Culture matters: using a cultural contexts of health approach to enhance policy-making

This is the final version of the report. Freely available online from WHO via the link in this recordThis policy brief has been developed in response to the increasing awareness among policy-makers and the public health community of the important relationship between culture and health. By exploring the three key public health areas of nutrition, migration and environment, the policy brief demonstrates how cultural awareness is central to understanding health and well-being and to developing more effective and equitable health policies. Consequently, it argues that public health policy-making has much to gain from applying research from the health-related humanities and social sciencesWorld Health Organisatio

Pleiotropy of FRIGIDA enhances the potential for multivariate adaptation.

An evolutionary response to selection requires genetic variation; however, even if it exists, then the genetic details of the variation can constrain adaptation. In the simplest case, unlinked loci and uncorrelated phenotypes respond directly to multivariate selection and permit unrestricted paths to adaptive peaks. By contrast, 'antagonistic' pleiotropic loci may constrain adaptation by affecting variation of many traits and limiting the direction of trait correlations to vectors that are not favoured by selection. However, certain pleiotropic configurations may improve the conditions for adaptive evolution. Here, we present evidence that the Arabidopsis thaliana gene FRI (FRIGIDA) exhibits 'adaptive' pleiotropy, producing trait correlations along an axis that results in two adaptive strategies. Derived, low expression FRI alleles confer a 'drought escape' strategy owing to fast growth, low water use efficiency and early flowering. By contrast, a dehydration avoidance strategy is conferred by the ancestral phenotype of late flowering, slow growth and efficient water use during photosynthesis. The dehydration avoidant phenotype was recovered when genotypes with null FRI alleles were transformed with functional alleles. Our findings indicate that the well-documented effects of FRI on phenology result from differences in physiology, not only a simple developmental switch

iMaNGA: mock MaNGA galaxies based on IllustrisTNG and MaStar SSPs. -- III. Stellar metallicity drivers in MaNGA and TNG50

The iMaNGA project uses a forward-modelling approach to compare the predictions of cosmological simulations with observations from SDSS-IV/MaNGA. We investigate the dependency of age and metallicity radial gradients on galaxy morphology, stellar mass, stellar surface mass density ($\Sigma_*$), and environment. The key of our analysis is that observational biases affecting the interpretation of MaNGA data are emulated in the theoretical iMaNGA sample. The simulations reproduce the observed global stellar population scaling relations with positive correlations between galaxy mass and age/metallicity quite well and also produce younger stellar populations in late-type in agreement with observations. We do find interesting discrepancies, though, that can inform the physics and further development of the simulations. Ages of spiral galaxies and low-mass ellipticals are overestimated by about 2-4 Gyr. Radial metallicity gradients are steeper in iMaNGA than in MaNGA, a discrepancy most prominent in spiral and lenticular galaxies. Also, the observed steepening of metallicity gradients with increasing galaxy mass is not well matched by the simulations. We find that the theoretical radial profiles of surface mass density $\Sigma_*$ are steeper than in observations except for the most massive galaxies. In both MaNGA and iMaNGA [Z/H] correlates with $\Sigma_*$, however, the simulations systematically predict lower [Z/H] by almost a factor of 2 at any $\Sigma_*$. Most interestingly, for galaxies with stellar mass $\log M_*\leq 10.80 M_\odot$ the MaNGA data reveal a positive correlation between galaxy radius and [Z/H] at fixed $\Sigma_*$, which is not recovered in iMaNGA. Finally, the dependence on environmental density is negligible in both the theoretical iMaNGA and the observed MaNGA data

Structure–Activity Relationship Studies of Functionally Selective Kappa Opioid Receptor Agonists that Modulate ERK 1/2 Phosphorylation While Preserving G Protein Over βArrestin2 Signaling Bias

