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School of Biological Sciences

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https://hdl.handle.net/1853/70750

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College of Sciences

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Center for the Study of Systems Biology

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https://finding-aids.library.gatech.edu/agents/corporate_entities/1131

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Publication Search Results

Now showing 1 - 10 of 179

TASSER_WT: A protein structure prediction algorithm with accurate predicted contact restraints for difficult protein targets

(Georgia Institute of Technology, 2010-11) Lee, Seung Yup ; Skolnick, Jeffrey

To improve the prediction accuracy in the regime where template alignment quality is poor, an updated version of TASSER_2.0, namely TASSER_WT, was developed. TASSER_WT incorporates more accurate contact restraints from a new method, COMBCON. COMBCON uses confidence-weighted contacts from PROSPECTOR_3.5, the latest version, PROSPECTOR_4, and a new local structural fragment-based threading algorithm, STITCH, implemented in two variants depending on expected fragment prediction accuracy. TASSER_WT is tested on 622 Hard proteins, the most difficult targets (incorrect alignments and/or templates and incorrect side-chain contact restraints) in a comprehensive benchmark of 2591 nonhomologous, single domain proteins %200 residues that cover the PDB at 35% pairwise sequence identity. For 454 of 622 Hard targets, COMBCON provides contact restraints with higher accuracy and number of contacts per residue. As contact coverage with confidence weight R3 (FwtR3 cov) increases, the more improved are TASSER_WT models. When FwtR3 cov > 1.0 and > 0.4, the average root mean-square deviation of TASSER_WT (TASSER_2.0) models is 4.11 A° (6.72 A° ) and 5.03 A° (6.40A° ), respectively. Regarding a structure prediction as successful when a model has a TM-score to the native structureR0.4, when FwtR3 cov > 1.0 and > 0.4, the success rate of TASSER_WT (TASSER_2.0) is 98.8% (76.2%) and 93.7% (81.1%), respectively.
Temporal, spatial, and between-host comparisons of patterns of parasitism in lake zooplankton

(Georgia Institute of Technology, 2010-11) Duffy, Meghan A. ; Cáceres, Carla E. ; Hall, Spencer R. ; Tessier, Alan J. ; Ives, Anthony R.

In nature, multiple parasite species infect multiple host species and are influenced by processes operating across different spatial and temporal scales. Data sets incorporating these complexities offer exciting opportunities to examine factors that shape epidemics. We present a method using generalized linear mixed models in a multilevel modeling framework to analyze patterns of variances and correlations in binomially distributed prevalence data. We then apply it to a multi-lake, multiyear data set involving two Daphnia host species and nine microparasite species. We found that the largest source of variation in parasite prevalence was the species identities of host–parasite pairs, indicating strong host–parasite specificity. Within host–parasite combinations, spatial variation (among lakes) exceeded interannual variation. This suggests that factors promoting differences among lakes (e.g., habitat characteristics and species interactions) better explain variation in peak infection prevalence in our data set than factors driving differences among years (e.g., climate). Prevalences of parasites in D. dentifera were more positively correlated than those for D. pulicaria, suggesting that similar factors influenced epidemic size among parasites in D. dentifera. Overall, this study demonstrates a method for parsing patterns of variation and covariation in infection prevalence data, providing greater insight into the relative importance of different underlying drivers of parasitism.
Leprosy and the adaptation of human Toll-like receptor 1

(Georgia Institute of Technology, 2010-07) Wong, Sunny H. ; Gochhait, Sailesh ; Malhotra, Dheeraj ; Pettersson, Fredrik H. ; Teo, Yik Y. ; Khor, Chiea C. ; Rautanen, Anna ; Chapman, Stephen J. ; Mills, Tara C. ; Srivastava, Amit ; Rudko, Aleksey ; Freidin, Maxim B. ; Puzyrev, Valery P. ; Ali, Shafat ; Aggarwal, Shweta ; Chopra, Rupali ; Reddy, Belum S. N. ; Garg, Vijay K. ; Roy, Suchismita ; Meisner, Sarah ; Hazra, Sunil K. ; Saha, Bibhuti ; Floyd, Sian ; Keating, Brendan J. ; Kim, Cecilia ; Fairfax, Benjamin P. ; Knight, Julian C. ; Hill, Philip C. ; Adegbola, Richard A. ; Hakonarson, Hakon ; Fine, Paul E. M. ; Pitchappan, Ramasamy M. ; Bamezai, Rameshwar N. K. ; Hill, Adrian V. S. ; Vannberg, Fredrik O.

