2,418 research outputs found
Physiology and Emerging Biochemistry of the Glucagon-Like Peptide-1 Receptor
The glucagon-like peptide-1 (GLP-1) receptor is one of the best validated therapeutic targets for the treatment of type 2 diabetes mellitus (T2DM). Over several years, the accumulation of basic, translational, and clinical research helped define the physiologic roles of GLP-1 and its receptor in regulating glucose homeostasis and energy metabolism. These efforts provided much of the foundation for pharmaceutical development of the GLP-1 receptor peptide agonists, exenatide and liraglutide, as novel medicines for patients suffering from T2DM. Now, much attention is focused on better understanding the molecular mechanisms involved in ligand induced signaling of the GLP-1 receptor. For example, advancements in biophysical and structural biology techniques are being applied in attempts to more precisely determine ligand binding and receptor occupancy characteristics at the atomic level. These efforts should better inform three-dimensional modeling of the GLP-1 receptor that will help inspire more rational approaches to identify and optimize small molecule agonists or allosteric modulators targeting the GLP-1 receptor. This article reviews GLP-1 receptor physiology with an emphasis on GLP-1 induced signaling mechanisms in order to highlight new molecular strategies that help determine desired pharmacologic characteristics for guiding development of future nonpeptide GLP-1 receptor activators
Small Molecule Drug Discovery at the Glucagon-Like Peptide-1 Receptor
The therapeutic success of peptide glucagon-like peptide-1 (GLP-1) receptor agonists for the treatment of type 2 diabetes mellitus has inspired discovery efforts aimed at developing orally available small molecule GLP-1 receptor agonists. Although the GLP-1 receptor is a member of the structurally complex class B1 family of GPCRs, in recent years, a diverse array of orthosteric and allosteric nonpeptide ligands has been reported. These compounds include antagonists, agonists, and positive allosteric modulators with intrinsic efficacy. In this paper, a comprehensive review of currently disclosed small molecule GLP-1 receptor ligands is presented. In addition, examples of “ligand bias” and “probe dependency” for the GLP-1 receptor are discussed; these emerging concepts may influence further optimization of known molecules or persuade designs of expanded screening strategies to identify novel chemical starting points for GLP-1 receptor drug discovery
Flow Liner Slot Edge Replication Feasibility Study
Surface replication has been proposed as a method for crack detection in space shuttle main engine flowliner slots. The results of a feasibility study show that examination of surface replicas with a scanning electron microscope can result in the detection of cracks as small as 0.005 inch, and surface flaws as small as 0.001 inch, for the flowliner material
AT1 Receptor Induced Alterations in Histone H2A Reveal Novel Insights into GPCR Control of Chromatin Remodeling
Chronic activation of angiotensin II (AngII) type 1 receptor (AT1R), a prototypical G protein-coupled receptor (GPCR) induces gene regulatory stress which is responsible for phenotypic modulation of target cells. The AT1R-selective drugs reverse the gene regulatory stress in various cardiovascular diseases. However, the molecular mechanisms are not clear. We speculate that activation states of AT1R modify the composition of histone isoforms and post-translational modifications (PTM), thereby alter the structure-function dynamics of chromatin. We combined total histone isolation, FPLC separation, and mass spectrometry techniques to analyze histone H2A in HEK293 cells with and without AT1R activation. We have identified eight isoforms: H2AA, H2AG, H2AM, H2AO, H2AQ, Q96QV6, H2AC and H2AL. The isoforms, H2AA, H2AC and H2AQ were methylated and H2AC was phosphorylated. The relative abundance of specific H2A isoforms and PTMs were further analyzed in relationship to the activation states of AT1R by immunochemical studies. Within 2 hr, the isoforms, H2AA/O exchanged with H2AM. The monomethylated H2AC increased rapidly and the phosphorylated H2AC decreased, thus suggesting that enhanced H2AC methylation is coupled to Ser1p dephosphorylation. We show that H2A125Kme1 promotes interaction with the heterochromatin associated protein, HP1α. These specific changes in H2A are reversed by treatment with the AT1R specific inhibitor losartan. Our analysis provides a first step towards an awareness of histone code regulation by GPCRs
