34 research outputs found
Alt-X turns 10: unclassifiable writing triumphs
No full textDarren Tofts interviews American artist and author Mark Amerik
Dynamic contrast-enhanced MRI of the patellar bone: How to quantify perfusion
No full textPurpose: To identify the optimal combination of pharmacokinetic model and arterial input function (AIF) for quantitative analysis of blood perfusion in the patellar bone using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). Materials and Methods: This method design study used a random subset of five control subjects from an Institutional Review Board (IRB)-approved case–control study into patellofemoral pain, scanned on a 3T MR system with a contrast-enhanced time-resolved imaging of contrast kinetics (TRICKS) sequence. We systematically investigated the reproducibility of pharmacokinetic parameters for all combinations of Orton and Parker AIF models with Tofts, Extended Tofts (ETofts), and Brix pharmacokinetic models. Furthermore, we evaluated if the AIF should use literature parameters, be subject-specific, or group-specific. Model selection was based on the goodness-of-fit and the coefficient of variation of the pharmacokinetic parameters inside the patella. This extends previous studies that were not focused on the patella and did not evaluate as many combinations of arterial and pharmacokinetic models. Results: The vascular component in the ETofts model could not reliably be recovered (coefficient of variation [CV] of vp >50%) and the Brix model parameters showed high variability of up to 20% for kel across good AIF models. Compared to group-specific AIF, the subject-specific AIF's mostly had higher residual. The best reproducibility and goodness-of-fit were obtained by combining Tofts' pharmacokinetic model with the group-specific Parker AIF. Conclusion: We identified several good combinations of pharmacokinetic models and AIF for quantitative analysis of perfusion in the patellar bone. The recommended combination is Tofts pharmacokinetic model combined with a group-specific Parker AIF model. Level of Evidence: 2. Technical Efficacy: Stage 1. J. Magn. Reson. Imaging 2018;47:848–858.Accepted Author ManuscriptImPhys/Quantitative Imagin
EXACT SOLUTIONS TO FINITE STATE SIMULATION MODELS
No full textMany Monte Carlo simulation problems are essentially finite state.
We demonstrate how such problems may be represented within a probabilistic
process algebra. We demonstrate how it is possible to convert such
processes into linear probabilistic equations, and solve such equations
exactly with available computer algebra systems.We are currently acquiring citations for the work deposited into this collection. We recognize the distribution rights of this item may have been assigned to another entity, other than the author(s) of the work.If you can provide the citation for this work or you think you own the distribution rights to this work please contact the Institutional Repository Administrator at [email protected]
PROCESSES WITH PROBABILITIES, PRIORITY AND TIME
No full textA probabilistic calculus, derived from Milner's SCCS, WSCCS is
presented. We define a notion of bisimulation for probabilistic
processes and show that it is a congruence. A simple equational
characterisation is shown to be both sound and complete for finite
processes. We present many examples including some extended ones. The
larger examples show both the expressive power of WSCCS and the
availability of simple proof methods for some complex systems.We are currently acquiring citations for the work deposited into this collection. We recognize the distribution rights of this item may have been assigned to another entity, other than the author(s) of the work.If you can provide the citation for this work or you think you own the distribution rights to this work please contact the Institutional Repository Administrator at [email protected]
Mutations in the BRWD3 gene cause X-linked mental retardation associated with macrocephaly
No full textIn the course of systematic screening of the X-chromosome coding sequences in 250 families with nonsyndromic X-linked mental retardation (XLMR), two families were identified with truncating mutations in BRWD3, a gene encoding a bromodomain and WD-repeat domain–containing protein. In both families, the mutation segregates with the phenotype in affected males. Affected males have macrocephaly with a prominent forehead, large cupped ears, and mild-to-moderate intellectual disability. No truncating variants were found in 520 control X chromosomes. BRWD3 is therefore a new gene implicated in the etiology of XLMR associated with macrocephaly and may cause disease by altering intracellular signaling pathways affecting cellular proliferation.Michael Field, Patrick S. Tarpey, Raffaella Smith, Sarah Edkins, Sarah O’Meara, Claire Stevens, Calli Tofts, Jon Teague, Adam Butler, Ed Dicks, Syd Barthorpe, Gemma Buck, Jennifer Cole, Kristian Gray, Kelly Halliday, Katy Hills, Andrew Jenkinson, David Jones, Andrew Menzies, Tatiana Mironenko, Janet Perry, Keiran Raine, David Richardson, Rebecca Shepherd, Alexandra Small, Jennifer Varian, Sofie West, Sara Widaa, Uma Mallya, Richard Wooster, Jenny Moon, Ying Luo, Helen Hughes, Marie Shaw, Kathryn L. Friend, Mark Corbett, Gillian Turner, Michael Partington, John Mulley, Martin Bobrow, Charles Schwartz, Roger Stevenson, Jozef Gecz, Michael R. Stratton, P. Andrew Futreal, F. Lucy Raymon
