The free fatty acid receptor GPR40 has been proposed as a potential target for type 2 diabetes (T2D) pharmacotherapy. This idea has been validated in both preclinical and clinical studies, in which ...activation of GPR40 was shown to improve glycaemic control by stimulating glucose‐dependent insulin secretion; however, the recent termination of phase III clinical trials using the GPR40 agonist TAK‐875 (fasiglifam) has raised important questions regarding the long‐term safety and viability of targeting GPR40 and, more specifically, about our understanding of this receptor's basic biology. In the present review, we provide a summary of established and novel concepts related to GPR40's pharmacobiology and discuss the current status and future outlook for GPR40‐based drug development for the treatment of T2D.
ABSTRACT
We derive constraints on a coupled quintessence model with pure momentum exchange from the public ∼1000 deg2 cosmic shear measurements from the Kilo-Degree Survey and the Planck 2018 cosmic ...microwave background data. We compare this model with Lambda cold dark matter and find similar χ2 and log-evidence values. We accelerate parameter estimation by sourcing cosmological power spectra from the neural network emulator CosmoPower. We highlight the necessity of such emulator-based approaches to reduce the computational runtime of future similar analyses, particularly from Stage IV surveys. As an example, we present Markov Chain Monte Carlo forecasts on the same coupled quintessence model for a Euclid-like survey, revealing degeneracies between the coupled quintessence parameters and the baryonic feedback and intrinsic alignment parameters, but also highlighting the large increase in constraining power Stage IV surveys will achieve. The contours are obtained in a few hours with CosmoPower, as opposed to the few months required with a Boltzmann code.
Cosmic shear is one of the primary probes to test gravity with current and future surveys. There are two main techniques to analyse a cosmic shear survey: a tomographic method, where correlations ...between the lensing signals in different redshift bins are used to recover redshift information, and a 3D approach, where the full redshift information is carried through the entire analysis. Here we compare the two methods, by forecasting cosmological constraints for future surveys like Euclid. We extend the 3D formalism for the first time to theories beyond the standard model, belonging to the Horndeski class. This includes the majority of universally coupled extensions to ΛCDM with one scalar degree of freedom in addition to the metric, still in agreement with current observations. Given a fixed background, the evolution of linear perturbations in Horndeski gravity is described by a set of four functions of time only. We model their time evolution assuming proportionality to the dark energy density fraction and place Fisher matrix constraints on the proportionality coefficients. We find that a 3D analysis can constrain Horndeski theories better than a tomographic one, in particular with a decrease in the errors of the order of 20|${{\ \rm per\ cent}}$|. This paper shows for the first time a quantitative comparison on an equal footing between Fisher matrix forecasts for both a fully 3D and a tomographic analysis of cosmic shear surveys. The increased sensitivity of the 3D formalism comes from its ability to retain information on the source redshifts along the entire analysis.
Animal studies have linked the estrogenic properties of bisphenol A (BPA) to adverse effects on the endocrine system. Because of concerns for similar effects in humans, there is a desire to replace ...BPA in consumer products, and a search for BPA replacements that lack endocrine-disrupting bioactivity is ongoing. We used multiple cell-based models, including an established multi-parametric, high throughput microscopy-based platform that incorporates engineered HeLa cell lines with visible ERα- or ERβ-regulated transcription loci, to discriminate the estrogen-like and androgen-like properties of previously uncharacterized substituted bisphenol derivatives and hydroquinone. As expected, BPA induced 70-80% of the estrogen-like activity via ERα and ERβ compared to E2 in the HeLa prolactin array cell line. 2,2' BPA, Bisguaiacol F, CHDM 4-hydroxybuyl acrylate, hydroquinone, and TM modified variants of BPF showed very limited estrogen-like or androgen-like activity (< 10% of that observed with the control compounds). Interestingly, TM-BFP and CHDM 4-hydroxybuyl acrylate, but not their derivatives, demonstrated evidence of anti-estrogenic and anti-androgenic activity. Our findings indicate that Bisguaiacol F, TM-BFP-ER and TM-BPF-DGE demonstrate low potential for affecting estrogenic or androgenic endocrine activity. This suggest that the tested compounds could be suitable commercially viable alternatives to BPA.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
