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1.  An Idiosyncratic Reaction to Clopidogrel 
The Permanente Journal  2015;19(1):74-76.
Clopidogrel is an irreversible antiplatelet agent that antagonizes the adenosine diphosphate P2Y12 receptor on platelets disrupting fibrinogen—platelet complex formation. The authors report on a rare but clinically significant case of clopidogrel-induced hepatotoxicity in an elderly white woman.
Clopidogrel is an irreversible antiplatelet agent belonging to the thienopyridine group that acts to antagonize the adenosine diphosphate P2Y12 receptor on platelets. It thus inhibits the activation of platelet glycoprotein GPIIb/IIIa complex, which is essential for fibrinogen—platelet complex formation. Clopidogrel has widely replaced ticlopidine because of a much better clinical safety profile. Clopidogrel is a prodrug that requires hepatic activation to exert its antiplatelet effect. Hepatotoxicity with use of clopidogrel is a rare but clinically significant phenomenon. We report a case of clopidogrel-induced hepatotoxicity in an elderly white woman.
PMCID: PMC4315382  PMID: 25663208
2.  Current scientific evidence for integrated community case management (iCCM) in Africa: Findings from the iCCM Evidence Symposium 
Journal of Global Health  2014;4(2):020101.
In March 2014, over 400 individuals from 35 countries in sub-Saharan Africa and 59 international partner organizations gathered in Accra, Ghana for an integrated Community Case Management (iCCM) Evidence Review Symposium. The objective was 2-fold: first, to review the current state of the art of iCCM implementation and second, to assist African countries to integrate lessons learned and best practices presented during the symposium into their programmes. Based on the findings from the symposium this supplement includes a comprehensive set of articles that provide the latest evidence for improving iCCM programs and ways to better monitor and evaluate such programs.
PMCID: PMC4267091  PMID: 25520783
3.  Community case management of childhood illness in sub–Saharan Africa – findings from a cross–sectional survey on policy and implementation 
Journal of Global Health  2014;4(2):020401.
Community case management (CCM) involves training, supporting, and supplying community health workers (CHWs) to assess, classify and manage sick children with limited access to care at health facilities, in their communities. This paper aims to provide an overview of the status in 2013 of CCM policy and implementation in sub–Saharan African countries.
We undertook a cross–sectional, descriptive, quantitative survey amongst technical officers in Ministries of Health and UNICEF offices in 2013. The survey aim was to describe CCM policy and implementation in 45 countries in sub–Saharan Africa, focusing on: CHW profile, CHW activities, and financing.
42 countries responded. 35 countries in sub–Saharan Africa reported implementing CCM for diarrhoea, 33 for malaria, 28 for pneumonia, 6 for neonatal sepsis, 31 for malnutrition and 28 for integrated CCM (treatment of 3 conditions: diarrhoea, malaria and pneumonia) – an increase since 2010. In 27 countries, volunteers were providing CCM, compared to 14 countries with paid CHWs. User fees persisted for CCM in 6 countries and mark–ups on commodities in 10 countries. Most countries had a national policy, memo or written guidelines for CCM implementation for diarrhoea, malaria and pneumonia, with 20 countries having this for neonatal sepsis. Most countries plan gradual expansion of CCM but many countries’ plans were dependent on development partners. A large group of countries had no plans for CCM for neonatal sepsis.
28 countries in sub–Saharan Africa now report implementing CCM for pneumonia, diarrhoea and malaria, or “iCCM”. Most countries have developed some sort of written basis for CCM activities, yet the scale of implementation varies widely, so a focus on implementation is now required, including monitoring and evaluation of performance, quality and impact. There is also scope for expansion for newborn care. Key issues include financing and sustainability (with development partners still providing most funding), gaps in data on CCM activities, and the persistence of user fees and mark–ups in several countries. National health management information systems should also incorporate CCM activities.
PMCID: PMC4267096  PMID: 25520791
6.  Setting global research priorities for integrated community case management (iCCM): Results from a CHNRI (Child Health and Nutrition Research Initiative) exercise 
Journal of Global Health  2014;4(2):020413.
