| 11. |
- Casewell, Nicholas R, et al.
(författare)
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Solenodon genome reveals convergent evolution of venom in eulipotyphlan mammals.
- 2019
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 116:51, s. 25745-25755
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Tidskriftsartikel (refereegranskat)abstract
- Venom systems are key adaptations that have evolved throughout the tree of life and typically facilitate predation or defense. Despite venoms being model systems for studying a variety of evolutionary and physiological processes, many taxonomic groups remain understudied, including venomous mammals. Within the order Eulipotyphla, multiple shrew species and solenodons have oral venom systems. Despite morphological variation of their delivery systems, it remains unclear whether venom represents the ancestral state in this group or is the result of multiple independent origins. We investigated the origin and evolution of venom in eulipotyphlans by characterizing the venom system of the endangered Hispaniolan solenodon (Solenodon paradoxus). We constructed a genome to underpin proteomic identifications of solenodon venom toxins, before undertaking evolutionary analyses of those constituents, and functional assessments of the secreted venom. Our findings show that solenodon venom consists of multiple paralogous kallikrein 1 (KLK1) serine proteases, which cause hypotensive effects in vivo, and seem likely to have evolved to facilitate vertebrate prey capture. Comparative analyses provide convincing evidence that the oral venom systems of solenodons and shrews have evolved convergently, with the 4 independent origins of venom in eulipotyphlans outnumbering all other venom origins in mammals. We find that KLK1s have been independently coopted into the venom of shrews and solenodons following their divergence during the late Cretaceous, suggesting that evolutionary constraints may be acting on these genes. Consequently, our findings represent a striking example of convergent molecular evolution and demonstrate that distinct structural backgrounds can yield equivalent functions.
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| 12. |
- Cooper, K., et al.
(författare)
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New Grid Scheduling and Rescheduling Methods in the GrADS Project
- 2004
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Konferensbidrag (refereegranskat)abstract
- Summary form only given. The goal of the Grid Application Development Software (GrADS) project is to provide programming tools and an execution environment to ease program development for the grid. We present recent extensions to the GrADS software framework: 1. A new approach to scheduling workflow computations, applied to a 3D image reconstruction application; 2. A simple stop/migrate/restart approach to rescheduling grid applications, applied to a QR 3. A process-swapping approach to rescheduling, applied to an N-body simulation. Experiments validating these methods were carried out on both the GrADS MacroGrid (a small but functional grid) and the MicroGrid (a controlled emulation of the grid) and the results were demonstrated at the SC2003 conference.
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| 13. |
- Kennedy, K., et al.
(författare)
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Telescoping languages : A strategy for automatic generation of scientific problem-solving systems from annotated libraries
- 2001
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Ingår i: Journal of Parallel and Distributed Computing. - : Elsevier BV. - 0743-7315 .- 1096-0848. ; 61:12, s. 1803-1826
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Tidskriftsartikel (refereegranskat)abstract
- As machines and programs have become more complex., the process of programming applications that can exploit the power of high-performance systems has become more difficult and correspondingly more labor-intensive. This has substantially widened the software gap the discrepancy between the need for new software and the aggregate capacity of the workforce to produce it. This problem has been compounded by the slow growth of programming productivity, especially for high-performance programs, over the past two decades. One way to bridge this gap is to make it possible for end users to develop programs in high-level domain-specific programming systems. In the past, a major impediment to the acceptance of such systems has been the poor performance of the resulting applications. To address this problem, we are developing a new compiler-based infrastructure, called TeleGen, that will make it practical to construct efficient domain-specific high-level languages from annotated component libraries. We call these languages telescoping languages, because they can be nested within one another. For programs written in telescoping languages. high performance and reasonable compilation times can be achieved by exhaustively analyzing the component libraries in advance to produce a language processor that recognizes and optimizes library operations as primitives in the language. The key to making this strategy practical is to keep compile times low by generating a custom compiler with extensive built-in knowledge of the underlying libraries. The goal is to achieve compile times that tire linearly proportional to the size of the program presented by the user. rather than to the aggregate size of that program plus the base libraries.
