Pneumococcal within-host diversity during colonization, transmission and treatment

Characterizing the genetic diversity of pathogens within the host promises to greatly improve surveillance and reconstruction of transmission chains. For bacteria, it also informs our understanding of inter-strain competition and how this shapes the distribution of resistant and sensitive bacteria. Here we study the genetic diversity of Streptococcus pneumoniae within 468 infants and 145 of their mothers by deep sequencing whole pneumococcal populations from 3,761 longitudinal nasopharyngeal samples. We demonstrate that deep sequencing has unsurpassed sensitivity for detecting multiple colonization, doubling the rate at which highly invasive serotype 1 bacteria were detected in carriage compared with gold-standard methods. The greater resolution identified an elevated rate of transmission from mothers to their children in the first year of the child's life. Comprehensive treatment data demonstrated that infants were at an elevated risk of both the acquisition and persistent colonization of a multidrug-resistant bacterium following antimicrobial treatment. Some alleles were enriched after antimicrobial treatment, suggesting that they aided persistence, but generally purifying selection dominated within-host evolution. Rates of co-colonization imply that in the absence of treatment, susceptible lineages outcompeted resistant lineages within the host. These results demonstrate the many benefits of deep sequencing for the genomic surveillance of bacterial pathogens. Longitudinal population deep sequencing of Streptococcus pneumoniae sampled from infants and their mothers improves our understanding of the dynamics of colonization, transmission, inter-strain competition and the impact of antibiotic treatment.Peer reviewe

A systematic map of studies testing the relationship between temperature and animal reproduction

Funding: This work was funded by the European Society for Evolution (which funds a Special Topic Network on Evolutionary Ecology of Thermal Fertility Limits to CF, AB, RRS and TARP), the Natural Environment Research Council (NE/P002692/1 to TARP, AB and RRS, NE/X011550/1 to LRD and TARP), the Biotechnology and \Biological Sciences Research Council (BB/W016753/1 to AB, TARP and RRS) and a Heisenberg fellowship from the German Research Foundation (FR 2973/11-1 to CF).1. Exposure to extreme temperatures can negatively affect animal reproduction, by disrupting the ability of individuals to produce any offspring (fertility), or the number of offspring produced by fertile individuals (fecundity). This has important ecological consequences, because reproduction is the ultimate measure of population fitness: a reduction in reproductive output lowers the population growth rate and increases the extinction risk. Despite this importance, there have been no large‐scale summaries of the evidence for effect of temperature on reproduction. 2. We provide a systematic map of studies testing the relationship between temperature and animal reproduction. We systematically searched for published studies that statistically test for a direct link between temperature and animal reproduction, in terms of fertility, fecundity or indirect measures of reproductive potential (gamete and gonad traits). 3. Overall, we collated a large and rich evidence base, with 1654 papers that met our inclusion criteria, encompassing 1191 species. 4. The map revealed several important research gaps. Insects made up almost half of the dataset, but reptiles and amphibians were uncommon, as were non‐arthropod invertebrates. Fecundity was the most common reproductive trait examined, and relatively few studies measured fertility. It was uncommon for experimental studies to test exposure of different life stages, exposure to short‐term heat or cold shock, exposure to temperature fluctuations, or to independently assess male and female effects. Studies were most often published in journals focusing on entomology and pest control, ecology and evolution, aquaculture and fisheries science, and marine biology. Finally, while individuals were sampled from every continent, there was a strong sampling bias towards mid‐latitudes in the Northern Hemisphere, such that the tropics and polar regions are less well sampled. 5. This map reveals a rich literature of studies testing the relationship between temperature and animal reproduction, but also uncovers substantial missing treatment of taxa, traits, and thermal regimes. This database will provide a valuable resource for future quantitative meta‐analyses, and direct future studies aiming to fill identified gaps.Publisher PDFPeer reviewe

Intellectual enrichment and genetic modifiers of cognition and brain volume in Huntington's disease

