Structure Of 18'-Epivinblastine

Methyl {3aR-[3a-alpha,4-beta,5-beta,5a-beta,9(3R*,-5S*,7R*,9R*),10bR,13a-alpha]}-4-(acetyloxy)-3a-ethyl-9-[5-ethyl-1,4,5,6,7,8,9,10-octahydro-5-hydroxy-9-(methoxycarbonyl)-2H-3,7-methanoazacycloundecino[5,4-b]indol-9-yl]-3a,4,5,5a,6,11,12,13a-octahydro-5-hydroxy-8-methoxy-6-methyl-lH-indolizino-[8,1-c,d]carbazole-5-carboxy?? late methanol solvate, C46H58N4O9.2CH3OH (1), M(r) = 875.07, monoclinic, P2(1), a = 10.2759 (12), b = 22.353 (3), c = 10.4051 (12) angstrom, beta = 106.502 (9)-degrees, V = 2291.6 (5) angstrom 3, Z = 2, D(x) = 1.27 g cm-3, Mo K-alpha radiation, lambda = 0.7107 angstrom, mu = 0.8397 cm-1, F(000) = 940, T = 198 K, R = 0.0470 for 2751 reflections, F(o) greater-than-or-equal-to 4-sigma-(F(o)). The C ring of the vindoline moiety is in the boat conformation with the hydroxy group and the tertiary N in the bowsprit positions resulting in a fairly short intramolecular hydrogen-bonding interaction. The relevant parameters for O3-H3...N9 are O...N 2.651 (6), H...N 1.94 (5) angstrom and O-H...N 147 (5)-degrees. The D and E rings are in the sofa and envelope conformations, respectively. The piperidine ring of the catharanthine portion of the molecule assumes the chair conformation while the conformation of the azacyclononene ring is a boat-chair. An intramolecular hydrogen bond between the indolino NH of the catharanthine moiety and methoxy O (O25) of the vindoline moiety is also observed. The relevant parameters for N16'-H16'...O25 are N...O 2.827 (6), H...N2.14 (6) angstrom and O-H...N 136 (5)-degrees.National Institutes of Health (GM 29801)ChemistryBiochemistr

CpG binding protein (CFP1) occupies open chromatin regions of active genes, including enhancers and non-CpG islands.

Funding This work was supported by a University of Edinburgh Chancellor’s Fellowship to Douglas Vernimmen and by Institute Strategic Grant funding to the Roslin Institute from the BBSRC [BB/J004235/1] and [BB/P013732/1]. Louie N. van de Lagemaat was supported by Roslin Institute funding to Douglas Vernimmen. We are very grateful to Zhanyun Tang and Bob Roeder for the CFP1 antibody. We would like to thank our colleagues Alan Archibald, Philipp Voigt and Duncan Sproul for critically reading the manuscript. We also thank Jim Hughes for curating data sets obtained in Oxford. High-throughput sequencing was provided by the Oxford Genomics Centre (http://www.well.ox.ac.uk/ogc/ home/) and Edinburgh Genomics (http://genomics.ed.ac.uk).Peer reviewe

Generation of bivalent chromatin domains during cell fate decisions

<p>Abstract</p> <p>Background</p> <p>In self-renewing, pluripotent cells, bivalent chromatin modification is thought to silence (H3K27me3) lineage control genes while 'poising' (H3K4me3) them for subsequent activation during differentiation, implying an important role for epigenetic modification in directing cell fate decisions. However, rather than representing an equivalently balanced epigenetic mark, the patterns and levels of histone modifications at bivalent genes can vary widely and the criteria for identifying this chromatin signature are poorly defined.</p> <p>Results</p> <p>Here, we initially show how chromatin status alters during lineage commitment and differentiation at a single well characterised bivalent locus. In addition we have determined how chromatin modifications at this locus change with gene expression in both ensemble and single cell analyses. We also show, on a global scale, how mRNA expression may be reflected in the ratio of H3K4me3/H3K27me3.</p> <p>Conclusions</p> <p>While truly 'poised' bivalently modified genes may exist, the original hypothesis that all bivalent genes are epigenetically premarked for subsequent expression might be oversimplistic. In fact, from the data presented in the present work, it is equally possible that many genes that appear to be bivalent in pluripotent and multipotent cells may simply be stochastically expressed at low levels in the process of multilineage priming. Although both situations could be considered to be forms of 'poising', the underlying mechanisms and the associated implications are clearly different.</p

Kinetics and 28-day test-retest repeatability and reproducibility of [C-11]UCB-J PET brain imaging

