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"THOMAS, Alun"
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Automated size selection for short cell-free DNA fragments enriches for circulating tumor DNA and improves error correction during next generation sequencing
Circulating tumor-derived cell-free DNA (ctDNA) enables non-invasive diagnosis, monitoring, and treatment susceptibility testing in human cancers. However, accurate detection of variant alleles, particularly during untargeted searches, remains a principal obstacle to widespread application of cell-free DNA in clinical oncology. In this study, isolation of short cell-free DNA fragments is shown to enrich for tumor variants and improve correction of PCR- and sequencing-associated errors. Subfractions of the mononucleosome of circulating cell-free DNA (ccfDNA) were isolated from patients with melanoma, pancreatic ductal adenocarcinoma, and colorectal adenocarcinoma using a high-throughput-capable automated gel-extraction platform. Using a 128-gene (128 kb) custom next-generation sequencing panel, variant alleles were on average 2-fold enriched in the short fraction (median insert size: ~142 bp) compared to the original ccfDNA sample, while 0.7-fold reduced in the fraction corresponding to the principal peak of the mononucleosome (median insert size: ~167 bp). Size-selected short fractions compared to the original ccfDNA yielded significantly larger family sizes (i.e., PCR duplicates) during in silico consensus sequence interpretation via unique molecular identifiers. Increments in family size were associated with a progressive reduction of PCR and sequencing errors. Although consensus read depth also decreased at larger family sizes, the variant allele frequency in the short ccfDNA fraction remained consistent, while variant detection in the original ccfDNA was commonly lost at family sizes necessary to minimize errors. These collective findings support the automated extraction of short ccfDNA fragments to enrich for ctDNA while concomitantly reducing false positives through in silico error correction.
Journal Article
Timed daily exercise remodels circadian rhythms in mice
Regular exercise is important for physical and mental health. An underexplored and intriguing property of exercise is its actions on the body’s 24 h or circadian rhythms. Molecular clock cells in the brain’s suprachiasmatic nuclei (SCN) use electrical and chemical signals to orchestrate their activity and convey time of day information to the rest of the brain and body. To date, the long-lasting effects of regular physical exercise on SCN clock cell coordination and communication remain unresolved. Utilizing mouse models in which SCN intercellular neuropeptide signaling is impaired as well as those with intact SCN neurochemical signaling, we examined how daily scheduled voluntary exercise (SVE) influenced behavioral rhythms and SCN molecular and neuronal activities. We show that in mice with disrupted neuropeptide signaling, SVE promotes SCN clock cell synchrony and robust 24 h rhythms in behavior. Interestingly, in both intact and neuropeptide signaling deficient animals, SVE reduces SCN neural activity and alters GABAergic signaling. These findings illustrate the potential utility of regular exercise as a long-lasting and effective non-invasive intervention in the elderly or mentally ill where circadian rhythms can be blunted and poorly aligned to the external world.Using mice with disrupted neuropeptide signaling, Hughes et al. show that daily scheduled voluntary exercise (SVE) promotes suprachiasmatic nuclei (SCN) clock cell synchrony and robust 24 h rhythms in behavior. This study suggests the potential utility of regular exercise as a non-invasive intervention for the elderly or mentally ill, where circadian rhythms can be poorly aligned to the external world.
Journal Article
Editorial: The circadian circus – how our clocks keep us ticking
According to the above schema, circadian clocks can be divided into three conceptual components at the molecular level: (i) pacemakers, generating and sustaining circadian rhythms, and adjusting phase to match the environment; (ii) the input pathways, through which external time cues reach the pacemakers; and (iii) the output pathways, through which circadian clocks affect physiology (Koronowski and Sassone-Corsi, 2021). Circadian clocks are affected by an enormous variety of stimuli known to trigger intracellular signaling pathways, including pathways mediated protein kinase C, glucocorticoid, Wnt, tumor growth factor-b/activin, mitogen-activated protein kinases, calcium, and growth hormone (GH) (Schibler and Sassone-Corsi, 2002; Hirota and Fukada, 2004; Uchida et al., 2010). Delorme et al. evaluate the effects of long-term exposure of mice to abnormal lighting conditions, including DLAN, revealing that DLAN leads to altered circadian behavior and motor function. [...]the same authors provide evidence that these phenotypes are mediated by changes in neuronal coordination that does not involve the central clock in the SCN. [...]it is critical that we gain a better understanding of the association of diseases with the dysregulation of circadian clocks by environmental factors in modern society, and develop lifestyle intervention strategies to maintain proper circadian clock regulation.
