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1.  Soil-foraging animals alter the composition and co-occurrence of microbial communities in a desert shrubland 
The ISME Journal  2015;9(12):2671-2681.
Animals that modify their physical environment by foraging in the soil can have dramatic effects on ecosystem functions and processes. We compared bacterial and fungal communities in the foraging pits created by bilbies and burrowing bettongs with undisturbed surface soils dominated by biocrusts. Bacterial communities were characterized by Actinobacteria and Alphaproteobacteria, and fungal communities by Lecanoromycetes and Archaeosporomycetes. The composition of bacterial or fungal communities was not observed to vary between loamy or sandy soils. There were no differences in richness of either bacterial or fungal operational taxonomic units (OTUs) in the soil of young or old foraging pits, or undisturbed soils. Although the bacterial assemblage did not vary among the three microsites, the composition of fungi in undisturbed soils was significantly different from that in old or young foraging pits. Network analysis indicated that a greater number of correlations between bacterial OTUs occurred in undisturbed soils and old pits, whereas a greater number of correlations between fungal OTUs occurred in undisturbed soils. Our study suggests that digging by soil-disturbing animals is likely to create successional shifts in soil microbial and fungal communities, leading to functional shifts associated with the decomposition of organic matter and the fixation of nitrogen. Given the primacy of organic matter decomposition in arid and semi-arid environments, the loss of native soil-foraging animals is likely to impair the ability of these systems to maintain key ecosystem processes such as the mineralization of nitrogen and the breakdown of organic matter, and to recover from disturbance.
doi:10.1038/ismej.2015.70
PMCID: PMC4817632  PMID: 25932616
2.  British Society of Breast Radiology Annual Scientific Meeting 2016 
Azmil, Ameerah Mohd | Bansal, Gaurav Jyoti | Davies, Eleri | Wallis, Matthew | Kilburn-Toppin, Fleur | Taylor-Phillip, Sian | Buckley, Anne | Healy, Nuala | Quinn, Aine | O’Keeffe, Sylvia | Ang, Teri | Maxwell, Anthony | Lim, Yit Y. | Harkness, Elaine | Emsley, Richard | Astley, Susan | Gadde, Soujanya | Ang, Teri | Maxwell, Anthony | Lim, Yit Y. | Harkness, Elaine | Emsley, Richard | Astley, Susan | Gadde, Soujanya | Ferguson, Jennifer | Stevens, Guy | Hills, Robert | Thomas, Kate Gower | Rajan, Sabrina | Sharma, Nisha | Kishore, Ajit | O’ Dowd, John | Murphy, Claire | Lindsay, Ken | Dadayal, Guneesh | Moody, Anne Nielsen | Whitaker, Madeleine | Wolstenhulme, Stephen | Bull, Jane | Sharma, Nisha | Culpan, Anne-Marie | Roszkowski, Natalia | Grima, Alexis | Stahnke, Michaela | Rubin, Caroline | Walker, Ruth | Oeppen, Rachel | Puttagunta, Srikanth | Gray, Karen | Puri, Shama | Sharma, Nisha | Millican-Slater, Rebecca | Pascaline, Sana | Hajaj, Mohamad | Flinn, Janet | Thomson, Kim | Elsberger, Beatrix | Turnbull, Anne | Bagnall, Mark | York, Joanne | Benney, Stuart | Goyal, Amit | Topps, Ashley | Barr, Simon | Pikoulas, Panagiotis | Pritchard, Susan | Maxwell, Anthony | Greenhalgh, Sophie | Sreenivas, Muthyala | Greenhalgh, Sophie | Sreenivas, Muthyala | Greenhalgh, Sophie | Sreenivas, Muthyala | Nandhra, Anju | Sharma, Sheetal | Gulati, Archita | Razzaq, Furhan | Khan, Sana | McKillen, Jacqueline | Larkin, Rupert | Sreenivas, Muthyala | Kamat, Sachin | Goncalves, Carla | Tan, Alan | Eleti, Asha | Vidyaprakash, Nithya | McMahon, Michelle A. | Dall, Barbara J. G. | Sharma, Nisha | Majid, Faisal | Sreenivas, Muthyala | Rattehalli, Ramachadra | Gaur, Vandana | Mackenzie, Alistair | Warren, Lucy | Patel, Mishal | Halling-Brown, Mark | Wilkinson, Louise | Young, Kenneth | Tanner, James | Wallis, Matthew | Currie, Rachael | Balyes, Sharron | Wragg, Julie | Zamfir, Georgiana | Ayra, Pallavi | Marsden, Max | Butterworth, James | Sinha, Shona | Desai, Anil | Metafa, Anna | Whitaker, Madeleine | Nielsen-Moody, Anne | Wolstenhulme, Stephen | Sharma, Nisha | Bull, Jane | Ward, Laura | Heller, Samantha | Hudson, Sue | Wilkinson, Louise | Taylor, Kathryn | Xyda, Argyro | Turnbull, Anne | Allen, Steven | Orlowski, Elizabeth | York, Joanne | Downey, Kate | Sidebottom, Richard | Wallis, Matthew | Lodhi, Ahmad | Harkness, Elaine | Maxwell, Anthony | Howell, Anthony | Evans, Gareth | Gadde, Soujanya | Astley, Susan | Lim, Yit | Chen, Yan | Lepine-Williams, Elizabeth | Henderson, Steven | Litherland, Janet | Altaf, Naveed | Bury, Yvonne | Forester, Nerys | Chin, Mei Chan | Litherland, Janet | Taylor, Caroline | Skippage, Pippa | Sian, Aneet | McAvinchey, Rita | Evans, Tom | Stevens, Guy | Nisbet, Sian | Murray, Alex | Thomas, Kate Gower | Castillo, Raquel Clark | Markham, Hannah | Oeppen, Rachel | Thomas, Timothy | Jain, Anil | Molderson, Jaanilka | Wan, Joseph | Newman, Helen | Lowes, Simon | Lunt, Linsley | Sultana, Sadia | Chillal, Varun | Sreenivas, Muthyala | Dalton, Rebecca | Reeves, David | Sergeant, Jamie | Harkness, Elaine | Gadde, Soujanya | Maxwell, Anthony | Lim, Yit | Astley, Susan | Edwards, Liz | Jenkins, Kate | Stevens, Guy | Jain, Anil | Molderson, Jaanilka | Shaikh, Shaheeda | Sidebottom, Richard | O’Flynn, Elizabeth | Bombroffe, Laura | Hughes, Julie | Scurr, Erica | Wilson, Robin | Jones, Lyn | Govindarajulu, Sasirekha | Sahu, Ajay K. | Brown, Matthew | Allen, Steve | O’Flynn, Liz | deSouza, Nandita | Rahim, Rumana | Wasan, Rema | Goligher, Jane | Wijesuriya, Shalini | Morel, Juliet | Peacock, Clare | Michell, Michael | Iqbal, Asif | Evans, David | Batohi, Bhavna | Wasan, Tavleen | Phillips, Vivien | Manuel, Eden | Bowman, Gillian | Satchithananda, Keshthra | Batohi, Bhavna | Fang, Cheng | Michell, Michael | Morel, Juliet | Shah, Chirag | Wijesuriya, Shalini | Peacock, Clare | Rahim, Rumana | Wasan, Rema | Goligher, Jane | Satchithananda, Keshthra | Altaf, Naveed | Forester, Nerys | Hodkin, Leanne | Horgan, Keiran | Dodwell, David | Sharma, Nisha | Moloney, BM | Casey, M. C. | Breathnach, A. | Dwyer, R. M. | McLoughlin, R. | Sweeney, K. J. | Malone, C. | Healy, M. J. | Kerin, M. J. | Forester, Nerys | Lowes, Simon | Mitchell, Elizabeth | Twiddy, Maureen | Maxwell, Anthony | Sharma, Nisha | Dobson, Hilary | Vinnicombe, Sarah | Evans, Andrew | Grant, David | Bishop, Briony | Giggens, Roxanne | Bhuva, Shaheel | Royds, Jennifer | Camilleri, Francesca | Babu, Gauripriya | Beveridge, Carolyn | Geach, Rebecca | Klimczak, Katherine | Massey, Helen | Lyburn, Iain | Wan, Joseph | Jain, Anil | Molderson, Jaanilka | Salehi-Bird, Seema | Nishtala, Sahithi | Gunning, Liz | Changaradil, Deepthi Vinayan | Bansal, Jyoti | Davis, Joanna | Sharma, Ashwini | Del Voscovo, Elena | Etheridge, Harriet | Butler, Aisling | Fenne, David S. J. | Rubin, Gary | Burt, Helen | Ridley, Nick | Taylor, Sarah | Sreenivas, Muthyala | Seth, Subodh | Seth, Archana
Breast Cancer Research : BCR  2016;18(Suppl 1):1-20.
doi:10.1186/s13058-016-0766-5
PMCID: PMC5123431
3.  Multiple factors contribute to anautogenous reproduction by the mosquito Aedes aegypti 
Aedes aegypti is an anautogenous mosquito that must blood feed on a vertebrate host to produce and lay a clutch of eggs. The rockpool mosquito, Georgecraigius atropalpus, is related to A. aegypti but is a facultatively autogenous species that produces its first clutch of eggs shortly after emerging without blood feeding. Consumption of a blood meal by A. aegypti triggers the release of ovary ecdysteroidogenic hormone (OEH) and insulin-like peptide 3 (ILP3) from the brain, which stimulate egg formation. OEH and ILP3 also stimulate egg formation in G. atropalpus but are released at eclosion independently of blood feeding. These results collectively suggest that blood meal dependent release of OEH and ILP3 is one factor that prevents A. aegypti from reproducing autogenously. Here, we examined two other factors that potentially inhibit autogeny in A. aegypti: teneral nutrient reserves and the ability of OEH and ILP3 to stimulate egg formation in the absence of blood feeding. Measures of nutrient reserves showed that newly emerged A. aegypti females had similar wet weights but significantly lower protein and glycogen reserves than G. atropalpus females when larvae were reared under identical conditions. OEH stimulated non-blood fed A. aegypti females to produce ecdysteroid hormone and package yolk into oocytes more strongly than ILP3. OEH also reduced host seeking and blood feeding behavior, yet females produced few mature eggs. Overall, our results indicate that multiple factors prevent A. aegypti from reproducing autogenously.
doi:10.1016/j.jinsphys.2015.08.001
PMCID: PMC4630150  PMID: 26255841
neuropeptide; autogeny; reproduction; oogenesis; hormone; endocrine
4.  A comparison of seasonal trends in asthma exacerbations among children from geographic regions with different climates 
Allergy and Asthma Proceedings  2016;37(6):475-481.
Background:
The fall peak in childhood asthma exacerbations is thought to be related to an increase in viral infections and allergen exposure when children return to school. Whether the seasonality of asthma attacks among children from different geographic regions follows similar trends is unclear.
Objective:
To compare seasonal trends in asthma exacerbations among school-age children who lived in different geographic locations, with different climates, within the United States.
Methods:
Hospital billing data bases were examined to determine the monthly number of school-age children who were hospitalized or treated in the emergency department (ED) for asthma exacerbations. Data from four cities within three states were compared. Climate data were obtained from archives of the National Climate Data Center, U.S. Department of Commerce.