To systematically identify global research gaps and resource priorities for integrated community case management (iCCM).
An iCCM Child Health and Nutrition Research Initiative (CHNRI) Advisory Group, in collaboration with the Community Case Management Operational Research Group (CCM ORG) identified experts to participate in a CHNRI research priority setting exercise. These experts generated and systematically ranked research questions for iCCM. Research questions were ranked using a “Research Priority Score” (RPS) and the “Average Expert Agreement” (AEA) was calculated for every question. Our groups of experts were comprised of both individuals working in Ministries of Health or Non Governmental Organizations (NGOs) in low– and middle–income countries (LMICs) and individuals working in high–income countries (HICs) in academia or NGO headquarters. A Spearman’s Rho was calculated to determine the correlation between the two groups’ research questions’ ranks.
The overall RPS ranged from 64.58 to 89.31, with a median score of 81.43. AEA scores ranged from 0.54 to 0.86. Research questions involving increasing the uptake of iCCM services, research questions concerning the motivation, retention, training and supervision of Community Health Workers (CHWs) and concerning adding additional responsibilities including counselling for infant and young child feeding (IYCF) and treatment of severe acute malnutrition (SAM) ranked highly. There was weak to moderate, statistically significant, correlation between scores by representatives of high–income countries and those working in–country or regionally (Spearman’s ρ = 0.35034, P < 0.01).
Operational research to determine optimal training, supervision and modes of motivation and retention for the CHW is vital for improving iCCM, globally, as is research to motivate caregivers to take advantage of iCCM services. Experts working in–country or regionally in LMICs prioritized different research questions than those working in organization headquarters in HICs. Further exploration is needed to determine the nature of this divergence.
PMCID: PMC4267102  PMID: 25520803
8.  The cranial osteology of Tyrannoneustes lythrodectikos (Crocodylomorpha: Metriorhynchidae) from the Middle Jurassic of Europe 
PeerJ  2014;2:e608.
Tyrannoneustes lythrodectikos is one of numerous metriorhynchid crocodylomorph species known from the Oxford Clay Formation of England (Callovian-Oxfordian; Middle-Late Jurassic). This taxon is of evolutionary importance, as it is the oldest and most basal known macrophagous metriorhynchid. It has a mosaic of plesiomorphic and derived feeding related characteristics, including: teeth with microscopic, poorly formed and non-contiguous denticles; increased tooth apicobasal length; ventrally displaced dentary tooth row (increased gape); reduced dentary tooth count; and a proportionally long mandibular symphysis. However the type specimen, and current referred specimens, all lack a preserved cranium. As such, the craniofacial morphology of this taxon, and its potential feeding ecology, remains poorly understood. Here we describe two skulls and two lower jaws which we refer to T. lythrodectikos. Previously these specimens were referred to ‘Metriorhynchus’ brachyrhynchus. They share with the T. lythrodectikos holotype: the in-line reception pits on the dentary, dorsal margin of the surangular is strongly concave in lateral view, and the most of the angular ventral margin is strongly convex. Based on our description of these specimens, the skull of T. lythrodectikos has three autapomorphies: very long posterior processes of the premaxilla terminating in line with the 4th or 5th maxillary alveoli, deep lateral notches on the lateral surface of the maxillary with reception pits for dentary teeth, and the premaxilla forms the anterior margin of the first maxillary alveoli. Our description of the cranial anatomy of Tyrannoneustes lythrodectikos confirms that some macrophagous characteristics evolved during the Middle Jurassic, and were not exclusive to the clade Geosaurini. Moreover, the skulls further highlight the mosaic nature of Tyrannoneustes lythrodectikos and wide-gape macrophagous evolution in Geosaurinae.
PMCID: PMC4185291  PMID: 25289192
Skull; Middle Jurassic; Marcrophagy; Metriorhynchidae; Tyrannoneustes
9.  Perturbation of the indigenous rat oral microbiome by ciprofloxacin dosing 
Molecular oral microbiology  2013;28(5):404-414.