Journal Article
Novel pedigree analysis implicates DNA repair and chromatin remodeling in multiple myeloma risk
The high-risk pedigree (HRP) design is an established strategy to discover rare, highly-penetrant, Mendelian-like causal variants. Its success, however, in complex traits has been modest, largely due to challenges of genetic heterogeneity and complex inheritance models. We describe a HRP strategy that addresses intra-familial heterogeneity, and identifies inherited segments important for mapping regulatory risk. We apply this new Shared Genomic Segment (SGS) method in 11 extended, Utah, multiple myeloma (MM) HRPs, and subsequent exome sequencing in SGS regions of interest in 1063 MM / MGUS (monoclonal gammopathy of undetermined significance-a precursor to MM) cases and 964 controls from a jointly-called collaborative resource, including cases from the initial 11 HRPs. One genome-wide significant 1.8 Mb shared segment was found at 6q16. Exome sequencing in this region revealed predicted deleterious variants in USP45 (p.Gln691* and p.Gln621Glu), a gene known to influence DNA repair through endonuclease regulation. Additionally, a 1.2 Mb segment at 1p36.11 is inherited in two Utah HRPs, with coding variants identified in ARID1A (p.Ser90Gly and p.Met890Val), a key gene in the SWI/SNF chromatin remodeling complex. Our results provide compelling statistical and genetic evidence for segregating risk variants for MM. In addition, we demonstrate a novel strategy to use large HRPs for risk-variant discovery more generally in complex traits.
Journal Article
The stochastic nature of errors in next-generation sequencing of circulating cell-free DNA
Challenges with distinguishing circulating tumor DNA (ctDNA) from next-generation sequencing (NGS) artifacts limits variant searches to established solid tumor mutations. Here we show early and random PCR errors are a principal source of NGS noise that persist despite duplex molecular barcoding, removal of artifacts due to clonal hematopoiesis of indeterminate potential, and suppression of patterned errors. We also demonstrate sample duplicates are necessary to eliminate the stochastic noise associated with NGS. Integration of sample duplicates into NGS analytics may broaden ctDNA applications by removing NGS-related errors that confound identification of true very low frequency variants during searches for ctDNA without a priori knowledge of specific mutations to target.
Journal Article
Linkage Analysis of Extended High-Risk Pedigrees Replicates a Cutaneous Malignant Melanoma Predisposition Locus on Chromosome 9q21
Three predisposition genes have been identified for cutaneous malignant melanoma (CMM), but they account for only ∼25% of melanoma clusters/pedigrees. Linkage analyses of melanoma pedigrees from many countries have failed to identify significant linkage evidence for the remaining predisposition genes that must exist. The Utah linkage analysis approach of using singly informative extended high-risk pedigrees combined with high-density single-nucleotide polymorphism (SNP) markers has successfully identified significant linkage evidence for two regions. This is, to our knowledge, the first genome-wide linkage analysis of the extended Utah high-risk CMM pedigrees, and it provides confirmation of linkage for a chromosome 9q region previously reported in Danish pedigrees. This report confirms that linkage analysis for common disorders can be successful in analysis of high-density markers in sets of singly informative high-risk pedigrees.
Journal Article
Exchange Rate and Foreign Interest Rate Linkages for Sub-Saharan Africa Floaters (PDF Download)
The paper considers the determinants of exchange rate movements among sub-Saharan countries that have flexible exchange rate regimes. The determinants are based on the law of one price and interest parity conditions. Results indicate that the exchange rates have responded significantly to changes in the US Treasury bill rate and to the EMBI spread in recent years. The effects are more important for countries with open capital accounts. On the other hand the paper does not provide any support for the interest rate parity theory because domestic interest rates have no bearing on exchange rate movements.
eBook
Do Debt-Service Savings and Grants Boost Social Expenditures?
This paper evaluates whether debt relief and grants can boost social expenditures in lowincome countries. It finds that declines in debt-service help raise social expenditures, but no relationship between grants and social expenditures. Moreover, since the mid-1980s, lowincome countries have managed to fully insulate social expenditures from the effects of budgetary tightening. The magnitude of the impact of these effects on social expenditures, however, is dwarfed by the resources needed to enable these countries to reach the Millennium Development Goals.
eBook
The Incidence and Effectiveness of Prior Actions in IMF-Supported Programs
Prior actions are measures that need to be implemented prior to Board approval of an IMFsupported program. This paper examines whether such prior actions can signal a willingness to implement reforms, especially when the member's track record is weak. We find some support for this signaling role, particularly for programs supported by the General Resources Account (GRA). Controlling for the member's previous track record, prior actions are associated with greater compliance with other structural conditions, suggesting their possible use as a screening device. Moreover, prior actions set at program approval serve as a useful screening device and strengthen the macroeconomic targets set out in the IMF-supported program. The results also reveal a demonstrable screening effect on growth over the medium term, since the growth impact of the ratio of prior actions at the outset versus the rest of the program is significantly positive while the total number of prior actions is not statistically significant.
eBook