Epigenetic mechanisms can regulate how DNA is expressed independently of sequence and are known to be associated with various diseases. Among those epigenetic mechanisms, DNA methylation (DNAm) is ...influenced by genotype and the environment, making it an important molecular interface for studying disease etiology and progression. In this study, we examined the whole blood DNA methylation profiles of a large group of people with (pw) multiple sclerosis (MS) compared to those of controls. We reveal that methylation differences in pwMS occur independently of known genetic risk loci and show that they more strongly differentiate disease (AUC = 0.85, 95% CI 0.82–0.89, p = 1.22 × 10−29) than known genetic risk loci (AUC = 0.72, 95% CI: 0.66–0.76, p = 9.07 × 10−17). We also show that methylation differences in MS occur predominantly in B cells and monocytes and indicate the involvement of cell-specific biological pathways. Overall, this study comprehensively characterizes the immune cell-specific epigenetic architecture of MS.
The influence of diets containing gamma-linolenic acid (GLA; 18:3n-6) on sciatic nerve conduction velocity (NCV) was determined in diabetic rats. NCV was lower in diabetic rats fed diets supplemented ...with olive oil or sunflower seed oil than in nondiabetic rats; rats supplemented with GLA during a 5-wk diabetic period, however, did not exhibit significantly lower NCV. The mean proportion of the phospholipid fatty acid linoleic acid (18:2n-6) was higher in the sciatic nerves of diabetic rats than in the nondiabetic groups irrespective of dietary lipid treatment. Additionally, the proportion of linoleic acid was higher in the diabetic rats fed sunflower oil than in all other groups. Dietary GLA supplementation did not significantly influence the fatty acid composition of nerve membrane phospholipids and there was no obvious correlation between the fatty acid composition of nerve membrane phospholipids and NCV. The content of fructose and glucose in sciatic nerves was higher, whereas that of myo-inositol was lower, in diabetic rats than in nondiabetic rats; however, this was not significantly influenced by dietary GLA. GLA administration did not significantly influence Na(+)-K(+)-exchanging ATPase or ouabain binding activity in sciatic nerve preparations, both of which remained nonsignificantly different in the diabetic and nondiabetic groups. The results suggest that dietary GLA can prevent the deficit in NCV induced by diabetes and that this effect is independent of the nerve phospholipid fatty acid profile, sugar and polyol content, Na(+)-K(+)-exchanging ATPase activity, and ouabain binding. GLA may prevent the deficit in NCV indirectly, possibly by its role as a precursor of vasodilatory prostaglandins. These results confirm that GLA is the active component of evening primrose oil.
Purpose
Three-dimensional printing (3DP), or additive manufacturing, is an emergent fabrication technology for surgical devices. As a production method, 3DP enables physical realisation of surgical ...implants from geometrically complex digital-models in computer-aided design. Spine surgery has been an innovative adopter of 3DP technology for both patient-specific (PS) and market-available ‘Off-The-Shelf’ (OTS) implants. The present study assessed clinical evidence for efficacy and safety of both PS and OTS 3DP spinal implants through review of the published literature. The aim was to evaluate the clinical utility of 3DP devices for spinal surgery.
Methods
A systematic literature review of peer-reviewed papers featured on online medical databases evidencing the application of 3DP (PS and OTS) surgical spine implants was conducted in accordance with PRISMA guidelines.
Results
Twenty-two peer-reviewed articles and one book-chapter were eligible for systematic review. The published literature was limited to case reports and case series, with a predominant focus on PS designs fabricated from titanium alloys for surgical reconstruction in cases where neoplasia, infection, trauma or degenerative processes of the spine have precipitated significant anatomical complexity.
Conclusion
PS and 3DP OTS surgical implants have demonstrated considerable utility for the surgical management of complex spine pathology. The reviewed literature indicated that 3DP spinal implants have also been used safely, with positive surgeon- and patient-reported outcomes. However, these conclusions are tentative as the follow-up periods are still relatively short and the number of high-powered studies was limited. Single case and small case series reporting would benefit greatly from more standardised reporting of clinical, radiographic and biomechanical outcomes.
Graphic abstract
These slides can be retrieved under Electronic Supplementary Material.