Mucosal surfaces such as the gut, vagina and oral cavity are colonized by microbiota that are an integral component of the healthy ecosystem. Recent molecular techniques make it feasible to correlate antimicrobial dosing levels with changes in microbiome composition. The objective of this study was to characterize the rat oral plaque microbiome composition at doses of ciprofloxacin that were considerably above and below nominal in vitro minimal inhibitory concentrations (MICs) of a variety of gram positive oral commensal bacteria. We exposed the oral cavities of rats to relatively low (0.1 µg/mL) and high (20 µg/mL) doses of ciprofloxacin in the drinking water over a 3 day period. Plaque microbiota were characterized using 454 pyrosequencing. The rat indigenous community was dominated by Rothia (74.4 %) and Streptococcus genera (4.7%). Dosing at 0.1 µg/mL was associated with changes in Rothia and Streptococcus genera which were not significant, while dosing at 20 µg/mL caused a pronounced (significant) reduction in the relative abundance of the Streptococcus genus. Taxonomic independent analysis indicated that the perturbation in the overall community structure attributed to dosing with ciprofloxacin at either the low or high dose was relatively low. The results suggest that it is feasible to use an antimicrobial dosing regime to selectively target a specific subset of a mucosal microbiome for elimination with minimal perturbation of the entire community.
PMCID: PMC3767763  PMID: 23844936
oral; periodontitis; ciprofloxacin; rat; microbiome
10.  Aggregatibacter actinomycetemcomitans biofilm killing by a targeted ciprofloxacin prodrug 
Biofouling  2013;29(8):10.1080/08927014.2013.823541.
A pH-sensitive ciprofloxacin prodrug was synthesized and targeted against biofilms of the periodontal pathogen Aggregatibacter actinomycetemcomitans (Aa). The dose required to reduce the viability of a mature biofilm of Aa by ~80% was in the range of ng cm−2 of colonized area (mean biofilm density 2.33 x109 cells cm−2). A mathematical model was formulated that predicts the temporal change in the concentration of ciprofloxacin in the Aa biofilm as the drug is released and diffuses into the bulk medium. The predictions of the model were consistent with the extent of killing obtained. The results demonstrate the feasibility of the strategy to induce mortality, and together with the mathematical model, provide the basis for design of targeted antimicrobial prodrugs for the topical treatment of oral infections such as periodontitis. The targeted prodrug approach offers the possibility of optimizing the dose of available antimicrobials in order to kill a chosen pathogen while leaving the commensal microbiota relatively undisturbed.
PMCID: PMC3818142  PMID: 23952779
Aggregatibacter actinomycetemcomitans; ciprofloxacin; prodrug; biofilm; periodontal disease
11.  Microsite affects willow sapling recovery from bank vole (Myodes glareolus) herbivory, but does not affect grazing risk 
Annals of Botany  2013;112(4):731-739.
Large herbivores are often removed or reduced as part of vegetation restoration programmes, but the resultant increase in vegetation biomass and changes in vegetation structure may favour small mammals. Small mammals may have large impacts on plant community composition via granivory and sapling herbivory, and increased small mammal populations may reduce any benefits of large herbivore removal for highly preferred species. This study tested the impacts of small mammal herbivory, microsite characteristics and their interaction on growth and survival of three montane willow species with differing chemical compositions, Salix lapponum, S. myrsinifolia and S. arbuscula.
In two separate years, 1-year-old saplings were planted within a 180 ha, large-mammal scrub regeneration exclosure, and either experimentally protected from or exposed to small mammals (bank voles). Saplings were planted in one of two microsite treatments, vegetation mown (to mimic a grazed sward) or disturbed (all above- and below-ground competition removed), and monitored throughout the first year of growth.