[C-11]UCB-J is a novel radioligand that binds to synaptic vesicle glycoprotein 2A (SV2A). The main objective of this study was to determine the 28-day test-retest repeatability (TRT) of quantitative [C-11]UCB-J brain positron emission tomography (PET) imaging in Alzheimer's disease (AD) patients and healthy controls (HCs). Nine HCs and eight AD patients underwent two 60 min dynamic [C-11]UCB-J PET scans with arterial sampling with an interval of 28 days. The optimal tracer kinetic model was assessed using the Akaike criteria (AIC). Micro-/macro-parameters such as tracer delivery (K-1) and volume of distribution (V-T) were estimated using the optimal model. Data were also analysed for simplified reference tissue model (SRTM) with centrum semi-ovale (white matter) as reference region. Based on AIC, both 1T2k_V-B and 2T4k_V-B described the [C-11]UCB-J kinetics equally well. Analysis showed that whole-brain grey matter TRT for V-T, DVR and SRTM BPND were -2.2% +/- 8.5, 0.4% +/- 12.0 and -8.0% +/- 10.2, averaged over all subjects. [C-11]UCB-J kinetics can be well described by a 1T2k_V-B model, and a 60 min scan duration was sufficient to obtain reliable estimates for both plasma input and reference tissue models. TRT for V-T, DVR and BPND wa

Automatic mapping of atoms across both simple and complex chemical reactions

Mapping atoms across chemical reactions is important for substructure searches, automatic extraction of reaction rules, identification of metabolic pathways, and more. Unfortunately, the existing mapping algorithms can deal adequately only with relatively simple reactions but not those in which expert chemists would benefit from computer&apos;s help. Here we report how a combination of algorithmics and expert chemical knowledge significantly improves the performance of atom mapping, allowing the machine to deal with even the most mechanistically complex chemical and biochemical transformations. The key feature of our approach is the use of few but judiciously chosen reaction templates that are used to generate plausible &quot;intermediate&quot; atom assignments which then guide a graph-theoretical algorithm towards the chemically correct isomorphic mappings. The algorithm performs significantly better than the available state-of-the-art reaction mappers, suggesting its uses in database curation, mechanism assignments, and - above all - machine extraction of reaction rules underlying modern synthesis-planning programs

Validation and test-retest repeatability performance of parametric methods for [11C]UCB-J PET

[(11)C]UCB-J is a PET radioligand that binds to the presynaptic vesicle glycoprotein 2A. Therefore, [(11)C]UCB-J PET may serve as an in vivo marker of synaptic integrity. The main objective of this study was to evaluate the quantitative accuracy and the 28-day test–retest repeatability (TRT) of various parametric quantitative methods for dynamic [(11)C]UCB-J studies in Alzheimer’s disease (AD) patients and healthy controls (HC). Eight HCs and seven AD patients underwent two 60-min dynamic [(11)C]UCB-J PET scans with arterial sampling over a 28-day interval. Several plasma-input based and reference-region based parametric methods were used to generate parametric images using metabolite corrected plasma activity as input function or white matter semi-ovale as reference region. Different parametric outcomes were compared regionally with corresponding non-linear regression (NLR) estimates. Furthermore, the 28-day TRT was assessed for all parametric methods. Spectral analysis (SA) and Logan graphical analysis showed high correlations with NLR estimates. Receptor parametric mapping (RPM) and simplified reference tissue model 2 (SRTM2) BP(ND), and reference Logan (RLogan) distribution volume ratio (DVR) regional estimates correlated well with plasma-input derived DVR and SRTM BP(ND). Among the multilinear reference tissue model (MRTM) methods, MRTM1 had the best correspondence with DVR and SRTM BP(ND). Among the parametric methods evaluated, spectral analysis (SA) and SRTM2 were the best plasma-input and reference tissue methods, respectively, to obtain quantitatively accurate and repeatable parametric images for dynamic [(11)C]UCB-J PET. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13550-021-00874-8

An Arabidopsis Example of Association Mapping in Structured Samples

A potentially serious disadvantage of association mapping is the fact that marker-trait associations may arise from confounding population structure as well as from linkage to causative polymorphisms. Using genome-wide marker data, we have previously demonstrated that the problem can be severe in a global sample of 95 Arabidopsis thaliana accessions, and that established methods for controlling for population structure are generally insufficient. Here, we use the same sample together with a number of flowering-related phenotypes and data-perturbation simulations to evaluate a wider range of methods for controlling for population structure. We find that, in terms of reducing the false-positive rate while maintaining statistical power, a recently introduced mixed-model approach that takes genome-wide differences in relatedness into account via estimated pairwise kinship coefficients generally performs best. By combining the association results with results from linkage mapping in F2 crosses, we identify one previously known true positive and several promising new associations, but also demonstrate the existence of both false positives and false negatives. Our results illustrate the potential of genome-wide association scans as a tool for dissecting the genetics of natural variation, while at the same time highlighting the pitfalls. The importance of study design is clear; our study is severely under-powered both in terms of sample size and marker density. Our results also provide a striking demonstration of confounding by population structure. While statistical methods can be used to ameliorate this problem, they cannot always be effective and are certainly not a substitute for independent evidence, such as that obtained via crosses or transgenic experiments. Ultimately, association mapping is a powerful tool for identifying a list of candidates that is short enough to permit further genetic study

