Publications by authors named "Richard J Hall"

84 Publications

Fragment-based drug discovery: opportunities for organic synthesis.

RSC Med Chem 2020 Dec 24;12(3):321-329. Epub 2020 Dec 24.

Astex Pharmaceuticals 436 Cambridge Science Park Cambridge CB4 0QA UK

This Review describes the increasing demand for organic synthesis to facilitate fragment-based drug discovery (FBDD), focusing on polar, unprotected fragments. In FBDD, X-ray crystal structures are used to design target molecules for synthesis with new groups added onto a fragment specific growth vectors. This requires challenging synthesis which slows down drug discovery, and some fragments are not progressed into optimisation due to synthetic intractability. We have evaluated the output from Astex's fragment screenings for a number of programs, including urokinase-type plasminogen activator, hematopoietic prostaglandin D2 synthase, and hepatitis C virus NS3 protease-helicase, and identified fragments that were not elaborated due, in part, to a lack of commercially available analogues and/or suitable synthetic methodology. This represents an opportunity for the development of new synthetic research to enable rapid access to novel chemical space and fragment optimisation.
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http://dx.doi.org/10.1039/d0md00375aDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8130625PMC
December 2020

Extended haplotype-phasing of long-read de novo genome assemblies using Hi-C.

Nat Commun 2021 04 28;12(1):1935. Epub 2021 Apr 28.

Pacific Biosciences, Menlo Park, CA, USA.

Haplotype-resolved genome assemblies are important for understanding how combinations of variants impact phenotypes. To date, these assemblies have been best created with complex protocols, such as cultured cells that contain a single-haplotype (haploid) genome, single cells where haplotypes are separated, or co-sequencing of parental genomes in a trio-based approach. These approaches are impractical in most situations. To address this issue, we present FALCON-Phase, a phasing tool that uses ultra-long-range Hi-C chromatin interaction data to extend phase blocks of partially-phased diploid assembles to chromosome or scaffold scale. FALCON-Phase uses the inherent phasing information in Hi-C reads, skipping variant calling, and reduces the computational complexity of phasing. Our method is validated on three benchmark datasets generated as part of the Vertebrate Genomes Project (VGP), including human, cow, and zebra finch, for which high-quality, fully haplotype-resolved assemblies are available using the trio-based approach. FALCON-Phase is accurate without having parental data and performance is better in samples with higher heterozygosity. For cow and zebra finch the accuracy is 97% compared to 80-91% for human. FALCON-Phase is applicable to any draft assembly that contains long primary contigs and phased associate contigs.
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http://dx.doi.org/10.1038/s41467-020-20536-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8081726PMC
April 2021

Light pollution affects West Nile virus exposure risk across Florida.

Proc Biol Sci 2021 03 24;288(1947):20210253. Epub 2021 Mar 24.

Department of Biological Sciences, California Polytechnic State University, 1 Grand Ave., San Luis Obispo, CA 93407, USA.

Emerging infectious diseases (EIDs) present global health threats, and their emergences are often linked to anthropogenic change. Artificial light at night (ALAN) is one form of anthropogenic change that spans beyond urban boundaries and may be relevant to EIDs through its influence on the behaviour and physiology of hosts and/or vectors. Although West Nile virus (WNV) emergence has been described as peri-urban, we hypothesized that exposure risk could also be influenced by ALAN in particular, which is testable by comparing the effects of ALAN on prevalence while controlling for other aspects of urbanization. By modelling WNV exposure among sentinel chickens in Florida, we found strong support for a nonlinear relationship between ALAN and WNV exposure risk in chickens with peak WNV risk occurring at low ALAN levels. Although our goal was not to discern how ALAN affected WNV relative to other factors, effects of ALAN on WNV exposure were stronger than other known drivers of risk (i.e. impervious surface, human population density). Ambient temperature in the month prior to sampling, but no other considered variables, strongly influenced WNV risk. These results indicate that ALAN may contribute to spatio-temporal changes in WNV risk, justifying future investigations of ALAN on other vector-borne parasites.
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http://dx.doi.org/10.1098/rspb.2021.0253DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8059973PMC
March 2021

Urban specialization reduces habitat connectivity by a highly mobile wading bird.

Mov Ecol 2020 Dec 7;8(1):49. Epub 2020 Dec 7.

Odum School of Ecology, University of Georgia, Athens, GA, USA.

Background: Mobile animals transport nutrients and propagules across habitats, and are crucial for the functioning of food webs and for ecosystem services. Human activities such as urbanization can alter animal movement behavior, including site fidelity and resource use. Because many urban areas are adjacent to natural sites, mobile animals might connect natural and urban habitats. More generally, understanding animal movement patterns in urban areas can help predict how urban expansion will affect the roles of highly mobile animals in ecological processes.

Methods: Here, we examined movements by a seasonally nomadic wading bird, the American white ibis (Eudocimus albus), in South Florida, USA. White ibis are colonial wading birds that forage on aquatic prey; in recent years, some ibis have shifted their behavior to forage in urban parks, where they are fed by people. We used a spatial network approach to investigate how individual movement patterns influence connectivity between urban and non-urban sites. We built a network of habitat connectivity using GPS tracking data from ibis during their non-breeding season and compared this network to simulated networks that assumed individuals moved indiscriminately with respect to habitat type.

