Loss of F-box only protein 2 (Fbxo2) disrupts levels and localization of select NMDA receptor subunits, and promotes aberrant synaptic connectivity

NMDA receptors (NMDARs) play an essential role in some forms of synaptic plasticity, learning, and memory. Therefore, these receptors are highly regulated with respect to their localization, activation, and abundance both within and on the surface of mammalian neurons. Fundamental questions remain, however, regarding how this complex regulation is achieved. Using cell-based models and F-box Only Protein 2 (Fbxo2) knock-out mice, we found that the ubiquitin ligase substrate adaptor protein Fbxo2, previously reported to facilitate the degradation of the NMDAR subunit GluN1 in vitro, also functions to regulate GluN1 and GluN2A subunit levels in the adult mouse brain. In contrast, GluN2B subunit levels are not affected by the loss of Fbxo2. The loss of Fbxo2 results in greater surface localization of GluN1 and GluN2A, together with increases in the synaptic markers PSD-95 and Vglut1. These synaptic changes do not manifest as neurophysiological differences or alterations in dendritic spine density in Fbxo2 knock-out mice, but result instead in increased axo-dendritic shaft synapses. Together, these findings suggest that Fbxo2 controls the abundance and localization of specific NMDAR subunits in the brain and may influence synapse formation and maintenance

Detection of SARS‐CoV‐2 in respiratory samples from cats in the UK associated with human‐to‐cat transmission

Objectives: The aim of the study was to find evidence of SARS‐CoV‐2 infection in UK cats. Design: Tissue samples were tested for SARS‐CoV‐2 antigen using immunofluorescence and for viral RNA by in situ hybridisation. A set of 387 oropharyngeal swabs that had been submitted for routine respiratory pathogen testing was tested for SARS‐CoV‐2 RNA using reverse transcriptase quantitative PCR. Results: Lung tissue collected post‐mortem from cat 1 tested positive for both SARS‐CoV‐2 nucleocapsid antigen and RNA. SARS‐CoV‐2 RNA was detected in an oropharyngeal swab collected from cat 2 that presented with rhinitis and conjunctivitis. High throughput sequencing of the viral genome revealed five single nucleotide polymorphisms (SNPs) compared to the nearest UK human SARS‐CoV‐2 sequence, and this human virus contained eight SNPs compared to the original Wuhan‐Hu‐1 reference sequence. An analysis of the viral genome of cat 2 together with nine other feline‐derived SARS‐CoV‐2 sequences from around the world revealed no shared cat‐specific mutations. Conclusions: These findings indicate that human‐to‐cat transmission of SARS‐CoV‐2 occurred during the COVID‐19 pandemic in the UK, with the infected cats developing mild or severe respiratory disease. Given the ability of the new coronavirus to infect different species, it will be important to monitor for human‐to‐cat, cat‐to‐cat and cat‐to‐human transmission

Diarrhoeal disease and subsequent risk of death in infants and children residing in low-income and middle-income countries: analysis of the GEMS case-control study and 12-month GEMS-1A follow-on study

