360 research outputs found
Regulation of Tcf7l1 DNA Binding and Protein Stability as Principal Mechanisms of Wnt/β-Catenin Signaling
SummaryWnt/β-catenin signal transduction requires direct binding of β-catenin to Tcf/Lef proteins, an event that is classically associated with stimulating transcription by recruiting coactivators. This molecular cascade plays critical roles throughout embryonic development and normal postnatal life by affecting stem cell characteristics and tumor formation. Here, we show that this pathway utilizes a fundamentally different mechanism to regulate Tcf7l1 (formerly named Tcf3) activity. β-catenin inactivates Tcf7l1 without a switch to a coactivator complex by removing it from DNA, which leads to Tcf7l1 protein degradation. Mouse genetic experiments demonstrate that Tcf7l1 inactivation is the only required effect of the Tcf7l1-β-catenin interaction. Given the expression of Tcf7l1 in pluripotent embryonic and adult stem cells, as well as in poorly differentiated breast cancer, these findings provide mechanistic insights into the regulation of pluripotency and the role of Wnt/β-catenin in breast cancer
Outsourcing with debt financing
This paper investigates the effect of capital structure on a firm’s choice between vertical integration and outsourcing. We model the production decision in a Principal-Agent framework and show that suppliers use debt as a strategic instrument to collect the surplus from outsourcing as their wealth constraint or limited liability ensures them more attractive compensation schemes. Investigating the buyer’s capital structure, we find that outsourcing with risky debt is more likely to occur for high values of the outsourcing surplus.info:eu-repo/semantics/publishedVersio
Tube Models for Rubber-Elastic Systems
In the first part of the paper we show that the constraining potentials
introduced to mimic entanglement effects in Edwards' tube model and Flory's
constrained junction model are diagonal in the generalized Rouse modes of the
corresponding phantom network. As a consequence, both models can formally be
solved exactly for arbitrary connectivity using the recently introduced
constrained mode model. In the second part, we solve a double tube model for
the confinement of long paths in polymer networks which is partially due to
crosslinking and partially due to entanglements. Our model describes a
non-trivial crossover between the Warner-Edwards and the Heinrich-Straube tube
models. We present results for the macroscopic elastic properties as well as
for the microscopic deformations including structure factors.Comment: 15 pages, 8 figures, Macromolecules in pres
Transmembrane protease serine 5: a novel Schwann cell plasma marker for CMT1A
OBJECTIVE: Development of biomarkers for Charcot-Marie-Tooth (CMT) disease is critical for implementing effective clinical trials. The most common form of CMT, type 1A, is caused by a genomic duplication surrounding the PMP22 gene. A recent report (Neurology 2018;90:e518-3524) showed elevation of neurofilament light (NfL) in plasma of CMT1A disease patients, which correlated with disease severity. However, no plasma/serum biomarker has been identified that is specific to Schwann cells, the most directly affected cells in CMT1A. METHODS: We used the Olink immuno PCR platform to profile CMT1A patient (n = 47, 2 cohorts) and normal control plasma (n = 41, two cohorts) on five different Olink panels to screen 398 unique proteins. RESULTS: The TMPRSS5 protein (Transmembrane protease serine 5) was elevated 2.07-fold (P = <0.0001) in two independent cohorts of CMT1A samples relative to controls. TMPRSS5 is most highly expressed in Schwann cells of peripheral nerve. Consistent with early myelination deficits in CMT1A, TMPRSS5 was not significantly correlated with disease score (CMTES-R, CMTNS-R), nerve conduction velocities (Ulnar CMAP, Ulnar MNCV), or with age. TMPRSS5 was not significantly elevated in smaller sample sets from patients with CMT2A, CMT2E, CMT1B, or CMT1X. The Olink immuno PCR assays confirmed elevated levels of NfL (average 1.58-fold, P < 0.0001), which correlated with CMT1A patient disease score. INTERPRETATION: These data identify the first Schwann cell-specific protein that is elevated in plasma of CMT1A patients, and may provide a disease marker and a potentially treatment-responsive biomarker with good disease specificity for clinical trials
The next generation of laser spectroscopy experiments using light muonic atoms
Precision spectroscopy of light muonic atoms provides unique information
about the atomic and nuclear structure of these systems and thus represents a