Key results
Approximately 40 % of saplings planted out in each year were damaged by bank voles, but direct mortality due to damage was very low (<2 %). There were no strong species differences in susceptibility to vole damage. Microsite treatment had no impact on the proportion of saplings attacked, but in 2004 saplings in mown microsites were more severely damaged and had smaller increases in size than those in disturbed microsites. In 2003, saplings in mown microsites had smaller increases in stem diameter following attack than those in disturbed microsites.
Planting 1-year-old willow saplings into disturbed microsites may aid growth, reduce the severity of small mammal damage and improve recovery following sub-lethal small mammal damage. Restoration management of montane willow scrub should therefore consider manipulating the planting site to provide disturbed areas of soil.
PMCID: PMC3736771  PMID: 23798601
Seedling herbivory; phenolics; Salicaceae; Salix arbuscula; Salix lapponum; Salix myrsinifolia; sapling growth rates; scrub restoration; small mammals; tree-line communities
12.  CRISPR-Induced Distributed Immunity in Microbial Populations 
PLoS ONE  2014;9(7):e101710.
In bacteria and archaea, viruses are the primary infectious agents, acting as virulent, often deadly pathogens. A form of adaptive immune defense known as CRISPR-Cas enables microbial cells to acquire immunity to viral pathogens by recognizing specific sequences encoded in viral genomes. The unique biology of this system results in evolutionary dynamics of host and viral diversity that cannot be fully explained by the traditional models used to describe microbe-virus coevolutionary dynamics. Here, we show how the CRISPR-mediated adaptive immune response of hosts to invading viruses facilitates the emergence of an evolutionary mode we call distributed immunity - the coexistence of multiple, equally-fit immune alleles among individuals in a microbial population. We use an eco-evolutionary modeling framework to quantify distributed immunity and demonstrate how it emerges and fluctuates in multi-strain communities of hosts and viruses as a consequence of CRISPR-induced coevolution under conditions of low viral mutation and high relative numbers of viral protospacers. We demonstrate that distributed immunity promotes sustained diversity and stability in host communities and decreased viral population density that can lead to viral extinction. We analyze sequence diversity of experimentally coevolving populations of Streptococcus thermophilus and their viruses where CRISPR-Cas is active, and find the rapid emergence of distributed immunity in the host population, demonstrating the importance of this emergent phenomenon in evolving microbial communities.
PMCID: PMC4084950  PMID: 25000306
13.  An intracellular P2X receptor required for osmoregulation in Dictyostelium discoideum 
Nature  2007;448(7150):200-203.
P2X receptors are membrane ion channels gated by extracellular ATP1,2 that are found widely in vertebrates, but not previously in microbes. Here we identify a weakly related gene in the genome of the social amoeba Dictyostelium discoideum, and show, with the use of heterologous expression in human embryonic kidney cells, that it encodes a membrane ion channel activated by ATP (30–100 μM). Site-directed mutagenesis revealed essential conservation of structure–function relations with P2X receptors of higher organisms. The receptor was insensitive to the usual P2X antagonists3 but was blocked by nanomolar concentrations of Cu2+ ions. In D. discoideum, the receptor was found on intracellular membranes, with prominent localization to an osmoregulatory organelle, the contractile vacuole. Targeted disruption of the gene in D. discoideum resulted in cells that were unable to regulate cell volume in hypotonic conditions. Cell swelling in these mutant cells was accompanied by a marked inhibition of contractile vacuole emptying. These findings demonstrate a new functional role for P2X receptors on intracellular organelles, in this case in osmoregulation.
PMCID: PMC3942652  PMID: 17625565
14.  The Alcohol Hangover Research Group Consensus Statement on Best Practice in Alcohol Hangover Research 
Current drug abuse reviews  2010;3(2):116-126.