Results: We found that the observed network was less connected than the simulated networks, that urban-urban and natural-natural connections were strong, and that individuals using urban sites had the least-variable habitat use. Importantly, the few ibis that used both urban and natural habitats contributed the most to connectivity.

Conclusions: Habitat specialization in urban-acclimated wildlife could reduce the exchange of propagules and nutrients between urban and natural areas, which has consequences both for beneficial effects of connectivity such as gene flow and for detrimental effects such as the spread of contaminants or pathogens.
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http://dx.doi.org/10.1186/s40462-020-00233-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7720518PMC
December 2020

Landscape-level toxicant exposure mediates infection impacts on wildlife populations.

Biol Lett 2020 11 18;16(11):20200559. Epub 2020 Nov 18.

Odum School of Ecology, College of Veterinary Medicine; University of Georgia, Athens, GA, USA.

Anthropogenic landscape modification such as urbanization can expose wildlife to toxicants, with profound behavioural and health effects. Toxicant exposure can alter the local transmission of wildlife diseases by reducing survival or altering immune defence. However, predicting the impacts of pathogens on wildlife across their ranges is complicated by heterogeneity in toxicant exposure across the landscape, especially if toxicants alter wildlife movement from toxicant-contaminated to uncontaminated habitats. We developed a mechanistic model to explore how toxicant effects on host health and movement propensity influence range-wide pathogen transmission, and zoonotic exposure risk, as an increasing fraction of the landscape is toxicant-contaminated. When toxicant-contaminated habitat is scarce on the landscape, costs to movement and survival from toxicant exposure can trap infected animals in contaminated habitat and reduce landscape-level transmission. Increasing the proportion of contaminated habitat causes host population declines from combined effects of toxicants and infection. The onset of host declines precedes an increase in the density of infected hosts in contaminated habitat and thus may serve as an early warning of increasing potential for zoonotic spillover in urbanizing landscapes. These results highlight how sublethal effects of toxicants can determine pathogen impacts on wildlife populations that may not manifest until landscape contamination is widespread.
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http://dx.doi.org/10.1098/rsbl.2020.0559DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7728674PMC
November 2020

Reactivation of latent infections with migration shapes population-level disease dynamics.

Proc Biol Sci 2020 09 16;287(1935):20201829. Epub 2020 Sep 16.

Center for the Ecology of Infectious Disease, College of Veterinary Medicine, University of Georgia, Athens, GA, USA.

Annual migration is common across animal taxa and can dramatically shape the spatial and temporal patterns of infectious disease. Although migration can decrease infection prevalence in some contexts, these energetically costly long-distance movements can also have immunosuppressive effects that may interact with transmission processes in complex ways. Here, we develop a mechanistic model for the reactivation of latent infections driven by physiological changes or energetic costs associated with migration (i.e. 'migratory relapse') and its effects on disease dynamics. We determine conditions under which migratory relapse can amplify or reduce infection prevalence across pathogen and host traits (e.g. infectious periods, virulence, overwinter survival, timing of relapse) and transmission phenologies. We show that relapse at either the start or end of migration can dramatically increase prevalence across the annual cycle and may be crucial for maintaining pathogens with low transmissibility and short infectious periods in migratory populations. Conversely, relapse at the start of migration can reduce the prevalence of highly virulent pathogens by amplifying culling of infected hosts during costly migration, especially for highly transmissible pathogens and those transmitted during migration or the breeding season. Our study provides a mechanistic foundation for understanding the spatio-temporal patterns of relapsing infections in migratory hosts, with implications for zoonotic surveillance and understanding how infection patterns will respond to shifts in migratory propensity associated with environmental change. Further, our work suggests incorporating within-host processes into population-level models of pathogen transmission may be crucial for reconciling the range of migration-infection relationships observed across migratory species.
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http://dx.doi.org/10.1098/rspb.2020.1829DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7542827PMC
September 2020

Identifying correlates of Guinea worm (Dracunculus medinensis) infection in domestic dog populations.

PLoS Negl Trop Dis 2020 09 14;14(9):e0008620. Epub 2020 Sep 14.

Odum School of Ecology, University of Georgia, Athens, Georgia, United States of America.

Few human infectious diseases have been driven as close to eradication as dracunculiasis, caused by the Guinea worm parasite (Dracunculus medinensis). The number of human cases of Guinea worm decreased from an estimated 3.5 million in 1986 to mere hundreds by the 2010s. In Chad, domestic dogs were diagnosed with Guinea worm for the first time in 2012, and the numbers of infected dogs have increased annually. The presence of the parasite in a non-human host now challenges efforts to eradicate D. medinensis, making it critical to understand the factors that correlate with infection in dogs. In this study, we evaluated anthropogenic and environmental factors most predictive of detection of D. medinensis infection in domestic dog populations in Chad. Using boosted regression tree models to identify covariates of importance for predicting D. medinensis infection at the village and spatial hotspot levels, while controlling for surveillance intensity, we found that the presence of infection in a village was predicted by a combination of demographic (e.g. fishing village identity, dog population size), geographic (e.g. local variation in elevation), and climatic (e.g. precipitation and temperature) factors, which differed between northern and southern villages. In contrast, the presence of a village in a spatial infection hotspot, was primarily predicted by geography and climate. Our findings suggest that factors intrinsic to individual villages are highly predictive of the detection of Guinea worm parasite presence, whereas village membership in a spatial infection hotspot is largely determined by location and climate. This study provides new insight into the landscape-scale epidemiology of a debilitating parasite and can be used to more effectively target ongoing research and possibly eradication and control efforts.
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http://dx.doi.org/10.1371/journal.pntd.0008620DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7515199PMC
September 2020

Movement rules determine nomadic species' responses to resource supplementation and degradation.