Maternal pre-pregnancy body mass index and risk of preterm birth: a collaboration using large routine health datasets

Background: Preterm birth (PTB) is a leading cause of child morbidity and mortality. Evidence suggests an increased risk with both maternal underweight and obesity, with some studies suggesting underweight might be a greater factor in spontaneous PTB (SPTB) and that the relationship might vary by parity. Previous studies have largely explored established body mass index (BMI) categories. Our aim was to compare associations of maternal pre-pregnancy BMI with any PTB, SPTB and medically indicated PTB (MPTB) among nulliparous and parous women across populations with differing characteristics, and to identify the optimal BMI with lowest risk for these outcomes. Methods: We used three UK datasets, two USA datasets and one each from South Australia, Norway and Denmark, together including just under 29 million pregnancies resulting in a live birth or stillbirth after 24 completed weeks gestation. Fractional polynomial multivariable logistic regression was used to examine the relationship of maternal BMI with any PTB, SPTB and MPTB, among nulliparous and parous women separately. The results were combined using a random effects meta-analysis. The estimated BMI at which risk was lowest was calculated via differentiation and a 95% confidence interval (CI) obtained using bootstrapping. Results: We found non-linear associations between BMI and all three outcomes, across all datasets. The adjusted risk of any PTB and MPTB was elevated at both low and high BMIs, whereas the risk of SPTB was increased at lower levels of BMI but remained low or increased only slightly with higher BMI. In the meta-analysed data, the lowest risk of any PTB was at a BMI of 22.5 kg/m2 (95% CI 21.5, 23.5) among nulliparous women and 25.9 kg/m2 (95% CI 24.1, 31.7) among multiparous women, with values of 20.4 kg/m2 (20.0, 21.1) and 22.2 kg/m2 (21.1, 24.3), respectively, for MPTB; for SPTB, the risk remained roughly largely constant above a BMI of around 25–30 kg/m2 regardless of parity. Conclusions: Consistency of findings across different populations, despite differences between them in terms of the time period covered, the BMI distribution, missing data and control for key confounders, suggests that severe under- and overweight may play a role in PTB risk

DNA methylation of intragenic CpG islands depends on their transcriptional activity during differentiation and disease

The human genome contains ∼30,000 CpG islands (CGIs). While CGIs associated with promoters nearly always remain unmethylated, many of the ∼9,000 CGIs lying within gene bodies become methylated during development and differentiation. Both promoter and intragenic CGIs may also become abnormally methylated as a result of genome rearrangements and in malignancy. The epigenetic mechanisms by which some CGIs become methylated but others, in the same cell, remain unmethylated in these situations are poorly understood. Analyzing specific loci and using a genome-wide analysis, we show that transcription running across CGIs, associated with specific chromatin modifications, is required for DNA methyltransferase 3B (DNMT3B)-mediated DNA methylation of many naturally occurring intragenic CGIs. Importantly, we also show that a subgroup of intragenic CGIs is not sensitive to this process of transcription-mediated methylation and that this correlates with their individual intrinsic capacity to initiate transcription in vivo. We propose a general model of how transcription could act as a primary determinant of the patterns of CGI methylation in normal development and differentiation, and in human disease.</p

Evolutionary Trajectory of White Spot Syndrome Virus (WSSV) Genome Shrinkage during Spread in Asia

Background - White spot syndrome virus (WSSV) is the sole member of the novel Nimaviridae family, and the source of major economic problems in shrimp aquaculture. WSSV appears to have rapidly spread worldwide after the first reported outbreak in the early 1990s. Genomic deletions of various sizes occur at two loci in the WSSV genome, the ORF14/15 and ORF23/24 variable regions, and these have been used as molecular markers to study patterns of viral spread over space and time. We describe the dynamics underlying the process of WSSV genome shrinkage using empirical data and a simple mathematical model. Methodology/Principal Findings - We genotyped new WSSV isolates from five Asian countries, and analyzed this information together with published data. Genome size appears to stabilize over time, and deletion size in the ORF23/24 variable region was significantly related to the time of the first WSSV outbreak in a particular country. Parameter estimates derived from fitting a simple mathematical model of genome shrinkage to the data support a geometric progression (