Results:
An annual peak in asthma exacerbations was observed during the fall months (September through November) among children who lived in Charlottesville, Virginia, as well as throughout the state of Virginia. An increase in exacerbations, which peaked in November, was observed for exacerbations among children who lived in Tucson, Arizona, and Yuma, Arizona. In contrast, exacerbations among children from New Orleans, Louisiana, increased in September but remained elevated throughout the school year. Although there was annual variation in the frequency of exacerbations over time, the seasonal patterns observed remained similar within the locations from year to year. A nadir in the frequency of attacks was observed during the summer months in all the locations.
Conclusion:
Seasonal peaks for asthma exacerbations varied among the children who lived in geographic locations with different climates, and were not restricted to the beginning of the school year.
doi:10.2500/aap.2016.37.3994
PMCID: PMC5080535  PMID: 27931303
Asthma; seasonal asthma exacerbations; wheezing; children; climate; hospitalizations; emergency department visits; viral respiratory infections; asthma treatment; rhinovirus
5.  Variations in Opioid Receptor Genes in Neonatal Abstinence Syndrome* 
Drug and alcohol dependence  2015;155:253-259.
Background
There is significant variability in the severity of neonatal abstinence syndrome (NAS) due to in-utero opioid exposure. We wanted to determine if single nucleotide polymorphisms (SNPs) in key candidate genes contribute to this variability.
Methods
Full-term opioid-exposed newborns and their mothers (n=86 pairs) were studied. DNA was genotyped for 80 SNPs from 14 genes utilizing a custom designed microarray. The association of each SNP with NAS outcomes was evaluated.
Results
SNPs in two opioid receptor genes in the infants were associated with worse NAS severity: 1) The PNOC rs732636 A allele (OR=3.8, p=0.004) for treatment with 2 medications and a longer hospital stay (LOS) of 5.8 days (p=0.01), and 2) The OPRK1 rs702764 C allele (OR=4.1, p=0.003) for treatment with 2 medications. The OPRM1 rs1799971 G allele (β= −6.9 days, p=0.02) and COMT rs740603 A allele (β= −5.3 days, p=0.01) were associated with shorter LOS. The OPRD1 rs204076 A allele in the mothers was associated with a longer LOS by 6.6 days (p=0.008). Results were significant point-wise but did not meet the experiment-wide significance level.
Conclusions
These findings suggest that SNPs in opioid receptor and the PNOC genes are associated with NAS severity. However, further testing in a large sample is warranted. This has important implications for prenatal prediction and personalized treatment regimens for infants at highest risk for severe NAS.
doi:10.1016/j.drugalcdep.2015.07.001
PMCID: PMC4581974  PMID: 26233486
Neonatal Abstinence Syndrome (NAS); Genetics; single nucleotide polymorphisms (SNPs); opioids
6.  Coronary artery disease secondary to familial hypercholesterolaemia: An infrequent cause of increasingly common pregnancy co-morbidity 
Obstetric Medicine  2015;8(3):152-154.
Background
Cardiovascular disease affects 0.2–4% of pregnancies. Coupled with the physiological stress of pregnancy, cardiovascular disease may present significant management challenges including appropriate risk:benefit analysis of medical and surgical management options.
Case
A 33-year-old gravida 4 para 1 miscarriage 2 presented at 18 weeks’ gestation to the high-risk pregnancy service with a history of coronary artery disease and homozygous familial hypercholesterolaemia. Pre-pregnancy echocardiogram showed probable aortic xanthoma and preserved cardiac function. Prior to planned interventional cardiology assessment for her coronary artery disease she became pregnant, taking aspirin and multivitamins only. She had exertional angina responsive to metoprolol, agreed to recommencing statin therapy when serum cholesterol worsened, but declined angiography during pregnancy. At 36 weeks’ gestation, she had further angina symptoms but no acute coronary syndrome. Induction in the High Dependency Unit with elective assisted vaginal delivery of a healthy female infant (birthweight 2460 g) occurred at 37 weeks. She underwent triple-vessel coronary artery bypass postpartum, recovering well.
Conclusion
Whilst this specific condition is rare, the increase in cardiovascular disease and cardiovascular risks in the obstetric population emphasises the need for clear, multidisciplinary management from the outset of pregnancy for these women.
doi:10.1177/1753495X15593451
PMCID: PMC4935017  PMID: 27512472
Cardiology; drugs (medication); high-risk pregnancy; general medicine; cardiovascular
7.  All that wheezes is not asthma: A cautionary case study of shortness of breath in pregnancy 
Obstetric Medicine  2015;8(3):149-151.
Background
Shortness of breath is a common physiological pregnancy presentation, secondary to both hormonal and mechanical effects. Its pathological causes are common (asthma exacerbation or infection); new-onset cardiac pathology is rarely considered.
Case
JC, a 39-year old G4P2T1, presented at 34 weeks’ gestation with shortness of breath unrelieved by salbutamol. History included asthma, poly-drug abuse and smoking. Initial presentation was consistent with asthma exacerbation and she was treated as such. There was deterioration of symptoms and on re-examination raised jugular venous pressure was noted with bibasal lung crepitations and cardiac systolic murmur. Echocardiogram showed severe cardiomyopathy (left ventricular ejection fraction 20%). JC was commenced on diuretics, digoxin and fluid restricted. Labour was induced at 35 weeks’ gestation, with birth of a healthy female infant (BW 2475 g) by elective assisted vaginal delivery. Cardiac function improved in subsequent weeks, confirming peripartum cardiomyopathy.
