894 research outputs found
Deconvoluting the Molecular Control of Binding and Signaling at the Amylin 3 Receptor: RAMP3 Alters Signal Propagation through Extracellular Loops of the Calcitonin Receptor
Amylin is coexpressed with insulin in pancreatic islet β-cells and has potent effects on gastric emptying and food intake. The effect of amylin on satiation has been postulated to involve AMY3 receptors (AMY3R) that are heteromers of the calcitonin receptor (CTR) and receptor activity-modifying protein 3 (RAMP3). Understanding the molecular control of signaling through the AMY3R is thus important for peptide drug targeting of this receptor. We have previously used alanine scanning mutagenesis to study the contribution of the extracellular surface of the CTR to binding and signaling initiated by calcitonin (CT) and related peptides (Dal Maso, E., et al. (2019) The molecular control of calcitonin receptor signaling. ACS Pharmacol. Transl. Sci.2, 31–51). That work revealed ligand- and pathway-specific effects of mutation, with extracellular loops (ECLs) 2 and 3 particularly important in the distinct propagation of signaling mediated by individual peptides. In the current study, we have used equivalent alanine scanning of ECL2 and ECL3 of the CTR in the context of coexpression with RAMP3 to form AMY3Rs, to examine functional affinity and efficacy of peptides in cAMP accumulation and extracellular signal-regulated kinase (ERK) phosphorylation (pERK). The effect of mutation was determined on representatives of the three major distinct classes of CT peptide, salmon CT (sCT), human CT (hCT), and porcine CT (pCT), as well as rat amylin (rAmy) or human α-CGRP (calcitonin gene-related peptide, hCGRP) whose potency is enhanced by RAMP interaction. We demonstrate that the dynamic nature of CTR ECL2 and ECL3 in propagation of signaling is fundamentally altered when complexed with RAMP3 to form the AMY3R, despite only having predicted direct interactions with ECL2. Moreover, the work shows that the role of these loops in receptor signaling is highly peptide dependent, illustrating that even subtle changes to peptide sequence may change signaling output downstream of the receptor
Activation of the GLP-1 receptor by a non-peptidic agonist
Class B G-protein-coupled receptors are major targets for the treatment of chronic diseases, including diabetes and obesity1. Structures of active receptors reveal peptide agonists engage deep within the receptor core, leading to an outward movement of extracellular loop 3 and the tops of transmembrane helices 6 and 7, an inward movement of transmembrane helix 1, reorganization of extracellular loop 2 and outward movement of the intracellular side of transmembrane helix 6, resulting in G-protein interaction and activation2,3,4,5,6. Here we solved the structure of a non-peptide agonist, TT-OAD2, bound to the glucagon-like peptide-1 (GLP-1) receptor. Our structure identified an unpredicted non-peptide agonist-binding pocket in which reorganization of extracellular loop 3 and transmembrane helices 6 and 7 manifests independently of direct ligand interaction within the deep transmembrane domain pocket. TT-OAD2 exhibits biased agonism, and kinetics of G-protein activation and signalling that are distinct from peptide agonists. Within the structure, TT-OAD2 protrudes beyond the receptor core to interact with the lipid or detergent, providing an explanation for the distinct activation kinetics that may contribute to the clinical efficacy of this compound series. This work alters our understanding of the events that drive the activation of class B receptors
Spatial and temporal dynamics of fucoid populations (Ascophyllum nodosum and Fucus serratus): A comparison between central and range edge populations
