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7 results on '"Digby H"'

3. Study Groups Can Help You Grow Personally And Professionally

Author

Cook, Digby H.

Subjects
Insurance industry -- Management, Discussion, Business, Insurance
Abstract

I started in the insurance business in Fairbanks, Alaska, some 400 miles from my General Office in Anchorage and my fellow New York Life colleagues. I moved to Newport, Oregon [...]

Published
2001

4. Widespread 3'UTR capped RNAs derive from G-rich regions in proximity to AGO2 binding sites.

Author

Haberman N, Digby H, Faraway R, Cheung R, Chakrabarti AM, Jobbins AM, Parr C, Yasuzawa K, Kasukawa T, Yip CW, Kato M, Takahashi H, Carninci P, Vernia S, Ule J, Sibley CR, Martinez-Sanchez A, and Lenhard B

Subjects
Binding Sites, Humans, RNA Caps metabolism, RNA, Messenger metabolism, RNA, Messenger genetics, HeLa Cells, 3' Untranslated Regions genetics, Argonaute Proteins metabolism, Argonaute Proteins genetics
Abstract

The 3' untranslated region (3'UTR) plays a crucial role in determining mRNA stability, localisation, translation and degradation. Cap analysis of gene expression (CAGE), a method for the detection of capped 5' ends of mRNAs, additionally reveals a large number of apparently 5' capped RNAs derived from locations within the body of the transcript, including 3'UTRs. Here, we provide direct evidence that these 3'UTR-derived RNAs are indeed capped and widespread in mammalian cells. By using a combination of AGO2 enhanced individual nucleotide resolution UV crosslinking and immunoprecipitation (eiCLIP) and CAGE following siRNA treatment, we find that these 3'UTR-derived RNAs likely originate from AGO2-binding sites, and most often occur at locations with G-rich motifs bound by the RNA-binding protein UPF1. High-resolution imaging and long-read sequencing analysis validate several 3'UTR-derived RNAs, showcase their variable abundance and show that they may not co-localise with the parental mRNAs. Taken together, we provide new insights into the origin and prevalence of 3'UTR-derived RNAs, show the utility of CAGE-seq for their genome-wide detection and provide a rich dataset for exploring new biology of a poorly understood new class of RNAs., (© 2024. The Author(s).)

Published
2024
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5. Creation of de novo cryptic splicing for ALS and FTD precision medicine.

Author

Wilkins OG, Chien MZYJ, Wlaschin JJ, Barattucci S, Harley P, Mattedi F, Mehta PR, Pisliakova M, Ryadnov E, Keuss MJ, Thompson D, Digby H, Knez L, Simkin RL, Diaz JA, Zanovello M, Brown AL, Darbey A, Karda R, Fisher EMC, Cunningham TJ, Le Pichon CE, Ule J, and Fratta P

Subjects
Animals, Humans, Mice, Deep Learning, Gene Editing, HEK293 Cells, RNA Splice Sites, RNA-Binding Proteins metabolism, RNA-Binding Proteins genetics, Amyotrophic Lateral Sclerosis genetics, Amyotrophic Lateral Sclerosis therapy, DNA-Binding Proteins genetics, DNA-Binding Proteins metabolism, Frontotemporal Dementia genetics, Frontotemporal Dementia therapy, Precision Medicine, RNA Splicing
Abstract

Loss of function of the RNA-binding protein TDP-43 (TDP-LOF) is a hallmark of amyotrophic lateral sclerosis (ALS) and other neurodegenerative disorders. Here we describe TDP-REG, which exploits the specificity of cryptic splicing induced by TDP-LOF to drive protein expression when and where the disease process occurs. The SpliceNouveau algorithm combines deep learning with rational design to generate customizable cryptic splicing events within protein-coding sequences. We demonstrate that expression of TDP-REG reporters is tightly coupled to TDP-LOF in vitro and in vivo. TDP-REG enables genomic prime editing to ablate the UNC13A cryptic donor splice site specifically upon TDP-LOF. Finally, we design TDP-REG vectors encoding a TDP-43/Raver1 fusion protein that rescues key pathological cryptic splicing events, paving the way for the development of precision therapies for TDP43-related disorders.

Published
2024
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6. Journal update monthly top five.

Author

Mclaughlan D, Barrett L, Hindley J, Digby H, Alves T, and McLoughlin T

Subjects
Humans, Emergency Medicine, Periodicals as Topic
Abstract

Competing Interests: Competing interests: None declared.

Published
2024
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7. Creation of de novo cryptic splicing for ALS/FTD precision medicine.

Author

Wilkins OG, Chien MZYJ, Wlaschin JJ, Pisliakova M, Thompson D, Digby H, Simkin RL, Diaz JA, Mehta PR, Keuss MJ, Zanovello M, Brown AL, Harley P, Darbey A, Karda R, Fisher EMC, Cunningham TJ, Le Pichon CE, Ule J, and Fratta P

Abstract

A system enabling the expression of therapeutic proteins specifically in diseased cells would be transformative, providing greatly increased safety and the possibility of pre-emptive treatment. Here we describe "TDP-REG", a precision medicine approach primarily for amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), which exploits the cryptic splicing events that occur in cells with TDP-43 loss-of-function (TDP-LOF) in order to drive expression specifically in diseased cells. In addition to modifying existing cryptic exons for this purpose, we develop a deep-learning-powered algorithm for generating customisable cryptic splicing events, which can be embedded within virtually any coding sequence. By placing part of a coding sequence within a novel cryptic exon, we tightly couple protein expression to TDP-LOF. Protein expression is activated by TDP-LOF in vitro and in vivo , including TDP-LOF induced by cytoplasmic TDP-43 aggregation. In addition to generating a variety of fluorescent and luminescent reporters, we use this system to perform TDP-LOF-dependent genomic prime editing to ablate the UNC13A cryptic donor splice site. Furthermore, we design a panel of tightly gated, autoregulating vectors encoding a TDP-43/Raver1 fusion protein, which rescue key pathological cryptic splicing events. In summary, we combine deep-learning and rational design to create sophisticated splicing sensors, resulting in a platform that provides far safer therapeutics for neurodegeneration, potentially even enabling preemptive treatment of at-risk individuals., Competing Interests: Competing interests: PF and OGW have filed a patent application relating to TDP-REG technology. PF, ALB, MJK and OGW have filed a patent application relating to the use of ASO therapies for correcting cryptic splicing in UNC13A.

Published
2023
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