Methylation of DNA is an essential epigenetic control mechanism in mammals. During embryonic development, cells are directed toward their future lineages, and DNA methylation poses a fundamental ...epigenetic barrier that guides and restricts differentiation and prevents regression into an undifferentiated state. DNA methylation also plays an important role in sex chromosome dosage compensation, the repression of retrotransposons that threaten genome integrity, the maintenance of genome stability, and the coordinated expression of imprinted genes. However, DNA methylation marks must be globally removed to allow for sexual reproduction and the adoption of the specialized, hypomethylated epigenome of the primordial germ cell and the preimplantation embryo. Recent technological advances in genome-wide DNA methylation analysis and the functional description of novel enzymatic DNA demethylation pathways have provided significant insights into the molecular processes that prepare the mammalian embryo for normal development.
With an eye toward extending optical wave-mixing techniques to the x-ray regime, we present the first experimental demonstration of a two-color x-ray free-electron laser at the Linac Coherent Light ...Source. We combine the emittance-spoiler technique with a magnetic chicane in the undulator section to control the pulse duration and relative delay between two intense x-ray pulses and we use differently tuned canted pole undulators such that the two pulses have different wavelengths as well. Two schemes are shown to produce two-color soft x-ray pulses with a wavelength separation up to ∼1.9% and a controllable relative delay up to 40 fs.
Water has a number of anomalous physical properties, and some of these become drastically enhanced on supercooling below the freezing point. Particular interest has focused on thermodynamic response ...functions that can be described using a normal component and an anomalous component that seems to diverge at about 228 kelvin (refs 1-3). This has prompted debate about conflicting theories that aim to explain many of the anomalous thermodynamic properties of water. One popular theory attributes the divergence to a phase transition between two forms of liquid water occurring in the 'no man's land' that lies below the homogeneous ice nucleation temperature (TH) at approximately 232 kelvin and above about 160 kelvin, and where rapid ice crystallization has prevented any measurements of the bulk liquid phase. In fact, the reliable determination of the structure of liquid water typically requires temperatures above about 250 kelvin. Water crystallization has been inhibited by using nanoconfinement, nanodroplets and association with biomolecules to give liquid samples at temperatures below TH, but such measurements rely on nanoscopic volumes of water where the interaction with the confining surfaces makes the relevance to bulk water unclear. Here we demonstrate that femtosecond X-ray laser pulses can be used to probe the structure of liquid water in micrometre-sized droplets that have been evaporatively cooled below TH. We find experimental evidence for the existence of metastable bulk liquid water down to temperatures of 227(-1)(+2) kelvin in the previously largely unexplored no man's land. We observe a continuous and accelerating increase in structural ordering on supercooling to approximately 229 kelvin, where the number of droplets containing ice crystals increases rapidly. But a few droplets remain liquid for about a millisecond even at this temperature. The hope now is that these observations and our detailed structural data will help identify those theories that best describe and explain the behaviour of water.
Key insights into the behavior of materials can be gained by observing their structure as they undergo lattice distortion. Laser pulses on the femtosecond time scale can be used to induce disorder in ...a "pump-probe" experiment with the ensuing transients being probed stroboscopically with femtosecond pulses of visible light, x-rays, or electrons. Here we report three-dimensional imaging of the generation and subsequent evolution of coherent acoustic phonons on the picosecond time scale within a single gold nanocrystal by means of an x-ray free-electron laser, providing insights into the physics of this phenomenon. Our results allow comparison and confirmation of predictive models based on continuum elasticity theory and molecular dynamics simulations.
Although it is known that OCT4-NANOG are required for maintenance of pluripotent cells in vitro, the upstream signals that regulate this circuit during early development in vivo have not been ...identified. Here we demonstrate, for the first time, signal transducers and activators of transcription 3 (STAT3)-dependent regulation of the OCT4-NANOG circuitry necessary to maintain the pluripotent inner cell mass (ICM), the source of in vitro-derived embryonic stem cells (ESCs). We show that STAT3 is highly expressed in mouse oocytes and becomes phosphorylated and translocates to the nucleus in the four-cell and later stage embryos. Using leukemia inhibitory factor (Lif)-null embryos, we found that STAT3 phosphorylation is dependent on LIF in four-cell stage embryos. In blastocysts, interleukin 6 (IL-6) acts in an autocrine fashion to ensure STAT3 phosphorylation, mediated by janus kinase 1 (JAK1), a LIF- and IL-6-dependent kinase. Using genetically engineered mouse strains to eliminate Stat3 in oocytes and embryos, we firmly establish that STAT3 is essential for maintenance of ICM lineages but not for ICM and trophectoderm formation. Indeed, STAT3 directly binds to the Oct4 and Nanog distal enhancers, modulating their expression to maintain pluripotency of mouse embryonic and induced pluripotent stem cells. These results provide a novel genetic model of cell fate determination operating through STAT3 in the preimplantation embryo and pluripotent stem cells in vivo.
