Wnts modulate cell proliferation, differentiation and stem cell self-renewal, by inducing β-catenin dependent signaling through Frizzled (Fzd) and Lrp5/6 to regulate cell fate decisions, and the growth and repair of a multitude of tissues1. The 19 mammalian Wnts interact promiscuously with the 10 Fzds, which has complicated the attribution of specific Fzd/Wnt subtype interactions to distinct biological functions. Furthermore, Wnts are post-translationally modified by palmitoylation, which is essential for Wnt secretion and functions as a critical site of interaction with Fzd 2–4. As a result of their acylation, Wnts are very hydrophobic proteins requiring detergents for purification, which presents major obstacles for the preparation and application of recombinant Wnts. This has hindered the delineation of the molecular mechanisms of Wnt signaling activation, understanding of the functional significance of Fzd subtypes, and the use of Wnts as therapeutics. Here we developed surrogate Wnt agonists, water-soluble Fzd-Lrp5/6 heterodimerizers, consisting of Fzd5/8-specific and broadly Fzd-reactive binding domains, that elicit a characteristic β-catenin signaling response in a Fzd-selective fashion, enhance osteogenic lineage commitment of primary mesenchymal stem cells (MSCs), and support the growth of a broad range of primary human organoid cultures comparably to Wnt3a. Furthermore, we demonstrate that the surrogates can be systemically expressed and exhibit Wnt activity in vivo, regulating metabolic liver zonation and promoting hepatocyte proliferation, resulting in hepatomegaly. These surrogates demonstrate that canonical Wnt signaling can be activated simply through bi-specific ligands that induce receptor heterodimerization. Furthermore, these easily produced non-lipidated Wnt surrogate agonists offer a new avenue to facilitate functional studies of Wnt signaling and the exploration of Wnt agonists for translational applications in regenerative medicine.
Indirect-drive hohlraum experiments at the National Ignition Facility have demonstrated symmetric capsule implosions at unprecedented laser drive energies of 0.7 MJ. 192 simultaneously fired laser beams heat ignition emulate hohlraums to radiation temperatures of 3.3 million Kelvin compressing 1.8-millimeter capsules by the soft x rays produced by the hohlraum. Self-generated plasma-optics gratings on either end of the hohlraum tune the laser power distribution in the hohlraum producing symmetric x-ray drive as inferred from the shape of the capsule self-emission. These experiments indicate conditions suitable for compressing deuterium-tritium filled capsules with the goal to achieve burning fusion plasmas and energy gain in the laboratory.With completion (1) and commissioning (2) of the National Ignition Facility (NIF) the quest for producing a burning fusion plasma has begun (3, 4). The goal of these experiments is to compress matter to densities and temperatures higher than the interior of the sun (5-7) which will initiate nuclear fusion and burn of hydrogen isotopes (8-10). This technique holds promise to demonstrate a highly efficient carbon-free process that will burn milligram quantities of nuclear fuel on each laser shot for producing energy gain in the laboratory.The NIF (11) consists of 192 laser beams that have been arranged into cones of beams to irradiate a target from the top and bottom hemispheres. This "indirect-drive" laser geometry has been chosen for the first experiments to heat the interior of centimeter-scale cylindrical gold hohlraums (8,(12)(13)(14)(15) through laser entrance holes (LEH) on the top and bottom end of the cylinder (Fig. 1). Hohlraums act as radiation enclosures that convert the optical laser light into soft x-rays that are characterized by the radiation temperature T RAD . Present ignition designs operate at temperatures of 270 to 305 eV or 3.1 to 3.5 million K. The radiation field compresses a spherical fusion capsule mounted in the center of the hohlraum by x-ray ablation of the outer shell. The ablation process compresses the cryogenically prepared solid deuterium-tritium fuel layer in a spherical rocket implosion. In the final stages, the fuel reaches densities 1000-times solid and the central hot spot temperatures will approach 100 million K to initiate the nuclear burn process.We have symmetrically imploded 1.8-mm diameter fusion capsules in cryogenically fielded centimeter-scale hohlraums at 20 K. These experiments show efficient hohlraum heating to radiation temperatures of 3.3 million K. In addition, the large scale-length plasmas encountered in these experiments have allowed us to use self-generated plasma optics gratings (16) to control the radiation symmetry (17) and to achieve symmetric fusion capsule implosions.Figure 2 A shows the laser power at the frequency-tripled wavelength of 351 nm versus time for two different pulse shapes. These 11-ns and 16-ns long pulses heat 8.4-mm long, 4.6-mm diameter hohlraums with 20% helium, 80% hydrogen (atomic) mixtures and ...
