Publications by authors named "J D Matthew Hughes"

6,028 Publications

Reactivation of a developmentally silenced embryonic globin gene.

Nat Commun 2021 07 21;12(1):4439. Epub 2021 Jul 21.

MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.

The α- and β-globin loci harbor developmentally expressed genes, which are silenced throughout post-natal life. Reactivation of these genes may offer therapeutic approaches for the hemoglobinopathies, the most common single gene disorders. Here, we address mechanisms regulating the embryonically expressed α-like globin, termed ζ-globin. We show that in embryonic erythroid cells, the ζ-gene lies within a ~65 kb sub-TAD (topologically associating domain) of open, acetylated chromatin and interacts with the α-globin super-enhancer. By contrast, in adult erythroid cells, the ζ-gene is packaged within a small (~10 kb) sub-domain of hypoacetylated, facultative heterochromatin within the acetylated sub-TAD and that it no longer interacts with its enhancers. The ζ-gene can be partially re-activated by acetylation and inhibition of histone de-acetylases. In addition to suggesting therapies for severe α-thalassemia, these findings illustrate the general principles by which reactivation of developmental genes may rescue abnormalities arising from mutations in their adult paralogues.
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http://dx.doi.org/10.1038/s41467-021-24402-3DOI Listing
July 2021

Large palindromes on the primate X Chromosome are preserved by natural selection.

Genome Res 2021 Jul 21. Epub 2021 Jul 21.

Whitehead Institute, Cambridge, Massachusetts 02142, USA.

Mammalian sex chromosomes carry large palindromes that harbor protein-coding gene families with testis-biased expression. However, there are few known examples of sex-chromosome palindromes conserved between species. We identified 26 palindromes on the human X Chromosome, constituting more than 2% of its sequence, and characterized orthologous palindromes in the chimpanzee and the rhesus macaque using a clone-based sequencing approach that incorporates full-length nanopore reads. Many of these palindromes are missing or misassembled in the current reference assemblies of these species' genomes. We find that 12 human X palindromes have been conserved for at least 25 million years, with orthologs in both chimpanzee and rhesus macaque. Insertions and deletions between species are significantly depleted within the X palindromes' protein-coding genes compared to their noncoding sequence, demonstrating that natural selection has preserved these gene families. The spacers that separate the left and right arms of palindromes are a site of localized structural instability, with seven of 12 conserved palindromes showing no spacer orthology between human and rhesus macaque. Analysis of the 1000 Genomes Project data set revealed that human X-palindrome spacers are enriched for deletions relative to arms and flanking sequence, including a common spacer deletion that affects 13% of human X Chromosomes. This work reveals an abundance of conserved palindromes on primate X Chromosomes and suggests that protein-coding gene families in palindromes (most of which remain poorly characterized) promote X-palindrome survival in the face of ongoing structural instability.
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http://dx.doi.org/10.1101/gr.275188.120DOI Listing
July 2021

Temporal and regional variation in catch across an extensive coastal recreational fishery: Exploring the utility of survey methods to guide and assess spatio-temporal management initiatives.

PLoS One 2021 21;16(7):e0254388. Epub 2021 Jul 21.

Kewagama Research, Doonan, Queensland, Australia.

As global research into recreational fishing gains momentum due to the pursuit's biological, social and economic impacts, information on regional and temporal patterns of recreational exploitation will continue to enable objective assessment and development of management initiatives for exploited species. This paper demonstrates the utility of offsite survey methods in assessing spatial and temporal differences in recorded catches from a large, diffuse and heterogenous coastal recreational fishery. Using the estuarine recreational fishery that operates along the coast of New South Wales, Australia as a case study, survey data was employed to quantify annual (June 2013-May 2014) state-wide estuarine catch. Generalized linear mixed effects models were then applied to expanded catch estimates from surveyed households to examine the influence of zone and season on the kept and released numbers of snapper (Pagrus auratus), dusky flathead (Platycephalus fuscus) and bream (Acanthopagrus spp. complex comprised of A. butcheri, A. australis and their hybrids). For kept bream, significant differential seasonal effects were observed in all regions except the Mid-South Coast. For released bream, numbers were greatest in Sydney and during Summer and Winter. For kept snapper, the greatest harvest was recorded in the Mid-South Coast but season had no effect. Differential seasonal effects were found in each zone for released snapper. For kept dusky flathead, the greatest numbers were recorded in Sydney and the Mid-South Coast but season had no effect. We conclude by assessing some current spatial and temporal management initiatives in light of the uncovered patterns of recreational catch and consider the implications of these patterns in terms of future ecosystem-based management recommendations aimed at achieving ecological, social and economic sustainability in fisheries.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0254388PLOS
July 2021

Calculation algorithms and penumbra: underestimation of dose in organs at risk in dosimetry audits.

