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"Lloyd, Thomas"
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Literary experiments in magazine publishing : beyond serialisation
As the nineteenth century came to an end, a number of voices within the British and American magazine industries pushed back against serialisation as the dominant publication mode, experimenting instead with less conventional magazine formats. This book explores these formats, focusing (in particular) on the ways in which the periodical press first published 'The Adventures of Huckleberry Finn', 'The Picture of Dorian Gray' and 'The Return of Sherlock Holmes'.
Book
Disruption of axonal transport in neurodegeneration
Neurons are markedly compartmentalized, which makes them reliant on axonal transport to maintain their health. Axonal transport is important for anterograde delivery of newly synthesized macromolecules and organelles from the cell body to the synapse and for the retrograde delivery of signaling endosomes and autophagosomes for degradation. Dysregulation of axonal transport occurs early in neurodegenerative diseases and plays a key role in axonal degeneration. Here, we provide an overview of mechanisms for regulation of axonal transport; discuss how these mechanisms are disrupted in neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, Huntington's disease, hereditary spastic paraplegia, amyotrophic lateral sclerosis, and Charcot-Marie-Tooth disease; and discuss therapeutic approaches targeting axonal transport.
Journal Article
The C9orf72 repeat expansion disrupts nucleocytoplasmic transport
The hexanucleotide repeat expansion (HRE) GGGGCC (G
4
C
2
) in
C9orf72
is the most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Recent studies support an HRE RNA gain-of-function mechanism of neurotoxicity, and we previously identified protein interactors for the G
4
C
2
RNA including RanGAP1. A candidate-based genetic screen in
Drosophila
expressing 30 G
4
C
2
repeats identified RanGAP (
Drosophila
orthologue of human RanGAP1), a key regulator of nucleocytoplasmic transport, as a potent suppressor of neurodegeneration. Enhancing nuclear import or suppressing nuclear export of proteins also suppresses neurodegeneration. RanGAP physically interacts with HRE RNA and is mislocalized in HRE-expressing flies, neurons from
C9orf72
ALS patient-derived induced pluripotent stem cells (iPSC-derived neurons), and in
C9orf72
ALS patient brain tissue. Nuclear import is impaired as a result of HRE expression in the fly model and in
C9orf72
iPSC-derived neurons, and these deficits are rescued by small molecules and antisense oligonucleotides targeting the HRE G-quadruplexes. Nucleocytoplasmic transport defects may be a fundamental pathway for ALS and FTD that is amenable to pharmacotherapeutic intervention.
A candidate-based genetic screen in
Drosophila
expressing 30 G
4
C
2
-repeat-containing RNAs finds that RanGAP, a key regulator of nucleocytoplasmic transport, is a potent suppressor of neurodegeneration; the defects caused by the G
4
C
2
repeat expansions can be rescued with antisense oligonucleotides or small molecules targeting the G-quadruplexes.
A novel mechanism of neurodegeneration
The most common cause of the debilitating disease amyotrophic lateral sclerosis (ALS) is a hexanucleotide repeat expansion GGGGCC (G4C2) in the
C9orf72
gene. Two studies in this issue use contrasting methods to arrive at a molecular mechanism that may cause a familial form of the disease. Using a candidate-based genetic screen in
Drosophila
expressing 30 G
4
C
2
repeats (Ke Zhang
et al
.) or an unbiased genetic screen in
Drosophila
expressing 8, 28 or 58 G
4
C
2
repeat-containing transcripts (Brian Freibaum
et al
.), the two groups sought genes that enhance or suppress the disease phenotype. Zhang
et al
. identify the gene encoding RanGAP, a key regulator of nucleocytoplasmic transport, and Freibaum
et al
. identifies genes that encode components of the nuclear pore and the nucleocytoplasmic transport machinery. Both papers show deficits in nucleocytoplasmic transport in
Drosophila
cells expressing G
4
C
2
repeats and in iPSC-derived neurons from ALS patients. Zhang
et al
. show that these defects can be rescued with antisense oligonucleotides or small molecules targeting the G-quadruplexes.
Journal Article
TDP-43 and RNA form amyloid-like myo-granules in regenerating muscle
A dominant histopathological feature in neuromuscular diseases, including amyotrophic lateral sclerosis and inclusion body myopathy, is cytoplasmic aggregation of the RNA-binding protein TDP-43. Although rare mutations in
TARDBP
—the gene that encodes TDP-43—that lead to protein misfolding often cause protein aggregation, most patients do not have any mutations in
TARDBP
. Therefore, aggregates of wild-type TDP-43 arise in most patients by an unknown mechanism. Here we show that TDP-43 is an essential protein for normal skeletal muscle formation that unexpectedly forms cytoplasmic, amyloid-like oligomeric assemblies, which we call myo-granules, during regeneration of skeletal muscle in mice and humans. Myo-granules bind to mRNAs that encode sarcomeric proteins and are cleared as myofibres mature. Although myo-granules occur during normal skeletal-muscle regeneration, myo-granules can seed TDP-43 amyloid fibrils in vitro and are increased in a mouse model of inclusion body myopathy. Therefore, increased assembly or decreased clearance of functionally normal myo-granules could be the source of cytoplasmic TDP-43 aggregates that commonly occur in neuromuscular disease.
Cytoplasmic, amyloid-like oligomeric assemblies that contain TDP-43 are increased in damaged tissues with elevated regeneration, thereby enhancing the possibility of amyloid fibre formation and/or aggregation of TDP-43 in disease.