Kappa opioid receptor (KOR) modulation is a promising target for drug discovery efforts due to KOR involvement in pain, depression, and addiction behaviors. We recently reported a new class of triazole KOR agonists that displays significant bias toward G protein signaling over βarrestin2 recruitment; interestingly, these compounds also induce less activation of ERK1/2 map kinases than the balanced agonist, U69,593. We have identified structure–activity relationships around the triazole scaffold that allows for decreasing the bias for G protein signaling over ERK1/2 activation while maintaining the bias for G protein signaling over βarrestin2 recruitment. The development of novel compounds, with different downstream signaling outcomes, independent of G protein/βarrestin2 bias, provides a more diverse pharmacological toolset for use in defining complex KOR signaling and elucidating the significance of KOR-mediated signaling

LC-MS/MS quantification of salvinorin A from biological fluids

A facile method for quantifying the concentration of the powerful and widely available hallucinogen salvinorin A (a selective kappa opioid agonist) from non-human primate cerebrospinal fluid (CSF) and human plasma has been developed using liquid chromatography-tandem mass spectrometry (LC-MS/MS) in positive electrospray ionization (ESI) mode. With CSF solid phase extraction can be avoided completely by simply diluting each sample to 10 % (v/v) acetonitrile, 1 % (v/v) formic acid and injecting under high aqueous conditions for analyte focusing. Extensive plasma sample preparation was investigated including protein precipitation, SPE column selection, and plasma particulate removal. Human plasma samples were centrifuged at 21,000 × gravity for 4 minutes to obtain clear particulate-free plasma, from which 300 μl was spiked with internal standard and loaded onto a C18 SPE column with a 100 mg mL−1 loading capacity. Guard columns (C18, hand packed 1 mm × 20 mm) were exchanged after backpressure increased above 4600psi, about 250 injections. A shallow acetonitrile/water gradient was used, 29 to 33% CH3CN over 8 minutes to elute salvinorin A. Reduction of chemical noise was achieved using tandem mass spectrometry with multiple reaction monitoring while sensitivity increases were observed using a 50 μL injection volume onto a small bore analytical column (C18, 1 mm ID × 50 mm) thus increasing peak concentration. Limits of quantification were found to be 0.0125 ng mL−1 (CSF) and 0.05 ng mL−1 (plasma) with interday precision and accuracy below 1.7 % and 9.42 % (CSF) and 3.47 % and 12.37 % (plasma) respectively. This method was used to determine the concentration of salvinorin A from an in vivo Rhesus monkey study and a trial of healthy human research participants, using behaviorally active doses

Semisynthetic Neoclerodanes as Kappa Opioid Receptor Probes

Modification of the furan ring of salvinorin A (1), the main active component of Salvia divinorum, has resulted in novel neoclerodane diterpenes with opioid receptor affinity and activity. Conversion of the furan ring to an aldehyde at the C-12 position (5) has allowed for the synthesis of analogues with new carbon-carbon bonds at that position. Previous methods for forming these bonds, such as Grignard and Stille conditions, have met with limited success. We report a palladium catalyzed Liebeskind-Srogl cross-coupling reaction of a thioester and a boronic acid that occurs at neutral pH and ambient temperature to produce ketone analogs at C-12. To the best of our knowledge, this is the first reported usage of the Liebeskind-Srogl reaction to diversify a natural product scaffold. We also describe a one-step protocol for the conversion of 1 to 12-epi-1 (3) through microwave irradiation. Previously, this synthetically challenging process has required multiple steps. Additionally, we report in this study that alkene 9 and aromatic analogues 12, 19, 23, 25, and 26 were discovered to retain affinity and selectivity at kappa opioid receptors (KOP). Finally, we report that the furan-2-yl analog of 1 (31) has similar affinity to 1. Collectively, these findings suggest that different aromatic groups appended directly to the decalin core may be well tolerated by KOP receptors, and may generate further ligands with affinity and activity at KOP receptors

Components of the ribosome biogenesis pathway underlie establishment of telomere length set point in Arabidopsis