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| 14. |
- McGurnaghan, S. J., et al.
(författare)
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Development and validation of a cardiovascular risk prediction model in type 1 diabetes
- 2021
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Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 0012-186X .- 1432-0428. ; 64, s. 2001-2011
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Tidskriftsartikel (refereegranskat)abstract
- Aims/hypothesis We aimed to report current rates of CVD in type 1 diabetes and to develop a CVD risk prediction tool for type 1 diabetes. Methods A cohort of 27,527 people with type 1 diabetes without prior CVD was derived from the national register in Scotland. Incident CVD events during 199,552 person-years of follow-up were ascertained using hospital admissions and death registers. A Poisson regression model of CVD was developed and then validated in the Swedish National Diabetes Register (n = 33,183). We compared the percentage with a high 10 year CVD risk (i.e., >= 10%) using the model with the percentage eligible for statins using current guidelines by age. Results The age-standardised rate of CVD per 100,000 person-years was 4070 and 3429 in men and women, respectively, with type 1 diabetes in Scotland, and 4014 and 3956 in men and women in Sweden. The final model was well calibrated (Hosmer- Lemeshow test p > 0.05) and included a further 22 terms over a base model of age, sex and diabetes duration (C statistic 0.82; 95% CI 0.81, 0.83). The model increased the base model C statistic foam 0.66 to 0.80, from 0.60 to 0.75 and from 0.62 to 0.68 in those aged <40, 40-59 and >= 60 years, respectively (alp values <0.005). The model required minimal calibration in Sweden and had a C statistic of 0.85. Under current guidelines, >90% of those aged 20-39 years and 100% of those >= 40 years with type 1 diabetes were eligible for statins, but it was not until age 65 upwards that 100% had a modelled risk of CVD >= 10% in 10 years. Conclusions/interpretation A prediction tool such as that developed here can provide individualised risk predictions. This 10 year CVD risk prediction tool could facilitate patient discussions regarding appropriate statin prescribing. Apart from 10 year risk, such discussions may also consider longer-term CVD risk, the potential for greater benefits from early vs later statin intervention. the potential impact on quality of life of an early CVD event and evidence on safety, all of which could influence treatment decisions, particularly in younger people with type 1 diabetes.
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| 15. |
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| 16. |
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| 17. |
- Mandal, A., et al.
(författare)
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Scheduling Strategies for Mapping Application Workflows onto the Grid
- 2005
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Ingår i: 14th IEEE International Symposium on High Performance Distributed Computing, Proceedings. - : IEEE. - 0780390377 ; , s. 125-134
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Konferensbidrag (refereegranskat)abstract
- In this work, we describe new strategies for scheduling and executing workflow applications on grid resources using the GrADS [Ken Kennedy et al., 2002] infrastructure. Workflow scheduling is based on heuristic scheduling strategies that use application component performance models. The workflow is executed using a novel strategy to bind and launch the application onto heterogeneous resources. We apply these strategies in the context of executing EMAN, a bio-imaging workflow application, on the grid. The results of our experiments show that our strategy of performance model based, in-advance heuristic workflow scheduling results in 1.5 to 2.2 times better makespan than other existing scheduling strategies. This strategy also achieves optimal load balance across the different grid sites for this application.
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| 18. |
- Mellor, Russell H, et al.
(författare)
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Lymphatic dysfunction, not aplasia, underlies Milroy disease.
