Publications by authors named "Ian McDonald"

88 Publications

Value improvement at the point of care: engaging and empowering front-line teams with a new quality improvement methodology.

BMJ Open Qual 2021 05;10(2)

Performance Improvement, Heart Hospital, Hamad Medical Corporation, Doha, Qatar.

Background: Healthcare organisations require systems to consistently meet the needs of their patients while providing excellent quality of care. The value improvement (VI) approach was developed by the Institute for healthcare improvement and successfully piloted at Raigmore Hospital, Scotland. It showed positive results in improving outcomes and reducing costs. Our multidisciplinary team from a tertiary care cardiac hospital in Doha, Qatar wanted to see if we could improve value in a clinically and geographically distinct context. We sought to understand the effectiveness of this approach as an integrative management philosophy that aims for continuous improvement in the quality of services by increasing efficiency and reducing waste.

Methods: This study evaluates the outcomes achieved from applying the VI methodology. The method is rooted in a framework that emphasises standardisation, continuous process improvement and rightsizing capacity to demand. The main tools include a data box score, a visual management board and weekly communication huddles.

Results: As a result of the VI methodology, our team achieved improvements across performance, staff capacity and cost domains. Compared with the 4-8 weeks baseline data collection period, these improvements included an increase in discharges before 13:00 hour by 61%, a reduction in the number of blood samples per patient per day by 20%, an increase in nursing time spent in direct patient care by 18%, and an increase in staff satisfaction to 40%.

Conclusions: We found that the VI approach offered a systematic method for continuously improving the quality of care by focusing attention each week on safety, efficiency and patient experience. The team improved numerous processes and outcomes resulting in a positive impact on patients and families and increased the engagement of staff in continuous improvement. In this way, we improved our capacity to undertake and complete quality projects.
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http://dx.doi.org/10.1136/bmjoq-2020-001233DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8160168PMC
May 2021

AZD1222 vaccine-related coagulopathy and thrombocytopenia without thrombosis in a young female.

Br J Haematol 2021 Aug 25;194(3):553-556. Epub 2021 May 25.

Department of Haematology, Tallaght University Hospital, Dublin, Ireland.

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http://dx.doi.org/10.1111/bjh.17530DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8239588PMC
August 2021

Comparative systematic review and meta-analysis of reactogenicity, immunogenicity and efficacy of vaccines against SARS-CoV-2.

NPJ Vaccines 2021 May 13;6(1):74. Epub 2021 May 13.

Department of Infectious Disease, Faculty of Medicine, Imperial College London, London, UK.

As SARS-CoV-2 vaccines are deployed worldwide, a comparative evaluation is important to underpin decision-making. We here report a systematic literature review and meta-analysis of Phase I/II/III human trials and non-human primates (NHP) studies, comparing reactogenicity, immunogenicity and efficacy across different vaccine platforms for comparative evaluation (updated to March 22, 2021). Twenty-three NHP and 32 human studies are included. Vaccines result in mostly mild, self-limiting adverse events. Highest spike neutralizing antibody (nAb) responses are identified for the mRNA-1273-SARS-CoV and adjuvanted NVX-CoV2373-SARS-CoV-2 vaccines. ChAdOx-SARS-CoV-2 produces the highest T cell ELISpot responses. Pre-existing nAb against vaccine viral vector are identified following AdH-5-SARS-CoV-2 vaccination, halving immunogenicity. The mRNA vaccines depend on boosting to achieve optimal immunogenicity especially in the elderly. BNT162b2, and mRNA-1273 achieve >94%, rAd26/5 > 91% and ChAdOx-SARS-CoV-2 > 66.7% efficacy. Across different vaccine platforms there are trade-offs between antibody binding, functional nAb titers, T cell frequency, reactogenicity and efficacy. Emergence of variants makes rapid mass rollout of high efficacy vaccines essential to reduce any selective advantage.
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http://dx.doi.org/10.1038/s41541-021-00336-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8116645PMC
May 2021

A quality improvement programme to reduce hospital-acquired pressure injuries.

BMJ Open Qual 2020 07;9(3)

Quality and Patient Safety, Hamad Medical Corporation, Doha, Qatar.

Background: At Heart Hospital in Doha, Qatar (HH), 127 pressure injuries (PI) were identified in 2014, corresponding to an incidence of 6.1/1000 patient-days in first 4 months of 2014. Hospital-acquired pressure injury (HAPI) is one of the most common preventable complications of hospitalisation. HAPI significantly increases healthcare costs, including use of resources (dressings, support surfaces, nursing care time and medications). They also have a significant impact on patients in terms of pain, worsened quality of life, psychological trauma and increased length of stay. Working with the Institute for Healthcare Improvement (IHI), we implemented evidence-based practices in all In patient Units at HH with the aim of reducing the number of HAPIs by 60% within 2 years.

Methods: In collaboration with IHI, our multidisciplinary clinical and risk assessment teams tested several changes and implemented a successful programme. The Surface, Skin inspection, Keep moving, Incontinence and Nutrition bundle was implemented. Signs, turning clocks and PI incidence 'calendars' were used in the units as reminders. Attention was paid to endotracheal tube ties in order to address device-related pressure injuries. Counts of HAPI (incidence) and number of PIs per 100 patients surveyed (prevalence) were prominently displayed. Changes were tested using the Plan-Do-Study-Act methodology. Statistical analysis using the independent t-test was applied to detect the significance of any difference in the incidence of HAPI before and after implementation of the changes.

Results: The incidence of HAPI dropped from 6.1/1000 patient-days to 1.1/1000 patient-days, an 83.5% reduction. The prevalence, based on quarterly survey fell from 9.7/100 patients surveyed to 2.0/100 patients surveyed, a 73.4% decline.

Conclusions: The interventions proved to be successful, reducing the incidence of PI by >80%. The outcomes were sustained over a 4-year period.
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http://dx.doi.org/10.1136/bmjoq-2019-000905DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7394182PMC
July 2020

Enigmatic MELK: The controversy surrounding its complex role in cancer.

J Biol Chem 2020 06 29;295(24):8195-8203. Epub 2020 Apr 29.

