325 research outputs found
DNM1 encephalopathy: A new disease of vesicle fission.
ObjectiveTo evaluate the phenotypic spectrum caused by mutations in dynamin 1 (DNM1), encoding the presynaptic protein DNM1, and to investigate possible genotype-phenotype correlations and predicted functional consequences based on structural modeling.MethodsWe reviewed phenotypic data of 21 patients (7 previously published) with DNM1 mutations. We compared mutation data to known functional data and undertook biomolecular modeling to assess the effect of the mutations on protein function.ResultsWe identified 19 patients with de novo mutations in DNM1 and a sibling pair who had an inherited mutation from a mosaic parent. Seven patients (33.3%) carried the recurrent p.Arg237Trp mutation. A common phenotype emerged that included severe to profound intellectual disability and muscular hypotonia in all patients and an epilepsy characterized by infantile spasms in 16 of 21 patients, frequently evolving into Lennox-Gastaut syndrome. Two patients had profound global developmental delay without seizures. In addition, we describe a single patient with normal development before the onset of a catastrophic epilepsy, consistent with febrile infection-related epilepsy syndrome at 4 years. All mutations cluster within the GTPase or middle domains, and structural modeling and existing functional data suggest a dominant-negative effect on DMN1 function.ConclusionsThe phenotypic spectrum of DNM1-related encephalopathy is relatively homogeneous, in contrast to many other genetic epilepsies. Up to one-third of patients carry the recurrent p.Arg237Trp variant, which is now one of the most common recurrent variants in epileptic encephalopathies identified to date. Given the predicted dominant-negative mechanism of this mutation, this variant presents a prime target for therapeutic intervention
The Canadian Healthy Infant Longitudinal Development (CHILD) birth cohort study: Assessment of environmental exposures
The Canadian Healthy Infant Longitudinal Development birth cohort was designed to elucidate interactions between environment and genetics underlying development of asthma and allergy. Over 3600 pregnant mothers were recruited from the general population in four provinces with diverse environments. The child is followed to age 5 years, with prospective characterization of diverse exposures during this critical period. Key exposure domains include indoor and outdoor air pollutants, inhalation, ingestion and dermal uptake of chemicals, mold, dampness, biological allergens, pets and pests, housing structure, and living behavior, together with infections, nutrition, psychosocial environment, and medications. Assessments of early life exposures are focused on those linked to inflammatory responses driven by the acquired and innate immune systems. Mothers complete extensive environmental questionnaires including time-activity behavior at recruitment and when the child is 3, 6, 12, 24, 30, 36, 48, and 60 months old. House dust collected during a thorough home assessment at 3–4 months, and biological specimens obtained for multiple exposure-related measurements, are archived for analyses. Geo-locations of homes and daycares and land-use regression for estimating traffic-related air pollution complement time-activity-behavior data to provide comprehensive individual exposure profiles. Several analytical frameworks are proposed to address the many interacting exposure variables and potential issues of co-linearity in this complex data set
Low-Mass X-ray Binaries and Globular Clusters in Centaurus A
We present results of Hubble Space Telescope and Chandra X-ray Observatory
observations of globular clusters (GCs) and low-mass X-ray binaries (LMXBs) in
the central regions of Centaurus A. Out of 440 GC candidates we find that 41
host X-ray point sources that are most likely LMXBs. We fit King models to our
GC candidates in order to measure their structural parameters. We find that GCs
that host LMXBs are denser and more compact, and have higher encounter rates
and concentrations than the GC population as a whole. We show that the higher
concentrations and masses are a consequence of the dependence of LMXB incidence
on central density and size plus the general trend for denser GCs to have
higher masses and concentrations. We conclude that neither concentration nor
mass are fundamental variables in determining the presence of LMXBs in GCs, and
that the more fundamental parameters relate to central density and size.Comment: 4 pages, 2 figures. Accepted for publication in ApJ Letter
Resource utilization and costs during the initial years of lung cancer screening with computed tomography in Canada
Background
It is estimated that millions of North Americans would qualify for lung cancer screening and that billions of dollars of national health expenditures would be required to support population-based computed tomography lung cancer screening programs. The decision to implement such programs should be informed by data on resource utilization and costs.
Methods
Resource utilization data were collected prospectively from 2059 participants in the Pan-Canadian Early Detection of Lung Cancer Study using low-dose computed tomography (LDCT). Participants who had 2% or greater lung cancer risk over 3 years using a risk prediction tool were recruited from seven major cities across Canada. A cost analysis was conducted from the Canadian public payer's perspective for resources that were used for the screening and treatment of lung cancer in the initial years of the study.