Mutations in ZDHHC9, which encodes a palmitoyltransferase of NRAS and HRAS, cause X-linked mental retardation associated with a marfanoid habitus
No full textWe have identified one frameshift mutation, one splice-site mutation, and two missense mutations in highly conserved residues in ZDHHC9 at Xq26.1 in 4 of 250 families with X-linked mental retardation (XLMR). In three of the families, the mental retardation phenotype is associated with a Marfanoid habitus, although none of the affected individuals meets the Ghent criteria for Marfan syndrome. ZDHHC9 is a palmitoyltransferase that catalyzes the posttranslational modification of NRAS and HRAS. The degree of palmitoylation determines the temporal and spatial location of these proteins in the plasma membrane and Golgi complex. The finding of mutations in ZDHHC9 suggests that alterations in the concentrations and cellular distribution of target proteins are sufficient to cause disease. This is the first XLMR gene to be reported that encodes a posttranslational modification enzyme, palmitoyltransferase. Furthermore, now that the first palmitoyltransferase that causes mental retardation has been identified, defects in other palmitoylation transferases become good candidates for causing other mental retardation syndromes.F. Lucy Raymond, Patrick S. Tarpey, Sarah Edkins, Calli Tofts, Sarah O’Meara, Jon Teague, Adam Butler, Claire Stevens, Syd Barthorpe, Gemma Buck, Jennifer Cole, Ed Dicks, Kristian Gray, Kelly Halliday, Katy Hills, Jonathon Hinton, David Jones, Andrew Menzies, Janet Perry, Keiran Raine, Rebecca Shepherd, Alexandra Small, Jennifer Varian, Sara Widaa, Uma Mallya, Jenny Moon, Ying Luo, Marie Shaw, Jackie Boyle, Bronwyn Kerr, Gillian Turner, Oliver Quarrell, Trevor Cole, Douglas F. Easton, Richard Wooster, Martin Bobrow, Charles E. Schwartz, Jozef Gecz, Michael R. Stratton, P. Andrew Futrea
A retrospective sort of arrangement': Ulysses and the poetics of hypertextuality
No full textHypertextuality is a term that we have come to associate with digital connectivity, hypertext and the computer revolution. It is also a term that has, in retrospect, be applied to James Joyce's Ulysses. Indeed, David Gold, in a detailed case study of the text, suggests that Ulysses is 'the perfect hypertext subject.'1 Such a view assumes some kind of correspondence between Ulysses and the emergent electronic architecture of hypertext, an acknowledgment that Ulysses is somehow like hypertext. On the basis of this homology, Ulysses is seen to be eminently eligible for hypertextualisation. However, the relationship between a literary work such as Ulysses and electronic hypertext is a problematic one. While the nomenclature of hypertext and hypertextuality dates back to the late 1960s, it was for many years unknown to literary criticism. Nevertheless, its association with literature as a form of poetics can be traced back to those formative years of hypertext research and development. Ted Nelson, author of Literary Machines and originator of the term hypertext, had clearly defined it in 1965 as a literary phenomenon. The importance for Ulysses scholarship of thinking of the literary in machinic terms, and the broader logic of hypertextual poetics, will hopefully become apparent in this paper
Mutations in CUL4B which encodes a ubiquitin E3 ligase subunit cause an X-linked mental retardation syndrome associated with aggressive outbursts seizures relative macrocephaly central obesity hypogonadism pes cavus and tremor
No full textWe have identified three truncating, two splice-site, and three missense variants at conserved amino acids in the CUL4B gene on Xq24 in 8 of 250 families with X-linked mental retardation (XLMR). During affected subjects' adolescence, a syndrome emerged with delayed puberty, hypogonadism, relative macrocephaly, moderate short stature, central obesity, unprovoked aggressive outbursts, fine intention tremor, pes cavus, and abnormalities of the toes. This syndrome was first described by Cazebas et al., in a family that was included in our study and that carried a CUL4B missense variant. CUL4B is a ubiquitin E3 ligase subunit implicated in the regulation of several biological processes, and CUL4B is the first XLMR gene that encodes an E3 ubiquitin ligase. The relatively high frequency of CUL4B mutations in this series indicates