Conclusion
Peripartum cardiomyopathy affects 1 in 2500–4000 live births. Over 90% of women regain normal cardiac function postpartum with optimal medical management. Peripartum cardiomyopathy presents a diagnostic conundrum as its primary symptoms mimic not only those of normal pregnancy but also a number of other, more common conditions.
It is important to consider cardiac causes of shortness of breath initially, and vital to revisit an initial non-cardiac shortness of breath diagnosis if there is no sustained improvement with treatment. In this case, asthma history and initial wheeze on examination impeded correct diagnosis; however, the situation was re-evaluated and correct diagnosis made when the patient’s shortness of breath deteriorated.
Subsequent multidisciplinary management and birth in an appropriate setting facilitated the best outcome for both mother and baby.
doi:10.1177/1753495X15590020
PMCID: PMC4935024  PMID: 27512471
Cardiovascular; complications; general medicine; high-risk pregnancy; intensive care medicine
8.  A horizon scan of future threats and opportunities for pollinators and pollination 
PeerJ  2016;4:e2249.
Background. Pollinators, which provide the agriculturally and ecologically essential service of pollination, are under threat at a global scale. Habitat loss and homogenisation, pesticides, parasites and pathogens, invasive species, and climate change have been identified as past and current threats to pollinators. Actions to mitigate these threats, e.g., agri-environment schemes and pesticide-use moratoriums, exist, but have largely been applied post-hoc. However, future sustainability of pollinators and the service they provide requires anticipation of potential threats and opportunities before they occur, enabling timely implementation of policy and practice to prevent, rather than mitigate, further pollinator declines.
Methods.Using a horizon scanning approach we identified issues that are likely to impact pollinators, either positively or negatively, over the coming three decades.
Results.Our analysis highlights six high priority, and nine secondary issues. High priorities are: (1) corporate control of global agriculture, (2) novel systemic pesticides, (3) novel RNA viruses, (4) the development of new managed pollinators, (5) more frequent heatwaves and drought under climate change, and (6) the potential positive impact of reduced chemical use on pollinators in non-agricultural settings.
Discussion. While current pollinator management approaches are largely driven by mitigating past impacts, we present opportunities for pre-emptive practice, legislation, and policy to sustainably manage pollinators for future generations.
doi:10.7717/peerj.2249
PMCID: PMC4991895  PMID: 27602260
Horizon scanning; Pollinator; Pollination; Ecosystem services; Conservation
9.  Editorial: Anthropogenic Impacts on the Microbial Ecology and Function of Aquatic Environments 
doi:10.3389/fmicb.2016.01044
PMCID: PMC4934117  PMID: 27458441
pollution and global change; climate change impacts; aquatic microbiology; resistance gene reservoirs; microbial community disturbance
10.  Gut bacteria differentially affect egg production in the anautogenous mosquito Aedes aegypti and facultatively autogenous mosquito Aedes atropalpus (Diptera: Culicidae) 
Parasites & Vectors  2016;9:375.
Background
Aedes aegypti and A. atropalpus are related mosquitoes that differ reproductively. Aedes aegypti must blood-feed to produce eggs (anautogenous) while A. atropalpus always produces a first clutch of eggs without blood-feeding (facultatively autogenous). We recently characterized the gut microbiota of A. aegypti and A. atropalpus that were reared identically in the laboratory. Here, we assessed the effects of specific members of the gut microbiota in A. aegypti and A. atropalpus on female fitness including egg production.
Methods
Gnotobiotic A. aegypti and A. atropalpus larvae were colonized by specific members of the gut microbiota. Survival, development time, size and egg production for each treatment was then compared to axenic and conventionally reared larvae.
Results
Most species of bacteria we tested supported normal development and egg production by A. aegypti but only one betaproteobacterium, a Comamonas, supported development and egg production by A. atropalpus to equivalent levels as conventionally reared females. Aedes atropalpus females colonized by Comamonas contained similar stores of glycogen and protein as conventionally reared females, whereas females colonized by Aquitalea did not. Small differences in bacterial loads were detected between gnotobiotic and conventionally reared A. aegypti and A. atropalpus, but this variation did not correlate with the beneficial effects of Comamonas in A. atropalpus.
Conclusions
Specific members of the gut microbiota more strongly affected survival, size and egg production by A. atropalpus than A. aegypti.
Electronic supplementary material
The online version of this article (doi:10.1186/s13071-016-1660-9) contains supplementary material, which is available to authorized users.
doi:10.1186/s13071-016-1660-9
PMCID: PMC4929711  PMID: 27363842
Microbiota; Development; Reproduction; Oogenesis; Clutch size
11.  Elevated virulence of an emerging viral genotype as a driver of honeybee loss 
Emerging infectious diseases (EIDs) have contributed significantly to the current biodiversity crisis, leading to widespread epidemics and population loss. Owing to genetic variation in pathogen virulence, a complete understanding of species decline requires the accurate identification and characterization of EIDs. We explore this issue in the Western honeybee, where increasing mortality of populations in the Northern Hemisphere has caused major concern. Specifically, we investigate the importance of genetic identity of the main suspect in mortality, deformed wing virus (DWV), in driving honeybee loss. Using laboratory experiments and a systematic field survey, we demonstrate that an emerging DWV genotype (DWV-B) is more virulent than the established DWV genotype (DWV-A) and is widespread in the landscape. Furthermore, we show in a simple model that colonies infected with DWV-B collapse sooner than colonies infected with DWV-A. We also identify potential for rapid DWV evolution by revealing extensive genome-wide recombination in vivo. The emergence of DWV-B in naive honeybee populations, including via recombination with DWV-A, could be of significant ecological and economic importance. Our findings emphasize that knowledge of pathogen genetic identity and diversity is critical to understanding drivers of species decline.
doi:10.1098/rspb.2016.0811
PMCID: PMC4936039  PMID: 27358367
virulence; emerging infectious disease; pollinator; decline
12.  Characterisation of the Novel Mixed Mu-NOP Peptide Ligand Dermorphin-N/OFQ (DeNo) 
PLoS ONE  2016;11(6):e0156897.