Results
The average per-person cost for screening individuals with LDCT was USD453 (95% confidence interval [CI], USD400–USD505) for the initial 18-months of screening following a baseline scan. The screening costs were highly dependent on the detected lung nodule size, presence of cancer, screening intervention, and the screening center. The mean per-person cost of treating lung cancer with curative surgery was USD33,344 (95% CI, USD31,553–USD34,935) over 2 years. This was lower than the cost of treating advanced-stage lung cancer with chemotherapy, radiotherapy, or supportive care alone, (USD47,792; 95% CI, USD43,254–USD52,200; p = 0.061).
Conclusion
In the Pan-Canadian study, the average cost to screen individuals with a high risk for developing lung cancer using LDCT and the average initial cost of curative intent treatment were lower than the average per-person cost of treating advanced stage lung cancer which infrequently results in a cure
A global perspective on the trophic geography of sharks
Sharks are a diverse group of mobile predators that forage across varied spatial scales and have the potential to influence food web dynamics. The ecological consequences of recent declines in shark biomass may extend across broader geographic ranges if shark taxa display common behavioural traits. By tracking the original site of photosynthetic fixation of carbon atoms that were ultimately assimilated into muscle tissues of 5,394 sharks from 114 species, we identify globally consistent biogeographic traits in trophic interactions between sharks found in different habitats. We show that populations of shelf-dwelling sharks derive a substantial proportion of their carbon from regional pelagic sources, but contain individuals that forage within additional isotopically diverse local food webs, such as those supported by terrestrial plant sources, benthic production and macrophytes. In contrast, oceanic sharks seem to use carbon derived from between 30° and 50° of latitude. Global-scale compilations of stable isotope data combined with biogeochemical modelling generate hypotheses regarding animal behaviours that can be tested with other methodological approaches.This research was conducted as part of C.S.B.’s Ph.D dissertation, which was funded by the University of Southampton and NERC (NE/L50161X/1), and through a NERC Grant-in-Kind from the Life Sciences Mass Spectrometry Facility (LSMSF; EK267-03/16). We thank A. Bates, D. Sims, F. Neat, R. McGill and J. Newton for their analytical contributions and comments on the manuscripts.Peer reviewe
The evolution of non-small cell lung cancer metastases in TRACERx
Metastatic disease is responsible for the majority of cancer-related deaths1. We report the longitudinal evolutionary analysis of 126 non-small cell lung cancer (NSCLC) tumours from 421 prospectively recruited patients in TRACERx who developed metastatic disease, compared with a control cohort of 144 non-metastatic tumours. In 25% of cases, metastases diverged early, before the last clonal sweep in the primary tumour, and early divergence was enriched for patients who were smokers at the time of initial diagnosis. Simulations suggested that early metastatic divergence more frequently occurred at smaller tumour diameters (less than 8 mm). Single-region primary tumour sampling resulted in 83% of late divergence cases being misclassified as early, highlighting the importance of extensive primary tumour sampling. Polyclonal dissemination, which was associated with extrathoracic disease recurrence, was found in 32% of cases. Primary lymph node disease contributed to metastatic relapse in less than 20% of cases, representing a hallmark of metastatic potential rather than a route to subsequent recurrences/disease progression. Metastasis-seeding subclones exhibited subclonal expansions within primary tumours, probably reflecting positive selection. Our findings highlight the importance of selection in metastatic clone evolution within untreated primary tumours, the distinction between monoclonal versus polyclonal seeding in dictating site of recurrence, the limitations of current radiological screening approaches for early diverging tumours and the need to develop strategies to target metastasis-seeding subclones before relaps
The evolution of non-small cell lung cancer metastases in TRACERx.
Metastatic disease is responsible for the majority of cancer-related deaths1. We report the longitudinal evolutionary analysis of 126 non-small cell lung cancer (NSCLC) tumours from 421 prospectively recruited patients in TRACERx who developed metastatic disease, compared with a control cohort of 144 non-metastatic tumours. In 25% of cases, metastases diverged early, before the last clonal sweep in the primary tumour, and early divergence was enriched for patients who were smokers at the time of initial diagnosis. Simulations suggested that early metastatic divergence more frequently occurred at smaller tumour diameters (less than 8 mm). Single-region primary tumour sampling resulted in 83% of late divergence cases being misclassified as early, highlighting the importance of extensive primary tumour sampling. Polyclonal dissemination, which was associated with extrathoracic disease recurrence, was found in 32% of cases. Primary lymph node disease contributed to metastatic relapse in less than 20% of cases, representing a hallmark of metastatic potential rather than a route to subsequent recurrences/disease progression. Metastasis-seeding subclones exhibited subclonal expansions within primary tumours, probably reflecting positive selection. Our findings highlight the importance of selection in metastatic clone evolution within untreated primary tumours, the distinction between monoclonal versus polyclonal seeding in dictating site of recurrence, the limitations of current radiological screening approaches for early diverging tumours and the need to develop strategies to target metastasis-seeding subclones before relapse
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Cancer therapy shapes the fitness landscape of clonal hematopoiesis.
