Comparison of activity, structure, and dynamics of SF-1 and LRH-1 complexed with small molecule modulators.

Steroidogenic factor-1 (SF-1) is a phospholipid-sensing nuclear receptor expressed in the adrenal glands, gonads, and hypothalamus which controls steroidogenesis and metabolism. There is significant therapeutic interest in SF-1 because of its oncogenic properties in adrenocortical cancer. Synthetic modulators are attractive for targeting SF-1 for clinical and laboratory purposes due to the poor pharmaceutical properties of its native phospholipid ligands.

Ligand dependent interaction between PC-TP and PPARδ mitigates diet-induced hepatic steatosis in male mice.

Phosphatidylcholine transfer protein (PC-TP; synonym StarD2) is a soluble lipid-binding protein that transports phosphatidylcholine (PC) between cellular membranes. To better understand the protective metabolic effects associated with hepatic PC-TP, we generated a hepatocyte-specific PC-TP knockdown (L-Pctp) in male mice, which gains less weight and accumulates less liver fat compared to wild-type mice when challenged with a high-fat diet. Hepatic deletion of PC-TP also reduced adipose tissue mass and decreases levels of triglycerides and phospholipids in skeletal muscle, liver and plasma.

Deep mutational scanning identifies SARS-CoV-2 Nucleocapsid escape mutations of currently available rapid antigen tests.

The effects of mutations in continuously emerging variants of SARS-CoV-2 are a major concern for the performance of rapid antigen tests. To evaluate the impact of mutations on 17 antibodies used in 11 commercially available antigen tests with emergency use authorization, we measured antibody binding for all possible Nucleocapsid point mutations using a mammalian surface-display platform and deep mutational scanning. The results provide a complete map of the antibodies' epitopes and their susceptibility to mutational escape.

Differential Modulation of Nuclear Receptor LRH-1 through Targeting Buried and Surface Regions of the Binding Pocket.

Liver receptor homologue-1 (LRH-1) is a phospholipid-sensing nuclear receptor that has shown promise as a target for alleviating intestinal inflammation and metabolic dysregulation in the liver. LRH-1 contains a large ligand-binding pocket, but generating synthetic modulators has been challenging. We have had recent success generating potent and efficacious agonists through two distinct strategies.

A phospholipid mimetic targeting LRH-1 ameliorates colitis.

Phospholipids are ligands for nuclear hormone receptors (NRs) that regulate transcriptional programs relevant to normal physiology and disease. Here, we demonstrate that mimicking phospholipid-NR interactions is a robust strategy to improve agonists of liver receptor homolog-1 (LRH-1), a therapeutic target for colitis. Conventional LRH-1 modulators only partially occupy the binding pocket, leaving vacant a region important for phospholipid binding and allostery.

A miniaturized, low-cost lens tube based laser-induced fluorescence detection system for automated microfluidic analysis of primary amines.

In situ analyses are essential to ascertain potential past or present habitability in celestial bodies. One technique that provides the sensitivity and miniaturization needed to successfully detect trace organics in the outer Solar System is laser-induced fluorescence (LIF) detection, which, when coupled with microfluidic systems, provides a powerful wet chemistry platform that can meet the size and resource consumption constraints of a remote analysis mission. Herein, a portable LIF detection module (44-mm long, 18-mm wide) was prototyped and utilized to quantify bulk organics in a liquid sample via manual and automated analysis utilizing a programmable microfluidic architecture.

Development of a new class of liver receptor homolog-1 (LRH-1) agonists by photoredox conjugate addition.

LRH-1 is a nuclear receptor that regulates lipid metabolism and homeostasis, making it an attractive target for the treatment of diabetes and non-alcoholic fatty liver disease. Building on recent structural information about ligand binding from our labs, we have designed a series of new LRH-1 agonists that further engage LRH-1 through added polar interactions. While the current synthetic approach to this scaffold has, in large part, allowed for decoration of the agonist core, significant variation of the bridgehead substituent is mechanistically precluded.

Genome-Wide Analysis of Cell Cycle-Regulating Genes in the Symbiotic Dinoflagellate .

A delicate relationship exists between reef-building corals and their photosynthetic endosymbionts. Unfortunately, this relationship can be disrupted, with corals expelling these algae when temperatures rise even marginally above the average summer maximum. Interestingly, several studies indicate that failure of corals to regulate symbiont cell divisions at high temperatures may underlie this disruption; increased proliferation of symbionts may stress host cells by over-production of reactive oxygen species or by disrupting the flow of nutrients.

Exploring Relative Thermodynamic Stabilities of Formic Acid and Formamide Dimers - Role of Low-Frequency Hydrogen-Bond Vibrations.

The low-frequency fundamentals together with the high-frequency modes, responsible for hydrogen bonding (OH/NH stretching modes), were analyzed to correlate the intensities with the hydrogen-bond strengths/binding energies of the formic acid and formamide dimers using Møller-Plesset second-order perturbation (MP2) and coupled cluster computations with explicit anharmonicity corrections. Linear correlations were observed for both the formic acid and formamide dimers, and as consequence of such correlation an additive properties of binding energies with respect to the local hydrogen-bond energies of fragments involved (for these dimers) has been proposed. It has been further observed that (i) the nature of their six low-frequency fundamentals are very similar, and (ii) the in-plane bending and stretch-bend fundamentals of different dimers of these two species (depending on the dimer structure), in this low-frequency region, modulate their strength of hydrogen-bond/binding hence their relative stability order.

Simulations of nanocylinders self-assembled from cyclic β-tripeptides.

This paper examines the self-assembly of cyclic β-tripeptides using density functional theory. On the basis of literature precedents, these cyclic peptides were expected to self-assemble into cylindrical structures by stacking through backbone-backbone hydrogen bonding. Our calculations show that such stacking is energetically favorable, that the association energy per cyclic peptide decreases (becomes more favorable), and that the overall macrodipole moment of the cylindrical assembly increases with the number of stacked rings, for up to eight rings.