Biosynthesis of bioactive diterpenoids in the medicinal plant Vitex agnus‐castus

Vitex agnus‐castus L. (Lamiaceae) is a medicinal plant historically used throughout the Mediterranean region to treat menstrual cycle disorders, and is still used today as a clinically effective treatment for premenstrual syndrome. The pharmaceutical activity of the plant extract is linked to its ability to lower prolactin levels. This feature has been attributed to the presence of dopaminergic diterpenoids that can bind to dopamine receptors in the pituitary gland. Phytochemical analyses of V. agnus‐castus show that it contains an enormous array of structurally related diterpenoids and, as such, holds potential as a rich source of new dopaminergic drugs. The present work investigated the localisation and biosynthesis of diterpenoids in V. agnus‐castus . With the assistance of matrix‐assisted laser desorption ionisation‐mass spectrometry imaging (MALDI‐MSI), diterpenoids were localised to trichomes on the surface of fruit and leaves. Analysis of a trichome‐specific transcriptome database, coupled with expression studies, identified seven candidate genes involved in diterpenoid biosynthesis: three class II diterpene synthases (diTPSs); three class I diTPSs; and a cytochrome P450 (CYP). Combinatorial assays of the diTPSs resulted in the formation of a range of different diterpenes that can account for several of the backbones of bioactive diterpenoids observed in V. agnus‐castus . The identified CYP, Vac CYP76BK1, was found to catalyse 16‐hydroxylation of the diol‐diterpene, peregrinol, to labd‐13Z ‐ene‐9,15,16‐triol when expressed in Saccharomyces cerevisiae . Notably, this product is a potential intermediate in the biosynthetic pathway towards bioactive furan‐ and lactone‐containing diterpenoids that are present in this species

Single-Proton Removal Reaction Study of 16B

The low-lying level structure of the unbound system $^{16}$B has been investigated via single-proton removal from a 35 MeV/nucleon $^{17}$C beam. The coincident detection of the beam velocity $^{15}$B fragment and neutron allowed the relative energy of the in-flight decay of $^{16}$B to be reconstructed. The resulting spectrum exhibited a narrow peak some 85 keV above threshold. It is argued that this feature corresponds to a very narrow ($\Gamma \ll$100 keV) resonance, or an unresolved multiplet, with a dominant $\pi (p_{3/2})^{-1} \otimes \nu (d_{5/2}^3)_{J=3/2^+}$ + $\pi (p_{3/2})^{-1} \otimes \nu (d_{5/2}^2,s_{1/2})_{J=3/2^+}$ configuration which decays by d-wave neutron emission.Comment: 16 pages, 5 figures, 1 table, submitted to Phys. Lett.

Comparison and Implementation of a Rigid and a Flexible Multibody Planetary Gearbox Model

We propose algorithms for developing (1) a rigid (constrained) and (2) a flexible planetary gearbox model. The two methods are compared against each other and advantages/disadvantages of each method are discussed. The rigid model (1) has gear tooth reaction forces expressed by Lagrange multipliers. The flexible approach (2) is being compared with the gear tooth forces from the rigid approach, first without damping and second the influence of damping is examined. Variable stiffness as a function of base circle arc length is implemented in the flexible approach such that it handles the realistic switch between one and two gear teeth in mesh. The final results are from modelling the planetary gearbox in a 500 kW wind turbine which we also described in Jørgensen et.al (2013)

