An isotope dilution model for partitioning of phenylalanine and tyrosine uptake by the liver of lactating dairy cows

An isotope dilution model to describe the partitioning of phenylalanine (PHE) and tyrosine (TYR) in the bovine liver was developed. The model comprises four intracellular and six extracellular pools and various flows connecting these pools and external blood. Conservation of mass principles were applied to generate the fundamental equations describing the behaviour of the system in the steady state. The model was applied to datasets from multi-catheterised dairy cattle during a constant infusion of [1-13C] phenylalanine and [2,3,5,6-2H] tyrosine tracers. Model solutions described the extraction of PHE and TYR from the liver via the portal vein and hepatic artery. In addition, the exchange of free PHE and TYR between extracellular and intracellular pools was explained and the hydroxylation of PHE to TYR was estimated. The model was effective in providing information about the fates of PHE and TYR in the liver and could be used as part of a more complex system describing amino acid metabolism in the whole animal

The covalent reactivity of functionalized 5-hydroxy-butyrolactams is the basis for targeting of fatty acid binding protein 5 (FABP5) by the neurotrophic agent MT-21

Covalently acting compounds experience a strong interest within chemical biology both as molecular probes in studies of fundamental biological mechanisms and/or as novel drug candidates. In this context, the identification of new classes of reactive groups is particularly important as these can expose novel reactivity modes and, consequently, expand the ligandable proteome. Here, we investigated the electrophilic reactivity of the 3-acyl-5-hydroxy-1,5-dihydro-2H-pyrrole-2-one (AHPO) scaffold, a heterocyclic motif that is e.g. present in various bioactive natural products. Our investigations were focused on the compound MT-21 - a simplified structural analogue of the natural product epolactaene - which is known to have both neurotrophic activity and ability to trigger apoptotic cell death. We found that the central N-acyl hemiaminal group of MT-21 can function as an electrophilic centre enabling divergent reactivity with both amine- and thiokbased nucleophiles, which furthermore translated to reactivity with proteins in both cell lysates and live cells. We found that in live cells MT-21 strongly engaged the lipid transport protein fatty acid-binding protein 5 (FABP5) by direct binding to a cysteine residue in the bottom of the ligand binding pocket. Through preparation of a series of MT-21 derivatives, we probed the specificity of this interaction which was found to be strongly dependent on subtle structural changes. Our study suggests that MT-21 may be employed as a tool compound in future studies of the biology of FABP5, which remains incompletely understood. Furthermore, our study has also made dear that other natural products containing the AHPO-motif may likewise possess covalent reactivity and that this property may underlie their biological activity.Molecular Physiolog

Density functional theory based screening of ternary alkali-transition metal borohydrides: A computational material design project

The dissociation of molecules, even the most simple hydrogen molecule, cannot be described accurately within density functional theory because none of the currently available functionals accounts for strong on-site correlation. This problem led to a discussion of properties that the local Kohn-Sham potential has to satisfy in order to correctly describe strongly correlated systems. We derive an analytic expression for the nontrivial form of the Kohn-Sham potential in between the two fragments for the dissociation of a single bond. We show that the numerical calculations for a one-dimensional two-electron model system indeed approach and reach this limit. It is shown that the functional form of the potential is universal, i.e., independent of the details of the two fragments.We acknowledge funding by the Spanish MEC (Grant No. FIS2007-65702-C02-01), “Grupos Consolidados UPV/EHU del Gobierno Vasco” (Grant No. IT-319-07), and the European Community through e-I3 ETSF project (Grant Agreement No. 211956).Peer reviewe

The Physics of Star Cluster Formation and Evolution

© 2020 Springer-Verlag. The final publication is available at Springer via https://doi.org/10.1007/s11214-020-00689-4.Star clusters form in dense, hierarchically collapsing gas clouds. Bulk kinetic energy is transformed to turbulence with stars forming from cores fed by filaments. In the most compact regions, stellar feedback is least effective in removing the gas and stars may form very efficiently. These are also the regions where, in high-mass clusters, ejecta from some kind of high-mass stars are effectively captured during the formation phase of some of the low mass stars and effectively channeled into the latter to form multiple populations. Star formation epochs in star clusters are generally set by gas flows that determine the abundance of gas in the cluster. We argue that there is likely only one star formation epoch after which clusters remain essentially clear of gas by cluster winds. Collisional dynamics is important in this phase leading to core collapse, expansion and eventual dispersion of every cluster. We review recent developments in the field with a focus on theoretical work.Peer reviewe

