Early LQT2 Nonsense Mutation Generates N-Terminally Truncated hERG Channels with Altered Gating Properties by the Reinitiation of Translation

Mutations in the human ether-a-go-go-related gene (hERG) result in long QT syndrome type 2 (LQT2). The hERG gene encodes a K+ channel that contributes to the repolarization of the cardiac action potential. We have previously shown that hERG mRNA transcripts that contain premature termination codon mutations are rapidly degraded by nonsense-mediated mRNA decay (NMD). In this study, we identified a LQT2 nonsense mutation, Q81X, which escapes degradation by the reinitiation of translation and generates N-terminally truncated channels. RNA analysis of hERG minigenes revealed equivalent levels of wild-type and Q81X mRNA while the mRNA expressed from minigenes containing the LQT2 frameshift mutation, P141fs+2X, was significantly reduced by NMD. Western blot analysis revealed that Q81X minigenes expressed truncated channels. Q81X channels exhibited decreased tail current levels and increased deactivation kinetics compared to wild-type channels. These results are consistent with the disruption of the N-terminus, which is known to regulate hERG deactivation. Site-specificmutagenesis studies showed that translation of the Q81X transcript is reinitiated atMet124 following premature termination. Q81X co-assembled with hERG to form heteromeric channels that exhibited increased deactivation rates compared to wild-type channels. Mutant channels also generated less outward current and transferred less charge at late phases of repolarization during ventricular action potential clamp. These results provide new mechanistic insight into the prolongation of the QT interval in LQT2 patients. Our findings indicate that the reinitiation of translation may be an important pathogenic mechanism in patients with nonsense and frameshift LQT2 mutations near the 5′ end of the hERG gene

Classification of Generalized Multiresolution Analyses

We discuss how generalized multiresolution analyses (GMRAs), both classical and those defined on abstract Hilbert spaces, can be classified by their multiplicity functions $m$ and matrix-valued filter functions $H$. Given a natural number valued function $m$ and a system of functions encoded in a matrix $H$ satisfying certain conditions, a construction procedure is described that produces an abstract GMRA with multiplicity function $m$ and filter system $H$. An equivalence relation on GMRAs is defined and described in terms of their associated pairs $(m,H)$. This classification system is applied to classical examples in $L^2 (\mathbb R^d)$ as well as to previously studied abstract examples.Comment: 18 pages including bibliograp

Clinical reasoning in feline epilepsy: Which combination of clinical information is useful?

We sought to identify the association between clinical risk factors and the diagnosis of idiopathic epilepsy (IE) or structural epilepsy (SE) in cats, using statistical models to identify combinations of discrete parameters from the patient signalment, history and neurological examination findings that could suggest the most likely diagnosis. Data for 138 cats with recurrent seizures were reviewed, of which 110 were valid for inclusion. Seizure aetiology was classified as IE in 57% and SE in 43% of cats. Binomial logistic regression analyses demonstrated that pedigree status, older age at seizure onset (particularly >7 years old), abnormal neurological examinations, and ictal vocalisation were associated with a diagnosis of SE compared to IE, and that ictal salivation was more likely to be associated with a diagnosis of IE than SE. These findings support the importance of considering inter-ictal neurological deficits and seizure history in clinical reasoning

The StoryPlaces Authoring Tool: Pattern Centric Authoring

Building authoring environments for constraint-based inter- active narratives (sculptural hypertexts) is challenging, as dealing di- rectly with functions and variables is alien to many authors and requires them to think at a lower level than story structure. We propose an ap- proach that uses higher level constructs based on common structural patterns, which are then translated behind the scenes into a set of con- straints for a sculptural engine. We present the StoryPlaces authoring tool that applies this idea with the patterns of Locking and Phasing and allows for the creation of constraint-based locative hypertext ction. Our work shows how the poetics of interactive narratives can be used in the software design process to create more accessible authoring tools

Generalized multiresolution analyses with given multiplicity functions

Generalized multiresolution analyses are increasing sequences of subspaces of a Hilbert space \H that fail to be multiresolution analyses in the sense of wavelet theory because the core subspace does not have an orthonormal basis generated by a fixed scaling function. Previous authors have studied a multiplicity function $m$ which, loosely speaking, measures the failure of the GMRA to be an MRA. When the Hilbert space \H is $L^2(\mathbb R^n)$, the possible multiplicity functions have been characterized by Baggett and Merrill. Here we start with a function $m$ satisfying a consistency condition which is known to be necessary, and build a GMRA in an abstract Hilbert space with multiplicity function $m$.Comment: 16 pages including bibliograph