906 research outputs found
Spinal muscular atrophy: Factors that modulate motor neurone vulnerability.
Spinal muscular atrophy (SMA), a leading genetic cause of infant death, is a neurodegenerative disease characterised by the selective loss of particular groups of motor neurones in the anterior horn of the spinal cord with concomitant muscle weakness. To date, no effective treatment is available, however, there are ongoing clinical trials are in place which promise much for the future. However, there remains an ongoing problem in trying to link a single gene loss to motor neurone degeneration. Fortunately, given successful disease models that have been established and intensive studies on SMN functions in the past ten years, we are fast approaching the stage of identifying the underlying mechanisms of SMA pathogenesis Here we discuss potential disease modifying factors on motor neurone vulnerability, in the belief that these factors give insight into the pathological mechanisms of SMA and therefore possible therapeutic targets
TDP43 proteinopathy is associated with aberrant DNA methylation in human amyotrophic lateral sclerosis
Background
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by motor neurone (MN) degeneration and death. ALS can be sporadic (sALS) or familial, with a number of associated gene mutations, including C9orf72 (C9ALS). DNA methylation is an epigenetic mechanism whereby a methyl group is attached to a cytosine (5mC), resulting in gene expression repression. 5mC can be further oxidized to 5‐hydroxymethylcytosine (5hmC). DNA methylation has been studied in other neurodegenerative diseases, but little work has been conducted in ALS.
Aims
To assess differences in DNA methylation in individuals with ALS and the relationship between DNA methylation and TDP43 pathology.
Methods
Post mortem tissue from controls, sALS cases and C9ALS cases were assessed by immunohistochemistry for 5mC and 5hmC in spinal cord, motor cortex and prefrontal cortex. LMNs were extracted from a subset of cases using laser capture microdissection. DNA from these underwent analysis using the MethylationEPIC array to determine which molecular processes were most affected.
Results
There were higher levels of 5mC and 5hmC in sALS and C9ALS in the residual lower motor neurones (LMNs) of the spinal cord. Importantly, in LMNs with TDP43 pathology there was less nuclear 5mC and 5hmC compared to the majority of residual LMNs that lacked TDP43 pathology. Enrichment analysis of the array data suggested RNA metabolism was particularly affected.
Conclusions
DNA methylation is a contributory factor in ALS LMN pathology. This is not so for glia or neocortical neurones
Decoherence in elastic and polaronic transport via discrete quantum states
Here we study the effect of decoherence on elastic and polaronic transport
via discrete quantum states. The calculations are performed with the help of
nonperturbative computational scheme, based on the Green's function theory
within the framework of polaron transformation (GFT-PT), where the many-body
electron-phonon interaction problem is mapped exactly into a single-electron
multi-channel scattering problem. In particular, the influence of dephasing and
relaxation processes on the shape of the electrical current and shot noise
curves is discussed in detail under the linear and nonlinear transport
conditions.Comment: 11 pages, 3 figure
Modeling transport through single-molecule junctions
Non-equilibrium Green's functions (NEGF) formalism combined with extended
Huckel (EHT) and charging model are used to study electrical conduction through
single-molecule junctions. Analyzed molecular complex is composed of asymmetric
1,4-Bis((2'-para-mercaptophenyl)-ethinyl)-2-acetyl-amino-5-nitro-benzene
molecule symmetrically coupled to two gold electrodes [Reichert et al., Phys.
Rev. Lett. Vol.88 (2002), pp. 176804]. Owing to this model, the accurate values
of the current flowing through such junction can be obtained by utilizing basic
fundamentals and coherently deriving model parameters. Furthermore, the
influence of the charging effect on the transport characteristics is
emphasized. In particular, charging-induced reduction of conductance gap,
charging-induced rectification effect and charging-generated negative value of
the second derivative of the current with respect to voltage are observed and
examined for molecular complex.Comment: 8 pages, 3 figure
Domain-swapped T cell receptors improve the safety of TCR gene therapy
T cells engineered to express a tumor-specific {alpha}{beta} T cell receptor (TCR) mediate anti-tumor immunity. However, mispairing of the therapeutic {alpha}{beta} chains with endogenous {alpha}{beta} chains reduces therapeutic TCR surface expression and generates self-reactive TCRs. We report a general strategy to prevent TCR mispairing: swapping constant domains between the {alpha} and {beta} chains of a therapeutic TCR. When paired, domain-swapped (ds)TCRs assemble with CD3, express on the cell surface, and mediate antigen-specific T cell responses. By contrast, dsTCR chains mispaired with endogenous chains cannot properly assemble with CD3 or signal, preventing autoimmunity. We validate this approach in cell-based assays and in a mouse model of TCR gene transfer-induced graft-versus-host disease. We also validate a related approach whereby replacement of {alpha}{beta} TCR domains with corresponding {gamma}{delta} TCR domains yields a functional TCR that does not mispair. This work enables the design of safer TCR gene therapies for cancer immunotherapy
Current Profiles of Molecular Nanowires; DFT Green Function Representation
The Liouville-space Green function formalism is used to compute the current