Spin dependence in high pT2p^{2}_{T} elastic pp and np scattering

Using the polarized proton capability of the Argonne ZGS the authors recently made 90 degrees /sub cm/ measurements of elastic pp scattering from 6 to 11.75 GeV/c, determining the parallel and anti- parallel pure initial spin state cross sections and the associated spin-spin parameter A/sub nn/ with the spins normal to the scattering plane. They find that the parallel to anti-parallel cross section ratio rises dramatically from 1.2+or-.06 at p/sub t//sup 2/=3.3 (GeV /c)/sup 2/ to 3.2+or-.4 at 4.8 (GeV/c)/sup 2/, similar to the p/sub T //sup 2/ dependence previously observed at the fixed laboratory momentum of 11.75 GeV/c. They have also extended the measurements at 6 GeV/c and find that A/sub nn/ has a small but sharp rise at 90 degrees /sub cm/. In addition a month of 12 GeV/c polarized deuteron acceleration in the ZGS enabled them to measure two A/sub nn/ at two points at 6 GeV/c for np elastic scattering: A/sub nn/=-.17+or-.04 at p/sub T//sup 2/=.8, A/sub nn/=-.19+or-.05 at P/sub T//sup 2/=1.0. These values are opposite in sign from the pp results at the same momentum. (4 refs)

The nuclear energy density functional formalism

The present document focuses on the theoretical foundations of the nuclear energy density functional (EDF) method. As such, it does not aim at reviewing the status of the field, at covering all possible ramifications of the approach or at presenting recent achievements and applications. The objective is to provide a modern account of the nuclear EDF formalism that is at variance with traditional presentations that rely, at one point or another, on a {\it Hamiltonian-based} picture. The latter is not general enough to encompass what the nuclear EDF method represents as of today. Specifically, the traditional Hamiltonian-based picture does not allow one to grasp the difficulties associated with the fact that currently available parametrizations of the energy kernel $E[g',g]$ at play in the method do not derive from a genuine Hamilton operator, would the latter be effective. The method is formulated from the outset through the most general multi-reference, i.e. beyond mean-field, implementation such that the single-reference, i.e. "mean-field", derives as a particular case. As such, a key point of the presentation provided here is to demonstrate that the multi-reference EDF method can indeed be formulated in a {\it mathematically} meaningful fashion even if $E[g',g]$ does {\it not} derive from a genuine Hamilton operator. In particular, the restoration of symmetries can be entirely formulated without making {\it any} reference to a projected state, i.e. within a genuine EDF framework. However, and as is illustrated in the present document, a mathematically meaningful formulation does not guarantee that the formalism is sound from a {\it physical} standpoint. The price at which the latter can be enforced as well in the future is eventually alluded to.Comment: 64 pages, 8 figures, submitted to Euroschool Lecture Notes in Physics Vol.IV, Christoph Scheidenberger and Marek Pfutzner editor

An Integrated TCGA Pan-Cancer Clinical Data Resource to Drive High-Quality Survival Outcome Analytics

For a decade, The Cancer Genome Atlas (TCGA) program collected clinicopathologic annotation data along with multi-platform molecular profiles of more than 11,000 human tumors across 33 different cancer types. TCGA clinical data contain key features representing the democratized nature of the data collection process. To ensure proper use of this large clinical dataset associated with genomic features, we developed a standardized dataset named the TCGA Pan-Cancer Clinical Data Resource (TCGA-CDR), which includes four major clinical outcome endpoints. In addition to detailing major challenges and statistical limitations encountered during the effort of integrating the acquired clinical data, we present a summary that includes endpoint usage recommendations for each cancer type. These TCGA-CDR findings appear to be consistent with cancer genomics studies independent of the TCGA effort and provide opportunities for investigating cancer biology using clinical correlates at an unprecedented scale. Analysis of clinicopathologic annotations for over 11,000 cancer patients in the TCGA program leads to the generation of TCGA Clinical Data Resource, which provides recommendations of clinical outcome endpoint usage for 33 cancer types

Exploring bodily sensations experienced during flow states in professional national hunt jockeys: a connecting analysis

