Therapeutic Potential of a Novel Vitamin D3 Oxime Analogue, VD1-6, with CYP24A1 Enzyme Inhibitory Activity and Negligible Vitamin D Receptor Binding

Abstract: The regulation of vitamin D3 actions in humans occurs mainly through the Cytochrome P450 24-hydroxylase (CYP24A1) enzyme activity. CYP24A1 hydroxylates both 25-hydroxycholecalciferol (25(OH)D3) and 1,25-dihydroxycholecalciferol (1,25(OH)2D3), which is the first step of vitamin D catabolism. An abnormal status of the upregulation of CYP24A1 occurs in many diseases, including chronic kidney disease (CKD). CYP24A1 upregulation in CKD and diminished activation of vitamin D3 contribute to secondary hyperparathyroidism (SHPT), progressive bone deterioration, and soft tissue and cardiovascular calcification. Previous studies have indicated that CYP24A1 inhibition may be an effective strategy to increase endogenous vitamin D activity and decrease SHPT. This study has designed and synthesized a novel C-24 O-methyloxime analogue of vitamin D3 (VD1-6) to have specific CYP24A1 inhibitory properties. VD1-6 did not bind to the vitamin D receptor (VDR) in concentrations up to 10-7 M, assessed by a VDR binding assay. The absence of VDR binding by VD1-6 was confirmed in human embryonic kidney HEK293T cultures through the lack of CYP24A1 induction. However, in silico docking experiments demonstrated that VD1-6 was predicted to have superior binding to CYP24A1, when compared to that of 1,25(OH)2D3. The inhibition of CYP24A1 by VD1-6 was also evident by the synergistic potentiation of 1,25(OH)2D3-mediated transcription and reduced 1,25(OH)2D3 catabolism over 24 h. A further indication of CYP24A1 inhibition by VD1-6 was the reduced accumulation of the 24,25(OH)D3, the first metabolite of 25(OH)D catabolism by CYP24A1. Our findings suggest the potent CYP24A1 inhibitory properties of VD1-6 and its potential for testing as an alternative therapeutic candidate for treating SHPT.Ali K. Alshabrawy, Yingjie Cui, Cyan Sylvester, Dongqing Yang, Emilio S. Petito, Kate R. Barratt, Rebecca K. Sawyer, Jessica K. Heatlie, Ruhi Polara, Matthew J. Sykes, Gerald J. Atkins, Shane M. Hickey, Michael D. Wiese, Andrea M. Stringer, Zhaopeng Liu, and Paul H. Anderso

Biometric conversion factors as a unifying platform for comparative assessment of invasive freshwater bivalves

Invasive bivalves continue to spread and negatively impact freshwater ecosystems worldwide. As different metrics for body size and biomass are frequently used within the literature to standardise bivalve-related ecological impacts (e.g. respiration and filtration rates), the lack of broadly applicable conversion equations currently hinders reliable comparison across bivalve populations. To facilitate improved comparative assessment among studies originating from disparate geographical locations, we report body size and biomass conversion equations for six invasive freshwater bivalves (or species complex members) worldwide: Corbicula fluminea, C. largillierti, Dreissena bugensis, D. polymorpha, Limnoperna fortunei and Sinanodonta woodiana, and tested the reliability (i.e. precision and accuracy) of these equations. Body size (length, width and height) and biomass metrics of living-weight (LW), wet-weight (WW), dry-weight (DW), dry shell-weight (SW), shell free dry-weight (SFDW) and ash-free dry-weight (AFDW) were collected from a total of 44 bivalve populations located in Asia, the Americas and Europe. Relationships between body size and individual biomass metrics, as well as proportional weight-to-weight conversion factors, were determined. For most species, although inherent variation existed between sampled populations, body size directional measurements were found to be good predictors of all biomass metrics (e.g. length to LW, WW, SW or DW: R2 = 0.82–0.96), with moderate to high accuracy for mean absolute error (MAE): ±9.14%–24.19%. Similarly, narrow 95% confidence limits and low MAE were observed for most proportional biomass relationships, indicating high reliability for the calculated conversion factors (e.g. LW to AFDW; CI range: 0.7–2.0, MAE: ±0.7%–2.0%). Synthesis and applications. Our derived biomass prediction equations can be used to rapidly estimate the biologically active biomass of the assessed species, based on simpler biomass or body size measurements for a wide range of situations globally. This allows for the calculation of approximate average indicators that, when combined with density data, can be used to estimate biomass per geographical unit-area and contribute to quantification of population-level effects. These general equations will support meta-analyses, and allow for comparative assessment of historic and contemporary data. Overall, these equations will enable conservation managers to better understand and predict ecological impacts of these bivalves. © 2021 The Authors. Journal of Applied Ecology published by John Wiley & Sons Ltd on behalf of British Ecological Societ

Palaeoenvironmental control on distribution of crinoids in the Bathonian (Middle Jurassic) of England and France

