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Dose-dependent and tissue-specific adverse effects of exogenous glucocorticoids: insights for optimizing clinical practice
Get PDFPurpose: There is limited data on dose-specific metabolic effects of exogenous glucocorticoids (GC) doses. This study aimed to investigate the differential tissue-specific and dose-dependent effects of low-to-intermediate prednisolone doses on insulin sensitivity and bone metabolism in healthy individuals. Methods: We performed a post-hoc pooled analysis of three independent clinical trials, each administering one week of daily prednisolone at 10 mg, 15 mg, or 20 mg, in a total of 30 different healthy male volunteers (aged 18–65; BMI 20–35 kg/m²; normal kidney function). Outcome measures included: changes in liver (endogenous glucose production-EGP, β-hydroxybutyrate-OHB), muscle (M/I value, Glucose disposal-Gd) and adipose tissue (NEFA, glycerol) insulin sensitivity assessed across a hyperinsulinemic-euglycemic clamp. Bone turnover was evaluated through osteocalcin levels. Results: Prednisolone 10 mg had minimal impact on metabolic parameters. 15 mg and 20 mg caused similar reductions (no dose effects) in liver (time effect p < 0.05 for EGP and OHB) and skeletal muscle (time effect p < 0.05 for M/I and Gd) insulin sensitivity. However, detrimental effects on adipose tissue were dose dependent (dose*time interaction p < 0.05 for NEFA and glycerol). Osteocalcin levels decreased similarly after both 15 mg and 20 mg of prednisolone (p = 0.199). Conclusions: Prednisolone-induced insulin resistance exhibits tissue-specific and dose-dependent effects. While 15 mg daily for 7 days appears to induce clinically relevant metabolic changes in this population, the dose-dependent effects observed in adipose tissue suggest tissue-specific variability in response. These findings highlight the importance of dose selection in GC therapy, particularly in individuals predisposed to metabolic complications, though further studies are needed in populations with underlying metabolic disorders
Development and evaluation of the first fertility preservation patient decision aid to support boys and young men with cancer: The Cancer, Fertility and Me for Boys and Young Men research protocol
Get PDFIntroduction: Many cancer treatments can result in reduced fertility, impacting survivors’ opportunities for biological parenthood. Fertility preservation (FP) methods for boys and young men, such as cryopreservation of testicular tissue or sperm, offer hope but are currently underused among young male patients with cancer. Despite guidelines recommending early discussion of fertility implications, many newly diagnosed males do not receive FP counselling or referral to fertility services. Male cancer survivors face a higher likelihood of infertility than their peers, yet focused FP decision-making support is lacking. This study aims to address this gap by developing and evaluating the first dedicated patient decision aid (PtDA) for boys and young male patients with cancer aged 11–25 years old, to help them make informed FP decisions before receiving cancer treatment. Methods and analysis: The current study follows a multistage process: developing the PtDA, alpha testing for acceptability with former patients, parents and healthcare professionals, and beta testing in clinical settings to ensure effective integration into routine care. Using a combination of interviews and questionnaire data, this research will assess the PtDA’s acceptability and impact on decision-making. Ethics and dissemination: This study has been prospectively registered on the Research Registry (10273). Ethics approval has been obtained from Leeds Beckett University and the National Health Service/Health Research Authority before undertaking data collection. The final resource will be disseminated widely and made freely available online via our dedicated Cancer, Fertility and Me website, for use in clinical and research practice
The genome sequence of a phantom cranefly, <i>Ptychoptera contaminata</i> (Linnaeus, 1758)
Get PDFWe present a genome assembly from a male specimen of Ptychoptera contaminata (phantom cranefly; Arthropoda; Insecta; Diptera; Ptychopteridae). The genome sequence has a total length of 204.08 megabases. Most of the assembly (83.64%) is scaffolded into 6 chromosomal pseudomolecules, including the X and Y sex chromosomes. The mitochondrial genome has also been assembled, with a length of 17.64 kilobases. Gene annotation of this assembly on Ensembl identified 11,102 protein-coding genes
Impact of genetic variants linked to liver fat and liver volume on MRI-mapped body composition