An important step towards the development of treatments for cognitive impairment in ageing and neurodegenerative diseases is to identify genetic and environmental modifiers of cognitive function and understand the mechanism by which they exert an effect. In Huntington’s disease, the most common autosomal dominant dementia, a small number of studies have identified intellectual enrichment, i.e. a cognitively stimulating lifestyle and genetic polymorphisms as potential modifiers of cognitive function. The aim of our study was to further investigate the relationship and interaction between genetic factors and intellectual enrichment on cognitive function and brain atrophy in Huntington’s disease. For this purpose, we analysed data from Track-HD, a multi-centre longitudinal study in Huntington’s disease gene carriers and focused on the role of intellectual enrichment (estimated at baseline) and the genes FAN1, MSH3, BDNF, COMT and MAPT in predicting cognitive decline and brain atrophy. We found that carrying the 3a allele in the MSH3 gene had a positive effect on global cognitive function and brain atrophy in multiple cortical regions, such that 3a allele carriers had a slower rate of cognitive decline and atrophy compared with non-carriers, in agreement with its role in somatic instability. No other genetic predictor had a significant effect on cognitive function and the effect of MSH3 was independent of intellectual enrichment. Intellectual enrichment also had a positive effect on cognitive function; participants with higher intellectual enrichment, i.e. those who were better educated, had higher verbal intelligence and performed an occupation that was intellectually engaging, had better cognitive function overall, in agreement with previous studies in Huntington’s disease and other dementias. We also found that intellectual enrichment interacted with the BDNF gene, such that the positive effect of intellectual enrichment was greater in Met66 allele carriers than non-carriers. A similar relationship was also identified for changes in whole brain and caudate volume; the positive effect of intellectual enrichment was greater for Met66 allele carriers, rather than for non-carriers. In summary, our study provides additional evidence for the beneficial role of intellectual enrichment and carrying the 3a allele in MSH3 in cognitive function in Huntington’s disease and their effect on brain structure