J Anim Ecol 2020 11 13;89(11):2644-2656. Epub 2020 Sep 13.

Odum School of Ecology, University of Georgia, Athens, GA, USA.

In environments that vary unpredictably, many animals are nomadic, moving in an irregular pattern that differs from year to year. Exploring the mechanisms of nomadic movement is needed to understand how animals survive in highly variable environments, and to predict behavioural and population responses to environmental change. We developed a network model to identify plausible mechanisms of nomadic animal movement by comparing the performance of multiple movement rules along a continuum from nomadism to residency. Using simulations and analytical results, we explored how different types of habitat modifications (that augment or decrease resource availability) might affect the abundance and movement rates of animals following each of these rules. Movement rules for which departure from patches depended on resource availability and/or competition performed almost equally well and better than residency or uninformed movement under most conditions, even though animals using each rule moved at substantially different rates. Habitat modifications that stabilized resources, either by resource supplementation or degradation, eroded the benefits of informed nomadic movements, particularly for movements based on resource availability alone. These results suggest that simple movement rules can explain nomadic animal movements and determine species' responses to environmental change. In particular, landscape stabilization and supplementation might be useful strategies for promoting populations of resident animals, but would be less beneficial for managing highly mobile species, many of which are threatened by habitat disruption and changes in climate.
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http://dx.doi.org/10.1111/1365-2656.13318DOI Listing
November 2020

Multiple transmission routes sustain high prevalence of a virulent parasite in a butterfly host.

Proc Biol Sci 2019 09 4;286(1910):20191630. Epub 2019 Sep 4.

Odum School of Ecology, College of Veterinary Medicine, University of Georgia, Athens, GA, USA.

Understanding factors that allow highly virulent parasites to reach high infection prevalence in host populations is important for managing infection risks to human and wildlife health. Multiple transmission routes have been proposed as one mechanism by which virulent pathogens can achieve high prevalence, underscoring the need to investigate this hypothesis through an integrated modelling-empirical framework. Here, we examine a harmful specialist protozoan infecting monarch butterflies that commonly reaches high prevalence (50-100%) in resident populations. We integrate field and modelling work to show that a combination of three empirically-supported transmission routes (vertical, adult transfer and environmental transmission) can produce and sustain high infection prevalence in this system. Although horizontal transmission is necessary for parasite invasion, most new infections post-establishment arise from vertical transmission. Our study predicts that multiple transmission routes, coupled with high parasite virulence, can reduce resident host abundance by up to 50%, suggesting that the protozoan could contribute to declines of North American monarchs.
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http://dx.doi.org/10.1098/rspb.2019.1630DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6742984PMC
September 2019

Accurate circular consensus long-read sequencing improves variant detection and assembly of a human genome.

Nat Biotechnol 2019 10 12;37(10):1155-1162. Epub 2019 Aug 12.

Pacific Biosciences, Menlo Park, CA, USA.

The DNA sequencing technologies in use today produce either highly accurate short reads or less-accurate long reads. We report the optimization of circular consensus sequencing (CCS) to improve the accuracy of single-molecule real-time (SMRT) sequencing (PacBio) and generate highly accurate (99.8%) long high-fidelity (HiFi) reads with an average length of 13.5 kilobases (kb). We applied our approach to sequence the well-characterized human HG002/NA24385 genome and obtained precision and recall rates of at least 99.91% for single-nucleotide variants (SNVs), 95.98% for insertions and deletions <50 bp (indels) and 95.99% for structural variants. Our CCS method matches or exceeds the ability of short-read sequencing to detect small variants and structural variants. We estimate that 2,434 discordances are correctable mistakes in the 'genome in a bottle' (GIAB) benchmark set. Nearly all (99.64%) variants can be phased into haplotypes, further improving variant detection. De novo genome assembly using CCS reads alone produced a contiguous and accurate genome with a contig N50 of >15 megabases (Mb) and concordance of 99.997%, substantially outperforming assembly with less-accurate long reads.
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http://dx.doi.org/10.1038/s41587-019-0217-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6776680PMC
October 2019

Light pollution increases West Nile virus competence of a ubiquitous passerine reservoir species.

Proc Biol Sci 2019 07 24;286(1907):20191051. Epub 2019 Jul 24.

Center for Global Health Infectious Disease Research, University of South Florida, Tampa, FL 33620, USA.