Department of Pharmacology, University of North Carolina, Chapel Hill, North Carolina, USA

The Ser/Thr protein kinase MELK (maternal embryonic leucine zipper kinase) has been considered an attractive therapeutic target for managing cancer since 2005. Studies using expression analysis have indicated that MELK expression is higher in numerous cancer cells and tissues than in their normal, nonneoplastic counterparts. Further, RNAi-mediated MELK depletion impairs proliferation of multiple cancers, including triple-negative breast cancer (TNBC), and these growth defects can be rescued with exogenous WT MELK, but not kinase-dead MELK complementation. Pharmacological MELK inhibition with OTS167 (alternatively called OTSSP167) and NVS-MELK8a, among other small molecules, also impairs cancer cell growth. These collective results led to MELK being classified as essential for cancer proliferation. More recently, in 2017, the proliferation of TNBC and other cancer cell lines was reported to be unaffected by genetic CRISPR/Cas9-mediated MELK deletion, calling into question the essentiality of this kinase in cancer. To date, the requirement of MELK in cancer remains controversial, and mechanisms underlying the disparate growth effects observed with RNAi, pharmacological inhibition, and CRISPR remain unclear. Our objective with this review is to highlight the evidence on both sides of this controversy, to provide commentary on the purported requirement of MELK in cancer, and to emphasize the need for continued elucidation of the functions of MELK.
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http://dx.doi.org/10.1074/jbc.REV120.013433DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7294088PMC
June 2020

Abiotic factors influence patterns of bacterial diversity and community composition in the Dry Valleys of Antarctica.

FEMS Microbiol Ecol 2020 05;96(5)

School of Science, The University of Waikato, Private Bag 3105, Hamilton 3240, New Zealand.

The Dry Valleys of Antarctica are a unique ecosystem of simple trophic structure, where the abiotic factors that influence soil bacterial communities can be resolved in the absence of extensive biotic interactions. This study evaluated the degree to which aspects of topographic, physicochemical and spatial variation explain patterns of bacterial richness and community composition in 471 soil samples collected across a 220 square kilometer landscape in Southern Victoria Land. Richness was most strongly influenced by physicochemical soil properties, particularly soil conductivity, though significant trends with several topographic and spatial variables were also observed. Structural equation modeling (SEM) supported a final model in which variation in community composition was best explained by physicochemical variables, particularly soil water content, and where the effects of topographic variation were largely mediated through their influence on physicochemical variables. Community dissimilarity increased with distance between samples, and though most of this variation was explained by topographic and physicochemical variation, a small but significant relationship remained after controlling for this environmental variation. As the largest survey of terrestrial bacterial communities of Antarctica completed to date, this work provides fundamental knowledge of the Dry Valleys ecosystem, and has implications globally for understanding environmental factors that influence bacterial distributions.
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http://dx.doi.org/10.1093/femsec/fiaa042DOI Listing
May 2020

Mass spectrometry-based selectivity profiling identifies a highly selective inhibitor of the kinase MELK that delays mitotic entry in cancer cells.

J Biol Chem 2020 02 2;295(8):2359-2374. Epub 2020 Jan 2.

Department of Pharmacology, University of North Carolina, Chapel Hill, North Carolina 27599; Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina 27599; UNC Michael Hooker Proteomics Core Facility, University of North Carolina, Chapel Hill, North Carolina 27599. Electronic address:

The maternal embryonic leucine zipper kinase (MELK) has been implicated in the regulation of cancer cell proliferation. RNAi-mediated MELK depletion impairs growth and causes G/M arrest in numerous cancers, but the mechanisms underlying these effects are poorly understood. Furthermore, the MELK inhibitor OTSSP167 has recently been shown to have poor selectivity for MELK, complicating the use of this inhibitor as a tool compound to investigate MELK function. Here, using a cell-based proteomics technique called multiplexed kinase inhibitor beads/mass spectrometry (MIB/MS), we profiled the selectivity of two additional MELK inhibitors, NVS-MELK8a (8a) and HTH-01-091. Our results revealed that 8a is a highly selective MELK inhibitor, which we further used for functional studies. Resazurin and crystal violet assays indicated that 8a decreases triple-negative breast cancer cell viability, and immunoblotting revealed that impaired growth is due to perturbation of cell cycle progression rather than induction of apoptosis. Using double-thymidine synchronization and immunoblotting, we observed that MELK inhibition delays mitotic entry, which was associated with delayed activation of Aurora A, Aurora B, and cyclin-dependent kinase 1 (CDK1). Following this delay, cells entered and completed mitosis. Using live-cell microscopy of cells harboring fluorescent proliferating cell nuclear antigen, we confirmed that 8a significantly and dose-dependently lengthens G phase. Collectively, our results provide a rationale for using 8a as a tool compound for functional studies of MELK and indicate that MELK inhibition delays mitotic entry, likely via transient G/M checkpoint activation.
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http://dx.doi.org/10.1074/jbc.RA119.011083DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7039562PMC
February 2020

Lyn regulates creatine uptake in an imatinib-resistant CML cell line.

Biochim Biophys Acta Gen Subj 2020 04 24;1864(4):129507. Epub 2019 Dec 24.

Department of Pharmacology, University of North Carolina, Chapel Hill, NC 27599, United States of America; UNC Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, United States of America. Electronic address:

Background: Imatinib mesylate (imatinib) is the first-line treatment for newly diagnosed chronic myeloid leukemia (CML) due to its remarkable hematologic and cytogenetic responses. We previously demonstrated that the imatinib-resistant CML cells (Myl-R) contained elevated Lyn activity and intracellular creatine pools compared to imatinib-sensitive Myl cells.

Methods: Stable isotope metabolic labeling, media creatine depletion, and Na/K-ATPase inhibitor experiments were performed to investigate the origin of creatine pools in Myl-R cells. Inhibition and shRNA knockdown were performed to investigate the specific role of Lyn in regulating the Na/K-ATPase and creatine uptake.