way to access fundamental interactions, properties and constants. One
application comprises the determination of absolute nuclear charge radii with
unprecedented accuracy from measurements of the 2S-2P Lamb shift. Here,
we review recent results of nuclear charge radii extracted from muonic hydrogen
and helium spectroscopy and present experiment proposals to access light muonic
atoms with . In addition, our approaches towards a precise
measurement of the Zemach radii in muonic hydrogen (p) and helium
(He) are discussed. These results will provide new tests of
bound-state quantum-electrodynamics in hydrogen-like systems and can be used as
benchmarks for nuclear structure theories.Comment: 17 pages, 8 figure
Laser excitation of the 1s-hyperfine transition in muonic hydrogen
The CREMA collaboration is pursuing a measurement of the ground-state
hyperfine splitting (HFS) in muonic hydrogen (p) with 1 ppm accuracy by
means of pulsed laser spectroscopy to determine the two-photon-exchange
contribution with relative accuracy. In the proposed
experiment, the p atom undergoes a laser excitation from the singlet
hyperfine state to the triplet hyperfine state, {then} is quenched back to the
singlet state by an inelastic collision with a H molecule. The resulting
increase of kinetic energy after the collisional deexcitation is used as a
signature of a successful laser transition between hyperfine states. In this
paper, we calculate the combined probability that a p atom initially in
the singlet hyperfine state undergoes a laser excitation to the triplet state
followed by a collisional-induced deexcitation back to the singlet state. This
combined probability has been computed using the optical Bloch equations
including the inelastic and elastic collisions. Omitting the decoherence
effects caused by {the laser bandwidth and }collisions would overestimate the
transition probability by more than a factor of two in the experimental
conditions. Moreover, we also account for Doppler effects and provide the
matrix element, the saturation fluence, the elastic and inelastic collision
rates for the singlet and triplet states, and the resonance linewidth. This
calculation thus quantifies one of the key unknowns of the HFS experiment,
leading to a precise definition of the requirements for the laser system and to
an optimization of the hydrogen gas target where p is formed and the laser
spectroscopy will occur.Comment: 21 pages, 4 figure
Mutation of FIG4 causes neurodegeneration in the pale tremor mouse and patients with CMT4J
Membrane-bound phosphoinositides are signalling molecules that have a key role in vesicle trafficking in eukaryotic cells(1). Proteins that bind specific phosphoinositides mediate interactions between membrane-bounded compartments whose identity is partially encoded by cytoplasmic phospholipid tags. Little is known about the localization and regulation of mammalian phosphatidylinositol-3,5-bisphosphate ( PtdIns( 3,5)P-2), a phospholipid present in small quantities that regulates membrane trafficking in the endosome - lysosome axis in yeast(2). Here we describe a multi-organ disorder with neuronal degeneration in the central nervous system, peripheral neuronopathy and diluted pigmentation in the 'pale tremor' mouse. Positional cloning identified insertion of ETn2 beta ( early transposon 2 beta)(3) into intron 18 of Fig4 (A530089I17Rik), the homologue of a yeast SAC ( suppressor of actin) domain PtdIns(3,5) P-2 5-phosphatase located in the vacuolar membrane. The abnormal concentration of PtdIns( 3,5) P2 in cultured fibroblasts from pale tremor mice demonstrates the conserved biochemical function of mammalian Fig4. The cytoplasm of fibroblasts from pale tremor mice is filled with large vacuoles that are immunoreactive for LAMP-2 (lysosomal-associated membrane protein 2), consistent with dysfunction of the late endosome - lysosome axis. Neonatal neurodegeneration in sensory and autonomic ganglia is followed by loss of neurons from layers four and five of the cortex, deep cerebellar nuclei and other localized brain regions. The sciatic nerve exhibits reduced numbers of large-diameter myelinated axons, slowed nerve conduction velocity and reduced amplitude of compound muscle action potentials. We identified pathogenic mutations of human FIG4 (KIAA0274) on chromosome 6q21 in four unrelated patients with hereditary motor and sensory neuropathy. This novel form of autosomal recessive Charcot - Marie - Tooth disorder is designated CMT4J.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/62835/1/nature05876.pd
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