that it is one of the most commonly mutated genes underlying XLMR and suggests that its introduction into clinical diagnostics should be a high priority.Patrick S. Tarpey, F. Lucy Raymond, Sarah O’Meara, Sarah Edkins, Jon Teague, Adam Butler, Ed Dicks, Claire Stevens, Calli Tofts, Tim Avis, Syd Barthorpe, Gemma Buck, Jennifer Cole, Kristian Gray, Kelly Halliday, Rachel Harrison, Katy Hills, Andrew Jenkinson, David Jones, Andrew Menzies, Tatiana Mironenko, Janet Perry, Keiran Raine, David Richardson, Rebecca Shepherd, Alexandra Small, Jennifer Varian, Sofie West, Sara Widaa, Uma Mallya, Jenny Moon, Ying Luo, Susan Holder, Sarah F. Smithson, Jane A. Hurst, Jill Clayton-Smith, Bronwyn Kerr, Jackie Boyle, Marie Shaw, Lucianne Vandeleur, Jayson Rodriguez, Rachel Slaugh, Douglas F. Easton, Richard Wooster, Martin Bobrow, Anand K. Srivastava, Roger E. Stevenson, Charles E. Schwartz, Gillian Turner, Jozef Gecz, P. Andrew Futreal, Michael R. Stratton and Michael Partingtonhttp://www.ajhg.org
X-linked protocadherin 19 mutations cause female-limited epilepsy and cognitive impairment
No full textLink to a related website: https://unpaywall.org/10.1038/ng.149, Open Access via UnpaywallEpilepsy and mental retardation limited to females (EFMR) is a disorder with an X-linked mode of inheritance and an unusual expression pattern. Disorders arising from mutations on the X chromosome are typically characterized by affected males and unaffected carrier females. In contrast, EFMR spares transmitting males and affects only carrier females. Aided by systematic resequencing of 737 X chromosome genes, we identified different protocadherin 19 (PCDH19) gene mutations in seven families with EFMR. Five mutations resulted in the introduction of a premature termination codon. Study of two of these demonstrated nonsense-mediated decay of PCDH19 mRNA. The two missense mutations were predicted to affect adhesiveness of PCDH19 through impaired calcium binding. PCDH19 is expressed in developing brains of human and mouse and is the first member of the cadherin superfamily to be directly implicated in epilepsy or mental retardation.Leanne M Dibbens, Patrick S Tarpey, Kim Hynes, Marta A Bayly, Ingrid E Scheffer, Raffaella Smith, Jamee Bomar, Edwina Sutton, Lucianne Vandeleur, Cheryl Shoubridge, Sarah Edkins, Samantha J Turner, Claire Stevens, Sarah O'Meara, Calli Tofts, Syd Barthorpe, Gemma Buck, Jennifer Cole, Kelly Halliday, David Jones, Rebecca Lee, Mark Madison, Tatiana Mironenko, Jennifer Varian, Sofie West, Sara Widaa, Paul Wray, John Teague, Ed Dicks, Adam Butler, Andrew Menzies, Andrew Jenkinson, Rebecca Shepherd, James F Gusella, Zaid Afawi, Aziz Mazarib, Miriam Y Neufeld, Sara Kivity, Dorit Lev, Tally Lerman-Sagie, Amos D Korczyn, Christopher P Derry, Grant R Sutherland, Kathryn Friend, Marie Shaw, Mark Corbett, Hyung-Goo Kim, Daniel H Geschwind, Paul Thomas, Eric Haan, Stephen Ryan, Shane McKee, Samuel F Berkovic, P Andrew Futreal, Michael R Stratton, John C Mulley & Jozef Géc
Mutations in the gene encoding the sigma 2 subunit of the adaptor protein 1 complex, AP1S2, cause X-linked mental retardation
No full textIn a systematic sequencing screen of the coding exons of the X chromosome in 250 families with X-linked mental retardation (XLMR), we identified two nonsense mutations and one consensus splice-site mutation in the AP1S2 gene on Xp22 in three families. Affected individuals in these families showed mild-to-profound mental retardation. Other features included hypotonia early in life and delay in walking. AP1S2 encodes an adaptin protein that constitutes part of the adaptor protein complex found at the cytoplasmic face of coated vesicles located at the Golgi complex. The complex mediates the recruitment of clathrin to the vesicle membrane. Aberrant endocytic processing through disruption of adaptor protein complexes is likely to result from the AP1S2 mutations identified in the three XLMR-affected families, and such defects may plausibly cause abnormal synaptic development and function. AP1S2 is the first reported XLMR gene that encodes a protein directly involved in the assembly of endocytic vesicles.Patrick S. Tarpey, Claire Stevens, Jon Teague, Sarah Edkins, Sarah O’Meara, Tim Avis, Syd Barthorpe, Gemma Buck, Adam Butler, Jennifer Cole, Ed Dicks, Kristian Gray, Kelly Halliday, Rachel Harrison, Katy Hills, Jonathon Hinton, David Jones, Andrew Menzies, Tatiana Mironenko, Janet Perry, Keiran Raine, David Richardson, Rebecca Shepherd, Alexandra Small, Calli Tofts, Jennifer Varian, Sofie West, Sara Widaa, Andy Yates, Rachael Catford, Julia Butler, Uma Mallya, Jenny Moon, Ying Luo, Huw Dorkins, Deborah Thompson, Douglas F. Easton, Richard Wooster, Martin Bobrow, Nancy Carpente, Richard J. Simensen, Charles E. Schwartz, Roger E. Stevenson, Gillian Turner, Michael Partington, Jozef Gecz, Michael R. Stratton, P. Andrew Futreal and F. Lucy Raymon