Results: Inhibition of the Na/K-ATPase pump (ouabain, digitoxin), depletion of extracellular creatine or inhibition of Lyn kinase (ponatinib, dasatinib), demonstrated that enhanced creatine accumulation in Myl-R cells was dependent on uptake from the growth media. Creatine uptake was independent of the Na/creatine symporter (SLC6A8) expression or de novo synthesis. Western blot analyses showed that phosphorylation of the Na/K-ATPase on Tyr 10 (Y10), a known regulatory phosphorylation site, correlated with Lyn activity. Overexpression of Lyn in HEK293 cells increased Y10 phosphorylation (pY10) of the Na/K-ATPase, whereas Lyn inhibition or shRNA knockdown reduced Na/K-ATPase pY10 and decreased creatine accumulation in Myl-R cells. Consistent with enhanced uptake in Myl-R cells, cyclocreatine (Ccr), a cytotoxic creatine analog, caused significant loss of viability in Myl-R compared to Myl cells.

Conclusions: These data suggest that Lyn can affect creatine uptake through Lyn-dependent phosphorylation and regulation of the Na/K-ATPase pump activity.

General Significance: These studies identify kinase regulation of the Na/K-ATPase as pivotal in regulating creatine uptake and energy metabolism in cells.
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http://dx.doi.org/10.1016/j.bbagen.2019.129507DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7055176PMC
April 2020

Thermophilic methanotrophs: in hot pursuit.

FEMS Microbiol Ecol 2019 09;95(9)

School of Science, University of Waikato, Knighton Rd, Hamilton 3240, New Zealand.

Methane is a potent greenhouse gas responsible for 20-30% of global climate change effects. The global methane budget is ∼500-600 Tg y-1, with the majority of methane produced via microbial processes, including anthropogenic-mediated sources such as ruminant animals, rice fields, sewage treatment facilities and landfills. It is estimated that microbially mediated methane oxidation (methanotrophy) consumes >50% of global methane flux each year. Methanotrophy research has primarily focused on mesophilic methanotrophic representatives and cooler environments such as freshwater, wetlands or marine habitats from which they are sourced. Nevertheless, geothermal emissions of geological methane, produced from magma and lithosphere degassing micro-seepages, mud volcanoes and other geological sources, contribute an estimated 33-75 Tg y-1 to the global methane budget. The aim of this review is to summarise current literature pertaining to the activity of thermophilic and thermotolerant methanotrophs, both proteobacterial (Methylocaldum, Methylococcus, Methylothermus) and verrucomicrobial (Methylacidiphilum). We assert, on the basis of recently reported molecular and geochemical data, that geothermal ecosystems host hitherto unidentified species capable of methane oxidation at higher temperatures.
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http://dx.doi.org/10.1093/femsec/fiz125DOI Listing
September 2019

TLR3 in Chronic Human Itch: A Keratinocyte-Associated Mechanism of Peripheral Itch Sensitization.

J Invest Dermatol 2019 11 24;139(11):2393-2396.e6. Epub 2019 May 24.

Department of Dermatology, and HMC Translational Research Institute, Hamad Medical Corporation, Doha, Qatar; UCD Charles Institute for Dermatology, University College Dublin, Dublin, Ireland; Department of Dermatology, Weill Cornell University New York and Weill Cornell Medicine-Qatar, Doha, Qatar; School of Medicine, Qatar-University, Doha, Qatar.

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http://dx.doi.org/10.1016/j.jid.2019.04.018DOI Listing
November 2019

Mitochondrial Protease ClpP is a Target for the Anticancer Compounds ONC201 and Related Analogues.

ACS Chem Biol 2019 05 1;14(5):1020-1029. Epub 2019 May 1.

Department of Pharmacology and the Lineberger Comprehensive Cancer Center , University of North Carolina at Chapel Hill , Chapel Hill , North Carolina 27599 , United States.

ONC201 is a first-in-class imipridone molecule currently in clinical trials for the treatment of multiple cancers. Despite enormous clinical potential, the mechanism of action is controversial. To investigate the mechanism of ONC201 and identify compounds with improved potency, we tested a series of novel ONC201 analogues (TR compounds) for effects on cell viability and stress responses in breast and other cancer models. The TR compounds were found to be ∼50-100 times more potent at inhibiting cell proliferation and inducing the integrated stress response protein ATF4 than ONC201. Using immobilized TR compounds, we identified the human mitochondrial caseinolytic protease P (ClpP) as a specific binding protein by mass spectrometry. Affinity chromatography/drug competition assays showed that the TR compounds bound ClpP with ∼10-fold higher affinity compared to ONC201. Importantly, we found that the peptidase activity of recombinant ClpP was strongly activated by ONC201 and the TR compounds in a dose- and time-dependent manner with the TR compounds displaying a ∼10-100 fold increase in potency over ONC201. Finally, siRNA knockdown of ClpP in SUM159 cells reduced the response to ONC201 and the TR compounds, including induction of CHOP, loss of the mitochondrial proteins (TFAM, TUFM), and the cytostatic effects of these compounds. Thus, we report that ClpP directly binds ONC201 and the related TR compounds and is an important biological target for this class of molecules. Moreover, these studies provide, for the first time, a biochemical basis for the difference in efficacy between ONC201 and the TR compounds.
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http://dx.doi.org/10.1021/acschembio.9b00222DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6528275PMC
May 2019

Biotic interactions are an unexpected yet critical control on the complexity of an abiotically driven polar ecosystem.

Commun Biol 2019 15;2:62. Epub 2019 Feb 15.

School of Science, University of Waikato, Hamilton, 3240, New Zealand.

Abiotic and biotic factors control ecosystem biodiversity, but their relative contributions remain unclear. The ultraoligotrophic ecosystem of the Antarctic Dry Valleys, a simple yet highly heterogeneous ecosystem, is a natural laboratory well-suited for resolving the abiotic and biotic controls of community structure. We undertook a multidisciplinary investigation to capture ecologically relevant biotic and abiotic attributes of more than 500 sites in the Dry Valleys, encompassing observed landscape heterogeneities across more than 200 km. Using richness of autotrophic and heterotrophic taxa as a proxy for functional complexity, we linked measured variables in a parsimonious yet comprehensive structural equation model that explained significant variations in biological complexity and identified landscape-scale and fine-scale abiotic factors as the primary drivers of diversity. However, the inclusion of linkages among functional groups was essential for constructing the best-fitting model. Our findings support the notion that biotic interactions make crucial contributions even in an extremely simple ecosystem.
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http://dx.doi.org/10.1038/s42003-018-0274-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6377621PMC
April 2020

Microbial biogeography of 925 geothermal springs in New Zealand.