Get PDFBackground & aimsA quarter of the world population is estimated to have metabolic dysfunction-associated steatotic liver disease. Here, we aim to understand the impact of liver trait-associated genetic variants on fat content and tissue volume across organs and body compartments and on a large set of biomarkers.MethodsGenome-wide association analyses were performed on liver fat and liver volume estimated with magnetic resonance imaging in up to 27,243 unrelated European participants from the UK Biobank. Identified variants were assessed for associations with fat fraction and tissue volume in >2 million 'Imiomics' image elements in 22,261 individuals and with circulating biomarkers in 310,224 individuals.ResultsWe confirmed four liver fat and nine liver volume previously reported genetic variants (p values -8). We further found evidence suggestive of a novel liver volume locus, ADH4, where each additional T allele increased liver volume by 0.05 SD (SE = 0.01, p value = 3.3 × 10-8). The Imiomics analyses showed that liver fat-increasing variants were specifically associated with fat fraction of the liver tissue (p values -3) and with higher inflammation, liver and renal injury biomarkers, and lower lipid levels. Associations of liver volume variants with fat content, tissue volume, and biomarkers were more heterogeneous, for example the liver volume-increasing alleles at CENPW and PPP1R3B were associated with higher skeletal muscle volumes and were more pronounced in men, whereas the GCKR variant was negatively associated with lower skeletal muscle volumes in women (p values -3).ConclusionsLiver fat-increasing variants were mostly linked to fat fraction of the liver and were positively associated with some adverse metabolic biomarkers and negatively with lipids. In contrast, liver volume-associated variants showed a less consistent pattern across organs and biomarkers.Impact and implicationsLiver fat and liver volume are common metabolic traits with a strong genetic component, yet the extent to which they exert organ-specific vs. systemic effects remains poorly defined. By integrating genome-wide association analyses and high-resolution neck-to-knee magnetic resonance imaging data through the Imiomics framework, this study reveals distinct genetic architectures for liver fat and liver volume, including sex-specific effects. These findings provide new insights into the biological, organ-level, tissue-specific, and systemic characteristics of steatotic liver disease and its genetic determinants. The results may inform the development of precision imaging genetic approaches, biomarker discovery, and stratified risk assessment strategies, while reinforcing the importance of incorporating sex-specific analyses in future research and clinical applications
The Departure of Mary in Six Books and the 6th-century Syriac Cult of the Virgin
No full textThis dissertation presents the first monograph-length study of the Syriac cult of the Virgin and a late-antique account of Mary’s passing, the Departure of Mary in six books, also known as the Syriac Transitus Mariae and the Six Books Dormition Apocryphon (CANT 123-4; BHO 620-630). Previous scholarship analyzed the Departure primarily as part of a multi-lingual corpus of early Dormition and Assumption texts, usually examining questions of theology and literary transmission. A few chapter-length studies treating Mary’s cult in the Departure mostly ignored its Syriac context. In part, this was due to uncertainty about the Departure’s dating and its exact relationship with similar Greek, Arabic, and Ethiopic works. More fundamentally, there was no consensus about which extant Syriac recension witnessed to the earliest form of the Departure. This study explores the Departure’s dating, literary development, and provenance to lay the groundwork for a historical study of the cult of the Virgin. Chapter 2 determines that early recensions descend from a 6th-century Syriac recension – closest to the extant Long Recension (LR) – of earlier Greek traditions originating in a Palestinian liturgical context. Chapter 3 demonstrates that the recension was edited for inclusion in a proto-Vita of the Virgin, a Syriac Book of Mary, circulating in the 6th-century. Chapter 4 confirms its extensive connections with Syriac miaphysite literature – particularly the Doctrina Addai – with Edessene roots. Chapter 5 distinguishes between literary and historical dimensions of the cult of Mary in the Departure. On a literary level, it analyzes the work’s Mariology, in particular, Mary’s uniquely anticipated reception of her eternal reward and her intercession for devotees in light of miaphysite Christology and Syriac eschatology regarding the sleep of souls. On a historical level, it tracks the late antique and medieval success of the Departure’s calendar of Marian feast days and hypothesizes the work’s mid-6th century promotion by a Syriac miaphysite hierarchy in exile after the rise of Justin I (518-527 CE)
m6A and the NEXT complex direct Xist RNA turnover and X-inactivation dynamics