Previous research has suggested that distinct bodily sensations are experienced by athletes during flow states, and could represent a sport-specific characteristic of this phenomenon. This study aimed to enrich understanding about bodily sensations and flow states in sport by exploring this experience in national hunt jockeys. The interspecies nature of horse-rider partnerships accentuates the importance of bodily awareness in equestrian sports. Therefore, horse racing provided a fertile context in which to investigate bodily sensations experienced during flow states in sport. In-depth, semi-structured interviews exploring the experience of flow in horse racing were undertaken with 10 professional national hunt jockeys (M age = 28.1 years). Data were interpreted iteratively using inductive categorising/thematic and connecting analyses. Present findings suggested that flow states in jockeys produce an idiosyncratic and multifaceted sensory experience, and indicated that altered physical perceptions during flow were not restricted to kinaesthetic properties. Jockeys explained that distinct bodily sensations were experienced during flow states, and described alterations in their perceptions of kinaesthetic ‘feel’, balance, arousal and strength of touch. Each of these bodily sensations was discussed in relation to sensory information received from the horse, and a connecting analysis enlightened the factors underlying the realisation of these unique bodily sensations that accompanied flow states. Findings are discussed with respect to the existing literature on flow in sport and recommendations for future research are outlined. Further, possible considerations regarding the inclusion of bodily sensations as a characteristic of the flow experience in sport are outlined

Re-examining the transition into the N=20 island of inversion: structure of 30Mg

Intermediate energy single-neutron removal from $^{31}$Mg has been employed to investigate the transition into the N=20 island of inversion. Levels up to 5~MeV excitation energy in $^{30}$Mg were populated and spin-parity assignments were inferred from the corresponding longitudinal momentum distributions and $\gamma$-ray decay scheme. Comparison with eikonal-model calculations also permitted spectroscopic factors to be deduced. Surprisingly, the 0$^{+}_{2}$ level in $^{30}$Mg was found to have a strength much weaker than expected in the conventional picture of a predominantly $2p - 2h$ intruder configuration having a large overlap with the deformed $^{31}$Mg ground state. In addition, negative parity levels were identified for the first time in $^{30}$Mg, one of which is located at low excitation energy. The results are discussed in the light of shell-model calculations employing two newly developed approaches with markedly different descriptions of the structure of $^{30}$Mg. It is concluded that the cross-shell effects in the region of the island of inversion at Z=12 are considerably more complex than previously thought and that $np - nh$ configurations play a major role in the structure of $^{30}$Mg.Comment: Physics Letters B, Volume 779, 10 April 2018, Pages 124-12

Identification and Functional Characterization of G6PC2 Coding Variants Influencing Glycemic Traits Define an Effector Transcript at the G6PC2-ABCB11 Locus

Genome wide association studies (GWAS) for fasting glucose (FG) and insulin (FI) have identified common variant signals which explain 4.8% and 1.2% of trait variance, respectively. It is hypothesized that low-frequency and rare variants could contribute substantially to unexplained genetic variance. To test this, we analyzed exome-array data from up to 33,231 non-diabetic individuals of European ancestry. We found exome-wide significant (P<5×10-7) evidence for two loci not previously highlighted by common variant GWAS: GLP1R (p.Ala316Thr, minor allele frequency (MAF)=1.5%) influencing FG levels, and URB2 (p.Glu594Val, MAF = 0.1%) influencing FI levels. Coding variant associations can highlight potential effector genes at (non-coding) GWAS signals. At the G6PC2/ABCB11 locus, we identified multiple coding variants in G6PC2 (p.Val219Leu, p.His177Tyr, and p.Tyr207Ser) influencing FG levels, conditionally independent of each other and the non-coding GWAS signal. In vitro assays demonstrate that these associated coding alleles result in reduced protein abundance via proteasomal degradation, establishing G6PC2 as an effector gene at this locus. Reconciliation of single-variant associations and functional effects was only possible when haplotype phase was considered. In contrast to earlier reports suggesting that, paradoxically, glucose-raising alleles at this locus are protective against type 2 diabetes (T2D), the p.Val219Leu G6PC2 variant displayed a modest but directionally consistent association with T2D risk. Coding variant associations for glycemic traits in GWAS signals highlight PCSK1, RREB1, and ZHX3 as likely effector transcripts. These coding variant association signals do not have a major impact on the trait variance explained, but they do provide valuable biological insights