Background: The Global Enteric Multicenter Study (GEMS) was a 3-year case-control study that measured the burden, aetiology, and consequences of moderate-to-severe diarrhoea (MSD) in children aged 0–59 months. GEMS-1A, a 12-month follow-on study, comprised two parallel case-control studies, one assessing MSD and the other less-severe diarrhoea (LSD). In this report, we analyse the risk of death with each diarrhoea type and the specific pathogens associated with fatal outcomes. Methods: GEMS was a prospective, age-stratified, matched case-control study done at seven sites in Africa and Asia. Children aged 0–59 months with MSD seeking care at sentinel health centres were recruited along with one to three randomly selected matched community control children without diarrhoea. In the 12-month GEMS-1A follow-on study, children with LSD and matched controls, in addition to children with MSD and matched controls, were recruited at six of the seven sites; only cases of MSD and controls were enrolled at the seventh site. We compared risk of death during the period between enrolment and one follow-up household visit done about 60 days later (range 50–90 days) in children with MSD and LSD and in their respective controls. Approximately 50 pathogens were detected using, as appropriate, classic bacteriology, immunoassays, gel-based PCR and reverse transcriptase PCR, and quantitative real-time PCR (qPCR). Specimens from a subset of GEMS cases and controls were also tested by a TaqMan Array Card that compartmentalised probe-based qPCR for 32 enteropathogens. Findings: 223 (2·0%) of 11 108 children with MSD and 43 (0·3%) of 16369 matched controls died between study enrolment and the follow-up visit at about 60 days (hazard ratio [HR] 8·16, 95% CI 5·69–11·68, p<0·0001). 12 (0·4%) of 2962 children with LSD and seven (0·2%) of 4074 matched controls died during the follow-up period (HR 2·78, 95% CI 0·95–8·11, p=0·061). Risk of death was lower in children with dysenteric MSD than in children with nondysenteric MSD (HR 0·20, 95% CI 0·05–0·87, p=0·032), and lower in children with LSD than in those with nondysenteric MSD (HR 0·29, 0·14–0·59, p=0·0006). In children younger than 24 months with MSD, infection with typical enteropathogenic Escherichia coli, enterotoxigenic E coli encoding heat-stable toxin, enteroaggregative E coli, Shigella spp (non-dysentery cases), Aeromonas spp, Cryptosporidium spp, and Entamoeba histolytica increased risk of death. Of 61 deaths in children aged 12–59 months with non-dysenteric MSD, 31 occurred among 942 children qPCRpositive for Shigella spp and 30 deaths occurred in 1384 qPCR-negative children (HR 2·2, 95% CI 1·2–3·9, p=0·0090), showing that Shigella was strongly associated with increased risk of death. Interpretation: Risk of death is increased following MSD and, to a lesser extent, LSD. Considering there are approximately three times more cases of LSD than MSD in the population, more deaths are expected among children with LSD than in those with MSD. Because the major attributable LSD-associated and MSD-associated pathogens are the same, implementing vaccines and rapid diagnosis and treatment interventions against these major pathogens are rational investments

The Burden of Cryptosporidium Diarrheal Disease among Children < 24 Months of Age in Moderate/High Mortality Regions of Sub-Saharan Africa and South Asia, Utilizing Data from the Global Enteric Multicenter Study (GEMS).

Background: The importance of Cryptosporidium as a pediatric enteropathogen in developing countries is recognized. Methods: Data from the Global Enteric Multicenter Study (GEMS), a 3-year, 7-site, case-control study of moderate-to-severe diarrhea (MSD) and GEMS-1A (1-year study of MSD and less-severe diarrhea [LSD]) were analyzed. Stools from 12,110 MSD and 3,174 LSD cases among children aged <60 months and from 21,527 randomly-selected controls matched by age, sex and community were immunoassay-tested for Cryptosporidium. Species of a subset of Cryptosporidium-positive specimens were identified by PCR; GP60 sequencing identified anthroponotic C. parvum. Combined annual Cryptosporidium-attributable diarrhea incidences among children aged <24 months for African and Asian GEMS sites were extrapolated to sub-Saharan Africa and South Asian regions to estimate region-wide MSD and LSD burdens. Attributable and excess mortality due to Cryptosporidium diarrhea were estimated. Findings: Cryptosporidium was significantly associated with MSD and LSD below age 24 months. Among Cryptosporidium-positive MSD cases, C. hominis was detected in 77.8% (95% CI, 73.0%-81.9%) and C. parvum in 9.9% (95% CI, 7.1%-13.6%); 92% of C. parvum tested were anthroponotic genotypes. Annual Cryptosporidium-attributable MSD incidence was 3.48 (95% CI, 2.27–4.67) and 3.18 (95% CI, 1.85–4.52) per 100 child-years in African and Asian infants, respectively, and 1.41 (95% CI, 0.73–2.08) and 1.36 (95% CI, 0.66–2.05) per 100 child-years in toddlers. Corresponding Cryptosporidium-attributable LSD incidences per 100 child-years were 2.52 (95% CI, 0.33–5.01) and 4.88 (95% CI, 0.82–8.92) in infants and 4.04 (95% CI, 0.56–7.51) and 4.71 (95% CI, 0.24–9.18) in toddlers. We estimate 2.9 and 4.7 million Cryptosporidium-attributable cases annually in children aged <24 months in the sub-Saharan Africa and India/Pakistan/Bangladesh/Nepal/Afghanistan regions, respectively, and ~202,000 Cryptosporidium-attributable deaths (regions combined). ~59,000 excess deaths occurred among Cryptosporidium-attributable diarrhea cases over expected if cases had been Cryptosporidium-negative. Conclusions: The enormous African/Asian Cryptosporidium disease burden warrants investments to develop vaccines, diagnostics and therapies