Composite repetition-aware data structures
In highly repetitive strings, like collections of genomes from the same
species, distinct measures of repetition all grow sublinearly in the length of
the text, and indexes targeted to such strings typically depend only on one of
these measures. We describe two data structures whose size depends on multiple
measures of repetition at once, and that provide competitive tradeoffs between
the time for counting and reporting all the exact occurrences of a pattern, and
the space taken by the structure. The key component of our constructions is the
run-length encoded BWT (RLBWT), which takes space proportional to the number of
BWT runs: rather than augmenting RLBWT with suffix array samples, we combine it
with data structures from LZ77 indexes, which take space proportional to the
number of LZ77 factors, and with the compact directed acyclic word graph
(CDAWG), which takes space proportional to the number of extensions of maximal
repeats. The combination of CDAWG and RLBWT enables also a new representation
of the suffix tree, whose size depends again on the number of extensions of
maximal repeats, and that is powerful enough to support matching statistics and
constant-space traversal.Comment: (the name of the third co-author was inadvertently omitted from
previous version
Fluctuations of water near extended hydrophobic and hydrophilic surfaces
We use molecular dynamics simulations of the SPC-E model of liquid water to
derive probability distributions for water density fluctuations in probe
volumes of different shapes and sizes, both in the bulk as well as near
hydrophobic and hydrophilic surfaces. To obtain our results, we introduce a
biased sampling of coarse-grained densities, which in turn biases the actual
solvent density. The technique is easily combined with molecular dynamics
integration algorithms. Our principal result is that the probability for
density fluctuations of water near a hydrophobic surface, with or without
surface-water attractions, is akin to density fluctuations at the water-vapor
interface. Specifically, the probability of density depletion near the surface
is significantly larger than that in bulk. In contrast, we find that the
statistics of water density fluctuations near a model hydrophilic surface are
similar to that in the bulk
Ehrlichia chaffeensis Infection in the Reservoir Host (White-Tailed Deer) and in an Incidental Host (Dog) Is Impacted by Its Prior Growth in Macrophage and Tick Cell Environments
Citation: Nair, A. D. S., Cheng, C., Jaworski, D. C., Willard, L. H., Sanderson, M. W., & Ganta, R. R. (2014). Ehrlichia chaffeensis Infection in the Reservoir Host (White-Tailed Deer) and in an Incidental Host (Dog) Is Impacted by Its Prior Growth in Macrophage and Tick Cell Environments. PLOS ONE, 9(10), e109056. https://doi.org/10.1371/journal.pone.0109056Ehrlichia chaffeensis, transmitted from Amblyomma americanum ticks, causes human monocytic ehrlichiosis. It also infects white-tailed deer, dogs and several other vertebrates. Deer are its reservoir hosts, while humans and dogs are incidental hosts. E. chaffeensis protein expression is influenced by its growth in macrophages and tick cells. We report here infection progression in deer or dogs infected intravenously with macrophage- or tick cell-grown E. chaffeensis or by tick transmission in deer. Deer and dogs developed mild fever and persistent rickettsemia; the infection was detected more frequently in the blood of infected animals with macrophage inoculum compared to tick cell inoculum or tick transmission. Tick cell inoculum and tick transmission caused a drop in tick infection acquisition rates compared to infection rates in ticks fed on deer receiving macrophage inoculum. Independent of deer or dogs, IgG antibody response was higher in animals receiving macrophage inoculum against macrophage-derived Ehrlichia antigens, while it was significantly lower in the same animals against tick cell-derived Ehrlichia antigens. Deer infected with tick cell inoculum and tick transmission caused a higher antibody response to tick cell cultured bacterial antigens compared to the antibody response for macrophage cultured antigens for the same animals. The data demonstrate that the host cell-specific E. chaffeensis protein expression influences rickettsemia in a host and its acquisition by ticks. The data also reveal that tick cell-derived inoculum is similar to tick transmission with reduced rickettsemia, IgG response and tick acquisition of E. chaffeensis
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