Among the many anthropogenic changes that impact humans and wildlife, one of the most pervasive but least understood is light pollution. Although detrimental physiological and behavioural effects resulting from exposure to light at night are widely appreciated, the impacts of light pollution on infectious disease risk have not been studied. Here, we demonstrate that artificial light at night (ALAN) extends the infectious-to-vector period of the house sparrow (Passer domesticus), an urban-dwelling avian reservoir host of West Nile virus (WNV). Sparrows exposed to ALAN maintained transmissible viral titres for 2 days longer than controls but did not experience greater WNV-induced mortality during this window. Transcriptionally, ALAN altered the expression of gene regulatory networks including key hubs (OASL, PLBD1 and TRAP1) and effector genes known to affect WNV dissemination (SOCS). Despite mounting anti-viral immune responses earlier, transcriptomic signatures indicated that ALAN-exposed individuals probably experienced pathogen-induced damage and immunopathology, potentially due to evasion of immune effectors. A simple mathematical modelling exercise indicated that ALAN-induced increases of host infectious-to-vector period could increase WNV outbreak potential by approximately 41%. ALAN probably affects other host and vector traits relevant to transmission, and additional research is needed to advise the management of zoonotic diseases in light-polluted areas.
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http://dx.doi.org/10.1098/rspb.2019.1051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6661335PMC
July 2019

Modeling the Effects of Resource-Driven Immune Defense on Parasite Transmission in Heterogeneous Host Populations.

Authors:
Richard J Hall

Integr Comp Biol 2019 11;59(5):1253-1263

Odum School of Ecology, University of Georgia, Athens, GA, USA.

Individuals experience heterogeneous environmental conditions that can affect within-host processes such as immune defense against parasite infection. Variation among individuals in parasite shedding can cause some hosts to contribute disproportionately to population-level transmission, but we currently lack mechanistic theory that predicts when environmental conditions can result in large disease outbreaks through the formation of immunocompromised superspreading individuals. Here, I present a within-host model of a microparasite's interaction with the immune system that links an individual host's resource intake to its infectious period. For environmental scenarios driving population-level heterogeneity in resource intake (resource scarcity and resource subsidy relative to baseline availability), I generate a distribution of infectious periods and simulate epidemics on these heterogeneous populations. I find that resource scarcity can result in large epidemics through creation of superspreading individuals, while resource subsidies can reduce or prevent transmission of parasites close to their invasion threshold by homogenizing resource allocation to immune defense. Importantly, failure to account for heterogeneity in competence can result in under-prediction of outbreak size, especially when parasites are close to their invasion threshold. More generally, this framework suggests that differences in conditions experienced by individual hosts can lead to superspreading via differences in resource allocation to immune defense alone, even in the absence of other heterogeneites such as host contacts.
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http://dx.doi.org/10.1093/icb/icz074DOI Listing
November 2019

Trichomonosis due to Trichomonas gallinae infection in barn owls (Tyto alba) and barred owls (Strix varia) from the eastern United States.

Vet Parasitol Reg Stud Reports 2019 04 7;16:100281. Epub 2019 Mar 7.

Southeastern Cooperative Wildlife Disease Study, 589 D.W. Brooks Drive, Wildlife Health Building, College of Veterinary Medicine, The University of Georgia, Athens, GA 30602, USA; Warnell School of Forestry and Natural Resources, 180 E Green Street, University of Georgia, Athens, GA 30602, USA. Electronic address:

Trichomonosis is an important cause of mortality in multiple avian species; however, there have been relatively few reports of this disease in owls. Two barn owls (Tyto alba) and four barred owls (Strix varia) submitted for diagnostic examination had lesions consistent with trichomonosis including caseous necrosis and inflammation in the oropharynx. Microscopically, these lesions were often associated with trichomonads and molecular testing, if obtainable, confirmed the presence of Trichomonas gallinae, the species most commonly associated with trichomonosis in birds. The T. gallinae genotype in one barn owl and two barred owls was identified as ITS-OBT-Tg-1 by sequence analysis. Columbids are the primary hosts for T. gallinae, and columbid remains found within the nest box of the barn owls were the likely source of infection. This study is the first to formally describe the strains and genetic variation of T. gallinae samples from clinical cases of trichomonosis in barn and barred owls in the eastern USA.
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http://dx.doi.org/10.1016/j.vprsr.2019.100281DOI Listing
April 2019

Assessing the contributions of intraspecific and environmental sources of infection in urban wildlife: Salmonella enterica and white ibis as a case study.

J R Soc Interface 2018 12;15(149):20180654

1 Odum School of Ecology, University of Georgia , Athens, GA , USA.

Conversion of natural habitats into urban landscapes can expose wildlife to novel pathogens and alter pathogen transmission pathways. Because transmission is difficult to quantify for many wildlife pathogens, mathematical models paired with field observations can help select among competing transmission pathways that might operate in urban landscapes. Here we develop a mathematical model for the enteric bacteria Salmonella enterica in urban-foraging white ibis ( Eudocimus albus) in south Florida as a case study to determine (i) the relative importance of contact-based versus environmental transmission among ibis and (ii) whether transmission can be supported by ibis alone or requires external sources of infection. We use biannual field prevalence data to restrict model outputs generated from a Latin hypercube sample of parameter space and select among competing transmission scenarios. We find the most support for transmission from environmental uptake rather than between-host contact and that ibis-ibis transmission alone could maintain low infection prevalence. Our analysis provides the first parameter estimates for Salmonella shedding and uptake in a wild bird and provides a key starting point for predicting how ibis response to urbanization alters their exposure to a multi-host zoonotic enteric pathogen. More broadly, our study provides an analytical roadmap to assess transmission pathways of multi-host wildlife pathogens in the face of scarce infection data.
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http://dx.doi.org/10.1098/rsif.2018.0654DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6303792PMC
December 2018

Antarctic Penguins as Reservoirs of Diversity for Avian Avulaviruses.