There is increasing interest in using nonblood measures of glucocorticoids to assess the physiological response to chronic stress conditions. In sheep, cortisol has been measured in various matrices ...including saliva, feces, and wool, but comprehensive studies of the relationship between plasma concentrations of cortisol and concentrations in these nonblood matrices are lacking. Therefore, we tested the hypothesis that administration of cortisol to sheep would result in elevated concentrations of cortisol in blood, saliva, feces, and wool. Merino ewes were administered with saline or 2 mg/kg BW/d hydrocortisone acetate (HCA) by intramuscular (i.m.) injection for 28 d. This treatment was imposed to mimic circulating cortisol concentrations experienced during periods of chronic stress. Cortisol and cortisone were directly measured in plasma, saliva, and wool before, during, and after treatment with saline or HCA. A 14-d pre-treatment and a 14-d post-treatment period were used to measure time taken for glucocorticoid concentrations in each of the matrices to return to baseline levels. Cortisol was also measured in feces before, during, and after treatment. Wool growth was also measured. Before treatment, there was no difference in the concentration of cortisol or cortisone in plasma, saliva, feces, or wool in animals treated with saline or HCA. In contrast, treatment with HCA increased (P < 0.05) concentrations of both cortisol and cortisone in plasma, saliva, and wool and of cortisol in feces. In plasma, cortisol concentrations were higher than cortisone (P < 0.05), whereas saliva cortisol and cortisone concentrations did not differ significantly. In wool, the concentration of cortisone was about 19-fold higher than that of cortisol during treatment and post-treatment periods. Treatment with HCA inhibited wool growth. These results demonstrate that an increase in glucocorticoids in the blood of sheep is reflected in increases in saliva (after 7 d of treatment), feces (21 d), and wool (14 d). Therefore, measures of glucocorticoids in these matrices may provide a measure of activation of the adrenal glands over time in sheep, thereby providing a retrospective indicator of chronic stress. With respect to wool, it appears that cortisol is predominantly metabolized to cortisone in the skin or wool follicle and is stored as cortisone. Therefore wool cortisone may also provide an important measure in quantifiying chronic stress in sheep.
•Cortisol and cortisone concentrations differ significantly within each matrix.•Measuring chronic stress by glucocorticoids is day-dependent within each matrix.•Wool cortisone was 19-fold higher than cortisol in the during-and post-treatment periods.•Wool cortisone may provide a measure of chronic stress in merino sheep.
Global changes in DNA methylation are observed in development and disease, and single-cell analyses are highlighting the heterogeneous regulation of these processes. However, technical challenges ...associated with single-cell analysis of DNA methylation limit these studies. We present single-cell transposable element methylation sequencing (scTEM-seq) for cost-effective estimation of average DNA methylation levels. By targeting high-copy SINE Alu elements, we achieve amplicon bisulphite sequencing with thousands of loci covered in each scTEM-seq library. Parallel transcriptome analysis is also performed to link global DNA methylation estimates with gene expression. We apply scTEM-seq to KG1a acute myeloid leukaemia (AML) cells, and primary AML cells. Our method reveals global DNA methylation heterogeneity induced by decitabine treatment of KG1a cells associated with altered expression of immune process genes. We also compare global DNA methylation estimates to expression of transposable elements and find a predominance of negative correlations. Finally, we observe co-ordinated upregulation of many transposable elements in a sub-set of decitabine treated cells. By linking global DNA methylation heterogeneity with transcription, scTEM-seq will refine our understanding of epigenetic regulation in cancer and beyond.
The Xiangshan U deposit, the largest hydrothermal U deposit in China, is hosted in late Jurassic felsic volcanic rocks although the U mineralization post dates the volcanics by at least 20 Ma. The ...mineralization coincides with intrusion of local mantle-derived mafic dykes formed during Cretaceous crustal extension in South China. Ore-forming fluids are rich in CO
2, and U in the fluid is thought to have been dissolved in the form of UO
2 (CO
3)
2
2− and UO
2 (CO
3)
3
4− complexes.