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

Cancer Biomarker Discovery: The Entropic Hallmark

Background: It is a commonly accepted belief that cancer cells modify their transcriptional state during the progression of the disease. We propose that the progression of cancer cells towards malignant phenotypes can be efficiently tracked using high-throughput technologies that follow the gradual changes observed in the gene expression profiles by employing Shannon's mathematical theory of communication. Methods based on Information Theory can then quantify the divergence of cancer cells' transcriptional profiles from those of normally appearing cells of the originating tissues. The relevance of the proposed methods can be evaluated using microarray datasets available in the public domain but the method is in principle applicable to other high-throughput methods. Methodology/Principal Findings: Using melanoma and prostate cancer datasets we illustrate how it is possible to employ Shannon Entropy and the Jensen-Shannon divergence to trace the transcriptional changes progression of the disease. We establish how the variations of these two measures correlate with established biomarkers of cancer progression. The Information Theory measures allow us to identify novel biomarkers for both progressive and relatively more sudden transcriptional changes leading to malignant phenotypes. At the same time, the methodology was able to validate a large number of genes and processes that seem to be implicated in the progression of melanoma and prostate cancer. Conclusions/Significance: We thus present a quantitative guiding rule, a new unifying hallmark of cancer: the cancer cell's transcriptome changes lead to measurable observed transitions of Normalized Shannon Entropy values (as measured by high-throughput technologies). At the same time, tumor cells increment their divergence from the normal tissue profile increasing their disorder via creation of states that we might not directly measure. This unifying hallmark allows, via the the Jensen-Shannon divergence, to identify the arrow of time of the processes from the gene expression profiles, and helps to map the phenotypical and molecular hallmarks of specific cancer subtypes. The deep mathematical basis of the approach allows us to suggest that this principle is, hopefully, of general applicability for other diseases

BHPR research: qualitative1. Complex reasoning determines patients' perception of outcome following foot surgery in rheumatoid arhtritis

Background: Foot surgery is common in patients with RA but research into surgical outcomes is limited and conceptually flawed as current outcome measures lack face validity: to date no one has asked patients what is important to them. This study aimed to determine which factors are important to patients when evaluating the success of foot surgery in RA Methods: Semi structured interviews of RA patients who had undergone foot surgery were conducted and transcribed verbatim. Thematic analysis of interviews was conducted to explore issues that were important to patients. Results: 11 RA patients (9 ♂, mean age 59, dis dur = 22yrs, mean of 3 yrs post op) with mixed experiences of foot surgery were interviewed. Patients interpreted outcome in respect to a multitude of factors, frequently positive change in one aspect contrasted with negative opinions about another. Overall, four major themes emerged. Function: Functional ability & participation in valued activities were very important to patients. Walking ability was a key concern but patients interpreted levels of activity in light of other aspects of their disease, reflecting on change in functional ability more than overall level. Positive feelings of improved mobility were often moderated by negative self perception ("I mean, I still walk like a waddling duck”). Appearance: Appearance was important to almost all patients but perhaps the most complex theme of all. Physical appearance, foot shape, and footwear were closely interlinked, yet patients saw these as distinct separate concepts. Patients need to legitimize these feelings was clear and they frequently entered into a defensive repertoire ("it's not cosmetic surgery; it's something that's more important than that, you know?”). Clinician opinion: Surgeons' post operative evaluation of the procedure was very influential. The impact of this appraisal continued to affect patients' lasting impression irrespective of how the outcome compared to their initial goals ("when he'd done it ... he said that hasn't worked as good as he'd wanted to ... but the pain has gone”). Pain: Whilst pain was important to almost all patients, it appeared to be less important than the other themes. Pain was predominately raised when it influenced other themes, such as function; many still felt the need to legitimize their foot pain in order for health professionals to take it seriously ("in the end I went to my GP because it had happened a few times and I went to an orthopaedic surgeon who was quite dismissive of it, it was like what are you complaining about”). Conclusions: Patients interpret the outcome of foot surgery using a multitude of interrelated factors, particularly functional ability, appearance and surgeons' appraisal of the procedure. While pain was often noted, this appeared less important than other factors in the overall outcome of the surgery. Future research into foot surgery should incorporate the complexity of how patients determine their outcome Disclosure statement: All authors have declared no conflicts of interes