Journal Article
Ernst Ludwig Kirchner : imaginary travels
Throughout Ernst Ludwig Kirchner's career, one unifying theme emerges - the search for what he saw as unadulterated and primal. This volume explores the far-reaching influence of non-western art on Kirchner's oeuvre and the importance of his life in Davos, Switzerland, where he found a temporary peace despite the impending threat of censorship by the Nazis. Throughout the chapters of this book are reproductions of Kirchner's paintings as well as his sculptures, woodcuts, sketches, drawings, textiles, carvings, and furniture. Archival material in the form of letters and diary entries offer an unprecedented look into the artist's creative process. This study of one of the most talented and influential German Expressionist painters draws compelling conclusions about the influence of the imaginary on his work.
Book
IL-1-driven stromal–neutrophil interactions define a subset of patients with inflammatory bowel disease that does not respond to therapies
Current inflammatory bowel disease (IBD) therapies are ineffective in a high proportion of patients. Combining bulk and single-cell transcriptomics, quantitative histopathology and in situ localization across three cohorts of patients with IBD (total
n
= 376), we identify coexpressed gene modules within the heterogeneous tissular inflammatory response in IBD that map to distinct histopathological and cellular features (pathotypes). One of these pathotypes is defined by high neutrophil infiltration, activation of fibroblasts and vascular remodeling at sites of deep ulceration. Activated fibroblasts in the ulcer bed display neutrophil-chemoattractant properties that are IL-1R, but not TNF, dependent. Pathotype-associated neutrophil and fibroblast signatures are increased in nonresponders to several therapies across four independent cohorts (total
n
= 343). The identification of distinct, localized, tissular pathotypes will aid precision targeting of current therapeutics and provides a biological rationale for IL-1 signaling blockade in ulcerating disease.
Transcriptomic and histological profiling of gut biopsies from multiple independent cohorts of patients with inflammatory bowel disease identifies distinct histopathological, molecular and cellular features associated with treatment response, providing insights for patient stratification and precision therapy.
Journal Article
Thigh muscle MRI in immune-mediated necrotising myopathy: extensive oedema, early muscle damage and role of anti-SRP autoantibodies as a marker of severity
ObjectivesThe aims of this study were to define the pattern of muscle involvement in patients with immune-mediated necrotising myopathy (IMNM) relative to those with other inflammatory myopathies and to compare patients with IMNM with different autoantibodies.MethodsAll Johns Hopkins Myositis Longitudinal Cohort subjects with a thigh MRI (tMRI) who fulfilled criteria for IMNM, dermatomyositis (DM), polymyositis (PM), inclusion body myositis (IBM) or clinically amyopathic DM (CADM) were included in the study. Muscles were assessed for intramuscular and fascial oedema, atrophy and fatty replacement. Disease subgroups were compared using univariate and multivariate analyses. Patients with IMNM with anti-signal recognition particle (SRP) autoantibodies were compared with those with IMNM with anti-HMG-CoA reductase (HMGCR) autoantibodies.ResultsThe study included 666 subjects (101 IMNM, 176 PM, 219 DM, 17 CADM and 153 IBM). Compared with DM or PM, IMNM was characterised by a higher proportion of thigh muscles with oedema, atrophy and fatty replacement (p<0.01). Patients with IMNM with anti-SRP had more atrophy (19%, p=0.003) and fatty replacement (18%, p=0.04) than those with anti-HMGCR. In IMNM, muscle abnormalities were especially common in the lateral rotator and gluteal groups. Fascial involvement was most widespread in DM. Fatty replacement of muscle tissue began early during the course of disease in IMNM and the other groups. An optimal combination of tMRI features had only a 55% positive predictive value for diagnosing IMNM.ConclusionsCompared with patients with DM or PM, IMNM is characterised by more widespread muscle involvement. Anti-SRP-positive patients have more severe muscle involvement than anti-HMGCR-positive patients.
Journal Article
Multi-omic analysis of selectively vulnerable motor neuron subtypes implicates altered lipid metabolism in ALS
Amyotrophic lateral sclerosis (ALS) is a devastating disorder in which motor neurons degenerate, the causes of which remain unclear. In particular, the basis for selective vulnerability of spinal motor neurons (sMNs) and resistance of ocular motor neurons to degeneration in ALS has yet to be elucidated. Here, we applied comparative multi-omics analysis of human induced pluripotent stem cell-derived sMNs and ocular motor neurons to identify shared metabolic perturbations in inherited and sporadic ALS sMNs, revealing dysregulation in lipid metabolism and its related genes. Targeted metabolomics studies confirmed such findings in sMNs of 17 ALS (
SOD1
,
C9ORF72
,
TDP43 (TARDBP)
and sporadic) human induced pluripotent stem cell lines, identifying elevated levels of arachidonic acid. Pharmacological reduction of arachidonic acid levels was sufficient to reverse ALS-related phenotypes in both human sMNs and in vivo in
Drosophila
and
SOD1
G93A
mouse models. Collectively, these findings pinpoint a catalytic step of lipid metabolism as a potential therapeutic target for ALS.
By comparing human induced pluripotent stem cell-derived spinal and ocular motor neurons, the authors identify low levels of a natural 5-lipoxygenase inhibitor in amyotrophic lateral sclerosis (ALS) spinal motor neurons. Functional analogs of 5-lipoxygenase inhibitors can ameliorate in vitro and in vivo ALS phenotypes.
Journal Article