J Virol 2019 06 15;93(11). Epub 2019 May 15.

WHO Collaborating Centre for Reference and Research on Influenza, The Peter Doherty Institute for Infection and Immunity, Melbourne, Australia

Wild birds harbor a huge diversity of avian avulaviruses (formerly avian paramyxoviruses). Antarctic penguin species have been screened for avian avulaviruses since the 1980s and, as such, are known hosts of these viruses. In this study, we screened three penguin species from the South Shetland Islands and the Antarctic Peninsula for avian avulaviruses. We show that Adelie penguins () are hosts for four different avian avulavirus species, the recently described avian avulaviruses 17 to 19 and avian avulavirus 10-like, never before isolated in Antarctica. A total of 24 viruses were isolated and sequenced; avian avulavirus 17 was the most common, and phylogenetic analysis demonstrated patterns of occurrence, with different genetic clusters corresponding to penguin age and location. Following infection in specific-pathogen-free (SPF) chickens, all four avian avulavirus species were shed from the oral cavity for up to 7 days postinfection. There was limited shedding from the cloaca in a proportion of infected chickens, and all but one bird seroconverted by day 21. No clinical signs were observed. Taken together, we propose that penguin species, including Antarctic penguins, may be the central reservoir for a diversity of avian avulavirus species and that these viruses have the potential to infect other avian hosts. Approximately 99% of all viruses are still to be described, and in our changing world, any one of these unknown viruses could potentially expand their host range and cause epidemic disease in wildlife, agricultural animals, or humans. Avian avulavirus 1 causes outbreaks in wild birds and poultry and is thus well described. However, for many avulavirus species, only a single specimen has been described, and their viral ecology and epidemiology are unknown. Through the detection of avian avulaviruses in penguins from Antarctica, we have been able to expand upon our understanding of three avian avulavirus species (avian avulaviruses 17 to 19) and report a potentially novel avulavirus species. Importantly, we show that penguins appear to play a key role in the epidemiology of avian avulaviruses, and we encourage additional sampling of this avian group.
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http://dx.doi.org/10.1128/JVI.00271-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6532105PMC
June 2019

Crystallographic screening using ultra-low-molecular-weight ligands to guide drug design.

Drug Discov Today 2019 05 14;24(5):1081-1086. Epub 2019 Mar 14.

Astex Pharmaceuticals,436 Cambridge Science Park, Milton Road, Cambridge, CB4 0QA, UK. Electronic address:

We present a novel crystallographic screening methodology (MiniFrags) that employs high-concentration aqueous soaks with a chemically diverse and ultra-low-molecular-weight library (heavy atom count 5-7) to identify ligand-binding hot and warm spots on proteins. We propose that MiniFrag screening represents a highly effective method for guiding optimisation of fragment-derived lead compounds or chemical tools and that the high screening hit rates reflect enhanced sampling of chemical space.
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http://dx.doi.org/10.1016/j.drudis.2019.03.009DOI Listing
May 2019

Comparative Genome Analysis of an Extensively Drug-Resistant Isolate of Avian Sequence Type 167 Strain Sanji with Novel Serotype O89b:H9.

mSystems 2019 Jan-Feb;4(1). Epub 2019 Feb 26.

College of Life Sciences, Fujian Agriculture and Forestry University, Fuzhou, China.

Extensive drug resistance (XDR) is an escalating global problem. Escherichia coli strain Sanji was isolated from an outbreak of pheasant colibacillosis in Fujian province, China, in 2011. This strain has XDR properties, exhibiting sensitivity to carbapenems but no other classes of known antibiotics. Whole-genome sequencing revealed a total of 32 known antibiotic resistance genes, many associated with insertion sequence 26 (IS) elements. These were found on the Sanji chromosome and 2 of its 6 plasmids, pSJ_255 and pSJ_82. The Sanji chromosome also harbors a type 2 secretion system (T2SS), a type 3 secretion system (T3SS), a type 6 secretion system (T6SS), and several putative prophages. Sanji and other ST167 strains have a previously uncharacterized O-antigen (O89b) that is most closely related to serotype O89 as determined on the basis of analysis of the genes and serotyping. This O89b-antigen gene cluster was also found in the genomes of a few other pathogenic sequence type 617 (ST617) and ST10 complex strains. A time-scaled phylogeny inferred from comparative single nucleotide variant analysis indicated that development of these O89b-containing lineages emerged about 30 years ago. Comparative sequence analysis revealed that the core genome of Sanji is nearly identical to that of several recently sequenced strains of pathogenic XDR E. coli belonging to the ST167 group. Comparison of the mobile elements among the different ST167 genomes revealed that each genome carries a distinct set of multidrug resistance genes on different types of plasmids, indicating that there are multiple paths toward the emergence of XDR in E. coli. E. coli strain Sanji is the first sequenced and analyzed genome of the recently emerged pathogenic XDR strains with sequence type ST167 and novel serotype O89b:H9. Comparison of the genomes of Sanji with other ST167 strains revealed distinct sets of different plasmids, mobile IS elements, and antibiotic resistance genes in each genome, indicating that there exist multiple paths toward achieving XDR. The emergence of these pathogenic ST167 E. coli strains with diverse XDR capabilities highlights the difficulty of preventing or mitigating the development of XDR properties in bacteria and points to the importance of better understanding of the shared underlying virulence mechanisms and physiology of pathogenic bacteria.
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http://dx.doi.org/10.1128/mSystems.00242-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6392093PMC
February 2019

On the relationship between body condition and parasite infection in wildlife: a review and meta-analysis.