Alcohol-induced hangover, defined by a series of symptoms, is the most commonly reported consequence of excessive alcohol consumption. Alcohol hangovers contribute to workplace absenteeism, impaired job performance, reduced productivity, poor academic achievement, and may compromise potentially dangerous daily activities such as driving a car or operating heavy machinery. These socioeconomic consequences and health risks of alcohol hangover are much higher when compared to various common diseases and other health risk factors. Nevertheless, unlike alcohol intoxication the hangover has received very little scientific attention and studies have often yielded inconclusive results. Systematic research is important to increase our knowledge on alcohol hangover and its consequences. This consensus paper of the Alcohol Hangover Research Group discusses methodological issues that should be taken into account when performing future alcohol hangover research. Future research should aim to (1) further determine the pathology of alcohol hangover, (2) examine the role of genetics, (3) determine the economic costs of alcohol hangover, (4) examine sex and age differences, (5) develop common research tools and methodologies to study hangover effects, (6) focus on factor that aggravate hangover severity (e.g., congeners), and (7) develop effective hangover remedies.
PMCID: PMC3827719  PMID: 20712593
Alcohol hangover; methodology; guidelines; research
16.  Insights into a Viral Lytic Pathway from an Archaeal Virus-Host System 
Journal of Virology  2013;87(4):2186-2192.
Archaeal host cells infected by Sulfolobus turreted icosahedral virus (STIV) and Sulfolobus islandicus rod-shaped virus 2 (SIRV2) produce unusual pyramid-like structures on the cell surface prior to virus-induced cell lysis. This viral lysis process is distinct from known viral lysis processes associated with bacterial or eukaryal viruses. The STIV protein C92 and the SIRV2 protein 98 are the only viral proteins required for the formation of the pyramid lysis structures of STIV and SIRV2, respectively. Since SIRV2 and STIV have fundamentally different morphotypes and genome sequences, it is surprising that they share this lysis system. In this study, we have constructed a collection of C92/P98 chimeric proteins and tested their abilities, both in the context of virus replication and alone, to form pyramid lysis structures in S. solfataricus. The results of this study illustrate that these proteins are functionally homologous when expressed as individual chimeric proteins but not when expressed in the context of complete STIV infection.
PMCID: PMC3571470  PMID: 23221563
17.  Soil strength and macropore volume limit root elongation rates in many UK agricultural soils 
Annals of Botany  2012;110(2):259-270.
Background and Aims
Simple indicators of crop and cultivar performance across a range of soil types and management are needed for designing and testing sustainable cropping practices. This paper determined the extent to which soil chemical and physical properties, particularly soil strength and pore-size distribution influences root elongation in a wide range of agricultural top soils, using a seedling-based indicator.
Intact soil cores were sampled from the topsoil of 59 agricultural fields in Scotland, representing a wide geographic spread, range of textures and management practices. Water release characteristics, dry bulk density and needle penetrometer resistance were measured on three cores from each field. Soil samples from the same locations were sieved, analysed for chemical characteristics, and packed to dry bulk density of 1·0 g cm−3 to minimize physical constraints. Root elongation rates were determined for barley seedlings planted in both intact field and packed soil cores at a water content close to field capacity (–20 kPa matric potential).
Key Results
Root elongation in field soil was typically less than half of that in packed soils. Penetrometer resistance was typically between 1 and 3 MPa for field soils, indicating the soils were relatively hard, despite their moderately wet condition (compared with <0·2 MPa for packed soil). Root elongation was strongly linked to differences in physical rather than chemical properties. In field soil root elongation was related most closely to the volume of soil pores between 60 µm and 300 µm equivalent diameter, as estimated from water-release characteristics, accounting for 65·7 % of the variation in the elongation rates.
Root elongation rate in the majority of field soils was slower than half of the unimpeded (packed) rate. Such major reductions in root elongation rates will decrease rooting volumes and limit crop growth in soils where nutrients and water are scarce.
PMCID: PMC3394656  PMID: 22684682
Root elongation; abiotic stress; soil chemistry; soil porosity; soil strength; Scotland; macroporosity; dry bulk density; barley; Hordeum vulgare; pore diameter
18.  Obstructive Jaundice as an Initial Manifestation of Non-Hodgkin Lymphoma: Treatment Dilemma and High Mortality 
Case Reports in Medicine  2013;2013:259642.