This paper provides He and Ar isotope data of fluid inclusions in pyrites and C isotope data of calcites associated with U mineralization (pitchblende) in the Xiangshan U deposit. He isotopic compositions range between 0.1 and 2.0Ra (where Ra is the
3He/
4He ratio of air
=
1.39
×
10
−
6
) and correlates with
40Ar/
36Ar; although there is potential for significant
3He production via
6Li(
n,
α)
3H(
β)
3He reactions in a U deposit (due to abundant neutrons), nucleogenic production cannot account for either the
3He concentration in these fluids, nor the correlations between He and Ar isotopic compositions. It is more likely that the high
3He/
4He ratios represent trapped mantle-derived gases. A mantle origin for the volatiles of Xiangshan is consistent with the
δ
13C values of calcites, which vary from −
3.5‰ to −
7.7‰, overlapping the range of mantle CO
2.
The He, Ar and CO
2 characteristics of the ore-forming fluids responsible for the deposit are consistent with mixing between
3He- and CO
2-rich mantle-derived fluids and CO
2-poor meteoric fluids. These fluids were likely produced during Cretaceous extension and dyke intrusion which permitted mantle-derived CO
2 to migrate upward and remobilize U from the acid volcanic source rocks, resulting in the formation of the U deposit. Subsequent decay of U within the fluid inclusions has reduced the
3He/
4He ratio, and variations in U/
3He result in the range in
3He/
4He observed with U/
3He ratios in the range 5–17
×
10
3 likely corresponding to U concentrations in the fluids <
0.2 ppm.
The Xikuangshan antimony mine located at Central Hunan, China, is the largest antimony deposit in the world. Hydrothermal calcites from the Xikuangshan Mine display relatively large variations in REE ...abundance and Sm/Nd ratios and are characterized by MREE- and HREE-enriched and LREE-depleted patterns. Sm–Nd isotopic compositions of syn-sulfide calcites fall on well-defined lines in the isochron plot. Calcites from early- and late-stage mineralization form two distinct isochrons corresponding to 155.5±1.1 and 124.1±3.7 Ma, respectively. The isochron ages suggest that Sb mineralization took place during the Late Jurassic–Early Cretaceous Period in the Xikuangshan district, consistent with previous geological observations and with independent isotope data. Samarium–neodymium dating of calcites shows potential for determining ages of hydrothermal mineralization.
The helium isotope composition of air might have changed since the industrial revolution due to the release of 4He-rich crustal helium during exploitation of fossil fuels. Thereby, variation of the ...atmospheric helium isotope ratio (3He/4He) has been proposed as a possible new atmospheric tracer of industrial activity. However, the magnitude of such change is debated, with possible values ranging from 0 to about 2‰/yr (Sano et al., 1989; Hoffman and Nier, 1993; Pierson-Wickmann et al., 2001; Brennwald et al., 2013; Lupton and Evans, 2013). A new analytical facility for high precision (2‰, 2σ) analysis of the 3He/4He ratio of air has been developed at CRPG Nancy (France) capable of investigating permil level variations. Previously, Brennwald et al. (2013) analyzed a selection of air samples archived since 1978 at Cape Grim, Tasmania, by the Commonwealth Scientific and Industrial Research Organisation (CSIRO). They reported a mean temporal decrease of the 3He/4He ratio of 0.23–0.30‰/yr. Re-analysis of aliquots of the same samples using the new high-precision instrument showed no significant temporal decrease of the 3He/4He ratio (0.0095±0.033‰/yr, 2σ) in the time interval 1978–2011. These new data constrain the mean He content of globally produced natural gas to about 0.034% or less, which is about 3× lower than commonly quoted.
•High-precision measurements for helium isotopes from the Cape Grim Air Archive are presented.•No statistically significant temporal decrease of the 3He/4He ratio observed in from 1978–2011.•The maximum rate of 3He/4He decrease consistent with the data is 0.033–0.042 ‰/yr (2σ).•This data implies a maximum global mean helium content of natural gas around 0.034%.
Materials trapped and preserved in comets date from the earliest history of the solar system. Particles captured by the Stardust spacecraft from comet 81P/Wild 2 are indisputable cometary matter ...available for laboratory study. Here we report measurements of noble gases in Stardust material. Neon isotope ratios are within the range observed in "phase Q," a ubiquitous, primitive organic carrier of noble gases in meteorites. Helium displays ³He/⁴He ratios twice those in phase Q and in Jupiter's atmosphere. Abundances per gram are surprisingly large, suggesting implantation by ion irradiation. The gases are probably carried in high-temperature igneous grains similar to particles found in other Stardust studies. Collectively, the evidence points to gas acquisition in a hot, high ion-flux nebular environment close to the young Sun.
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