Introduction
Opioid receptors are currently classified as Mu (μ), Delta (δ), Kappa (κ) plus the opioid related nociceptin/orphanin FQ (N/OFQ) peptide receptor (NOP). Despite compelling evidence for interactions and benefits of targeting more than one receptor type in producing analgesia, clinical ligands are Mu agonists. In this study we have designed a Mu-NOP agonist named DeNo. The Mu agonist component is provided by dermorphin, a peptide isolated from the skin of Phyllomedusa frogs and the NOP component by the endogenous agonist N/OFQ.
Methods
We have assessed receptor binding profile of DeNo and compared with dermorphin and N/OFQ. In a series of functional screens we have assessed the ability to (i) increase Ca2+ in cells coexpressing recombinant receptors and a the chimeric protein Gαqi5, (ii) stimulate the binding of GTPγ[35S], (iii) inhibit cAMP formation, (iv) activate MAPKinase, (v) stimulate receptor-G protein and arrestin interaction using BRET, (vi) electrically stimulated guinea pig ileum (gpI) assay and (vii) ability to produce analgesia via the intrathecal route in rats.
Results
DeNo bound to Mu (pKi; 9.55) and NOP (pKi; 10.22) and with reasonable selectivity. This translated to increased Ca2+ in Gαqi5 expressing cells (pEC50 Mu 7.17; NOP 9.69), increased binding of GTPγ[35S] (pEC50 Mu 7.70; NOP 9.50) and receptor-G protein interaction in BRET (pEC50 Mu 8.01; NOP 9.02). cAMP formation was inhibited and arrestin was activated (pEC50 Mu 6.36; NOP 8.19). For MAPK DeNo activated p38 and ERK1/2 at Mu but only ERK1/2 at NOP. In the gpI DeNO inhibited electrically-evoked contractions (pEC50 8.63) that was sensitive to both Mu and NOP antagonists. DeNo was antinociceptive in rats.
Conclusion
Collectively these data validate the strategy used to create a novel bivalent Mu-NOP peptide agonist by combining dermorphin (Mu) and N/OFQ (NOP). This molecule behaves essentially as the parent compounds in vitro. In the antonocicoeptive assays employed in this study DeNo displays only weak antinociceptive properties.
doi:10.1371/journal.pone.0156897
PMCID: PMC4896453  PMID: 27272042
13.  White matter disease and cognitive impairment in FMR1 premutation carriers 
Neurology  2015;84(21):2146-2152.
Objective:
This cross-sectional, observational study examined the role of white matter involvement in the cognitive impairment of individuals with the fragile X mental retardation 1 (FMR1) premutation.
Methods:
Eight asymptomatic premutation carriers, 5 participants with fragile X tremor/ataxia syndrome (FXTAS), and 7 noncarrier controls were studied. The mean age of the asymptomatic premutation carriers, participants with FXTAS, and noncarrier controls was 60, 71, and 67 years, respectively. Magnetic resonance spectroscopy (MRS) and diffusion tensor imaging (DTI) were used to examine the middle cerebellar peduncles (MCP) and the genu and splenium of the corpus callosum in relation to executive function and processing speed. MRS measures were N-acetyl aspartate/creatine (NAA/Cr) and choline/creatine, and fractional anisotropy (FA) was used for DTI. Executive function was assessed with the Behavioral Dyscontrol Scale and the Controlled Oral Word Association Test (COWAT), and processing speed with the Symbol Digit Modalities Test.
Results:
Among all 13 FMR1 premutation carriers, significant correlations were found between N-acetyl aspartate/creatine and choline/creatine in the MCP and COWAT scores, and between FA in the genu and performance on the Behavioral Dyscontrol Scale, COWAT, and Symbol Digit Modalities Test; a correlation was also found between FA in the splenium and COWAT performance. In all regions studied, participants with FXTAS had the lowest mean FA.
Conclusion:
Microstructural white matter disease as determined by MRS and DTI correlated with executive dysfunction and slowed processing speed in these FMR1 premutation carriers. Neuroimaging abnormalities in the genu and MCP suggest that disruption of white matter within frontocerebellar networks has an important role in the cognitive impairment associated with the FMR1 premutation.
doi:10.1212/WNL.0000000000001612
PMCID: PMC4451047  PMID: 25925982
14.  Introducing BASE: the Biomes of Australian Soil Environments soil microbial diversity database 
GigaScience  2016;5:21.
Background
Microbial inhabitants of soils are important to ecosystem and planetary functions, yet there are large gaps in our knowledge of their diversity and ecology. The ‘Biomes of Australian Soil Environments’ (BASE) project has generated a database of microbial diversity with associated metadata across extensive environmental gradients at continental scale. As the characterisation of microbes rapidly expands, the BASE database provides an evolving platform for interrogating and integrating microbial diversity and function.
Findings
BASE currently provides amplicon sequences and associated contextual data for over 900 sites encompassing all Australian states and territories, a wide variety of bioregions, vegetation and land-use types. Amplicons target bacteria, archaea and general and fungal-specific eukaryotes. The growing database will soon include metagenomics data. Data are provided in both raw sequence (FASTQ) and analysed OTU table formats and are accessed via the project’s data portal, which provides a user-friendly search tool to quickly identify samples of interest. Processed data can be visually interrogated and intersected with other Australian diversity and environmental data using tools developed by the ‘Atlas of Living Australia’.