Ecol Lett 2018 Dec 4;21(12):1869-1884. Epub 2018 Oct 4.

Odum School of Ecology, University of Georgia, Athens, GA, USA.

Body condition metrics are widely used to infer animal health and to assess costs of parasite infection. Since parasites harm their hosts, ecologists might expect negative relationships between infection and condition in wildlife, but this assumption is challenged by studies showing positive or null condition-infection relationships. Here, we outline common condition metrics used by ecologists in studies of parasitism, and consider mechanisms that cause negative, positive, and null condition-infection relationships in wildlife systems. We then perform a meta-analysis of 553 condition-infection relationships from 187 peer-reviewed studies of animal hosts, analysing observational and experimental records separately, and noting whether authors measured binary infection status or intensity. Our analysis finds substantial heterogeneity in the strength and direction of condition-infection relationships, a small, negative average effect size that is stronger in experimental studies, and evidence for publication bias towards negative relationships. The strongest predictors of variation in study outcomes are host thermoregulation and the methods used to evaluate body condition. We recommend that studies aiming to assess parasite impacts on body condition should consider host-parasite biology, choose condition measures that can change during the course of infection, and employ longitudinal surveys or manipulate infection status when feasible.
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http://dx.doi.org/10.1111/ele.13160DOI Listing
December 2018

Host Dispersal Responses to Resource Supplementation Determine Pathogen Spread in Wildlife Metapopulations.

Am Nat 2018 10 15;192(4):503-517. Epub 2018 Aug 15.

Many wildlife species occupy landscapes that vary in the distribution, abundance, and quality of food resources. Increasingly, urbanized and agricultural habitats provide supplemental food resources that can have profound consequences for host distributions, movement patterns, and pathogen exposure. Understanding how host and pathogen dispersal across landscapes is affected by the spatial extent of food-supplemented habitats is therefore important for predicting the consequences for pathogen spread and impacts on host occupancy. Here we develop a generalizable metapopulation model to understand how the relative abundance of provisioned habitats across the landscape and how the host dispersal responses to provisioning and infection influence patch occupancy by hosts and their pathogens. We find that pathogen invasion and landscape-level infection prevalence are greatest when provisioning increases patch attractiveness and disperser production and when infection has minimal costs on dispersal success. Alternatively, if provisioning promotes site fidelity or reduces disperser production, increasing the fraction of food-supplemented habitats can reduce landscape-scale infection prevalence and minimize disease-induced declines in host occupancy. This work highlights the importance of considering how resources and infection jointly influence host dispersal for predicting how changing resource distributions influence the spread of infectious diseases.
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http://dx.doi.org/10.1086/699477DOI Listing
October 2018

Dim light at night: physiological effects and ecological consequences for infectious disease.

Integr Comp Biol 2018 11;58(5):995-1007

Department of Global Health, University of South Florida, Tampa, FL, USA.

Light pollution has emerged as a pervasive component of land development over the past century. Several detrimental impacts of this anthropogenic influence have been identified in night shift workers, laboratory rodents, and a plethora of wildlife species. Circadian, or daily, patterns are interrupted by the presence of light at night and have the capacity to alter rhythmic physiological or behavioral characteristics. Indeed, biorhythm disruption can lead to metabolic, reproductive, and immunological dysfunction depending on the intensity, timing, duration, and wavelength of light exposure. Light pollution, in many forms and by many pathways, is thus apt to affect the nature of host-pathogen interactions. However, no research has yet investigated this possibility. The goal of this manuscript is to outline how dim light at night, a relevant and common form of light pollution, may affect disease dynamics by interrupting circadian rhythms and regulation of immune responses as well as opportunities for host-parasite interactions and subsequent transmission risk including spillover into humans. We close by proposing some promising interventions including alternative lighting methods or vector control efforts.
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http://dx.doi.org/10.1093/icb/icy080DOI Listing
November 2018

Migratory behaviour predicts greater parasite diversity in ungulates.

Proc Biol Sci 2018 03;285(1875)

Odum School of Ecology, University of Georgia, Athens GA, USA.

Long-distance animal movements can increase exposure to diverse parasites, but can also reduce infection risk through escape from contaminated habitats or culling of infected individuals. These mechanisms have been demonstrated within and between populations in single-host/single-parasite interactions, but how long-distance movement behaviours shape parasite diversity and prevalence across host taxa is largely unknown. Using a comparative approach, we analyse the parasite communities of 93 migratory, nomadic and resident ungulate species. We find that migrants have higher parasite species richness than residents or nomads, even after considering other factors known to influence parasite diversity, such as body size and host geographical range area. Further analyses support a novel 'environmental tracking' hypothesis, whereby migration allows parasites to experience environments favourable to transmission year-round. In addition, the social aggregation and large group sizes that facilitate migration might increase infection risk for migrants. By contrast, we find little support for previously proposed hypotheses, including migratory escape and culling, in explaining the relationship between host movement and parasitism in mammals at this cross-species scale. Our findings, which support mechanistic links between long-distance movement and increased parasite richness at the species level, could help predict the effects of future environmental change on parasitism in migratory animals.
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http://dx.doi.org/10.1098/rspb.2018.0089DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5897646PMC
March 2018

Resolving the complete genome of Kuenenia stuttgartiensis from a membrane bioreactor enrichment using Single-Molecule Real-Time sequencing.