Leprosy is an infectious disease caused by the obligate intracellular pathogen Mycobacterium leprae and remains endemic in many parts of the world. Despite several major studies on susceptibility to leprosy, few genomic loci have been replicated independently. We have conducted an association analysis of more than 1,500 individuals from different case-control and family studies, and observed consistent associations between genetic variants in both TLR1 and the HLA-DRB1/DQA1 regions with susceptibility to leprosy (TLR1 I602S, case-control P = 5.7x10⁻⁸, OR = 0.31, 95% CI = 0.20–0.48, and HLA-DQA1 rs1071630, case-control P = 4.9x10⁻¹⁴, OR = 0.43, 95% CI = 0.35–0.54). The effect sizes of these associations suggest that TLR1 and HLA-DRB1/DQA1 are major susceptibility genes in susceptibility to leprosy. Further population differentiation analysis shows that the TLR1 locus is extremely differentiated. The protective dysfunctional 602S allele is rare in Africa but expands to become the dominant allele among individuals of European descent. This supports the hypothesis that this locus may be under selection from mycobacteria or other pathogens that are recognized by TLR1 and its co-receptors. These observations provide insight into the long standing host-pathogen relationship between human and mycobacteria and highlight the key role of the TLR pathway in infectious diseases.
Why Are Daphnia in Some Lakes Sicker? Disease Ecology, Habitat Structure, and the Plankton

(Georgia Institute of Technology, 2010-05) Hall, Spencer R. ; Smyth, Robyn ; Becker, Claes R. ; Duffy, Meghan A. ; Knight, Christine J. ; MacIntyre, Sally ; Tessier, Alan J. ; Cáceres, Carla E.

Some aspects of habitat seem to enhance the spread of disease whereas others inhibit it. Here, we illustrate and identify mechanisms that connect habitat to epidemiology using a case study of disease in plankton. We see a pronounced relationship between the basin shapes of lakes and fungal (Metschnikowia bicuspidata) disease in the zooplankton grazer Daphnia dentifera. As we work through seven mechanisms that could explain why Daphnia in some lakes are sicker, we can eliminate some hypotheses (i.e., those relating an index of lake productivity to disease through host density, links between resource quality and transmission rate, and variation in host susceptibility) and find support for others involving food-web actors (e.g., selective predation on infected hosts by fishes, “sloppy predation” by an invertebrate, a possible dilution effect in V-shaped lakes). Furthermore, we identify physical mechanisms (gravity currents, turbulence) that could lead to greater transport of fungal spores to habitat occupied by Daphnia hosts in U-shaped lakes. These results highlight how habitat structure, through its effects on food-web structure and physical processes, can shape wildlife disease.
Pathogenic Polyglutamine Tracts Are Potent Inducers of Spontaneous Sup35 and Rnq1 Amyloidogenesis

(Georgia Institute of Technology, 2010-03-10) Goehler, Heike ; Dröge, Anja ; Lurz, Rudi ; Schnoegl, Sigrid ; Chernoff, Yury O. ; Wanker, Erich E.

The glutamine/asparagine (Q/N)-rich yeast prion protein Sup35 has a low intrinsic propensity to spontaneously self-assemble into ordered, β-sheet-rich amyloid fibrils. In yeast cells, de novo formation of Sup35 aggregates is greatly facilitated by high protein concentrations and the presence of preformed Q/N-rich protein aggregates that template Sup35 polymerization. Here, we have investigated whether aggregation-promoting polyglutamine (polyQ) tracts can stimulate the de novo formation of ordered Sup35 protein aggregates in the absence of Q/N-rich yeast prions. Fusion proteins with polyQ tracts of different lengths were produced and their ability to spontaneously self-assemble into amlyloid structures was analyzed using in vitro and in vivo model systems. We found that Sup35 fusions with pathogenic (≥54 glutamines), as opposed to non-pathogenic (19 glutamines) polyQ tracts efficiently form seeding-competent protein aggregates. Strikingly, polyQ-mediated de novo assembly of Sup35 protein aggregates in yeast cells was independent of pre-existing Q/N-rich protein aggregates. This indicates that increasing the content of aggregation-promoting sequences enhances the tendency of Sup35 to spontaneously self-assemble into insoluble protein aggregates. A similar result was obtained when pathogenic polyQ tracts were linked to the yeast prion protein Rnq1, demonstrating that polyQ sequences are generic inducers of amyloidogenesis. In conclusion, long polyQ sequences are powerful molecular tools that allow the efficient production of seeding-competent amyloid structures.
An experimental test of Darwin's naturalization hypothesis