Conclusions
Developed within an open data framework, the BASE project is the first Australian soil microbial diversity database. The database will grow and link to other global efforts to explore microbial, plant, animal, and marine biodiversity. Its design and open access nature ensures that BASE will evolve as a valuable tool for documenting an often overlooked component of biodiversity and the many microbe-driven processes that are essential to sustain soil function and ecosystem services.
doi:10.1186/s13742-016-0126-5
PMCID: PMC4870752  PMID: 27195106
Microbiology; Microbial ecology; Soil biology; Australia; Database; Microbial diversity; Metagenomics
15.  Plasma and cerebrospinal fluid biomarkers predict cerebral injury in HIV-infected individuals on stable combination antiretroviral therapy 
Objectives
HIV-associated brain injury persists despite antiretroviral therapy (cART), but contributing factors remain poorly understood. We postulated that inflammation-associated biomarkers will be associated with cerebral injury on proton magnetic resonance spectroscopy (MRS) in chronically HIV-infected subjects.
Methods
Five biomarkers were measured in 197 HIV-infected subjects: soluble CD14, MCP-1, IP-10, MIP-1β, and fractalkine. Levels of N-acetyl aspartate (NAA), Choline (Cho), Myoinositol (MI), Glutamate+Glutamine (Glx), and Creatine (Cr) were acquired in the midfrontal cortex (MFC), frontal white matter (FWM), and basal ganglia (BG). Predictive models were built via linear regression and the best models were chosen using the Akaike Information Criterion.
Results
Increases in plasma or CSF MCP-1 were associated with lower NAA/Cr in the MFC and BG while metabolite changes in the FWM for NAA/Cr, GlxCr and Cho/Cr were explained almost exclusively by a single factor, sCD14. Plasma and CSF levels of this factor were also significantly associated with Glx/Cr in MFC and BG. Higher CSF FKN was associated with higher NAA/Cr in BG. Best predictors for higher Cho/Cr in BG and MFC were CSF sCD14 and CSF MIP-1β. Plasma and CSF IP-10 were only associated with Cho/Cr in MFC. Of the three models that simultaneously accounted for both plasma and CSF, there were more associations between CSF biomarkers and MRS metabolites.
Conclusions
Markers of inflammation and immune activation, in particular MCP-1 and sCD14, predominantly reflecting CNS sources, contribute to the persistence of brain injury in a metabolite and region dependent manner in chronically HIV-infected patients on stable cART.
doi:10.1097/QAI.0000000000000532
PMCID: PMC4424074  PMID: 25622053
HIV; AIDS; HIV-associated neurocognitive disorder; cerebrospinal fluid
16.  Improving performance in the detection and management of cystic fibrosis-related diabetes in the Mountain West Cystic Fibrosis Consortium 
Objective
Cystic fibrosis (CF)-related diabetes (CFRD) is associated with increased morbidity and mortality. Improved detection and management may improve outcomes; however, actual practice falls short of published guidelines. We studied efforts to improve CFRD screening and management in the Mountain West CF Consortium (MWCFC).
Research design and methods
This is a prospective observational cohort study evaluating quality improvement by accredited CF centers in Arizona, Colorado, New Mexico, and Utah performed between 2002 and 2008. After Institutional Review Board (IRB) approval, centers evaluated adherence with CF Foundation guidelines for CFRD. Each center developed and implemented quality improvement plans to improve both screening and management. Centers were reassessed 1 year later.
Results
Initially, each CF center had low adherence with screening recommendations (26.5% of eligible patients) that did not improve during the study. However, patients with confirmed CFRD markedly increased (141 (12% of MWCFC patients) to 224 (17%), p<0.001), and with improved adherence to management guidelines, patients with CFRD had increased weight (56.8–58.9 kg, p<0.001), body mass index (21.1–21.4, p=0.003), and weight-for-age z-score (−1.42 to –0.84, p<0.001). Quality improvement methods were specific to the practice settings of each center but shared the common goal of adhering to CFRD care guidelines. 1 year after implementation, no center significantly differed from any other in level of adherence to guidelines.
Conclusions
Improving adherence with CFRD care guidelines requires substantial effort and may be incompletely successful, particularly for CFRD screening, but the effort may significantly improve patient monitoring and clinically relevant outcomes such as weight.
doi:10.1136/bmjdrc-2015-000183
PMCID: PMC4853804  PMID: 27158517
Cystic Fibrosis; Guideline Adherence; Quality Improvement; Weight
17.  A sting in the spit: widespread cross‐infection of multiple RNA viruses across wild and managed bees 
The Journal of Animal Ecology  2015;84(3):615-624.
Summary
Declining populations of bee pollinators are a cause of concern, with major repercussions for biodiversity loss and food security. RNA viruses associated with honeybees represent a potential threat to other insect pollinators, but the extent of this threat is poorly understood.This study aims to attain a detailed understanding of the current and ongoing risk of emerging infectious disease (EID) transmission between managed and wild pollinator species across a wide range of RNA viruses.Within a structured large‐scale national survey across 26 independent sites, we quantify the prevalence and pathogen loads of multiple RNA viruses in co‐occurring managed honeybee (Apis mellifera) and wild bumblebee (Bombus spp.) populations. We then construct models that compare virus prevalence between wild and managed pollinators.Multiple RNA viruses associated with honeybees are widespread in sympatric wild bumblebee populations. Virus prevalence in honeybees is a significant predictor of virus prevalence in bumblebees, but we remain cautious in speculating over the principle direction of pathogen transmission. We demonstrate species‐specific differences in prevalence, indicating significant variation in disease susceptibility or tolerance. Pathogen loads within individual bumblebees may be high and in the case of at least one RNA virus, prevalence is higher in wild bumblebees than in managed honeybee populations.Our findings indicate widespread transmission of RNA viruses between managed and wild bee pollinators, pointing to an interconnected network of potential disease pressures within and among pollinator species. In the context of the biodiversity crisis, our study emphasizes the importance of targeting a wide range of pathogens and defining host associations when considering potential drivers of population decline.
