The amount of AC sets a limit on cardiac beta-adrenergic signaling in vivo, and increased AC, independent of betaAR number and G-protein content, provides a means to regulate cardiac responsiveness to betaAR stimulation. Overexpressing an effector (AC) does not alter transmembrane signaling except when receptors are activated, in contrast to receptor/G-protein overexpression, which yields continuous activation and has detrimental consequences. Our findings establish the importance of AC content in modulating beta-adrenergic signaling in the heart, suggesting a new target for safely increasing cardiac responsiveness to betaAR stimulation.
The tight junction (TJ) is a specialized intercellular structure responsible for the regulation of ionic and macromolecular flux across cell monolayers. Because plasma leakage is believed to occur mainly across the microvasculature, we hypothesized that microvascular endothelial cells (MVEC) may form more intact, regulatable TJ than other endothelial cell (EC) types, allowing further insight into the control of EC permeability. Primary cultures of MVEC monolayers produced transmonolayer electrical resistances (TER) of 120-155 omega.cm2, approximately 10 times that of large-vessel EC. Treatment with tumor necrosis factor and interferon-gamma caused a 50% decrease in the TER and a striking fragmentation of the basal, continuous interendothelial cell zonula occludens-1 protein (ZO-1) distribution determined by immunofluorescence. Fragmentation was inhibited by cytochalasin D, and confocal microscopy demonstrated a colocalization between F actin and ZO-1. These findings suggest that the F actin cytoskeleton plays a central role in endothelial TJ barrier regulation and that dynamic cytoskeletal alterations may primarily control vascular permeability.
The transmission of SARS-CoV-2 coronavirus has led to the COVID-19 pandemic. Nucleic acid testing while specific has limitations for mass surveillance. One alternative is the main protease (M pro ) due to its functional importance in mediating the viral life cycle. Here, we describe a combination of modular substrate and gold colloids to detect M pro via visual readout. The strategy involves zwitterionic peptide that carries opposite charges at the C-/N-terminus to exploit the specific recognition by M pro . Autolytic cleavage releases a positively charged moiety that assembles the nanoparticles with rapid color changes (t < 10 min). We determine a limit of detection for M pro in breath condensate matrices < 10 nM. We further assayed ten COVID-negative subjects and found no false-positive result. In the light of simplicity, our test for viral protease is not limited to an equipped laboratory, but also is amenable to integrating as portable point-of-care devices including those on face-coverings.
G protein-coupled receptor 119 (GPR119) is largely restricted to pancreatic insulin-producing beta-cells and intestinal glucagon-like peptide-1-producing L-cells. Synthetic agonists of this receptor elicit glucose-dependent release of these endocrine factors, thereby enhancing glycemic control. Oleoylethanolamide also activates GPR119, but it remains unclear whether endogenous production of this lipid modulates GPR119 activity under normal or dysglycemic conditions. We show here that a relatively diverse set of lipid amides activate GPR119. Among these, the endovallinoid N-oleoyldopamine (OLDA) stimulated cAMP accumulation in GPR119-transfected cells as effectively as oleoylethanolamide and the previously described synthetic agonist AR231453. None of these lipid amides increased cAMP in control-transfected cells or in cells transfected with a number of other G protein-coupled receptors. OLDA stimulated both cAMP accumulation and insulin release in HIT-T15 cells, which express GPR119 endogenously, and in GPR119-transfected RIN-5F cells. Oral administration of OLDA to C57bl/6 mice elicited significant improvement in glucose tolerance, whereas GPR119-deficient mice were essentially unresponsive. OLDA also acutely elevated plasma gastric inhibitory peptide levels, a known hallmark of GPR119 activation. OLDA represents a possible paracrine modulator of GPR119 in pancreatic islets, where markers of dopamine synthesis correlated well with GPR119 expression. However, no such correlation was seen in the colon. Collectively, these studies indicate that multiple, distinct classes of lipid amides, acting via GPR119, may be important modulators of glucose homeostasis.
Emergent color centers with accessible spins hosted by van der Waals materials have attracted substantial interest in recent years due to their significant potential for implementing transformative quantum sensing technologies. Hexagonal boron nitride (hBN) is naturally relevant in this context due to its remarkable ease of integration into devices consisting of low-dimensional materials. Taking advantage of boron vacancy spin defects in hBN, we report nanoscale quantum imaging of low-dimensional ferromagnetism sustained in Fe3GeTe2/hBN van der Waals heterostructures. Exploiting spin relaxometry methods, we have further observed spatially varying magnetic fluctuations in the exfoliated Fe3GeTe2 flake, whose magnitude reaches a peak value around the Curie temperature. Our results demonstrate the capability of spin defects in hBN of investigating local magnetic properties of layered materials in an accessible and precise way, which can be extended readily to a broad range of miniaturized van der Waals heterostructure systems.
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