111 research outputs found
Molecular dissection of Wnt3a-Frizzled8 interaction reveals essential and modulatory determinants of Wnt signaling activity
Background: Wnt proteins are a family of secreted signaling molecules that regulate key developmental processes in metazoans. The molecular basis of Wnt binding to Frizzled and LRP5/6 co-receptors has long been unknown due to the lack of structural data on Wnt ligands. Only recently, the crystal structure of the Wnt8-Frizzled8-cysteine-rich-domain (CRD) complex was solved, but the significance of interaction sites that influence Wnt signaling has not been assessed. Results: Here, we present an extensive structure-function analysis of mouse Wnt3a in vitro and in vivo. We provide evidence for the essential role of serine 209, glycine 210 (site 1) and tryptophan 333 (site 2) in Fz binding. Importantly, we discovered that valine 337 in the site 2 binding loop is critical for signaling without contributing to binding. Mutations in the presumptive second CRD binding site (site 3) partly abolished Wnt binding. Intriguingly, most site 3 mutations increased Wnt signaling, probably by inhibiting Wnt-CRD oligomerization. In accordance, increasing amounts of soluble Frizzled8-CRD protein modulated Wnt3a signaling in a biphasic manner. Conclusions: We propose a concentration-dependent switch in Wnt-CRD complex formation from an inactive aggregation state to an activated high mobility state as a possible modulatory mechanism in Wnt signaling gradients
Approaching the Gamow Window with Stored Ions : Direct Measurement of Xe 124 (p,γ) in the ESR Storage Ring
© 2019 American Physical Society. All rights reserved.We report the first measurement of low-energy proton-capture cross sections of Xe124 in a heavy-ion storage ring. Xe12454+ ions of five different beam energies between 5.5 and 8 AMeV were stored to collide with a windowless hydrogen target. The Cs125 reaction products were directly detected. The interaction energies are located on the high energy tail of the Gamow window for hot, explosive scenarios such as supernovae and x-ray binaries. The results serve as an important test of predicted astrophysical reaction rates in this mass range. Good agreement in the prediction of the astrophysically important proton width at low energy is found, with only a 30% difference between measurement and theory. Larger deviations are found above the neutron emission threshold, where also neutron and γ widths significantly impact the cross sections. The newly established experimental method is a very powerful tool to investigate nuclear reactions on rare ion beams at low center-of-mass energies.Peer reviewedFinal Published versio
A Hybrid of Metabolic Flux Analysis and Bayesian Factor Modeling for Multiomic Temporal Pathway Activation.
The
growing availability of multiomic data provides a highly comprehensive
view of cellular processes at the levels of mRNA, proteins, metabolites,
and reaction fluxes. However, due to probabilistic interactions between
components depending on the environment and on the time course, casual,
sometimes rare interactions may cause important effects in the cellular
physiology. To date, interactions at the pathway level cannot be measured
directly, and methodologies to predict pathway cross-correlations
from reaction fluxes are still missing. Here, we develop a multiomic
approach of flux-balance analysis combined with Bayesian factor modeling
with the aim of detecting pathway cross-correlations and predicting
metabolic pathway activation profiles. Starting from gene expression
profiles measured in various environmental conditions, we associate
a flux rate profile with each condition. We then infer pathway cross-correlations
and identify the degrees of pathway activation with respect to the
conditions and time course using Bayesian factor modeling. We test
our framework on the most recent metabolic reconstruction of Escherichia coli in both static and dynamic environments,
thus predicting the functionality of particular groups of reactions
and how it varies over time. In a dynamic environment, our method
can be readily used to characterize the temporal progression of pathway
activation in response to given stimuli
Cell Type–Specific Thalamic Innervation in a Column of Rat Vibrissal Cortex
This is the concluding article in a series of 3 studies that investigate the anatomical determinants of thalamocortical (TC) input to excitatory neurons in a cortical column of rat primary somatosensory cortex (S1). We used viral synaptophysin-enhanced green fluorescent protein expression in thalamic neurons and reconstructions of biocytin-labeled cortical neurons in TC slices to quantify the number and distribution of boutons from the ventral posterior medial (VPM) and posteromedial (POm) nuclei potentially innervating dendritic arbors of excitatory neurons located in layers (L)2–6 of a cortical column in rat somatosensory cortex. We found that 1) all types of excitatory neurons potentially receive substantial TC input (90–580 boutons per neuron); 2) pyramidal neurons in L3–L6 receive dual TC input from both VPM and POm that is potentially of equal magnitude for thick-tufted L5 pyramidal neurons (ca. 300 boutons each from VPM and POm); 3) L3, L4, and L5 pyramidal neurons have multiple (2–4) subcellular TC innervation domains that match the dendritic compartments of pyramidal cells; and 4) a subtype of thick-tufted L5 pyramidal neurons has an additional VPM innervation domain in L4. The multiple subcellular TC innervation domains of L5 pyramidal neurons may partly explain their specific action potential patterns observed in vivo. We conclude that the substantial potential TC innervation of all excitatory neuron types in a cortical column constitutes an anatomical basis for the initial near-simultaneous representation of a sensory stimulus in different neuron types
Determination of luminosity for in-ring reactions:A new approach for the low-energy domain
Luminosity is a measure of the colliding frequency between beam and target
and it is a crucial parameter for the measurement of absolute values, such as
reaction cross sections. In this paper, we make use of experimental data from
the ESR storage ring to demonstrate that the luminosity can be precisely
determined by modelling the measured Rutherford scattering distribution. The
obtained results are in good agreement with an independent measurement based on
the x-ray normalization method. Our new method provides an alternative way to
precisely measure the luminosity in low-energy stored-beam configurations. This
can be of great value in particular in dedicated low-energy storage rings where
established methods are difficult or impossible to apply.Comment: 8 pages, 5 figure
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