Sci Rep 2018 03 15;8(1):4580. Epub 2018 Mar 15.

Leiden Genome Technology Center, Leiden University Medical Center, Leiden, The Netherlands.

Anaerobic ammonium-oxidizing (anammox) bacteria are a group of strictly anaerobic chemolithoautotrophic microorganisms. They are capable of oxidizing ammonium to nitrogen gas using nitrite as a terminal electron acceptor, thereby facilitating the release of fixed nitrogen into the atmosphere. The anammox process is thought to exert a profound impact on the global nitrogen cycle and has been harnessed as an environment-friendly method for nitrogen removal from wastewater. In this study, we present the first closed genome sequence of an anammox bacterium, Kuenenia stuttgartiensis MBR1. It was obtained through Single-Molecule Real-Time (SMRT) sequencing of an enrichment culture constituting a mixture of at least two highly similar Kuenenia strains. The genome of the novel MBR1 strain is different from the previously reported Kuenenia KUST reference genome as it contains numerous structural variations and unique genomic regions. We find new proteins, such as a type 3b (sulf)hydrogenase and an additional copy of the hydrazine synthase gene cluster. Moreover, multiple copies of ammonium transporters and proteins regulating nitrogen uptake were identified, suggesting functional differences in metabolism. This assembly, including the genome-wide methylation profile, provides a new foundation for comparative and functional studies aiming to elucidate the biochemical and metabolic processes of these organisms.
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http://dx.doi.org/10.1038/s41598-018-23053-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5854607PMC
March 2018

Food for contagion: synthesis and future directions for studying host-parasite responses to resource shifts in anthropogenic environments.

Philos Trans R Soc Lond B Biol Sci 2018 05;373(1745)

Odum School of Ecology, College of Veterinary Medicine, University of Georgia, Athens, GA, USA.

Human-provided resource subsidies for wildlife are diverse, common and have profound consequences for wildlife-pathogen interactions, as demonstrated by papers in this themed issue spanning empirical, theoretical and management perspectives from a range of study systems. Contributions cut across scales of organization, from the within-host dynamics of immune function, to population-level impacts on parasite transmission, to landscape- and regional-scale patterns of infection. In this concluding paper, we identify common threads and key findings from author contributions, including the consequences of resource subsidies for (i) host immunity; (ii) animal aggregation and contact rates; (iii) host movement and landscape-level infection patterns; and (iv) interspecific contacts and cross-species transmission. Exciting avenues for future work include studies that integrate mechanistic modelling and empirical approaches to better explore cross-scale processes, and experimental manipulations of food resources to quantify host and pathogen responses. Work is also needed to examine evolutionary responses to provisioning, and ask how diet-altered changes to the host microbiome influence infection processes. Given the massive public health and conservation implications of anthropogenic resource shifts, we end by underscoring the need for practical recommendations to manage supplemental feeding practices, limit human-wildlife conflicts over shared food resources and reduce cross-species transmission risks, including to humans.This article is part of the theme issue 'Anthropogenic resource subsidies and host-parasite dynamics in wildlife'.
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http://dx.doi.org/10.1098/rstb.2017.0102DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5881886PMC
May 2018

Consequences of resource supplementation for disease risk in a partially migratory population.

Philos Trans R Soc Lond B Biol Sci 2018 05;373(1745)

Odum School of Ecology, University of Georgia, 140 E. Green St., Athens, GA 30602, USA.

Anthropogenic landscape features such as urban parks and gardens, landfills and farmlands can provide novel, seasonally reliable food sources that impact wildlife ecology and distributions. In historically migratory species, food subsidies can cause individuals to forgo migration and form partially migratory or entirely sedentary populations, eroding a crucial benefit of migration: pathogen avoidance through seasonal abandonment of transmission sites and mortality of infected individuals during migration. Since many migratory taxa are declining, and wildlife populations in urban areas can harbour zoonotic pathogens, understanding the mechanisms by which anthropogenic resource subsidies influence infection dynamics and the persistence of migration is important for wildlife conservation and public health. We developed a mathematical model for a partially migratory population and a vector-borne pathogen transmitted at a shared breeding ground, where food subsidies increase the nonbreeding survival of residents. We found that higher resident nonbreeding survival increased infection prevalence in residents and migrants, and lowered the fraction of the population that migrated. The persistence of migration may be especially threatened if residency permits emergence of more virulent pathogens, if resource subsidies reduce costs of infection for residents, and if infection reduces individual migratory propensity.This article is part of the theme issue 'Anthropogenic resource subsidies and host-parasite dynamics in wildlife'.
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http://dx.doi.org/10.1098/rstb.2017.0095DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5883001PMC
May 2018

Anthropogenic resource subsidies and host-parasite dynamics in wildlife.

Philos Trans R Soc Lond B Biol Sci 2018 05;373(1745)

Odum School of Ecology, College of Veterinary Medicine, University of Georgia, Athens, GA, USA.

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http://dx.doi.org/10.1098/rstb.2017.0086DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5882992PMC
May 2018

Host and parasite thermal ecology jointly determine the effect of climate warming on epidemic dynamics.