Introduction. Non Hodgkin lymphoma (NHL) presenting with obstructive jaundice is a rare occurrence. Because of rarity of combination, it is seldom considered in differential diagnosis of patients presenting with obstructive jaundice. It is considered treatable due to the chemosensitive nature of the disease and the recent advances in chemotherapy. Case Series. We present a case series of 2 patients with NHL presenting with obstructive jaundice as an initial manifestation. Both patients presented with obstructive jaundice and were diagnosed by CT guided liver biopsy. One patient died of sepsis and multiorgan failure before initiating chemotherapy and the second patient did not choose to undergo chemotherapy. Conclusion. Biliary obstruction is a sign of poor prognosis. The diagnosis of NHL needs to be considered in patients presenting with biliary obstruction. It can be associated with high mortality and poses treatment dilemma.
PMCID: PMC3683444  PMID: 23818904
19.  Setting Research Priorities to Reduce Mortality and Morbidity of Childhood Diarrhoeal Disease in the Next 15 Years 
PLoS Medicine  2013;10(5):e1001446.
Zulfi Bhutta and colleagues lay out research priorities for global child diarrheal disease over the next 15 years, which they developed using the Child Health and Nutrition Research Initiative (CHNRI) method.
Please see later in the article for the Editors' Summary
PMCID: PMC3653794  PMID: 23690756
20.  Hepatic Artery Mycotic Aneurysm Associated with Staphylococcal Endocarditis with Successful Treatment: Case Report with Review of the Literature 
Case Reports in Hepatology  2013;2013:610818.
Mycotic hepatic artery aneurysm is a vascular pathology associated with bacterial endocarditis. It is rare in occurrence after the introduction of effective antibiotics. We present a young patient with injection drug abuse associated staphylococcal endocarditis which was successfully treated with antibiotics and valve replacement who presented with abdominal pain. He was found to have mycotic aneurysm of hepatic artery which was successfully treated with coil embolization.
PMCID: PMC4208385  PMID: 25379298
21.  Supramolecular protein cage composite MR contrast agents with extremely efficient relaxivity properties 
Nano letters  2009;9(12):4520-4526.
A DTPA-Gd containing polymer was grown in the interior of a heat shock protein cage resulting in T1 particle relaxivities of 4,200mM-1 sec-1 for the 12nm particle. Relaxivity parameters were determined and this analysis suggests that the rotational correlation time has been optimized while the water exchange life time is slower than optimal. This synthetic approach holds much promise for the development of next generation contrast agents and this report will aid in their design.
PMCID: PMC3625947  PMID: 19888720
22.  Structural studies of E73 from a hyperthermophilic archaeal virus identify the “RH3” domain, an elaborated ribbon-helix-helix motif involved in DNA recognition† 
Biochemistry  2012;51(13):2899-2910.
Hyperthermophilic archaeal viruses including Sulfolobus spindle-shaped viruses (SSVs) such as SSV-1 and SSV-Ragged Hills exhibit remarkable morphology and genetic diversity. However, they remain poorly understood, in part because their genomes exhibit limited or unrecognizable sequence similarity to genes with known function. Here we report structural and functional studies of E73, a 73-residue homodimeric protein encoded within the SSV-Ragged Hills genome. Despite lacking significant sequence similarity, the NMR structure reveals clear similarity to ribbon-helix-helix (RHH) domains present in numerous proteins involved in transcriptional regulation. In vitro dsDNA binding experiments confirm the ability of E73 to bind dsDNA in a non-specific manner with micromolar affinity, and characterization of the K11E variant confirms the location of the predicted DNA binding surface. E73 is distinct, however, from known RHHs. The RHH motif is elaborated upon by the insertion of a third helix that is tightly integrated into the structural domain, giving rise to the “RH3” fold. Within the homodimer, this helix results in the formation of a conserved, symmetric cleft distal to the DNA binding surface, where it may mediate protein-protein interactions, or contribute to the high thermal stability of E73. Analysis of backbone amide dynamics by NMR provides evidence for a rigid core, and fast ps-ns timescale NH bond vector motions for residues located within the antiparallel β-sheet region of the proposed DNA-binding surface, and slower μs to ms timescale motions for residues in the α1-α2 loop. The role of E73 and its SSV homologs in the viral life cycle are discussed.