(Georgia Institute of Technology, 2010-02-19) Jiang, Lin ; Tan, Jiaqi ; Pu, Zhichao

One of the oldest ideas in invasion biology, known as Darwin’s naturalization hypothesis, suggests that introduced species are more successful in communities in which their close relatives are absent. We conducted the first experimental test of this hypothesis in laboratory bacterial communities varying in phylogenetic relatedness between resident and invading species with and without a protist bacterivore. As predicted, invasion success increased with phylogenetic distance between the invading and the resident bacterial species in both the presence and the absence of protistan bacterivory. The frequency of successful invader establishment was best explained by average phylogenetic distance between the invader and all resident species, possibly indicating limitation by the availability of the unexploited niche (i.e., organic substances in the medium capable of supporting the invader growth); invader abundance was best explained by phylogenetic distance between the invader and its nearest resident relative, possibly indicating limitation by the availability of the unexploited optimal niche (i.e., the subset of organic substances supporting the best invader growth). These results were largely driven by one resident bacterium (a subspecies of Serratia marcescens) posting the strongest resistance to the alien bacterium (another subspecies of S. marcescens). Overall, our findings support phylogenetic relatedness as a useful predictor of species invasion success.
Impact of Herbivore Identity on Algal Succession and Coral Growth on a Caribbean Reef

(Georgia Institute of Technology, 2010-01-29) Burkepile, Deron E. ; Hay, Mark E.

Herbivory is an important top-down force on coral reefs that regulates macroalgal abundance, mediates competitive interactions between macroalgae and corals, and provides resilience following disturbances such as hurricanes and coral bleaching. However, reductions in herbivore diversity and abundance via disease or over-fishing may harm corals directly and may indirectly increase coral susceptibility to other disturbances. Methodology and Principal Findings In two experiments over two years, we enclosed equivalent densities and masses of either single-species or mixed-species of herbivorous fishes in replicate, 4 m2 cages at a depth of 17 m on a reef in the Florida Keys, USA to evaluate the effects of herbivore identity and species richness on colonization and development of macroalgal communities and the cascading effects of algae on coral growth. In Year 1, we used the redband parrotfish (Sparisoma aurofrenatum) and the ocean surgeonfish (Acanthurus bahianus); in Year 2, we used the redband parrotfish and the princess parrotfish (Scarus taeniopterus). On new substrates, rapid grazing by ocean surgeonfish and princess parrotfish kept communities in an early successional stage dominated by short, filamentous algae and crustose coralline algae that did not suppress coral growth. In contrast, feeding by redband parrotfish allowed an accumulation of tall filaments and later successional macroalgae that suppressed coral growth. These patterns contrast with patterns from established communities not undergoing primary succession; on established substrates redband parrotfish significantly reduced upright macroalgal cover while ocean surgeonfish and princess parrotfish allowed significant increases in late successional macroalgae. Significance This study further highlights the importance of biodiversity in affecting ecosystem function in that different species of herbivorous fishes had very different impacts on reef communities depending on the developmental stage of the community. The species-specific effects of herbivorous fishes suggest that a species-rich herbivore fauna can be critical in providing the resilience that reefs need for recovery from common disturbances such as coral bleaching and storm damage.
Epigenetic histone modifications of human transposable elements: genome defense versus exaptation

(Georgia Institute of Technology, 2010-01-25) Huda, Ahsan ; Mariño-Ramírez, Leonardo ; Jordan, I. King

Background: Transposition is disruptive in nature and, thus, it is imperative for host genomes to evolve mechanisms that suppress the activity of transposable elements (TEs). At the same time, transposition also provides diverse sequences that can be exapted by host genomes as functional elements. These notions form the basis of two competing hypotheses pertaining to the role of epigenetic modifications of TEs in eukaryotic genomes: the genome defense hypothesis and the exaptation hypothesis. To date, all available evidence points to the genome defense hypothesis as the best explanation for the biological role of TE epigenetic modifications. Results: We evaluated several predictions generated by the genome defense hypothesis versus the exaptation hypothesis using recently characterized epigenetic histone modification data for the human genome. To this end, we mapped chromatin immunoprecipitation sequence tags from 38 histone modifications, characterized in CD4+ T cells, to the human genome and calculated their enrichment and depletion in all families of human TEs. We found that several of these families are significantly enriched or depleted for various histone modifications, both active and repressive. The enrichment of human TE families with active histone modifications is consistent with the exaptation hypothesis and stands in contrast to previous analyses that have found mammalian TEs to be exclusively repressively modified. Comparisons between TE families revealed that older families carry more histone modifications than younger ones, another observation consistent with the exaptation hypothesis. However, data from within family analyses on the relative ages of epigenetically modified elements are consistent with both the genome defense and exaptation hypotheses. Finally, TEs located proximal to genes carry more histone modifications than the ones that are distal to genes, as may be expected if epigenetically modified TEs help to regulate the expression of nearby host genes. Conclusions: With a few exceptions, most of our findings support the exaptation hypothesis for the role of TE epigenetic modifications when vetted against the genome defense hypothesis. The recruitment of epigenetic modifications may represent an additional mechanism by which TEs can contribute to the regulatory functions of their host genomes.
Chemosensitization of cancer cells by siRNA using targeted nanogel delivery