- 2010
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Ingår i: Microcirculation. - : Wiley. - 1073-9688 .- 1549-8719. ; 17:4
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Milroy disease is an inherited autosomal dominant lymphoedema caused by mutations in the gene for vascular endothelial growth factor receptor-3 (VEGFR-3, also known as FLT4). The phenotype has to date been ascribed to lymphatic aplasia. We further investigated the structural and functional defects underlying the phenotype in humans.METHODS: The skin of the swollen foot and the non-swollen forearm was examined by (i) fluorescence microlymphangiography, to quantify functional initial lymphatic density in vivo; and (ii) podoplanin and LYVE-1 immunohistochemistry of biopsies, to quantify structural lymphatic density. Leg vein function was assessed by colour Doppler duplex ultrasound.RESULTS: Milroy patients exhibited profound (86-91%) functional failure of the initial lymphatics in the foot; the forearm was unimpaired. Dermal lymphatics were present in biopsies but density was reduced by 51-61% (foot) and 26-33% (forearm). Saphenous venous reflux was present in 9/10 individuals with VEGFR3 mutations, including two carriers.CONCLUSION: We propose that VEGFR3 mutations in humans cause lymphoedema through a failure of tissue protein and fluid absorption. This is due to a profound functional failure of initial lymphatics and is not explained by microlymphatic hypoplasia alone. The superficial venous valve reflux indicates the dual role of VEGFR-3 in lymphatic and venous development.
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| 19. |
- Mellor, Russell H, et al.
(författare)
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Mutations in FOXC2 in humans (lymphoedema distichiasis syndrome) cause lymphatic dysfunction on dependency.
- 2011
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Ingår i: Journal of Vascular Research. - : S. Karger AG. - 1018-1172 .- 1423-0135. ; 48:5
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Human lymphoedema distichiasis syndrome (LDS) results from germline mutations in transcription factor FOXC2. In a mouse model, lack of lymphatic and venous valves is observed plus abnormal smooth muscle cell recruitment to initial lymphatics. We investigated the mechanism of lymphoedema in humans with FOXC2 mutations, specifically the effect of gravitational forces on dermal lymphatic function.METHODS: We performed (1) quantitative fluorescence microlymphangiography (FML) on the skin of the forearm (non-swollen region) at heart level, and the foot (swollen region) below heart level (dependent) and then at heart level, and (2) immunohistochemical staining of microlymphatics in forearm and foot skin biopsies, using antibodies to podoplanin, LYVE-1 and smooth muscle actin.RESULTS: FML revealed a marked reduction in fluid uptake by initial lymphatics in the LDS foot during dependency, yet normal uptake (similar to controls) in the same foot at heart level and in LDS forearms. In control subjects, dependency did not impair initial lymphatic filling. Immunohistochemical microlymphatic density in forearm and foot did not differ between LDS and controls.CONCLUSIONS: FOXC2 mutations cause a functional failure of dermal initial lymphatics during gravitational stress (dependency), but not hypoplasia. The results reveal a pathophysiological mechanism contributing to swelling in LDS.
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| 20. |
- Peret, Benjamin, et al.
(författare)
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Sequential induction of auxin efflux and influx carriers regulates lateral root emergence
- 2013
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Ingår i: Molecular Systems Biology. - : Nature Publishing Group. - 1744-4292 .- 1744-4292. ; 9, s. Article number 699-
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Tidskriftsartikel (refereegranskat)abstract
- In Arabidopsis, lateral roots originate from pericycle cells deep within the primary root. New lateral root primordia ( LRP) have to emerge through several overlaying tissues. Here, we report that auxin produced in new LRP is transported towards the outer tissues where it triggers cell separation by inducing both the auxin influx carrier LAX3 and cell-wall enzymes. LAX3 is expressed in just two cell files overlaying new LRP. To understand how this striking pattern of LAX3 expression is regulated, we developed a mathematical model that captures the network regulating its expression and auxin transport within realistic three-dimensional cell and tissue geometries. Our model revealed that, for the LAX3 spatial expression to be robust to natural variations in root tissue geometry, an efflux carrier is required-later identified to be PIN3. To prevent LAX3 from being transiently expressed in multiple cell files, PIN3 and LAX3 must be induced consecutively, which we later demonstrated to be the case. Our study exemplifies how mathematical models can be used to direct experiments to elucidate complex developmental processes.
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