A subset of environmental chemicals acts as "obesogens" as they increase adipose mass and lipid content in livers of treated rodents. One of the most studied class of obesogens are the tin-containing ...chemicals that have as a central moiety tributyltin (TBT), which bind and activate two nuclear hormone receptors, Peroxisome Proliferator Activated Receptor Gamma (PPARG) and Retinoid X Receptor Alpha (RXRA), at nanomolar concentrations. Here, we have tested whether TBT chloride at such concentrations may affect the neutral lipid level in two cell line models of human liver. Indeed, using high content image analysis (HCA), TBT significantly increased neutral lipid content in a time- and concentration-dependent manner. Consistent with the observed increased lipid accumulation, RNA fluorescence in situ hybridization (RNA FISH) and RT-qPCR experiments revealed that TBT enhanced the steady-state mRNA levels of two key genes for de novo lipogenesis, the transcription factor SREBF1 and its downstream enzymatic target, FASN. Importantly, pre-treatment of cells with 2-deoxy-D-glucose reduced TBT-mediated lipid accumulation, thereby suggesting a role for active glycolysis during the process of lipid accumulation. As other RXRA binding ligands can promote RXRA protein turnover via the 26S proteasome, TBT was tested for such an effect in the two liver cell lines. We found that TBT, in a time- and dose-dependent manner, significantly reduced steady-state RXRA levels in a proteasome-dependent manner. While TBT promotes both RXRA protein turnover and lipid accumulation, we found no correlation between these two events at the single cell level, thereby suggesting an additional mechanism may be involved in TBT promotion of lipid accumulation, such as glycolysis.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Current research in meat color Mancini, R.A.; Hunt, M.C.
Meat science,
09/2005, Letnik:
71, Številka:
1
Journal Article, Conference Proceeding
Recenzirano
This review surveyed recent literature focused on factors that affect myoglobin chemistry, meat color, pigment redox stability, and methodology used to evaluate these properties. The appearance of ...meat and meat products is a complex topic involving animal genetics, ante- and postmortem conditions, fundamental muscle chemistry, and many factors related to meat processing, packaging, distribution, storage, display, and final preparation for consumption. These factors vary globally, but the variables that affect basic pigment chemistry are reasonably consistent between countries. Essential for maximizing meat color life is an understanding of the combined effects of two fundamental muscle traits, oxygen consumption and metmyoglobin reduction. In the antemortem sector of research, meat color is being related to genomic quantitative loci, numerous pre-harvest nutritional regimens, and housing and harvest environment. Our knowledge of postmortem chilling and pH effects, atmospheres used for packaging, antimicrobial interventions, and quality and safety of cooked color are now more clearly defined. The etiology of bone discoloration is now available. New color measurement methodology, especially digital imaging techniques, and improved modifications to existing methodology are now available. Nevertheless, unanswered questions regarding meat color remain. Meat scientists should continue to develop novel ways of improving muscle color and color stability while also focusing on the basic principles of myoglobin chemistry.
The mechanistic understanding of nascent RNAs in transcriptional control remains limited. Here, by a high sensitivity method methylation-inscribed nascent transcripts sequencing (MINT-seq), we ...characterized the landscapes of N6-methyladenosine (m6A) on nascent RNAs. We uncover heavy but selective m6A deposition on nascent RNAs produced by transcription regulatory elements, including promoter upstream antisense RNAs and enhancer RNAs (eRNAs), which positively correlates with their length, inclusion of m6A motif, and RNA abundances. m6A-eRNAs mark highly active enhancers, where they recruit nuclear m6A reader YTHDC1 to phase separate into liquid-like condensates, in a manner dependent on its C terminus intrinsically disordered region and arginine residues. The m6A-eRNA/YTHDC1 condensate co-mixes with and facilitates the formation of BRD4 coactivator condensate. Consequently, YTHDC1 depletion diminished BRD4 condensate and its recruitment to enhancers, resulting in inhibited enhancer and gene activation. We propose that chemical modifications of eRNAs together with reader proteins play broad roles in enhancer activation and gene transcriptional control.
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•MINT-seq is of high sensitivity to characterize m6A methylome on nascent RNAs•There is a pervasive but also selective m6A deposition to long and stable eRNAs•m6A-eRNAs recruit YTHDC1 to enhancers to stimulate enhancer and gene activation•m6A-eRNA/YTHDC1 phase separate to facilitate transcriptional condensate formation
Lee, Wang, Xiong, et al. characterized nascent RNA m6A methylome in human cells, finding a pervasive existence of m6A-marked eRNAs. These m6A-modified eRNAs recruit the nuclear m6A reader YTHDC1 to partition into liquid-like condensates, which facilitate formation of transcriptional activator condensates and therefore gene activation.