Nat Commun 2018 07 23;9(1):2876. Epub 2018 Jul 23.

Geomicrobiology Research Group, Department of Geothermal Sciences, GNS Science, Taupō, 3384, New Zealand.

Geothermal springs are model ecosystems to investigate microbial biogeography as they represent discrete, relatively homogenous habitats, are distributed across multiple geographical scales, span broad geochemical gradients, and have reduced metazoan interactions. Here, we report the largest known consolidated study of geothermal ecosystems to determine factors that influence biogeographical patterns. We measured bacterial and archaeal community composition, 46 physicochemical parameters, and metadata from 925 geothermal springs across New Zealand (13.9-100.6 °C and pH < 1-9.7). We determined that diversity is primarily influenced by pH at temperatures <70 °C; with temperature only having a significant effect for values >70 °C. Further, community dissimilarity increases with geographic distance, with niche selection driving assembly at a localised scale. Surprisingly, two genera (Venenivibrio and Acidithiobacillus) dominated in both average relative abundance (11.2% and 11.1%, respectively) and prevalence (74.2% and 62.9%, respectively). These findings provide an unprecedented insight into ecological behaviour in geothermal springs, and a foundation to improve the characterisation of microbial biogeographical processes.
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http://dx.doi.org/10.1038/s41467-018-05020-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6056493PMC
July 2018

Application of Integrated Drug Screening/Kinome Analysis to Identify Inhibitors of Gemcitabine-Resistant Pancreatic Cancer Cell Growth.

SLAS Discov 2018 09 9;23(8):850-861. Epub 2018 May 9.

1 Department of Pharmacology, University of North Carolina at Chapel Hill, NC, USA.

Continuous exposure of a pancreatic cancer cell line MIA PaCa-2 (Mia) to gemcitabine resulted in the formation of a gemcitabine-resistant subline (Mia). In an effort to discover kinase inhibitors that inhibited Mia growth, Mia cells were exposed to kinase inhibitors (PKIS-1 library) in a 384-well screening format. Three compounds (UNC10112721A, UNC10112652A, and UNC10112793A) were identified that inhibited the growth of Mia cells by more than 50% (at 50 nM). Two compounds (UNC10112721A and UNC10112652A) were classified as cyclin-dependent kinase (CDK) inhibitors, whereas UNC10112793A was reported to be a PLK inhibitor. Dose-response experiments supported the efficacy of these compounds to inhibit growth and increase apoptosis in 2D cultures of these cells. However, only UNC10112721A significantly inhibited the growth of 3D spheroids composed of Mia cells and GFP-tagged cancer-associated fibroblasts. Multiplexed inhibitor bead (MIB)-mass spectrometry (MS) kinome competition experiments identified CDK9, CLK1-4, DYRK1A, and CSNK1 as major kinase targets for UNC10112721A in Mia cells. Another CDK9 inhibitor (CDK-IN-2) replicated the growth inhibitory effects of UNC10112721A, whereas inhibitors against the CLK, DYRK, or CSNK1 kinases had no effect. In summary, these studies describe a coordinated approach to discover novel kinase inhibitors, evaluate their efficacy in 3D models, and define their specificity against the kinome.
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http://dx.doi.org/10.1177/2472555218773045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6102050PMC
September 2018

Measuring Kinase Activity-A Global Challenge.

J Cell Biochem 2017 11 31;118(11):3595-3606. Epub 2017 May 31.

Department of Pharmacology, University of North Carolina at Chapel Hill, Genetic Medicine Building, Campus Box #7365, 120 Mason Farm Rd., Chapel Hill, North Carolina, 27599.

The kinase enzymes within a cell, known collectively as the kinome, play crucial roles in many signaling pathways, including survival, motility, differentiation, stress response, and many more. Aberrant signaling through kinase pathways is often linked to cancer, among other diseases. A major area of scientific research involves understanding the relationships between kinases, their targets, and how the kinome adapts to perturbations of the cellular system. This review will discuss many of the current and developing methods for studying kinase activity, and evaluate their applications, advantages, and disadvantages. J. Cell. Biochem. 118: 3595-3606, 2017. © 2017 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/jcb.26103DOI Listing
November 2017

Kinome Profiling Identifies Druggable Targets for Novel Human Cytomegalovirus (HCMV) Antivirals.

Mol Cell Proteomics 2017 04 25;16(4 suppl 1):S263-S276. Epub 2017 Feb 25.

From the ‡Department of Microbiology & Immunology,

Human cytomegalovirus (HCMV) is a significant cause of disease in immune-compromised adults and immune naïve newborns. No vaccine exists to prevent HCMV infection, and current antiviral therapies have toxic side effects that limit the duration and intensity of their use. There is thus an urgent need for new strategies to treat HCMV infection. Repurposing existing drugs as antivirals is an attractive approach to limit the time and cost of new antiviral drug development. Virus-induced changes in infected cells are often driven by changes in cellular kinase activity, which led us to hypothesize that defining the complement of kinases (the kinome), whose abundance or expression is altered during infection would identify existing kinase inhibitors that could be repurposed as new antivirals. To this end, we applied a kinase capture technique, multiplexed kinase inhibitor bead-mass spectrometry (MIB-MS) kinome, to quantitatively measure perturbations in >240 cellular kinases simultaneously in cells infected with a laboratory-adapted (AD169) or clinical (TB40E) HCMV strain. MIB-MS profiling identified time-dependent increases and decreases in MIB binding of multiple kinases including cell cycle kinases, receptor tyrosine kinases, and mitotic kinases. Based on the kinome data, we tested the antiviral effects of kinase inhibitors and other compounds, several of which are in clinical use or development. Using a novel flow cytometry-based assay and a fluorescent reporter virus we identified three compounds that inhibited HCMV replication with IC values of <1 μm, and at doses that were not toxic to uninfected cells. The most potent inhibitor of HCMV replication was OTSSP167 (IC <1.2 nm), a MELK inhibitor, blocked HCMV early gene expression and viral DNA accumulation, resulting in a >3 log decrease in virus replication. These results show the utility of MIB-MS kinome profiling for identifying existing kinase inhibitors that can potentially be repurposed as novel antiviral drugs.
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http://dx.doi.org/10.1074/mcp.M116.065375DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5393402PMC
April 2017

Microbial community dynamics in Inferno Crater Lake, a thermally fluctuating geothermal spring.