Acquired mutations are pervasive across normal tissues. However, understanding of the processes that drive transformation of certain clones to cancer is limited. Here we study this phenomenon in the context of clonal hematopoiesis (CH) and the development of therapy-related myeloid neoplasms (tMNs). We find that mutations are selected differentially based on exposures. Mutations in ASXL1 are enriched in current or former smokers, whereas cancer therapy with radiation, platinum and topoisomerase II inhibitors preferentially selects for mutations in DNA damage response genes (TP53, PPM1D, CHEK2). Sequential sampling provides definitive evidence that DNA damage response clones outcompete other clones when exposed to certain therapies. Among cases in which CH was previously detected, the CH mutation was present at tMN diagnosis. We identify the molecular characteristics of CH that increase risk of tMN. The increasing implementation of clinical sequencing at diagnosis provides an opportunity to identify patients at risk of tMN for prevention strategies
Cancer therapy shapes the fitness landscape of clonal hematopoiesis.
Acquired mutations are pervasive across normal tissues. However, understanding of the processes that drive transformation of certain clones to cancer is limited. Here we study this phenomenon in the context of clonal hematopoiesis (CH) and the development of therapy-related myeloid neoplasms (tMNs). We find that mutations are selected differentially based on exposures. Mutations in ASXL1 are enriched in current or former smokers, whereas cancer therapy with radiation, platinum and topoisomerase II inhibitors preferentially selects for mutations in DNA damage response genes (TP53, PPM1D, CHEK2). Sequential sampling provides definitive evidence that DNA damage response clones outcompete other clones when exposed to certain therapies. Among cases in which CH was previously detected, the CH mutation was present at tMN diagnosis. We identify the molecular characteristics of CH that increase risk of tMN. The increasing implementation of clinical sequencing at diagnosis provides an opportunity to identify patients at risk of tMN for prevention strategies
Agribusiness Sheep Updates - 2004 part 2
Precision Pastures Using Species Diversity to Improve Pasture Performance Anyou Liu and Clinton Revell, Department of Agriculture, Western Australia New Annual Pasture Legumes for Sheep Graziers Phil Nichols, Angelo Loi, Brad Nutt and Darryl McClements Department of Agriculture Western Australia Pastures from Space – Can Satellite Estimates of Pasture Growth Rate be used to Increase Farm Profit? Lucy Anderton, Stephen Gherardi and Chris Oldham Department of Agriculture Western Australia Summer-active Perennial Grasses for Profitable Sheep Production Paul Sanford and John Gladman, Department of Agriculture, Western Australia Pastures From Space – Validation Of Predictions Of Pasture Growth Rates DONALD, G.E.A, EDIRISINGHE, A.A, HENRY, D.A.A, MATA, G.A, GHERARDI, S.G.B, OLDHAM, C.M.B, GITTINS, S.P.B AND SMITH, R. C. G.C ACSIRO, Livestock Industries, PMB 5, Wembley, WA, 6913. BDepartment of Agriculture Western Australia, Bentley, WA, 6983. C Department of Land Information Western Australia, Floreat, WA, 6214. Production and Management of Biserrula Pasture - Managing the Risk of Photosensitivity Dr Clinton Revell and Roy Butler, Department of Agriculture Western Australia Meat Quality of Sheep Grazed on a Saltbush-based Pasture Kelly Pearce1,2, David Masters1, David Pethick2, 1 CSIRO LIVESTOCK INDUSTRIES, WEMBLEY, WA 2 SCHOOL OF VETERINARY AND BIOMEDICAL SCIENCE, MURDOCH UNIVERSITY, MURDOCH, WA Precision Sheep Lifetime Wool – Carryover Effects on Subsequent Reproduction of the Ewe Flock Chris Oldham, Department of Agriculture Western Australia Andrew Thompson, Primary Industries Research Victoria (PIRVic), Dept of Primary Industries, Hamilton, Vic Ewe Productivity Trials - a Linked Analysis Ken Hart, Johan Greeff, Department of Agriculture Western Australia, Beth Paganoni, School of Animal Biology, Faculty of Natural and Agricultural Sciences, University of Western Australia. Grain Finishing Systems For Prime Lambs Rachel Kirby, Matt Ryan, Kira Buttler, Department of Agriculture, Western Australia The Effects of Nutrition and Genotype on the Growth and Development, Muscle Biochemistry and Consumer Response to Lamb Meat David Pethick, Department of Veterinary Science, Murdoch University, WA, Roger Heggarty and David Hopkins, New South Wales Agriculture ‘Lifetime Wool’ - Effects of Nutrition During Pregnancy and Lactation on Mortality of Progeny to Hogget Shearing Samantha Giles, Beth Paganoni and Tom Plaisted, Department of Agriculture Western Australia, Mark Ferguson and Darren Gordon, Primary Industries Research Victoria (PIRVic), Dept of Primary Industries, Hamilton, Vic Lifetime Wool - Target Liveweights for the Ewe Flock J. Young, Farming Systems Analysis Service, Kojonup, C. Oldham, Department of Agriculture Western Australia, A. Thompson, Primary Industries Research Victoria (PIRVic), Hamilton, VIC Lifetime Wool - Effects of Nutrition During Pregnancy and Lactation on the Growth and Wool Production of their Progeny at Hogget Shearing B. Paganoni, University of Western Australia, Nedlands WA, C. Oldham, Department of Agriculture Western Australia, M. Ferguson, A. Thompson, Primary Industries Research Victoria (PIRVic), Hamilton, VIC RFID Technology – Esperance Experiences Sandra Brown, Department of Agriculture Western Australia The Role of Radio Frequency Identification (RFID) Technology in Prime Lamb Production - a Case Study. Ian McFarland, Department of Agriculture, Western Australia. John Archer, Producer, Narrogin, Western Australia Win with Twins from Merinos John Milton, Rob Davidson, Graeme Martin and David Lindsay The University of Western Australia Precision Sheep Need Precision Wool Harvesters Jonathan England, Castle Carrock Merinos, Kingston SE, South Australia Business EBVs and Indexes – Genetic Tools for your Toolbox Sandra Brown, Department of Agriculture Western Australia Green Feed Budget Paddock Calculator Mandy Curnow, Department of Agriculture Western Australia Minimising the Impact of Drought - Evaluating Flock Recovery Options using the ImPack Model Karina P. Wood, Ashley K. White, B. Lloyd Davies, Paul M. Carberry, NSW Department of Primary Industries (NSW DPI), Lifetime Wool - Modifying GrazFeed® for WA Mike Hyder, Department of Agriculture Western Australia , Mike Freer, CSIRO Plant Industry, Canberra, A.C.T. , Andrew van Burgel, and Kazue Tanaka, Department of Agriculture Western Australia Profile Calculator – A Way to Manage Fibre Diameter Throughout the Year to Maximise Returns Andrew Peterson, Department of Agriculture, Western Australia Pasture Watch - a Farmer Friendly Tool for Downloading and Analysing Pastures from Space Data Roger Wiese,Fairport Technologies International, South Perth, WA, Stephen Gherardi, BDepartment of Agriculture Western Australia, Gonzalo Mata, CCSIRO, Livestock Industries, Wembley, Western Australia, and Chris Oldham, Department of Agriculture Western Australia Sy Sheep Cropping Systems An Analysis of a Cropping System Containing Sheep in a Low Rainfall Livestock System. Evan Burt, Amanda Miller, Anne Bennett, Department of Agriculture, Western Australia Lucerne-based Pasture for the Central Wheatbelt – is it Good Economics? Felicity FluggeA, Amir AbadiA,B and Perry DollingA,B,A CRC for Plant-based Management of Dryland Salinity: BDept. of Agriculture, WA Sheep and Biserrula can Control Annual Ryegrass Dean Thomas, John Milton, Mike Ewing and David Lindsay, The University of WA, Clinton Revell, Department of Agriculture, Western Australia Sustainable Management Pasture Utilisation, Fleece Weight and Weaning Rate are Integral to the Profitability of Dohnes and SAMMs. Emma Kopke,Department of Agriculture Western Australia, John Young, Farming Systems Analysis Service Environmental Impact of Sheep Confinement Feeding Systems E A Dowling and E K Crossley, Department of Agriculture, Western Australia Smart Grazing Management for Production and Environmental Outcomes Dr Brien E (Ben) Norton, Centre for the Management of Arid Environments, Curtin University of Technology, WA Common Causes of Plant Poisoning in the Eastern Wheatbelt of Western Australia. Roy Butler, Department of Agriculture, Western Australia Selecting Sheep for Resistance to Worms and Production Trait Responses John Karlsson, Johan Greeff, Department of Agriculture, Western Australia, Geoff Pollott, Imperial College, London UK Production and Water Use of Lucerne and French Serradella in Four Soil Types, Diana Fedorenko1,4, Darryl McClements2,4 and Robert Beard3,4, 12Department of Agriculture, Western Australia; 3Farmer, Meckering; 4CRC for Plant-based Management of Dryland Salinity. Worm Burdens in Sheep at Slaughter Brown Besier, Department of Agriculture Western Australia, Una Ryan, Caroline Bath, Murdoch Universit
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