On-orbit performance of the MIPS instrument

The Multiband Imaging Photometer for Spitzer (MIPS) provides long wavelength capability for the mission, in imaging bands at 24, 70, and 160 microns and measurements of spectral energy distributions between 52 and 100 microns at a spectral resolution of about 7%. By using true detector arrays in each band, it provides both critical sampling of the Spitzer point spread function and relatively large imaging fields of view, allowing for substantial advances in sensitivity, angular resolution, and efficiency of areal coverage compared with previous space far-infrared capabilities. The Si:As BIB 24 micron array has excellent photometric properties, and measurements with rms relative errors of 1% or better can be obtained. The two longer wavelength arrays use Ge:Ga detectors with poor photometric stability. However, the use of 1.) a scan mirror to modulate the signals rapidly on these arrays, 2.) a system of on-board stimulators used for a relative calibration approximately every two minutes, and 3.) specialized reduction software result in good photometry with these arrays also, with rms relative errors of less than 10%

Characteristics of Salmonella recovered from stools of children enrolled in the Global Enteric Multicenter Study

Background: The Global Enteric Multicenter Study (GEMS) determined the etiologic agents of moderate-To-severe diarrhea (MSD) in children under 5 years old in Africa and Asia. Here, we describe the prevalence and antimicrobial susceptibility of nontyphoidal Salmonella (NTS) serovars in GEMS and examine the phylogenetics of Salmonella Typhimurium ST313 isolates. Methods: Salmonella isolated from children with MSD or diarrhea-free controls were identified by classical clinical microbiology and serotyped using antisera and/or whole-genome sequence data. We evaluated antimicrobial susceptibility using the Kirby-Bauer disk-diffusion method. Salmonella Typhimurium sequence types were determined using multi-locus sequence typing, and whole-genome sequencing was performed to assess the phylogeny of ST313. Results: Of 370 Salmonella-positive individuals, 190 (51.4%) were MSD cases and 180 (48.6%) were diarrhea-free controls. The most frequent Salmonella serovars identified were Salmonella Typhimurium, serogroup O:8 (C2-C3), serogroup O:6,7 (C1), Salmonella Paratyphi B Java, and serogroup O:4 (B). The prevalence of NTS was low but similar across sites, regardless of age, and was similar among both cases and controls except in Kenya, where Salmonella Typhimurium was more commonly associated with cases than controls. Phylogenetic analysis showed that these Salmonella Typhimurium isolates, all ST313, were highly genetically related to isolates from controls. Generally, Salmonella isolates from Asia were resistant to ciprofloxacin and ceftriaxone, but African isolates were susceptible to these antibiotics. Conclusions: Our data confirm that NTS is prevalent, albeit at low levels, in Africa and South Asia. Our findings provide further evidence that multidrug-resistant Salmonella Typhimurium ST313 can be carried asymptomatically by humans in sub-Saharan Africa