ISME J 2017 05 10;11(5):1158-1167. Epub 2017 Jan 10.

GNS Science, Wairakei Research Centre, Wairakei, Taup, New Zealand.

Understanding how microbial communities respond and adjust to ecosystem perturbation is often difficult to interpret due to multiple and often simultaneous variations in observed conditions. In this research, we investigated the microbial community dynamics of Inferno Crater Lake, an acidic geothermal spring in New Zealand with a unique thermal cycle that varies between 30 and 80 °C over a period of 40-60 days. Using a combination of next-generation sequencing, geochemical analysis and quantitative PCR we found that the microbial community composition was predominantly chemolithotrophic and strongly associated with the thermal cycle. At temperatures >65 °C, the microbial community was dominated almost exclusively by sulphur-oxidising archaea (Sulfolobus-like spp.). By contrast, at mesophilic temperatures the community structure was more mixed, comprising both archaea and bacteria but dominated primarily by chemolithotrophic sulphur and hydrogen oxidisers. Multivariate analysis of physicochemical data confirmed that temperature was the only significant variable associated with community turnover. This research contributes to our understanding of microbial community dynamics in variable environments, using a naturally alternating system as a model and extends our limited knowledge of acidophile ecology in geothermal habitats.
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http://dx.doi.org/10.1038/ismej.2016.193DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5437927PMC
May 2017

The Chthonomonas calidirosea Genome Is Highly Conserved across Geographic Locations and Distinct Chemical and Microbial Environments in New Zealand's Taupō Volcanic Zone.

Appl Environ Microbiol 2016 06 31;82(12):3572-81. Epub 2016 May 31.

GNS Science, Extremophiles Research Group, Wairakei Research Centre, Taupō, New Zealand Department of Biostatistics, Harvard T. H. Chan School of Public Health, Boston, Massachusetts, USA Broad Institute, Cambridge, Massachusetts, USA Department of Microbiology and Immunology, University of Otago, Dunedin, New Zealand

Unlabelled: Chthonomonas calidirosea T49(T) is a low-abundance, carbohydrate-scavenging, and thermophilic soil bacterium with a seemingly disorganized genome. We hypothesized that the C. calidirosea genome would be highly responsive to local selection pressure, resulting in the divergence of its genomic content, genome organization, and carbohydrate utilization phenotype across environments. We tested this hypothesis by sequencing the genomes of four C. calidirosea isolates obtained from four separate geothermal fields in the Taupō Volcanic Zone, New Zealand. For each isolation site, we measured physicochemical attributes and defined the associated microbial community by 16S rRNA gene sequencing. Despite their ecological and geographical isolation, the genome sequences showed low divergence (maximum, 1.17%). Isolate-specific variations included single-nucleotide polymorphisms (SNPs), restriction-modification systems, and mobile elements but few major deletions and no major rearrangements. The 50-fold variation in C. calidirosea relative abundance among the four sites correlated with site environmental characteristics but not with differences in genomic content. Conversely, the carbohydrate utilization profiles of the C. calidirosea isolates corresponded to the inferred isolate phylogenies, which only partially paralleled the geographical relationships among the sample sites. Genomic sequence conservation does not entirely parallel geographic distance, suggesting that stochastic dispersal and localized extinction, which allow for rapid population homogenization with little restriction by geographical barriers, are possible mechanisms of C. calidirosea distribution. This dispersal and extinction mechanism is likely not limited to C. calidirosea but may shape the populations and genomes of many other low-abundance free-living taxa.

Importance: This study compares the genomic sequence variations and metabolisms of four strains of Chthonomonas calidirosea, a rare thermophilic bacterium from the phylum Armatimonadetes It additionally compares the microbial communities and chemistry of each of the geographically distinct sites from which the four C. calidirosea strains were isolated. C. calidirosea was previously reported to possess a highly disorganized genome, but it was unclear whether this reflected rapid evolution. Here, we show that each isolation site has a distinct chemistry and microbial community, but despite this, the C. calidirosea genome is highly conserved across all isolation sites. Furthermore, genomic sequence differences only partially paralleled geographic distance, suggesting that C. calidirosea genotypes are not primarily determined by adaptive evolution. Instead, the presence of C. calidirosea may be driven by stochastic dispersal and localized extinction. This ecological mechanism may apply to many other low-abundance taxa.
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http://dx.doi.org/10.1128/AEM.00139-16DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4959169PMC
June 2016

Thermorudis pharmacophila sp. nov., a novel member of the class Thermomicrobia isolated from geothermal soil, and emended descriptions of Thermomicrobium roseum, Thermomicrobium carboxidum, Thermorudis peleae and Sphaerobacter thermophilus.

Int J Syst Evol Microbiol 2015 Dec 14;65(12):4479-4487. Epub 2015 Sep 14.

GNS Science, Extremophiles Research Group, Private Bag 2000, Taupo¯ 3352, New Zealand.