Preeclampsia (PE) is a gestational hypertensive syndrome affecting between 5 and 8% of all pregnancies. Although PE is the leading cause of fetal and maternal morbidity and mortality, its molecular ...etiology is still unclear. Here, we show that ELABELA (ELA), an endogenous ligand of the apelin receptor (APLNR, or APJ), is a circulating hormone secreted by the placenta. Elabela but not Apelin knockout pregnant mice exhibit PE-like symptoms, including proteinuria and elevated blood pressure due to defective placental angiogenesis. In mice, infusion of exogenous ELA normalizes hypertension, proteinuria, and birth weight. ELA, which is abundant in human placentas, increases the invasiveness of trophoblast-like cells, suggesting that it enhances placental development to prevent PE. The ELA-APLNR signaling axis may offer a new paradigm for the treatment of common pregnancy-related complications, including PE.
Pink-beam serial crystallography Meents, A; Wiedorn, M O; Srajer, V ...
Nature communications,
11/2017, Volume:
8, Issue:
1
Journal Article
Peer reviewed
Open access
Serial X-ray crystallography allows macromolecular structure determination at both X-ray free electron lasers (XFELs) and, more recently, synchrotron sources. The time resolution for serial ...synchrotron crystallography experiments has been limited to millisecond timescales with monochromatic beams. The polychromatic, "pink", beam provides a more than two orders of magnitude increased photon flux and hence allows accessing much shorter timescales in diffraction experiments at synchrotron sources. Here we report the structure determination of two different protein samples by merging pink-beam diffraction patterns from many crystals, each collected with a single 100 ps X-ray pulse exposure per crystal using a setup optimized for very low scattering background. In contrast to experiments with monochromatic radiation, data from only 50 crystals were required to obtain complete datasets. The high quality of the diffraction data highlights the potential of this method for studying irreversible reactions at sub-microsecond timescales using high-brightness X-ray facilities.
The ultrafast evolution of microstructure is key to understanding high-pressure and strain-rate phenomena. However, the visualization of lattice dynamics at scales commensurate with those of ...atomistic simulations has been challenging. Here, we report femtosecond x-ray diffraction measurements unveiling the response of copper to laser shock-compression at peak normal elastic stresses of ~73 gigapascals (GPa) and strain rates of 10⁹ per second. We capture the evolution of the lattice from a one-dimensional (1D) elastic to a 3D plastically relaxed state within a few tens of picoseconds, after reaching shear stresses of 18 GPa. Our in situ high-precision measurement of material strength at spatial (< 1 micrometer) and temporal (< 50 picoseconds) scales provides a direct comparison with multimillion-atom molecular dynamics simulations.
The recently commissioned Linac Coherent Light Source is an X-ray free-electron laser at the SLAC National Accelerator Laboratory. It produces coherent soft and hard X-rays with peak brightness ...nearly ten orders of magnitude beyond conventional synchrotron sources and a range of pulse durations from 500 to <10 fs (10-15 s). With these beam characteristics this light source is capable of imaging the structure and dynamics of matter at atomic size and timescales. The facility is now operating at X-ray wavelengths from 22 to 1.2 A and is presently delivering this high-brilliance beam to a growing array of scientific researchers. We describe the operation and performance of this new 'fourth-generation light source'.
Ultrafast laser techniques have revealed extraordinary spin dynamics in magnetic materials that equilibrium descriptions of magnetism cannot explain. Particularly important for future applications is ...understanding non-equilibrium spin dynamics following laser excitation on the nanoscale, yet the limited spatial resolution of optical laser techniques has impeded such nanoscale studies. Here we present ultrafast diffraction experiments with an X-ray laser that probes the nanoscale spin dynamics following optical laser excitation in the ferrimagnetic alloy GdFeCo, which exhibits macroscopic all-optical switching. Our study reveals that GdFeCo displays nanoscale chemical and magnetic inhomogeneities that affect the spin dynamics. In particular, we observe Gd spin reversal in Gd-rich nanoregions within the first picosecond driven by the non-local transfer of angular momentum from larger adjacent Fe-rich nanoregions. These results suggest that a magnetic material's microstructure can be engineered to control transient laser-excited spins, potentially allowing faster (~ 1 ps) spin reversal than in present technologies.
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