Med Phys 2021 Jul 21. Epub 2021 Jul 21.

Physical Sciences, Peter MacCallum Cancer Centre, Melbourne, VIC, 3000, Australia.

Purpose: The aim of this study is to investigate overdose to organs at risk (OARs) observed in dosimetry audits in Monte Carlo (MC) algorithms and Linear Boltzmann Transport Equation (LBTE) algorithms. The impact of penumbra modelling on OAR dose was assessed with adjustment of MC modelling parameters and the clinical relevance of the audit cases was explored with a planning study of spine and head and neck (H&N) patient cases.

Methods: Dosimetric audits performed by the Australian Clinical Dosimetry Service (ACDS) of 43 anthropomorphic spine plans and 1318 C-shaped target plans compared the planned dose to doses measured with ion chamber, microdiamond, film, and ion chamber array. A MC EGSnrc model was created to simulate the C-shape target case. The electron cut-off energy E was set at 500 keV, 200 keV, and 10 keV, and differences between 1 mm and 3 mm voxel were calculated. A planning study with 10 patient stereotactic body radiotherapy (SBRT) spine plans and 10 patient H&N plans were calculated in both Acuros XB (AXB) v15.6.06 and Anisotropic Analytical Algorithm (AAA) v15.6.06. The patient contour was overridden to water as only the penumbral differences between the two different algorithms were under investigation.

Results: The dosimetry audit results show that for the SBRT spine case, plans calculated in AXB are colder than what is measured in the spinal cord by 5-10%. This was also observed for other audit cases where a C-shape target is wrapped around an OAR where the plans were colder by 3-10%. Plans calculated with Monaco MC were colder than measurements by approximately 7% with the OAR surround by a C-shape target, but these differences were not noted in the SBRT spine case. Results from the clinical patient plans showed the AXB was on average 7.4% colder than AAA when comparing the minimum dose in the spinal cord OAR. This average difference between AXB and AAA reduced to 4.5% when using the more clinically relevant metric of maximum dose in the spinal cord. For the H&N plans, AXB was cooler on average than AAA in the spinal cord OAR (1.1%), left parotid (1.7%), and right parotid (2.3%). The EGSnrc investigation also noted similar, but smaller differences. The beam penumbra modelled by E =500 keV was steeper than the beam penumbra modelled by E = 10keV as the full scatter is not accounted for, which resulted in less dose being calculated in a central OAR region where the penumbra contributes much of the dose. The dose difference when using 2.5 mm voxels of the centre of the OAR between 500keV and 10keV was 3%, reducing to 1% between 200keV and 10keV.

Conclusions: Lack of full penumbral modelling due to approximations in the algorithms in MC based or LBTE algorithms are a contributing factor as to why these algorithms under-predict the dose to OAR when the treatment volume is wrapped around the OAR. The penumbra modelling approximations also contributes to AXB plans predicting colder doses than AAA in areas that are in the vicinity of beam penumbra. This effect is magnified in regions where there are many beam penumbras, for example in the spinal cord for spine SBRT cases.
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http://dx.doi.org/10.1002/mp.15123DOI Listing
July 2021

Post-traumatic stress disorder is associated with alterations in evoked cortical activation during visual recognition of scenes.

Neuroimage Clin 2021 Jul 3;31:102752. Epub 2021 Jul 3.

National Intrepid Center of Excellence, Walter Reed National Military Medical Center, Bethesda, MD, USA; Behavioral Biology Branch, Walter Reed Army Institute of Research, Silver Spring, MD, USA. Electronic address:

We recorded magnetoencephalography data during a visual recognition task in participants with combat exposure (n = 40, age: 41.2 ± 7.2 years) to investigate the relationship between the evoked brain activity, behavioral performance, and the severity of their post-traumatic stress symptoms assessed using the PTSD Check List for DSM V version (PCL-5). In an initial study session, participants were presented with a series of images of outdoor scenes and were instructed to study the images for an upcoming recognition test. In a subsequent session, the original images were shown intermixed with novel images while participants performed the recognition task. PCL-5 scores were negatively correlated with discrimination performance and with the recognition accuracy for original images. During the recognition session, higher PCL-5 scores were associated with reduced relative power of the evoked response to original images from 100 ms to 300 ms following the image onset over a distributed brain network including the bilateral inferior frontal gyri, left middle frontal gyrus, left supramarginal gyrus, right precuneus and the bilateral superior temporal gyri. These findings indicate that the lower recognition performance in participants with higher PTSD symptom severity is associated with altered cortical activity in brain regions that are known to play a role in the elaboration on visual cues that supports recollection.
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http://dx.doi.org/10.1016/j.nicl.2021.102752DOI Listing
July 2021