Crop Updates 2002 - Farming Systems

This session covers forty one papers from different authors: INTRODUCTION 1. Future Farming Systems session for Crop Updates 2002 Peter Metcalf, FARMING SYSTEMS SUBPROGRAM MANAGER GRAINS PROGRAM Department of Agriculture 2. Perennial pastures in annual cropping systems: Lucerne and beyond, the ‘Big Picture’, Mike Ewing, Deputy CEO CRC for Plant-based Management of Dryland Salinity, Department of Agriculture 3. Perennial pastures in annual cropping systems: lucerne and beyond, Roy Latta and Keith Devenish, Department of Agriculture 4. Establishing Lucerne with a cover crop, Diana Fedorenko1, Clayton Butterly1, Chantelle Butterly1, Kim and Neil Diamond2, Stuart McAlpine2, Bill Bowden1, Jessica Johns3, 1Centre for Cropping Systems, Northam, 2Farmer, Buntine, 3Department of Agriculture 5. Overcropping: Chemical suppression of Lucerne, Terry Piper1, Diana Fedorenko1, Clayton Butterly1, Chantelle Butterly1, Stuart McAlpine2, Jessica Johns3, 1Centre for Cropping Systems, Northam, 2Farmer, Buntine, 3Department of Agriculture 6. Overcropping: Effect of Lucerne density on crop yield, Diana Fedorenko1, Bill Bowden1, Clayton Butterly1, Chantelle Butterly1, Stuart McAlpine2, Terry Piper1,1Centre for Cropping Systems, Department of Agriculture, Northam, 2Farmer, Buntine 7. Residual effect of weed management in the third year of Lucerne on the following wheat crop, Diana Fedorenko1, Clayton Butterly1, Chantelle Butterly1, Stuart McAlpine2,Terry Piper1, David Bowran1, Jessica Johns3,1Centre for Cropping Systems, Northam, 2Farmer, Buntine, 3Department of Agriculture 8. Production of Lucerne and serradella in four soil types, Diana Fedorenko1 Clayton Butterly1, Chantelle Butterly1, Robert Beard2 1Centre for Cropping Systems, Department of Agriculture, 2Farmer, Cunderdin 9. The effect of spray topping on newly established Lucerne, Keith Devenish, Agriculture Western Australia 10. Leakage from phase rotations involving Lucerne, Phil Ward, CSIRO Plant Industry 11. Fungal diseases present in Western Australian Lucerne crops, Dominie Wright and Nichole Burges, Department of Agriculture 12. Survey of Western Australian Lucerne stands reveals widespread virus infection, Roger Jones and Danae Harman, Crop Improvement Institute, Department of Agriculture, and Centre for Legumes in Mediterranean Agriculture, University of WA ANNUAL PASTURE SYSTEMS 13. The use of Twist Fungus as a biosecurity measure against Annual Ryegrass Toxicity (ARGT), Greg Shea, GrainGuard Coordinator and George Yan, Biological and Resource Technology 14.Limitations and opportunities for increasing water use by annual crops and pastures, David Tennant1, Phil Ward2and David Hall1 1Department of Agriculture, 2CSIRO, Plant Industries, Floreat Park 15. Developing pasture species mixtures for more productive and sustainable cropping systems – 2001 crop performance, Anyou Liu, Clinton Revell and Candy Hudson, Centre for Cropping Systems, Department of Agriculture 16. Developing pasture species mixtures for more productive and sustainable cropping systems – weed management in regenerating mixtures, Anyou Liu and Clinton Revell, Centre for Cropping Systems, Department of Agriculture 17. Aphid tolerance of annual pasture legumes, Andrew Blake, Natalie Lauritsen, Department of Agriculture 18. Selecting the right variety for phase pasture systems, Keith Devenish, Department of Agriculture 19. Responses of alternative annual pasture and forage legumes to challenge with infectious subterranean clover mottle virus, John Fosu-Nyarko, Roger Jones, Lisa Smith, Mike Jones and Geoff Dwyer, State Agricultural Biotechnology Centre and Centre for Bioinformatics and Biological Computing, Murdoch University, Department of Agriculture, and Centre for Legumes in Mediterranean Agriculture SOIL AND LAND MANAGEMENT 20. Nutrition in 2002: Decisions to be made as a result of last season, Bill Bowden,Western Australia Department of Agriculture 21. Profitability of deep banding lime, Michael O\u27Connell, Chris Gazey and David Gartner, Department of Agriculture 22. Lime efficiency percentage…the new measure of lime effectiveness for Western Australia, Amanda Miller, Department of Agriculture 23. Boron – should we be worried about it, Richard W. BellA, K. FrostA, Mike WongBand Ross BrennanC ASchool of Environmental Science, Murdoch University, BCSIRO Land and Water, CDepartment of Agriculture 24. Impact of claying and other amelioration on paddock profit, N.J. Blake1, G. McConnell2, D. Patabendige1and N. Venn11Department of Agriculture, 2PlanFarm P/L 25. Raised bed farming in the 2001 growing season, Derk Bakker, Greg Hamilton, Dave Houlbrooke and Cliff Spann, Department of Agriculture 26. Economics of tramline farming systems, Paul Blackwell and Bindi Webb, Department of Agriculture, Stuart McAlpine, Liebe Group. 27. Relay planting from Tramlines to increase water use and productivity os summer crops, Dr Paul Blackwell, Department of Agriculture, Neil and Kim Diamond, Buntine. Liebe Group 28.Evidence-based zone management of paddock variability to improve profits and environmental outcomes, M.T.F. WongA, D. PatabendigeB, G. LyleA and K. WittwerA ACSIRO Land and Water, BDepartment of Agriculture 29. How much soil water is lost over summer in sandy soils? Perry Dolling1, Senthold Asseng2, Ian Fillery2, Phil Ward2and Michael Robertson3 1University of Western Australia/Department of Agriculture Western Australia/CSIRO, 2CSIRO Plant Industry 3CSIRO Sustainable Ecosystems, Indooroopilly, Queensland FARMER DECISION SUPPORT AND ADOPTION 30. Economic comparisons of farming systems for the medium rainfall northern sandplain, No 1, Caroline Peek and David Rogers, Department of Agriculture 31. Sensitivity analysis of farming systems for the medium rainfall northern sandplain No 2, Caroline Peek and David Rogers, Department of Agriculture 32. Transition analysis of farming systems in the medium rainfall northern sandplain. No 3, Caroline Peek and David Rogers, Department of Agriculture 33. Implementing on-farm quality assurance, Peter Portmann, Manager Research and Development, The Grain Pool of Western Australia 34. On-farm research – principles of the ‘Test As You Grow’ kit, Jeff Russell, Department of Agriculture 35. Broadscale wheat variety comparisons featuring Wyalkatchem, Jeff Russell, Department of Agriculture 36. GrainGuardÔ - A biosecurity plan for the Canola Industry,Greg Shea Department of Agriculture 37. Are Western Australian broadacre farms efficient? Ben Henderson, University of Western Australia, Ross Kingwell, Department of Agriculture and University of Western Australia DISEASE MODELLING WORKSHOP 38. WORKSHOP: Pest and disease forecasts for you! An interactive forum, Tresslyn Walmsley, Jean Galloway, Debbie Thackray, Moin Salam and Art Diggle, Centre for Legumes in Mediterranean Agriculture and Department of Agriculture 39. Blackspot spread: Disease models are based in reality (Workshop paper 1), JeanGalloway,Department of Agriculture 40. Blackspot spread: Scaling-up field data to simulate ‘Baker’s farm’ (Workshop paper 2), Moin U. Salam, Jean Galloway, Art J. Diggle and William J. MacLeod, Department of Agriculture, Western Australia 41. A decision support system for control of aphids and CMV in lupin crops (Workshop paper 3), Debbie Thackray, Jenny Hawkes and Roger Jones, Centre for Legumes in Mediterranean Agriculture and Department of Agricultur

Copy number variants as modifiers of breast cancer risk for BRCA1/BRCA2 pathogenic variant carriers