An aerobic, thermophilic and cellulolytic bacterium, designated strain WKT50.2T, was isolated from geothermal soil at Waikite, New Zealand. Strain WKT50.2T grew at 53-76 °C and at pH 5.9-8.2. The DNA G+C content was 58.4 mol%. The major fatty acids were 12-methyl C18 : 0 and C18 : 0. Polar lipids were all linked to long-chain 1,2-diols, and comprised 2-acylalkyldiol-1-O-phosphoinositol (diolPI), 2-acylalkyldiol-1-O-phosphoacylmannoside (diolP-acylMan), 2-acylalkyldiol-1-O-phosphoinositol acylmannoside (diolPI-acylMan) and 2-acylalkyldiol-1-O-phosphoinositol mannoside (diolPI-Man). Strain WKT50.2T utilized a range of cellulosic substrates, alcohols and organic acids for growth, but was unable to utilize monosaccharides. Robust growth of WKT50.2T was observed on protein derivatives. WKT50.2T was sensitive to ampicillin, chloramphenicol, kanamycin, neomycin, polymyxin B, streptomycin and vancomycin. Metronidazole, lasalocid A and trimethoprim stimulated growth. Phylogenetic analysis of 16S rRNA gene sequences showed that WKT50.2T belonged to the class Thermomicrobia within the phylum Chloroflexi, and was most closely related to Thermorudis peleae KI4T (99.6% similarity). DNA-DNA hybridization between WKT50.2T and Thermorudis peleae DSM 27169T was 18.0%. Physiological and biochemical tests confirmed the phenotypic and genotypic differentiation of strain WKT50.2T from Thermorudis peleae KI4T and other members of the Thermomicrobia. On the basis of its phylogenetic position and phenotypic characteristics, we propose that strain WKT50.2T represents a novel species, for which the name Thermorudis pharmacophila sp. nov. is proposed, with the type strain WKT50.2T ( = DSM 26011T = ICMP 20042T). Emended descriptions of Thermomicrobium roseum, Thermomicrobium carboxidum, Thermorudis peleae and Sphaerobacter thermophilus are also proposed, and include the description of a novel respiratory quinone, MK-8 2,3-epoxide (23%), in Thermomicrobium roseum.
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http://dx.doi.org/10.1099/ijsem.0.000598DOI Listing
December 2015

Whole-Retina Reduced Electrophysiological Activity in Mice Bearing Retina-Specific Deletion of Vesicular Acetylcholine Transporter.

PLoS One 2015 30;10(7):e0133989. Epub 2015 Jul 30.

Department of Biology, The University of Western Ontario, London, Ontario, Canada N6A 5B7.

Background: Despite rigorous characterization of the role of acetylcholine in retinal development, long-term effects of its absence as a neurotransmitter are unknown. One of the unanswered questions is how acetylcholine contributes to the functional capacity of mature retinal circuits. The current study investigates the effects of disrupting cholinergic signalling in mice, through deletion of vesicular acetylcholine transporter (VAChT) in the developing retina, pigmented epithelium, optic nerve and optic stalk, on electrophysiology and structure of the mature retina.

Methods & Results: A combination of electroretinography, optical coherence tomography imaging and histological evaluation assessed retinal integrity in mice bearing retina- targeted (embryonic day 12.5) deletion of VAChT (VAChTSix3-Cre-flox/flox) and littermate controls at 5 and 12 months of age. VAChTSix3-Cre-flox/flox mice did not show any gross changes in nuclear layer cellularity or synaptic layer thickness. However, VAChTSix3-Cre-flox/flox mice showed reduced electrophysiological response of the retina to light stimulus under scotopic conditions at 5 and 12 months of age, including reduced a-wave, b-wave, and oscillatory potential (OP) amplitudes and decreased OP peak power and total energy. Reduced a-wave amplitude was proportional to the reduction in b-wave amplitude and not associated with altered a-wave 10%-90% rise time or inner and outer segment thicknesses.

Significance: This study used a novel genetic model in the first examination of function and structure of the mature mouse retina with disruption of cholinergic signalling. Reduced amplitude across the electroretinogram wave form does not suggest dysfunction in specific retinal cell types and could reflect underlying changes in the retinal and/or extraretinal microenvironment. Our findings suggest that release of acetylcholine by VAChT is essential for the normal electrophysiological response of the mature mouse retina.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0133989PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4520552PMC
May 2016

Benthic microbial communities of coastal terrestrial and ice shelf Antarctic meltwater ponds.

Front Microbiol 2015 27;6:485. Epub 2015 May 27.

International Centre for Terrestrial Antarctic Research, School of Science, University of Waikato Hamilton, New Zealand.

The numerous perennial meltwater ponds distributed throughout Antarctica represent diverse and productive ecosystems central to the ecological functioning of the surrounding ultra oligotrophic environment. The dominant taxa in the pond benthic communities have been well described however, little is known regarding their regional dispersal and local drivers to community structure. The benthic microbial communities of 12 meltwater ponds in the McMurdo Sound of Antarctica were investigated to examine variation between pond microbial communities and their biogeography. Geochemically comparable but geomorphologically distinct ponds were selected from Bratina Island (ice shelf) and Miers Valley (terrestrial) (<40 km between study sites), and community structure within ponds was compared using DNA fingerprinting and pyrosequencing of 16S rRNA gene amplicons. More than 85% of total sequence reads were shared between pooled benthic communities at different locations (OTU0.05), which in combination with favorable prevailing winds suggests aeolian regional distribution. Consistent with previous findings Proteobacteria and Bacteroidetes were the dominant phyla representing over 50% of total sequences; however, a large number of other phyla (21) were also detected in this ecosystem. Although dominant Bacteria were ubiquitous between ponds, site and local selection resulted in heterogeneous community structures and with more than 45% of diversity being pond specific. Potassium was identified as the most significant contributing factor to the cosmopolitan community structure and aluminum to the location unique community based on a BEST analysis (Spearman's correlation coefficient of 0.632 and 0.806, respectively). These results indicate that the microbial communities in meltwater ponds are easily dispersed regionally and that the local geochemical environment drives the ponds community structure.
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http://dx.doi.org/10.3389/fmicb.2015.00485DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4444838PMC
June 2015

Role of cytokines and chemokines in itch.

Handb Exp Pharmacol 2015 ;226:163-76

Department of Dermatology, Dept. of Dermatology and UCD Charles Institute of Translational Dermatology University College Dublin (UCD), Belfield, Dublin 4, Ireland.