No full textX-chromosome inactivation (XCI) in mammals is orchestrated by the noncoding RNA X-inactive-specific transcript (Xist) that, together with specific interacting proteins, functions in cis to silence an entire X chromosome. Defined sites on Xist RNA carry the N6-methyladenosine (m6A) modification and perturbation of the m6A writer complex has been found to abrogate Xist-mediated gene silencing. However, the relative contribution of m6A and its mechanism of action remain unclear. Here we investigate the role of m6A in XCI by applying rapid degron-mediated depletion of METTL3, the catalytic subunit of the m6A writer complex, an approach that minimizes indirect effects because of transcriptome-wide depletion of m6A. We find that acute loss of METTL3 and m6A accelerates Xist-mediated gene silencing and this correlates with increased levels and stability of Xist transcripts. We show that Xist RNA turnover is mediated by the nuclear exosome targeting complex but is independent of the principal nuclear m6A reader protein YTHDC1. Our findings demonstrate that the primary function of m6A on Xist RNA is to promote Xist RNA turnover, which in turn regulates XCI dynamics
Monitoring the effects of tropospheric ozone exposure on forests, a spectroscopic approach
Get PDFNear the Earth’s surface, tropospheric ozone (O3) is a highly oxidising and toxic pollutant. Tropospheric O3 concentrations have reached dangerously high concentrations around the world and are predicted to continue to increase. O3 pollution reduces the growth, productivity, and resilience of vegetation due to oxidative stress. Broadleaf trees are vulnerable to O3 damage, but the extent of O3 damage to forests is not well understood. O3 stress causes visible foliar symptoms which are currently used to monitor the impact of O3 on forests, but a high-throughput and remote technology would allow large-scale, accurate assessments of O3 damage to forests. O3 has been shown to affect the leaf reflectance profile of sensitive crops and some conifers, but the reflectance signature of O3 damage in broadleaf trees has not been explored. In this thesis I have used hyperspectral leaf reflectance to first identify the spectral signature of O3 damage in broadleaf saplings under controlled experimental conditions, and then to expand this to mature trees under natural conditions. I have found a consistent and robust signal of O3 damage in the hyperspectral leaf reflectance of broadleaf trees, using both vegetation indices and whole-spectra, machine learning approaches. O3 affected the width and intensity of the green reflectance peak of sapling and mature trees, and the vegetation index MCARI consistently responded to O3 exposure. In saplings there were also clear changes in the short-wavelength infrared reflectance proportional to O3 dosage. I also investigated the effect of future CO2 concentrations on leaf reflectance and found elevated CO2 broadly did not impact leaf reflectance, although one index linked to senescence did increase. Therefore elevated CO2 concentrations in the future should not affect the ability to detect O3 damage via leaf reflectance because the spectral signature of O3 damage is stronger and affects a distinct region of the spectra. Finally, I explored how the O3 damage signal could be scaled up to a remote sensing application, and trialled a simple satellite analysis using vegetation indices. As O3 concentrations continue to rise globally, understanding the extent of O3 damage to forests is crucial to effectively harness the carbon sequestration potential of forests. I demonstrate the exciting potential of spectral monitoring of O3 damage in broadleaf temperate forests
Closing the Circulation Budget
Get PDFCirculation budgets can identify physical processes underpinning tropical cyclones, mesoscale convective vortices, and other weather systems where there are interactions across scales. It is unclear, however, how well these budgets close in practice. The present study uses the rapid intensification of Tropical Cyclone Nepartak (2016) as a case study to quantify the practical limitations of calculating circulation budgets using standard reanalyzes and numerical weather model data. First, we evaluate the circulation budget with ERA5. The budget residual can be reduced considerably by including contributions to circulation changes from subgrid‐scale momentum transports, and reduced further with 24‐hr smoothing, which dampens the discontinuous effects of data assimilation. Second, using a high‐resolution Met Office Unified Model simulation, we examine how the choice of the path used (the domain boundary) affects the budget closure. Third, the truncation errors associated with numerical differentiation in time and space are investigated. The circulation budget improves as the model data are analyzed with more frequent time output intervals, and as the output grid spacing decreases. For the tropical convective examples evaluated here, the column mean budget residuals increase by up to 50% as the output intervals increase from 5 min to 3 hr. Errors also increase if the data are regridded to a coarser horizontal grid spacing and when convection straddles the domain boundary. A key result is that the circulation budget need not close for physical inferences made about the circulation and its evolution to be meaningful, thus validating the use of the technique in prior studies