 pmid:21476841 fatcat:kskd6zgztbgijkiuzmjoptvyzy
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