Cytokines classically are secreted "messenger" proteins that modulate cellular function of immune cells. Chemokines attract immune cells to the site where they exert various functions in inflammation, autoimmunity or cancer. Increasing evidence is emerging that cytokines or chemokines can act as "neuro-modulators" by activating high-affinity receptors on peripheral or central neurons, microglia cells or Schwann cells. Very recently, cytokines have been shown to act as pruritogens in rodents and humans, while a role of chemokines in itch has thus far been only demonstrated in mice. Upon stimulation, cytokines are released by skin or immune cells and form a "bridge of communication" between the immune and nervous system. For some cytokines such as IL-31 and TSLP, the evidence for this role is strong in rodents. For cytokines such as IL-4, there is some convincing evidence, while for cytokines such as oncostatin M, IL-2, IL-6, IL-8 and IL-13, direct evidence is currently limited. Current clinical trials support the idea that cytokines and chemokines and their receptors or signalling pathways are promising targets for the future therapy of certain subtypes of itch.
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http://dx.doi.org/10.1007/978-3-662-44605-8_9DOI Listing
July 2015

Molecular and Morphological Characterization of Inflammatory Infiltrate in Rosacea Reveals Activation of Th1/Th17 Pathways.

J Invest Dermatol 2015 Sep 7;135(9):2198-2208. Epub 2015 Apr 7.

Charles Institute for Translational Dermatology, University College Dublin, Dublin, Ireland; Department of Dermatology and Surgery, University of California, San Francisco, California, USA; Department of Dermatology, University of San Diego, USA. Electronic address:

Rosacea is a common chronic inflammatory skin disease of unknown etiology. Our knowledge about an involvement of the adaptive immune system is very limited. We performed detailed transcriptome analysis, quantitative real-time reverse-transcriptase-PCR, and quantitative immunohistochemistry on facial biopsies of rosacea patients, classified according to their clinical subtype. As controls, we used samples from patients with facial lupus erythematosus and healthy controls. Our study shows significant activation of the immune system in all subtypes of rosacea, characterizing erythematotelangiectatic rosacea (ETR) already as a disease with significant influx of proinflammatory cells. The T-cell response is dominated by Th1/Th17-polarized immune cells, as demonstrated by significant upregulation of IFN-γ or IL-17, for example. Chemokine expression patterns support a Th1/Th17 polarization profile of the T-cell response. Macrophages and mast cells are increased in all three subtypes of rosacea, whereas neutrophils reach a maximum in papulopustular rosacea. Our studies also provide evidence for the activation of plasma cells with significant antibody production already in ETR, followed by a crescendo pattern toward phymatous rosacea. In sum, Th1/Th17 polarized inflammation and macrophage infiltration are an underestimated hallmark in all subtypes of rosacea. Therapies directly targeting the Th1/Th17 pathway are promising candidates in the future treatment of this skin disease.
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http://dx.doi.org/10.1038/jid.2015.141DOI Listing
September 2015

Blistering psoriatic plaques during narrowband UVB phototherapy.

Photodermatol Photoimmunol Photomed 2015 May 3;31(3):167-9. Epub 2015 Mar 3.

National Photobiology Unit, Department of Dermatology, Mater Misericordiae University Hospital, Dublin, Ireland.

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http://dx.doi.org/10.1111/phpp.12167DOI Listing
May 2015

Straightforward assay for quantification of social avoidance in Drosophila melanogaster.

J Vis Exp 2014 Dec 13(94). Epub 2014 Dec 13.

Department of Biology, Western Ontario University;

Drosophila melanogaster is an emerging model to study different aspects of social interactions. For example, flies avoid areas previously occupied by stressed conspecifics due to an odorant released during stress known as the Drosophila stress odorant (dSO). Through the use of the T-maze apparatus, one can quantify the avoidance of the dSO by responder flies in a very affordable and robust assay. Conditions necessary to obtain a strong performance are presented here. A stressful experience is necessary for the flies to emit dSO, as well as enough emitter flies to cause a robust avoidance response to the presence of dSO. Genetic background, but not their group size, strongly altered the avoidance of the dSO by the responder flies. Canton-S and Elwood display a higher performance in avoiding the dSO than Oregon and Samarkand strains. This behavioral assay will allow identification of mechanisms underlying this social behavior, and the assessment of the influence of genes and environmental conditions on both emission and avoidance of the dSO. Such an assay can be included in batteries of simple diagnostic tests used to identify social deficiencies of mutants or environmental conditions of interest.
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http://dx.doi.org/10.3791/52011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4396940PMC
December 2014

Parenteral administration of GnRH constructs and adjuvants: immune responses and effects on reproductive tissues of male mice.

Vaccine 2014 Sep 15;32(43):5555-63. Epub 2014 Aug 15.

Commonwealth Scientific and Industrial Research Organisation (CSIRO), Biosecurity Flagship, GPO Box 1700, Canberra, ACT, Australia; Invasive Animals Cooperative Research Centre (IA CRC), University of Canberra, Canberra, ACT, Australia. Electronic address:

Two gonadotrophin releasing hormone (GnRH) constructs prepared by either chemical conjugation to keyhole limpet hemocyanin (GnRH-KLH) or as an expressed recombinant fusion protein (Multimer) were evaluated with or without adjuvants (immunostimulating complexes, ISCOMs, or cytosine-phosphate-guanosine oligodeoxynucleotides, CpG ODNs). After subcutaneous administration to Balb/c male mice at Weeks 0, 2 and 4, these preparations were assessed for induction of immune responses and effects on reproductive organs. GnRH-KLH plus ISCOMs formulation induced strong IgG immune responses from Week 4 through Week 12 resulting in consistent reproductive organ atrophy by Week 12 after subcutaneous administration. GnRH-KLH plus CpG ODNs generated immune responses but no atrophy of reproductive tissues by Week 12. Multimer plus ISCOMs induced poor immune responses and no effects on reproductive tissues by Week 12. In the absence of additional adjuvant, none of the GnRH constructs induced reproductive organ atrophy. GnRH-KLH induced stronger immune responses when formulated with ISCOMs or CpG ODN compared to Multimer. GnRH-KLH with ISCOMs could be an effective colloidal alternative for emulsion GnRH vaccine formulations.
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http://dx.doi.org/10.1016/j.vaccine.2014.07.075DOI Listing
September 2014

Characterisation of bacterioplankton communities in the meltwater ponds of Bratina Island, Victoria Land, Antarctica.