density profile across a single molecule attached to electrodes. Time ordering
is maintained in real, physical, time, avoiding the use of artificial time
loops and backward propagations. Closed expressions for molecular currents,
which only require DFT calculations for the isolated molecule, are derived to
fourth order in the molecule/electrode coupling.Comment: 21 page
Neuropathological characterisation of a novel TBK1 loss of function mutation associated with amyotrophic lateral sclerosis
Mutations in TANK binding kinase gene (TBK1) have been identified as causative in amyotrophic lateral sclerosis (ALS). Here, we examine the spectrum of TBK1 mutations in a cohort of ALS patients from Northern England, comparing missense and loss of function mutations with clinical phenotype. Analysis of 290 ALS cases identified seven variants, including one novel in-frame deletion (p.Ile85del). In silico analysis and review of the literature suggested that four variants, one nonsense mutation (p.Glu2Ter), two in-frame deletions (p.Ile85del, p.Glu643del) and one missense mutation (p.Gln565Pro) were pathogenic, whilst the remaining three missense mutations were variants of uncertain significance or benign. Post-mortem material was available from the patient with the novel in-frame deletion. Neuropathological examination established this individual had classical ALS pathology, with moderate phosphorylated TDP-43 neuronal and glial cytoplasmic inclusions in the motor cortex, skein-like inclusions in the lower motor neurons and “pre-inclusions” in the medulla. This corresponds to Type B FTLD-TDP pathology and is consistent with previously published literature on TBK1 mutants. In addition to demonstrating no changes in TBK1 staining, we are the first to show there was no differential expression of interferon regulatory factor IRF3, a downstream effector of TBK1 in the innate immunity pathway, in the TBK1-mutant tissue compared to controls. Comparison of clinical and neuropathological data, however, suggests that TBK1-ALS cases show classical ALS pathology but no specific phenotype
Carbon clusters near the crossover to fullerene stability
The thermodynamic stability of structural isomers of ,
, and , including
fullerenes, is studied using density functional and quantum Monte Carlo
methods. The energetic ordering of the different isomers depends sensitively on
the treatment of electron correlation. Fixed-node diffusion quantum Monte Carlo
calculations predict that a isomer is the smallest stable
graphitic fragment and that the smallest stable fullerenes are the
and clusters with and
symmetry, respectively. These results support proposals that a
solid could be synthesized by cluster deposition.Comment: 4 pages, includes 4 figures. For additional graphics, online paper
and related information see http://www.tcm.phy.cam.ac.uk/~prck
Technoscience and the modernization of freshwater fisheries assessment and management
Inland fisheries assessment and management are challenging given the inherent com-
plexity of working in diverse habitats (e.g., rivers, lakes, wetlands) that are dynamic
on organisms that are often cryptic and where fishers are often highly mobile. Yet,
technoscience is offering new tools that have the potential to reimagine how inland
fisheries are assessed and managed. So-called ‘‘technoscience’’ refers to instances in
which science and technology unfurl together, offering novel ways of spurring and
achieving meaningful change. This paper considers the role of technoscience and its
potential for modernizing the assessment and management of inland fisheries. It first
explores technoscience and its potential benefits, followed by presentation of a series
of synopses that explore the application (both successes and challenges) of new tech-
nologies such as environmental DNA (eDNA), genomics, electronic tags, drones, phone
apps, iEcology, and artificial intelligence to assessment and management. The paper
also considers the challenges and barriers that exist in adopting new technologies. The
paper concludes with a provocative assessment of the potential of technoscience to
reform and modernize inland fisheries assessment and management. Although these
tools are increasingly being embraced, there is a lack of platforms for aggregating these
data streams and providing managers with actionable information in a timely manner.
The ideas presented here should serve as a catalyst for beginning to work collectively
and collaboratively towards fisheries assessment and management systems that harness
the power of technology and serve to modernize inland fisheries management. Such
transformation is urgently needed given the dynamic nature of environmental change,
the evolving threat matrix facing inland waters, and the complex behavior of fishers.
Quite simply, a dynamic world demands dynamic fisheries management; technoscience
has made that within reach.publishedVersio
Celadonite and smectite formation in the Úrkút Mn-carbonate ore deposit (Hungary)
Synsedimentary and early diagenetic oxygen levels are estimated by evaluating celadonitesmectite formation in marine Jurassic black shale-hosted manganese-carbonates. Celadonite formed under suboxic-dysaerobic conditions, Al-rich Fe-smectite formed at suboxic-anaerobic conditions, and nontronite formed at anoxic-anaerobic conditions during sedimentary burial. A genetic pathway by direct precipitation from solution is proposed for the enormous mass of celadonite, based on mineral and textural evidence. Lamination of the manganese ore is independent of clay-mineral composition and was given by a series of mineralized microbial Ferich biomats
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