ABSTRACT
We present constraints on Horndeski gravity from a combined analysis of cosmic shear, galaxy–galaxy lensing and galaxy clustering from $450\, \mathrm{deg}^2$ of the Kilo-Degree Survey and ...the Galaxy And Mass Assembly survey.The Horndeski class of dark energy/modified gravity models includes the majority of universally coupled extensions to ΛCDM with one scalar field in addition to the metric. We study the functions of time that fully describe the evolution of linear perturbations in Horndeski gravity. Our results are compatible throughout with a ΛCDM model. By imposing gravitational wave constraints, we fix the tensor speed excess to zero and consider a subset of models including, e.g. quintessence and f(R) theories. Assuming proportionality of the Horndeski functions αB and αM (kinetic braiding and the Planck mass run rate, respectively) to the dark energy density fraction ΩDE(a) = 1 − Ωm(a), we find for the proportionality coefficients $\hat{\alpha }_\mathrm{ B} = 0.20_{-0.33}^{+0.20} \,$ and $\, \hat{\alpha }_\mathrm{ M} = 0.25_{-0.29}^{+0.19}$. Our value of $S_8 \equiv \sigma _8 \sqrt{\Omega _{\mathrm{m}}/0.3}$ is in better agreement with the Planck estimate when measured in the enlarged Horndeski parameter space than in a pure ΛCDM scenario. In our joint three-probe analysis, we report a downward shift of the S8 best-fitting value from the Planck measurement of $\Delta S_8 = 0.016_{-0.046}^{+0.048}$ in Horndeski gravity, compared to $\Delta S_8 = 0.059_{-0.039}^{+0.040}$ in ΛCDM. Our constraints are robust to the modelling uncertainty of the non-linear matter power spectrum in Horndeski gravity. Our likelihood code for multiprobe analysis in both ΛCDM and Horndeski gravity is publicly available at https://github.com/alessiospuriomancini/KiDSHorndeski.
Military life is characterized by regular transitions; thus, parents are positioned to serve as stable protective factors for adolescents. We investigated a theory‐informed model that assessed direct ...and indirect relationships between parental relationship quality, parental behaviors, and adolescent depressive symptomatology using cross‐sectional data of military families in the United States (US). Participant families (N = 229), recruited via convenience sampling to take a computer‐based survey, included an active duty father, his spouse, and an adolescent. Mother’s couple relationship quality was indirectly linked to adolescent depressive symptoms through maternal warmth. Conversely, father’s couple relationship quality was indirectly linked to adolescent depressive symptoms via paternal hostility. In other words, parental couple relationship quality was indirectly related to adolescent depressive symptoms, but this relationship differed by parent (i.e., warmth for mothers and hostility for fathers). Findings were similar for adolescent boys and girls.
Environmental toxicants affect human health in various ways. Of the thousands of chemicals present in the environment, those with adverse effects on the endocrine system are referred to as ...endocrine-disrupting chemicals (EDCs). Here, we focused on a subclass of EDCs that impacts the estrogen receptor (ER), a pivotal transcriptional regulator in health and disease. Estrogenic activity of compounds can be measured by many in vitro or cell-based high throughput assays that record various endpoints from large pools of cells, and increasingly at the single-cell level. To simultaneously capture multiple mechanistic ER endpoints in individual cells that are affected by EDCs, we previously developed a sensitive high throughput/high content imaging assay that is based upon a stable cell line harboring a visible multicopy ER responsive transcription unit and expressing a green fluorescent protein (GFP) fusion of ER. High content analysis generates voluminous multiplex data comprised of minable features that describe numerous mechanistic endpoints. In this study, we present a machine learning pipeline for rapid, accurate, and sensitive assessment of the endocrine-disrupting potential of benchmark chemicals based on data generated from high content analysis. The multidimensional imaging data was used to train a classification model to ultimately predict the impact of unknown compounds on the ER, either as agonists or antagonists. To this end, both linear logistic regression and nonlinear Random Forest classifiers were benchmarked and evaluated for predicting the estrogenic activity of unknown compounds. Furthermore, through feature selection, data visualization, and model discrimination, the most informative features were identified for the classification of ER agonists/antagonists. The results of this data-driven study showed that highly accurate and generalized classification models with a minimum number of features can be constructed without loss of generality, where these machine learning models serve as a means for rapid mechanistic/phenotypic evaluation of the estrogenic potential of many chemicals.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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