Persistence of populations at range edges relies on local population dynamics and fitness, in the case of geographically isolated populations of species with low dispersal potential. Focusing on spatial variations in demography helps to predict the long-term capability for persistence of populations across the geographical range of species' distribution. The demography of two ecological and phylogenetically close macroalgal species with different life history characteristics was investigated by using stochastic, stage-based matrix models. Populations of Ascophyllum nodosum and Fucus serratus were sampled for up to 4 years at central locations in France and at their southern range limits in Portugal. The stochastic population growth rate (lambda(s)) of A. nodosum was lower and more variable in central than in southern sites whilst for F. serratus this trend was reversed with lambda(s) much lower and more variable in southern than in central populations. Individuals were larger in central than in southern populations for both species, which was reflected in the lower transition probabilities of individuals to larger size classes and higher probability of shrinkage in the southern populations. In both central and southern populations elasticity analysis (proportional sensitivity) of population growth rate showed that fertility elements had a small contribution to lambda(s) that was more sensitive to changes in matrix transitions corresponding to survival. The highest elasticities were found for loop transitions in A. nodosum and for growth to larger size classes in F. serratus. Sensitivity analysis showed high selective pressure on individual growth for both species at both locations. The results of this study highlight the deterministic role of species-specific life-history traits in population demography across the geographical range of species. Additionally, this study demonstrates that individuals' life-transitions differ in vulnerability to environmental variability and shows the importance of vegetative compared to reproductive stages for the long-term persistence of populations.Portuguese Foundation for Science and Technology (FCT) [SFRH/BPD/75843/2011]; European Regional Development Fund (ERDF) through the COMPETE - Operational Competitiveness Programme; FCT [Pest-CIMAR LA 0015/2013, EXCL/AAG-GLO/0661/2012
Forward-Backward Asymmetry in Top Quark Production in ppbar Collisions at sqrt{s}=1.96 TeV
Reconstructable final state kinematics and charge assignment in the reaction
ppbar->ttbar allows tests of discrete strong interaction symmetries at high
energy. We define frame dependent forward-backward asymmetries for the outgoing
top quark in both the ppbar and ttbar rest frames, correct for experimental
distortions, and derive values at the parton-level. Using 1.9/fb of ppbar
collisions at sqrt{s}=1.96 TeV recorded with the CDF II detector at the
Fermilab Tevatron, we measure forward-backward top quark production asymmetries
in the ppbar and ttbar rest frames of A_{FB,pp} = 0.17 +- 0.08 and A_{FB,tt} =
0.24 +- 0.14.Comment: 7 pages, 2 figures, submitted to Phys.Rev.Lett, corrected references
and change of tex
Studying the Underlying Event in Drell-Yan and High Transverse Momentum Jet Production at the Tevatron
We study the underlying event in proton-antiproton collisions by examining
the behavior of charged particles (transverse momentum pT > 0.5 GeV/c,
pseudorapidity |\eta| < 1) produced in association with large transverse
momentum jets (~2.2 fb-1) or with Drell-Yan lepton-pairs (~2.7 fb-1) in the
Z-boson mass region (70 < M(pair) < 110 GeV/c2) as measured by CDF at 1.96 TeV
center-of-mass energy. We use the direction of the lepton-pair (in Drell-Yan
production) or the leading jet (in high-pT jet production) in each event to
define three regions of \eta-\phi space; toward, away, and transverse, where
\phi is the azimuthal scattering angle. For Drell-Yan production (excluding the
leptons) both the toward and transverse regions are very sensitive to the
underlying event. In high-pT jet production the transverse region is very
sensitive to the underlying event and is separated into a MAX and MIN
transverse region, which helps separate the hard component (initial and
final-state radiation) from the beam-beam remnant and multiple parton
interaction components of the scattering. The data are corrected to the
particle level to remove detector effects and are then compared with several
QCD Monte-Carlo models. The goal of this analysis is to provide data that can
be used to test and improve the QCD Monte-Carlo models of the underlying event
that are used to simulate hadron-hadron collisions.Comment: Submitted to Phys.Rev.