Integrative analysis of genomic variants reveals new associations of candidate haploinsufficient genes with congenital heart disease

Congenital Heart Disease (CHD) affects approximately 7-9 children per 1000 live births. Numerous genetic studies have established a role for rare genomic variants at the copy number variation (CNV) and single nucleotide variant level. In particular, the role of de novo mutations (DNM) has been highlighted in syndromic and non-syndromic CHD. To identify novel haploinsufficient CHD disease genes we performed an integrative analysis of CNVs and DNMs identified in probands with CHD including cases with sporadic thoracic aortic aneurysm (TAA). We assembled CNV data from 7,958 cases and 14,082 controls and performed a gene-wise analysis of the burden of rare genomic deletions in cases versus controls. In addition, we performed mutation rate testing for DNMs identified in 2,489 parent-offspring trios. Our combined analysis revealed 21 genes which were significantly affected by rare genomic deletions and/or constrained non-synonymous de novo mutations in probands. Fourteen of these genes have previously been associated with CHD while the remaining genes (FEZ1, MYO16, ARID1B, NALCN, WAC, KDM5B and WHSC1) have only been associated in singletons and small cases series, or show new associations with CHD. In addition, a systems level analysis revealed shared contribution of CNV deletions and DNMs in CHD probands, affecting protein-protein interaction networks involved in Notch signaling pathway, heart morphogenesis, DNA repair and cilia/centrosome function. Taken together, this approach highlights the importance of re-analyzing existing datasets to strengthen disease association and identify novel disease genes

The trans-ancestral genomic architecture of glycemic traits

Glycemic traits are used to diagnose and monitor type 2 diabetes and cardiometabolic health. To date, most genetic studies of glycemic traits have focused on individuals of European ancestry. Here we aggregated genome-wide association studies comprising up to 281,416 individuals without diabetes (30% non-European ancestry) for whom fasting glucose, 2-h glucose after an oral glucose challenge, glycated hemoglobin and fasting insulin data were available. Trans-ancestry and single-ancestry meta-analyses identified 242 loci (99 novel; P < 5 x 10(-8)), 80% of which had no significant evidence of between-ancestry heterogeneity. Analyses restricted to individuals of European ancestry with equivalent sample size would have led to 24 fewer new loci. Compared with single-ancestry analyses, equivalent-sized trans-ancestry fine-mapping reduced the number of estimated variants in 99% credible sets by a median of 37.5%. Genomic-feature, gene-expression and gene-set analyses revealed distinct biological signatures for each trait, highlighting different underlying biological pathways. Our results increase our understanding of diabetes pathophysiology by using trans-ancestry studies for improved power and resolution.A trans-ancestry meta-analysis of GWAS of glycemic traits in up to 281,416 individuals identifies 99 novel loci, of which one quarter was found due to the multi-ancestry approach, which also improves fine-mapping of credible variant sets.Diabetes mellitus: pathophysiological changes and therap

Considerations on the effect of sample size for the critical chloride content in concrete

In order to perform reliable service life predictions of reinforced concrete structures, realistic values for the critical chloride content are needed. With regard to the large scatter in the literature as well as the development of modern cement types, agreement has been reached that the test methods for this parameter must be improved. Many of the setups in use are not practice-related. In the present work, the effect of the size of reinforced concrete samples is discussed. It is shown that this parameter is not critical when considering electrochemical or physical aspects of the corrosion mechanism. From a probabilistic point of view, on the other hand, it has some implications since the critical chloride content decreases with increasing rebar length. Further research should concentrate on finding the critical sample size, i.e. the minimal specimen size that is required to give proper critical chloride contents. Moreover, some aspects of evaluating experimental results are pointed out