The risk of germline copy number variants (CNVs) in BRCA1 and BRCA2 pathogenic variant carriers in breast cancer is assessed, with CNVs overlapping SULT1A1 decreasing breast cancer risk in BRCA1 carriers.The contribution of germline copy number variants (CNVs) to risk of developing cancer in individuals with pathogenic BRCA1 or BRCA2 variants remains relatively unknown. We conducted the largest genome-wide analysis of CNVs in 15,342 BRCA1 and 10,740 BRCA2 pathogenic variant carriers. We used these results to prioritise a candidate breast cancer risk-modifier gene for laboratory analysis and biological validation. Notably, the HR for deletions in BRCA1 suggested an elevated breast cancer risk estimate (hazard ratio (HR) = 1.21), 95% confidence interval (95% CI = 1.09-1.35) compared with non-CNV pathogenic variants. In contrast, deletions overlapping SULT1A1 suggested a decreased breast cancer risk (HR = 0.73, 95% CI 0.59-0.91) in BRCA1 pathogenic variant carriers. Functional analyses of SULT1A1 showed that reduced mRNA expression in pathogenic BRCA1 variant cells was associated with reduced cellular proliferation and reduced DNA damage after treatment with DNA damaging agents. These data provide evidence that deleterious variants in BRCA1 plus SULT1A1 deletions contribute to variable breast cancer risk in BRCA1 carriers.Peer reviewe

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

Evaluating the Effects of SARS-CoV-2 Spike Mutation D614G on Transmissibility and Pathogenicity.

Global dispersal and increasing frequency of the SARS-CoV-2 spike protein variant D614G are suggestive of a selective advantage but may also be due to a random founder effect. We investigate the hypothesis for positive selection of spike D614G in the United Kingdom using more than 25,000 whole genome SARS-CoV-2 sequences. Despite the availability of a large dataset, well represented by both spike 614 variants, not all approaches showed a conclusive signal of positive selection. Population genetic analysis indicates that 614G increases in frequency relative to 614D in a manner consistent with a selective advantage. We do not find any indication that patients infected with the spike 614G variant have higher COVID-19 mortality or clinical severity, but 614G is associated with higher viral load and younger age of patients. Significant differences in growth and size of 614G phylogenetic clusters indicate a need for continued study of this variant

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Cortisol, cognition and the ageing prefrontal cortex

The structural and functional decline of the ageing human brain varies by brain region, cognitive function and individual. The underlying biological mechanisms are poorly understood. One potentially important mechanism is exposure to glucocorticoids (GCs; cortisol in humans); GC production is increasingly varied with age in humans, and chronic exposure to high levels is hypothesised to result in cognitive decline via cerebral remodelling. However, studies of GC exposure in humans are scarce and methodological differences confound cross-study comparison. Furthermore, there has been little focus on the effects of GCs on the frontal lobes and key white matter tracts in the ageing brain. This thesis therefore examines relationships among cortisol levels, structural brain measures and cognitive performance in 90 healthy, elderly community-dwelling males from the Lothian Birth Cohort 1936. Salivary cortisol samples characterised diurnal (morning and evening) and reactive profiles (before and after a cognitive test battery). Structural variables comprised Diffusion Tensor Imaging measures of major brain tracts and a novel manual parcellation method for the frontal lobes. The latter was based on a systematic review of current manual methods in the context of putative function and cytoarchitecture. Manual frontal lobe brain parcellation conferred greater spatial and volumetric accuracy when compared to both single- and multi-atlas parcellation at the lobar level. Cognitive ability was assessed via tests of general cognitive ability, and neuropsychological tests thought to show differential sensitivity to the integrity of frontal lobe sub-regions. The majority of, but not all frontal lobe test scores shared considerable overlap with general cognitive ability, and cognitive scores correlated most consistently with the volumes of the anterior cingulate. This is discussed in light of the diverse connective profile of the cingulate and a need to integrate information over more diffuse cognitive networks according to proposed de-differentiation or compensation in ageing. Individuals with higher morning, evening or pre-test cortisol levels showed consistently negative relationships with specific regional volumes and tract integrity. Participants whose cortisol levels increased between the start and end of cognitive testing showed selectively larger regional volumes and lower tract diffusivity (correlation magnitudes <.44). The significant relationships between cortisol levels and cognition indicated that flatter diurnal slopes or higher pre-test levels related to poorer test performance. In contrast, higher levels in the morning generally correlated with better scores (correlation magnitudes <.25). Interpretation of all findings was moderated by sensitivity to type I error, given the large number of comparisons conducted. Though there were limited candidates for mediation analysis, cortisol-function relationships were partially mediated by tract integrity (but not sub-regional frontal volumes) for memory and post-error slowing. This thesis offers a novel perspective on the complex interplay among glucocorticoids, cognition and the structure of the ageing brain. The findings suggest some role for cortisol exposure in determining age-related decline in complex cognition, mediated via brain structure