Precision measurement of the top quark mass from dilepton events at CDF II
We report a measurement of the top quark mass, M_t, in the dilepton decay
channel of
using an integrated luminosity of 1.0 fb^{-1} of p\bar{p} collisions collected
with the CDF II detector. We apply a method that convolutes a leading-order
matrix element with detector resolution functions to form event-by-event
likelihoods; we have enhanced the leading-order description to describe the
effects of initial-state radiation. The joint likelihood is the product of the
likelihoods from 78 candidate events in this sample, which yields a measurement
of M_{t} = 164.5 \pm 3.9(\textrm{stat.}) \pm 3.9(\textrm{syst.})
\mathrm{GeV}/c^2, the most precise measurement of M_t in the dilepton channel.Comment: 7 pages, 2 figures, version includes changes made prior to
publication by journa
Measurement of the Ratios of Branching Fractions B(Bs -> Ds pi pi pi) / B(Bd -> Dd pi pi pi) and B(Bs -> Ds pi) / B(Bd -> Dd pi)
Using 355 pb^-1 of data collected by the CDF II detector in \ppbar collisions
at sqrt{s} = 1.96 TeV at the Fermilab Tevatron, we study the fully
reconstructed hadronic decays B -> D pi and B -> D pi pi pi. We present the
first measurement of the ratio of branching fractions B(Bs -> Ds pi pi pi) /
B(Bd -> Dd pi pi pi) = 1.05 pm 0.10 (stat) pm 0.22 (syst). We also update our
measurement of B(Bs -> Ds pi) / B(Bd -> Dd pi) to 1.13 pm 0.08 (stat) pm 0.23
(syst) improving the statistical uncertainty by more than a factor of two. We
find B(Bs -> Ds pi) = [3.8 pm 0.3 (stat) pm 1.3 (syst)] \times 10^{-3} and B(Bs
-> Ds pi pi pi) = [8.4 pm 0.8 (stat) pm 3.2 (syst)] \times 10^{-3}.Comment: 7 pages, 2 figure
Cross Section Measurements of High- Dilepton Final-State Processes Using a Global Fitting Method
We present a new method for studying high- dilepton events
(, , ) and simultaneously
extracting the production cross sections of , , and p\bar{p} \to \ztt at a center-of-mass energy of TeV. We perform a likelihood fit to the dilepton data in a parameter
space defined by the missing transverse energy and the number of jets in the
event. Our results, which use of data recorded with the CDF
II detector at the Fermilab Tevatron Collider, are pb, pb, and
\sigma(\ztt) =291^{+50}_{-46} pb.Comment: 20 pages, 2 figures, to be submitted to PRD-R
Top Quark Mass Measurement from Dilepton Events at CDF II with the Matrix-Element Method
We describe a measurement of the top quark mass using events with two charged
leptons collected by the CDF II detector from collisions with TeV at the Fermilab Tevatron. The likelihood in top mass is
calculated for each event by convoluting the leading order matrix element
describing
with detector resolution functions. The presence of background events in the
data sample is modeled using similar calculations involving the matrix elements
for major background processes. In a data sample with integrated luminosity of
340 pb, we observe 33 candidate events and measure This
measurement represents the first application of this method to events with two
charged leptons and is the most precise single measurement of the top quark
mass in this channel.Comment: 21 pages, 14 figure
Search for New Physics in Lepton + Photon + X Events with L=305 pb-1 of ppbar Collisions at roots=1.96 TeV
We present results of a search for anomalous production of events containing
a charged lepton (either electron or muon) and a photon, both with high
transverse momentum, accompanied by additional signatures, X, including missing
transverse energy (MET) and additional leptons and photons. We use the same
kinematic selection criteria as in a previous CDF search, but with a
substantially larger data set, 305 pb-1, a ppbar collision energy of 1.96 TeV,
and the upgraded CDF II detector. We find 42 Lepton+Photon+MET events versus a
standard model expectation of 37.3 +- 5.4 events. The level of excess observed
in Run I, 16 events with an expectation of 7.6 +- 0.7 events (corresponding to
a 2.7 sigma effect), is not supported by the new data. In the signature of
Multi-Lepton+Photon+X we observe 31 events versus an expectation of 23.0 +- 2.7
events. In this sample we find no events with an extra photon or MET and so
find no events like the one ee+gg+MET event observed in Run I.Comment: 7 pages, 3 figures, 1 table. Accepted to PR
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