Bulk sampling of a number of different marine and marginal marine lithofacies in the British Bathonian has allowed us to assess the palaeoenvironmental distribution of crinoids for the first time. Although remains are largely fragmentary, many species have been identified by comparison with articulated specimens from elsewhere, whilst the large and unbiased sample sizes allowed assessment of relative proportions of different taxa. Results indicate that distribution of crinoids well corresponds to particular facies. Ossicles of Chariocrinus and Balanocrinus dominate in deeper-water and lower-energy facies,with the former extending further into shallower-water facies than the latter. Isocrinus dominates in shallower water carbonate facies, accompanied by rarer comatulids, and was also present in the more marine parts of lagoons. Pentacrinites remains are abundant in very high-energy oolite shoal lithofacies. The presence of millericrinids within one, partly allochthonous lithofacies suggests the presence of an otherwise unknown hard substrate from which they have been transported. These results are compared to crinoid assemblages from other Mesozoic localities, and it is evident that the same morphological ad-aptations are present within crinoids from similar lithofacies throughout the Jurassic and Early Cretaceous

Prospects for Studies of Stellar Evolution and Stellar Death in the JWST Era

I review the prospects for studies of the advanced evolutionary stages of low-, intermediate- and high-mass stars by the JWST and concurrent facilities, with particular emphasis on how they may help elucidate the dominant contributors to the interstellar dust component of galaxies. Observations extending from the mid-infrared to the submillimeter can help quantify the heavy element and dust species inputs to galaxies from AGB stars. JWST's MIRI mid-infrared instrument will be so sensitive that observations of the dust emission from individual intergalactic AGB stars and planetary nebulae in the Virgo Cluster will be feasible. The Herschel Space Observatory will enable the last largely unexplored spectral region, the far-IR to the submillimeter, to be surveyed for new lines and dust features, while SOFIA will cover the wavelength gap between JWST and Herschel, a spectral region containing important fine structure lines, together with key water-ice and crystalline silicate bands. Spitzer has significantly increased the number of Type II supernovae that have been surveyed for early-epoch dust formation but reliable quantification of the dust contributions from massive star supernovae of Type II, Type Ib and Type Ic to low- and high-redshift galaxies should come from JWST MIRI observations, which will be able to probe a volume over 1000 times larger than Spitzer.Comment: 24 pages, 19 figures. To appear in `Astrophysics in the Next Decade: JWST and Concurrent Facilities' (JWST Conference Proceedings), edited by H. A. Thronson, M. Stiavelli and A. G. G. M. Tielens; Springer Series: Astrophysics and Space Science Proceeding

Brain-based classification of youth with anxiety disorders: transdiagnostic examinations within the ENIGMA-Anxiety database using machine learning

Neuroanatomical findings on youth anxiety disorders are notoriously difficult to replicate, small in effect size and have limited clinical relevance. These concerns have prompted a paradigm shift toward highly powered (that is, big data) individual-level inferences, which are data driven, transdiagnostic and neurobiologically informed. Here we built and validated supervised neuroanatomical machine learning models for individual-level inferences, using a case–control design and the largest known neuroimaging database on youth anxiety disorders: the ENIGMA-Anxiety Consortium (N = 3,343; age = 10–25 years; global sites = 32). Modest, yet robust, brain-based classifications were achieved for specific anxiety disorders (panic disorder), but also transdiagnostically for all anxiety disorders when patients were subgrouped according to their sex, medication status and symptom severity (area under the receiver operating characteristic curve, 0.59–0.63). Classifications were driven by neuroanatomical features (cortical thickness, cortical surface area and subcortical volumes) in fronto-striato-limbic and temporoparietal regions. This benchmark study within a large, heterogeneous and multisite sample of youth with anxiety disorders reveals that only modest classification performances can be realistically achieved with machine learning using neuroanatomical data.NWORubicon 019.201SG.022Advanced Behavioural Research MethodsHealth and Well-bein

Mapping quantitative trait loci for flag leave senescence as a yield determinant in winter wheat under optimal and drought stressed environments

The timing of flag leaf senescence (FLS) is an important determinant of yield under stress and optimal environments. A doubled haploid population derived from crossing the photo period-sensitive variety Beaver,with the photo period-insensitive variety Soissons, varied significantly for this trait, measured as the percent green flag leaf area remaining at 14 days and 35 days after anthesis. This trait also showed a significantly positive correlation with yield under variable environmental regimes. QTL analysis based on a genetic map derived from 48 doubled haploid lines using amplified fragment length polymorphism (AFLP) and simple sequence repeat (SSR) markers, revealed the genetic control of this trait. The coincidence of QTL for senescence on chromosomes 2B and 2D under drought-stressed and optimal environments, respectively, indicate a complex genetic mechanism of this trait involving the re-mobilisation of resources from the source to the sink during senescence

SCUBA photometry of candidate Vega-like sources

New SCUBA measurements at millimetre wavelengths are presented for a sample of Vega-like stars. Six stars were detected, while sensitive upper limits were obtained for a further 11 sources. Most of the sample selected from a recent catalogue of Vega-like stars have infrared excesses similar to those of the prototype Vega-like stars α Lyr and α PsA. Their IR–submm spectral indices are steep, indicating that the submm emission from the discs is dominated by grains which are smaller than the wavelength of observation and that only small grains exist in those dusty discs. HD 98800 has an IR–submillimetre spectral index of less than two, which suggests that grains have grown to more than 0.3 mm in size. Hipparcos parallax data for HD 42137 and HD 123160 suggest that these two stars are giants rather than dwarfs, similar to the situation previously found for HD 233517. Dust masses, or upper limits, were derived for the sample; these indicate that most of the sources do not have as much dust as Herbig Ae/Be or T Tauri stars, but are likely to have dust masses comparable to those of the prototype Vega-like stars