Telomeres cap the physical ends of eukaryotic chromosomes to ensure complete DNA replication and genome stability. Heritable natural variation in telomere length exists in yeast, mice, plants and humans at birth; however, major effect loci underlying such polymorphism remain elusive. Here, we employ quantitative trait locus (QTL) mapping and transgenic manipulations to identify genes controlling telomere length set point in a multi-parent Arabidopsis thaliana mapping population. We detect several QTL explaining 63.7% of the total telomere length variation in the Arabidopsis MAGIC population. Loss-of-function mutants of the NOP2A candidate gene located inside the largest effect QTL and of two other ribosomal genes RPL5A and RPL5B establish a shorter telomere length set point than wild type. These findings indicate that evolutionarily conserved components of ribosome biogenesis and cell proliferation pathways promote telomere elongation

MIGHTEE: Deep 1.4 GHz Source Counts and the Sky Temperature Contribution of Star Forming Galaxies and Active Galactic Nuclei

We present deep 1.4 GHz source counts from $\sim$5 deg$^2$ of the continuum Early Science data release of the MeerKAT International Gigahertz Tiered Extragalactic Exploration (MIGHTEE) survey down to $S_{1.4\textrm{GHz}}\sim$15 $\mu$Jy. Using observations over two extragalactic fields (COSMOS and XMM-LSS), we provide a comprehensive investigation into correcting the incompleteness of the raw source counts within the survey to understand the true underlying source count population. We use a variety of simulations that account for: errors in source detection and characterisation, clustering, and variations in the assumed source model used to simulate sources within the field and characterise source count incompleteness. We present these deep source count distributions and use them to investigate the contribution of extragalactic sources to the sky background temperature at 1.4 GHz using a relatively large sky area. We then use the wealth of ancillary data covering{a subset of the COSMOS field to investigate the specific contributions from both active galactic nuclei (AGN) and star forming galaxies (SFGs) to the source counts and sky background temperature. We find, similar to previous deep studies, that we are unable to reconcile the sky temperature observed by the ARCADE 2 experiment. We show that AGN provide the majority contribution to the sky temperature contribution from radio sources, but the relative contribution of SFGs rises sharply below 1 mJy, reaching an approximate 15-25% contribution to the total sky background temperature ($T_b\sim$100 mK) at $\sim$15 $\mu$Jy.Comment: 24 pages, 12 figures; Accepted for publication in MNRA

Chaotic and Clumpy Galaxy Formation in an Extremely Massive Reionization-era Halo

© 2022. The Author(s). Published by the American Astronomical Society. Original content from this work may be used under the terms of the Creative Commons Attribution 4.0 licence. https://creativecommons.org/licenses/by/4.0/Abstract: The SPT 0311–58 system at z = 6.900 is an extremely massive structure within the reionization epoch and offers a chance to understand the formation of galaxies at an extreme peak in the primordial density field. We present 70 mas Atacama Large Millimeter/submillimeter Array observations of the dust continuum and [C ii] 158 μm emission in the central pair of galaxies and reach physical resolutions of ∼100–350 pc, among the most detailed views of any reionization-era system to date. The observations resolve the source into at least a dozen kiloparsec-size clumps. The global kinematics and high turbulent velocity dispersion within the galaxies present a striking contrast to recent claims of dynamically cold thin-disk kinematics in some dusty galaxies just 800 Myr later at z ∼ 4. We speculate that both gravitational interactions and fragmentation from massive parent disks have likely played a role in the overall dynamics and formation of clumps in the system. Each clump individually is comparable in mass to other 6 < z < 8 galaxies identified in rest-UV/optical deep field surveys, but with star formation rates elevated by a factor of ~3-5. Internally, the clumps themselves bear close resemblance to greatly scaled-up versions of virialized cloud-scale structures identified in low-redshift galaxies. Our observations are qualitatively similar to the chaotic and clumpy assembly within massive halos seen in simulations of high-redshift galaxies.Peer reviewe