doi:10.1111/1365-2656.12345
PMCID: PMC4832299  PMID: 25646973
Apis; Bombus; decline; pathogen; spillover
18.  Patients’ Views on Identifiability of Samples and Informed Consent for Genetic Research 
It is unclear whether the regulatory distinction between non-identifiable and identifiable information — information used to determine informed consent practices for the use of clinically derived samples for genetic research — is meaningful to patients. The objective of this study was to examine patients’ attitudes and preferences regarding use of anonymous and identifiable clinical samples for genetic research. Telephone interviews were conducted with 1,193 patients recruited from general medicine, thoracic surgery, or medical oncology clinics at five United States academic medical centers. Wanting to know about research being done was important to 72% of patients when samples would be anonymous and to 81% of patients when samples would be identifiable. Only 17% wanted to know about the identifiable scenario but not the anonymous scenario (i.e., following the regulatory distinction). Curiosity-based reasons were the most common (37%) among patients who wanted to know about anonymous samples. Of patients wanting to know about either scenario, approximately 57% would require researchers to seek permission, whereas 43% would be satisfied with notification only. Patients were more likely to support permission (versus notification) in the anonymous scenario if they had more education, were Black, less religious, in better health, more private, and less trusting of researchers. The sample, although not representative of the general population, does represent patients at academic medical centers whose clinical samples may be used for genetic research. Few patients expressed preferences consistent with the regulatory distinction between non-identifiable and identifiable information. Data from this study should cause policy-makers to question whether this distinction is useful in relation to research with previously collected clinically derived samples.
doi:10.1080/15265160802478404
PMCID: PMC4819322  PMID: 19003716
genetic research; identifiable information; informed consent; non-identifiable information; stored samples
19.  Islet amyloid induced cell death and bilayer integrity loss share a molecular origin targetable with oligopyridylamide-based α-helical mimetics 
Chemistry & biology  2015;22(3):369-378.
SUMMARY
Islet amyloid polypeptide (IAPP) is a hormone cosecreted with insulin. IAPP proceeds through a series of conformational changes from random coil to β-sheet via transient α-helical intermediates. An unknown subset of these events are associated with seemingly disparate gains-of-function including catalysis of self-assembly, membrane penetration, loss of membrane integrity, mitochondrial localization and finally cytotoxicity, a central component of diabetic pathology. A series of small molecule, α-helical mimetics, oligopyridylamides, was previously shown to target the membrane bound α-helical oligomeric intermediates of IAPP. In this study, we develop an improved, microwave assisted synthesis of oligopyridylamides. A series of designed tripyridylamides demonstrate that lipid-catalyzed self-assembly of IAPP can be deliberately targeted. These molecules additionally affect IAPP induced leakage of synthetic liposomes and cellular toxicity in insulin secreting cells. The tripyridylamides inhibit these processes with identical rank orders of effectiveness. This indicates a common molecular basis for the disparate set of observed effects of IAPP.
doi:10.1016/j.chembiol.2015.01.006
PMCID: PMC4384466  PMID: 25754474
Amylin; amyloidogenesis; membrane protein; synthetic helical mimetics; membrane permeabilization; INS-1 cell toxicity
20.  Over promised, over-sold and underperforming? – e-health in mental health 
doi:10.3109/09638237.2015.1124406
PMCID: PMC4776695  PMID: 26732733
21.  Delayed Skeletal Muscle Mitochondrial ADP Recovery in Youth With Type 1 Diabetes Relates to Muscle Insulin Resistance 
Diabetes  2014;64(2):383-392.
Insulin resistance (IR) increases cardiovascular morbidity and is associated with mitochondrial dysfunction. IR is now recognized to be present in type 1 diabetes; however, its relationship with mitochondrial function is unknown. We determined the relationship between IR and muscle mitochondrial function in type 1 diabetes using the hyperinsulinemic-euglycemic clamp and 31P-MRS before, during, and after near-maximal isometric calf exercise. Volunteers included 21 nonobese adolescents with type 1 diabetes and 17 nondiabetic control subjects with similar age, sex, BMI, Tanner stage, and activity levels. We found that youths with type 1 diabetes were more insulin resistant (median glucose infusion rate 10.1 vs. 18.9 mg/kglean/min; P < 0.0001) and had a longer time constant of the curve of ADP conversion to ATP (23.4 ± 5.3 vs. 18.8 ± 3.9 s, P < 0.001) and a lower rate of oxidative phosphorylation (median 0.09 vs. 0.21 mmol/L/s, P < 0.001). The ADP time constant (β = −0.36, P = 0.026) and oxidative phosphorylation (β = 0.02, P < 0.038) were related to IR but not HbA1c. Normal-weight youths with type 1 diabetes demonstrated slowed postexercise ATP resynthesis and were more insulin resistant than control subjects. The correlation between skeletal muscle mitochondrial dysfunction in type 1 diabetes and IR suggests a relationship between mitochondrial dysfunction and IR in type 1 diabetes.
doi:10.2337/db14-0765
PMCID: PMC4303961  PMID: 25157095
23.  Simulation of the Progression of Intervertebral Disc Degeneration due to Decreased Nutrition Supply 
Spine  2014;39(24):E1411-E1417.