PMCID: PMC3326356  PMID: 22409376
23.  A Survey of Protein Structures from Archaeal Viruses  
Life : Open Access Journal  2013;3(1):118-130.
Viruses that infect the third domain of life, Archaea, are a newly emerging field of interest. To date, all characterized archaeal viruses infect archaea that thrive in extreme conditions, such as halophilic, hyperthermophilic, and methanogenic environments. Viruses in general, especially those replicating in extreme environments, contain highly mosaic genomes with open reading frames (ORFs) whose sequences are often dissimilar to all other known ORFs. It has been estimated that approximately 85% of virally encoded ORFs do not match known sequences in the nucleic acid databases, and this percentage is even higher for archaeal viruses (typically 90%–100%). This statistic suggests that either virus genomes represent a larger segment of sequence space and/or that viruses encode genes of novel fold and/or function. Because the overall three-dimensional fold of a protein evolves more slowly than its sequence, efforts have been geared toward structural characterization of proteins encoded by archaeal viruses in order to gain insight into their potential functions. In this short review, we provide multiple examples where structural characterization of archaeal viral proteins has indeed provided significant functional and evolutionary insight.
PMCID: PMC4187194  PMID: 25371334
archaeal virus; thermophile; structural homology; archaea
24.  Proteomic Analysis of Sulfolobus solfataricus During Sulfolobus Turreted Icosahedral Virus Infection 
Journal of Proteome Research  2012;11(2):1420-1432.
Where there is life, there are viruses. The impact of viruses on evolution, global nutrient cycling, and disease has driven research on their cellular and molecular biology. Knowledge exists for a wide range of viruses, however, a major exception are viruses with archaeal hosts. Archaeal virus-host systems are of great interest because they have similarities to both eukaryotic and bacterial systems and often live in extreme environments. Here we report the first proteomics-based experiments on archaeal host response to viral infection. Sulfolobus Turreted Icosahedral Virus (STIV) infection of Sulfolobus solfataricus P2 was studied using 1D and 2D differential gel electrophoresis (DIGE) to measure abundance and redox changes. Cysteine reactivity was measured using novel fluorescent zwitterionic chemical probes that, together with abundance changes, suggest that virus and host are both vying for control of redox status in the cells. Proteins from nearly 50% of the predicted viral open reading frames were found along with a new STIV protein with a homolog in STIV2. This study provides insight to features of viral replication novel to the archaea, makes strong connections to well described mechanisms used by eukaryotic viruses such as ESCRT-III mediated transport, and emphasizes the complementary nature of different omics approaches.
PMCID: PMC3339632  PMID: 22217245
Archaea; virus infection; Sulfolobus solfataricus strain P2; STIV; Sulfolobus turreted icosahedral virus; Proteomics; virus–host interaction; LC/MS/MS; liquid chromatography mass spectrometry; differential gene expression; membrane protein; VAPs; Virus-associated pyramids; 2-D Fluorescence Difference Gel Electrophoresis; Thiol-reactive maleimide probe
25.  The Structure of an Archaeal Viral Integrase Reveals an Evolutionarily Conserved Catalytic Core yet Supports a Mechanism of DNA Cleavage in trans 
Journal of Virology  2012;86(15):8309-8313.
The first structure of a catalytic domain from a hyperthermophilic archaeal viral integrase reveals a minimal fold similar to that of bacterial HP1 integrase and defines structural elements conserved across three domains of life. However, structural superposition on bacterial Holliday junction complexes and similarities in the C-terminal tail with that of eukaryotic Flp suggest that the catalytic tyrosine and an additional active-site lysine are delivered to neighboring subunits in trans. An intramolecular disulfide bond contributes significant thermostability in vitro.
PMCID: PMC3421663  PMID: 22593158

Results 1-25 (85)