(Georgia Institute of Technology, 2010-01-11) Dickerson, Erin B. ; Blackburn, William H. ; Kapa, Laura B. ; Lyon, L. Andrew ; McDonald, John F.

Background. Chemoresistance is a major obstacle in cancer treatment. Targeted therapies that enhance cancer cell sensitivity to chemotherapeutic agents have the potential to increase drug efficacy while reducing toxic effects on untargeted cells. Targeted cancer therapy by RNA interference (RNAi) is a relatively new approach that can be used to reversibly silence genes in vivo by selectively targeting genes such as the epidermal growth factor receptor (EGFR), which has been shown to increase the sensitivity of cancer cells to taxane chemotherapy. However, delivery represents the main hurdle for the broad development of RNAi therapeutics. Methods. We report here the use of core/shell hydrogel nanoparticles (nanogels) functionalized with peptides that specially target the EphA2 receptor to deliver small interfering RNAs (siRNAs) targeting EGFR. Expression of EGFR was determined by immunoblotting, and the effect of decreased EGFR expression on chemosensitization of ovarian cancer cells after siRNA delivery was investigated. Results. Treatment of EphA2 positive Hey cells with siRNA-loaded, peptide-targeted nanogels decreased EGFR expression levels and significantly increased the sensitivity of this cell line to docetaxel (P < 0.05). Nanogel treatment of SK-OV-3 cells, which are negative for EphA2 expression, failed to reduce EGFR levels and did not increase docetaxel sensitivity (P > 0.05).
Biochemical Warfare on the Reef: The Role of Glutathione Transferases in Consumer Tolerance of Dietary Prostaglandins

(Georgia Institute of Technology, 2010-01-06) Whalen, Kristen E. ; Lane, Amy L. ; Kubanek, Julia ; Hahn, Mark E.

Background: Despite the profound variation among marine consumers in tolerance for allelochemically-rich foods, few studies have examined the biochemical adaptations underlying diet choice. Here we examine the role of glutathione Stransferases (GSTs) in the detoxification of dietary allelochemicals in the digestive gland of the predatory gastropod Cyphoma gibbosum, a generalist consumer of gorgonian corals. Controlled laboratory feeding experiments were used to investigate the influence of gorgonian diet on Cyphoma GST activity and isoform expression. Gorgonian extracts and semipurified fractions were also screened to identify inhibitors and possible substrates of Cyphoma GSTs. In addition, we investigated the inhibitory properties of prostaglandins (PGs) structurally similar to antipredatory PGs found in high concentrations in the Caribbean gorgonian Plexaura homomalla. Principal Findings: Cyphoma GST subunit composition was invariant and activity was constitutively high regardless of gorgonian diet. Bioassay-guided fractionation of gorgonian extracts revealed that moderately hydrophobic fractions from all eight gorgonian species examined contained putative GST substrates/inhibitors. LC-MS and NMR spectral analysis of the most inhibitory fraction from P. homomalla subsequently identified prostaglandin A2 (PGA2) as the dominant component. A similar screening of commercially available prostaglandins in series A, E, and F revealed that those prostaglandins most abundant in gorgonian tissues (e.g., PGA2) were also the most potent inhibitors. In vivo estimates of PGA2 concentration in digestive gland tissues calculated from snail grazing rates revealed that Cyphoma GSTs would be saturated with respect to PGA2 and operating at or near physiological capacity. Significance: The high, constitutive activity of Cyphoma GSTs is likely necessitated by the ubiquitous presence of GST substrates and/or inhibitors in this consumer’s gorgonian diet. This generalist’s GSTsmay operate as ‘all-purpose’ detoxification enzymes, capable of conjugating or sequestering a broad range of lipophilic gorgonian compounds, thereby allowing this predator to exploit a range of chemically-defended prey, resulting in a competitive dietary advantage for this species.