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The “High-Foot” platform manipulates the laser pulse-shape coming from the National Ignition Facility laser to create an indirect drive 3-shock implosion that is significantly more robust against instability growth involving the ablator and also modestly reduces implosion convergence ratio. This strategy gives up on theoretical high-gain in an inertial confinement fusion implosion in order to obtain better control of the implosion and bring experimental performance in-line with calculated performance, yet keeps the absolute capsule performance relatively high. In this paper, we will cover the various experimental and theoretical motivations for the high-foot drive as well as cover the experimental results that have come out of the high-foot experimental campaign. At the time of this writing, the high-foot implosion has demonstrated record total deuterium-tritium yields (9.3×1015) with low levels of inferred mix, excellent agreement with implosion simulations, fuel energy gains exceeding unity, and evidence for the “bootstrapping” associated with alpha-particle self-heating.
In an experimental study of the physics of fast ignition the characteristics of the hot electron source at laser intensities up to 10 " Wcm"2and the heating produced at depth by hot electrons have been measured. Efficient generation of hot electrons but less than the anticipated heating have been observed.The concept of isochoric fast ignition originated by Tabak et al. ' is of importance through its potential to give higher inertially confined fusion (ICF) gain than isobaric central spark ignition used in the more developed indirect and direct drive schemes 'and thereby to reduce the driver efficiency required for inertial fusion energy (IFE). The physics is new and challenging involving strongly relativistic laser plasma interactions and transport of energy by MeV electrons where electrostatic potentials and self generated magnetic fields may strongly modify the transport 3. Experimental and theoretical studies aimed at assessing the feasibilityof fastignitionas a newrouteto ICF arenowbeing carried out at many laboratories world wide including the Lawrence Livennore National Laboratory (LLNL), where the Nova laser facility has been adapted to generate petawatt pulses using chirped puke ampliilcation (CPA)4 . Experimental FaciIityTwo beam lines at Nova have been adapted for CPA operation and for experiments reported here, generated typically 20J and 500J pulses respectively of duration in the range 0.4 to 20 ps (maximum power up to 1 PW). Focusing of the two beams respectively was with an off axis f73parabolic mirror of focal length 42 cm in a focal spot of 15 yrn diameter 1 and an axial f14parabola of focal length 170 cm in an asymmetrical spot of 40 pm x 20SThe focal spots had a speckle ,pattern sub structure with a broad power spec& of intensity. Work is in progress to correct the wavefront using a deformable mirror. T&b eam line produced a power weighted average intensity on target in 0.45 ps pulses estimated at 210'9 Wcm"2. The 500J, beam line produced 10 N Wcm'2 in 1 PW, 0.45 ps pulses. A thick glass plate debris shield protected the parabola in the 500J beam line for longer pulse operation down to 5 ps. Non linear effects precluded the me of the debris shield for lPW shots and here a plasma mirror was used to reverse the beam direction thus projecting ablated target debris away from the un-protected parabola. The off axis parabola was used with a thin debris shield for all pulse lengths in the 20 J experiments. Targets in these experiments were exposed to ASE and leakage prepulses before the main pulse. ASE in a typically 3 ns period before the pulse varied in experiments reported here from 210-5 to 2104 of the main pulse energy. The energy of leakage pulses ranged from 104 to 10'2of the main pulse, occurring 2 ns or 4 ns before the main pulse but could be made as low as 104 with precise adjustment of Pockels cell gates. The hot electron sourceA central theme of the experimental work has been the characterization of the hot electron source produced at a solid target. Electrons directed into the t...
The polycomb repressive complex 2 (PRC2) histone methyltransferase plays a central role in epigenetic regulation in development and in cancer, and hence to interrogate its role in a specific developmental transition, methods are needed for disrupting function of the complex with high temporal and spatial precision. The catalytic and substrate recognition functions of PRC2 are coupled by binding of the N-terminal helix of the Ezh2 methylase to an extended groove on the EED trimethyl lysine binding subunit. Disrupting PRC2 function can in principle be achieved by blocking this single interaction, but there are few approaches for blocking specific protein-protein interactions in living cells and organisms. Here, we describe the computational design of proteins that bind to the EZH2 interaction site on EED with subnanomolar affinity in vitro and form tight and specific complexes with EED in living cells. Induction of the EED binding proteins abolishes H3K27 methylation in human embryonic stem cells (hESCs) and at all but the earliest stage blocks self-renewal, pinpointing the first critical repressive H3K27me3 marks in development.
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