Study Design
Simulate the progression of human disc degeneration.
Objective
The objective of this study was to quantitatively analyze and simulate the changes in cell density, nutrition level, proteoglycan content, water content, and volume change during human disc degeneration using a numerical method.
Summary of Background Data
Understanding the etiology and progression of intervertebral disc (IVD) degeneration is crucial for developing effective treatment strategies for IVD-degeneration related diseases. During tissue degeneration, the disc undergoes losses of cell viability and activities, changes in extracellular matrix composition and structure, and compromise of the tissue-level integrity and function, which is significantly influenced by the inter-coupled biological, chemical, electrical, and mechanical signals in the disc. Characterizing these signals in human discs in vivo is difficult.
Methods
A realistic 3D finite element model of the human IVD was developed based on biomechano-electrochemical continuum mixture theory. The theoretical framework and the constitutive relationships were all biophysics based. All the material properties were obtained from experimental results. The cell-mediated disc degeneration process caused by lowered nutrition levels at disc boundaries was simulated and validated by comparing with experimental results.
Results
Cell density reached equilibrium state in 30 days after reduced nutrition supply at the disc boundary, while the proteoglycan (PG) and water contents reached a new equilibrium state in 55 years. The simulated results for the distributions of PG and water contents within the disc were consistent with the results measured in the literature, except for the distribution of PG content in the sagittal direction.
Conclusions
Poor nutrition supply has a long-term effect on disc degeneration.
doi:10.1097/BRS.0000000000000560
PMCID: PMC4229452  PMID: 25188596
Biomechanics; Mechanobiology; Continuum mixture theory; Finite element method; modeling; Biophysics
24.  Behavioural evidence for self-medication in bumblebees? 
F1000Research  2015;4:73.
The presence of antimicrobial secondary metabolites in nectar suggests that pollinators, which are threatened globally by emergent disease, may benefit from the consumption of nectars rich in these metabolites. We tested whether nicotine, a nectar secondary metabolite common in Solanaceae and Tilia species, is used by parasitized bumblebees as a source of self-medication , using a series of toxicological, microbiological and behavioural experiments. Caged bees infected with Crithidia bombi had a slight preference for sucrose solution laced with the alkaloid and behavioural tests showed that the parasite infection induced an increased consumption of nicotine during foraging activity, though nicotine had an appetite-reducing effect overall. When ingested, nicotine delayed the progression of a gut infection in bumblebees by a few days, but dietary nicotine did not clear the infection, and after 10 days the parasite load approached that of control bees. Moreover, when pathogens were exposed to the alkaloid prior to host ingestion, the protozoan’s viability was not directly affected, suggesting that anti-parasite effects were relatively weak. Nicotine consumption in a single dose did not impose any cost even in starved bees but the alkaloid had detrimental effects on healthy bees if consistently consumed for weeks. These toxic effects disappeared in infected bees, suggesting that detoxification costs might have been counterbalanced by the advantages in slowing the progression of the infection. Nicotine consumption did not affect bee lifespan but the reduction in the parasite load may have other likely unexplored subtle benefits both for individual bees and their colony.  Potential evidence for self-medication is discussed. The contention that secondary metabolites in nectar may be under selection from pollinators, or used by plants to enhance their own reproductive success, remains to be confirmed.
doi:10.12688/f1000research.6262.2
PMCID: PMC4406194  PMID: 25949807
Bombus terrestris; Crithidia bombi; foraging; nicotine; pathogens; pollinators; pollinator-plant interactions; secondary metabolites
25.  Method for Controlled Mitochondrial Perturbation during Phosphorus MRS in Children 
Introduction
Insulin resistance (IR) is increasingly prevalent in children, and may be related to muscle mitochondrial dysfunction, necessitating development of mitochondrial assessment techniques. Recent studies used 31Phosphorus magnetic resonance spectroscopy (31P-MRS), a non-invasive technique appealing for clinical research. 31P-MRS requires exercise at a precise percentage of maximum volitional contraction (MVC). MVC measurement in children, particularly with disease, is problematic due to variability in perception of effort and motivation. We therefore developed a method to predict MVC, using maximal calf muscle cross-sectional area (MCSA) to assure controlled and reproducible muscle metabolic perturbations.
Methods
Data were collected from 66 sedentary 12–20 year-olds. Plantar flexion-volitional MVC was assessed using a MRI-compatible exercise treadle device. MCSA of the calf muscles were measured from MRI images. Data from the first 26 participants were utilized to model the relationship between MVC and MCSA (predicted MVC = 24.763+0.0047*MCSA). This model was then applied to the subsequent 40 participants.
Results
Volitional vs. model-predicted mean MVC was 43.9±0.8 kg vs. 44.2±1.81 (P=0.90). 31P-MRS results when predicted and volitional MVC were similar showed expected changes during volitional MVC-based exercise. In contrast, volitional MVC was markedly lower than predicted in 4 participants, and produced minimal metabolic perturbation. Upon repeat testing, these individuals could perform their predicted MVC with coaching, which produced expected metabolic perturbations.
Conclusions
Compared to using MVC testing alone, utilizing MRI to predict muscle strength allows for a more accurate and standardized 31P-MRS protocol during exercise in children. This method overcomes a major obstacle in assessing mitochondrial function in youth. These studies have importance as we seek to determine the role of mitochondrial function in youth with IR and diabetes and response to interventions.
doi:10.1249/MSS.0000000000000316
PMCID: PMC4145039  PMID: 24576856
31 P-MRS; muscle mitochondria; children; exercise perception

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