Proc Natl Acad Sci U S A 2018 01 8;115(4):744-749. Epub 2018 Jan 8.

Odum School of Ecology, University of Georgia, Athens, GA 30602.

Host-parasite systems have intricately coupled life cycles, but each interactor can respond differently to changes in environmental variables like temperature. Although vital to predicting how parasitism will respond to climate change, thermal responses of both host and parasite in key traits affecting infection dynamics have rarely been quantified. Through temperature-controlled experiments on an ectothermic host-parasite system, we demonstrate an offset in the thermal optima for survival of infected and uninfected hosts and parasite production. We combine experimentally derived thermal performance curves with field data on seasonal host abundance and parasite prevalence to parameterize an epidemiological model and forecast the dynamical responses to plausible future climate-warming scenarios. In warming scenarios within the coastal southeastern United States, the model predicts sharp declines in parasite prevalence, with local parasite extinction occurring with as little as 2 °C warming. The northern portion of the parasite's current range could experience local increases in transmission, but assuming no thermal adaptation of the parasite, we find no evidence that the parasite will expand its range northward under warming. This work exemplifies that some host populations may experience reduced parasitism in a warming world and highlights the need to measure host and parasite thermal performance to predict infection responses to climate change.
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http://dx.doi.org/10.1073/pnas.1705067115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5789902PMC
January 2018

Editorial: Virus Discovery by Metagenomics: The (Im)possibilities.

Front Microbiol 2017 8;8:1710. Epub 2017 Sep 8.

Department of Molecular Biology and Biochemistry, University of California, IrvineIrvine, CA, United States.

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http://dx.doi.org/10.3389/fmicb.2017.01710DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5596103PMC
September 2017

The Fragment Network: A Chemistry Recommendation Engine Built Using a Graph Database.

J Med Chem 2017 07 15;60(14):6440-6450. Epub 2017 Jul 15.

Astex Pharmaceuticals , 436 Cambridge Science Park, Milton Road, Cambridge CB4 0QA, United Kingdom.

The hit validation stage of a fragment-based drug discovery campaign involves probing the SAR around one or more fragment hits. This often requires a search for similar compounds in a corporate collection or from commercial suppliers. The Fragment Network is a graph database that allows a user to efficiently search chemical space around a compound of interest. The result set is chemically intuitive, naturally grouped by substitution pattern and meaningfully sorted according to the number of observations of each transformation in medicinal chemistry databases. This paper describes the algorithms used to construct and search the Fragment Network and provides examples of how it may be used in a drug discovery context.
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http://dx.doi.org/10.1021/acs.jmedchem.7b00809DOI Listing
July 2017

Assessing the Impact of Assemblers on Virus Detection in a De Novo Metagenomic Analysis Pipeline.

J Comput Biol 2017 Sep 17;24(9):874-881. Epub 2017 Apr 17.

3 Animal Health Laboratory, Investigation and Diagnostic Centres and Response, Ministry for Primary Industries-Manatū Ahu Matua , Upper Hutt, New Zealand .

Applying high-throughput sequencing to pathogen discovery is a relatively new field, the objective of which is to find disease-causing agents when little or no background information on disease is available. Key steps in the process are the generation of millions of sequence reads from an infected tissue sample, followed by assembly of these reads into longer, contiguous stretches of nucleotide sequences, and then identification of the contigs by matching them to known databases, such as those stored at GenBank or Ensembl. This technique, that is, de novo metagenomics, is particularly useful when the pathogen is viral and strong discriminatory power can be achieved. However, recently, we found that striking differences in results can be achieved when different assemblers were used. In this study, we test formally the impact of five popular assemblers (MIRA, VELVET, METAVELVET, SPADES, and OMEGA) on the detection of a novel virus and assembly of its whole genome in a data set for which we have confirmed the presence of the virus by empirical laboratory techniques, and compare the overall performance between assemblers. Our results show that if results from only one assembler are considered, biologically important reads can easily be overlooked. The impacts of these results on the field of pathogen discovery are considered.
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http://dx.doi.org/10.1089/cmb.2017.0008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5610382PMC
September 2017

Predicting "Hot" and "Warm" Spots for Fragment Binding.

J Med Chem 2017 05 21;60(9):4036-4046. Epub 2017 Apr 21.

Astex Pharmaceuticals , 436 Cambridge Science Park, Milton Road, Cambridge CB4 0QA, United Kingdom.

Computational fragment mapping methods aim to predict hotspots on protein surfaces where small fragments will bind. Such methods are popular for druggability assessment as well as structure-based design. However, to date researchers developing or using such tools have had no clear way of assessing the performance of these methods. Here, we introduce the first diverse, high quality validation set for computational fragment mapping. The set contains 52 diverse examples of fragment binding "hot" and "warm" spots from the Protein Data Bank (PDB). Additionally, we describe PLImap, a novel protocol for fragment mapping based on the Protein-Ligand Informatics force field (PLIff). We evaluate PLImap against the new fragment mapping test set, and compare its performance to that of simple shape-based algorithms and fragment docking using GOLD. PLImap is made publicly available from https://bitbucket.org/AstexUK/pli .
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http://dx.doi.org/10.1021/acs.jmedchem.7b00366DOI Listing
May 2017