FEMS Microbiol Ecol 2014 Aug 17;89(2):451-64. Epub 2014 Jun 17.

International Centre for Terrestrial Antarctic Research, School of Science, University of Waikato, Hamilton, New Zealand.

A unique collection of Antarctic aquatic environments (meltwater ponds) lies in close proximity on the rock and sediment-covered undulating surface of the McMurdo Ice Shelf, near Bratina Island (Victoria Land, Antarctica). During the 2009-10 mid-austral summer, sets of discrete water samples were collected across the vertical geochemical gradients of five meltwater ponds (Egg, P70E, Legin, Salt and Orange) for geochemical and microbial community structure analysis. Bacterial DNA fingerprints (using Automated Ribosomal Intergenic Spacer Analysis) statistically clustered communities within ponds based on anosim (R = 0.766, P = 0.001); however, one highly stratified pond (Egg) had two distinct depth-related bacterial communities (R = 0.975, P = 0.008). 454 pyrosequencing at three depths within Egg also identified phylum level shifts and increased diversity with depth, Bacteroidetes being the dominant phyla in the surface sample and Proteobacteria being dominant in the bottom two depths. best analysis, which attempts to link community structure and the geochemistry of a pond, identified conductivity and pH individually, and to a lesser extent Ag(109) , NO2 and V(51) as dominant influences to the microbial community structure in these ponds. Increasing abundances of major halo-tolerant OTUs across the strong conductivity gradient reinforce it as the primary driver of community structure in this study.
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http://dx.doi.org/10.1111/1574-6941.12358DOI Listing
August 2014

Evidence of global-scale aeolian dispersal and endemism in isolated geothermal microbial communities of Antarctica.

Nat Commun 2014 May 20;5:3875. Epub 2014 May 20.

1] Department of Biological Sciences, The University of Waikato, Private Bag 3105, Hamilton 3240, New Zealand [2] International Centre for Terrestrial Antarctic Research, Department of Biological Sciences, The University of Waikato, Hamilton 3240, New Zealand [3] College of Marine and Earth Studies, University of Delaware, Lewes, Delaware 19958, USA.

New evidence in aerobiology challenges the assumption that geographical isolation is an effective barrier to microbial transport. However, given the uncertainty with which aerobiological organisms are recruited into existing communities, the ultimate impact of microbial dispersal is difficult to assess. Here we use molecular genetic approaches to examine microbial communities inhabiting fumarolic soils on Mount Erebus, the southernmost geothermal site on Earth, to evaluate the ecological significance of global-scale microbial dispersal. There, hot, fumarolic soils provide an effective environmental filter to test the viability of organisms that have been distributed via aeolian transport over geological time. We find that cosmopolitan thermophiles dominate the surface, whereas endemic Archaea and members of poorly understood Bacterial candidate divisions dominate the immediate subsurface. These results imply that aeolian processes readily disperse viable organisms globally, where they are incorporated into pre-existing complex communities of endemic and cosmopolitan taxa.
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http://dx.doi.org/10.1038/ncomms4875DOI Listing
May 2014

Effect of long-term starvation on the survival, recovery, and carbon utilization profiles of a bovine Escherichia coli O157:H7 isolate from New Zealand.

Appl Environ Microbiol 2014 Jul 9;80(14):4383-90. Epub 2014 May 9.

Ministry of Primary Industries, Wellington, New Zealand.

The ability to maintain a dual lifestyle of colonizing the ruminant gut and surviving in nonhost environments once shed is key to the success of Escherichia coli O157:H7 as a zoonotic pathogen. Both physical and biological conditions encountered by the bacteria are likely to change during the transition between host and nonhost environments. In this study, carbon starvation at suboptimal temperatures in nonhost environments was simulated by starving a New Zealand bovine E. coli O157:H7 isolate in phosphate-buffered saline at 4 and 15°C for 84 days. Recovery of starved cells on media with different nutrient availabilities was monitored under aerobic and anaerobic conditions. We found that the New Zealand bovine E. coli O157:H7 isolate was able to maintain membrane integrity and viability over 84 days and that the level of recovery depended on the nutrient level of the recovery medium as well as the starvation temperature. In addition, a significant difference in carbon utilization was observed between starved and nonstarved cells.
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http://dx.doi.org/10.1128/AEM.00045-14DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4068667PMC
July 2014

Influence of soil properties on archaeal diversity and distribution in the McMurdo Dry Valleys, Antarctica.

FEMS Microbiol Ecol 2014 Aug 16;89(2):347-59. Epub 2014 Apr 16.

School of Science, University of Waikato, Hamilton, New Zealand.

Archaea are the least understood members of the microbial community in Antarctic mineral soils. Although their occurrence in Antarctic coastal soils has been previously documented, little is known about their distribution in soils across the McMurdo Dry Valleys, Victoria Land. In this study, terminal-restriction fragment length polymorphism (t-RFLP) analysis and 454 pyrosequencing were coupled with a detailed analysis of soil physicochemical properties to characterize archaeal diversity and identify environmental factors that might shape and maintain archaeal communities in soils of the three southern most McMurdo Dry Valleys (Garwood, Marshall, and Miers Valley). Archaea were successfully detected in all inland and coastal mineral soils tested, revealing a low overall richness (mean of six operational taxonomic units [OTUs] per sample site). However, OTU richness was higher in some soils and this higher richness was positively correlated with soil water content, indicating water as a main driver of archaeal community richness. In total, 18 archaeal OTUs were detected, predominately Thaumarchaeota affiliated with Marine Group 1.1b (> 80% of all archaeal sequences recovered). Less abundant OTUs (2% of all archaeal sequences) were loosely related to members of the phylum Euryarchaeota. This is the first comprehensive study showing a widespread presence and distribution of Archaea in inland Antarctic soils.
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http://dx.doi.org/10.1111/1574-6941.12322DOI Listing
August 2014
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