The generation of functional hepatocytes independent of donor liver organs is of great therapeutic interest with regard to regenerative medicine and possible cures for liver disease. Induced hepatic differentiation has been achieved previously using embryonic stem cells or induced pluripotent stem cells. Particularly, hepatocytes generated from a patient's own induced pluripotent stem cells could theoretically avoid immunological rejection. However, the induction of hepatocytes from induced pluripotent stem cells is a complicated process that would probably be replaced with the arrival of improved technology. Overexpression of lineage-specific transcription factors directly converts terminally differentiated cells into some other lineages, including neurons, cardiomyocytes and blood progenitors; however, it remains unclear whether these lineage-converted cells could repair damaged tissues in vivo. Here we demonstrate the direct induction of functional hepatocyte-like (iHep) cells from mouse tail-tip fibroblasts by transduction of Gata4, Hnf1α and Foxa3, and inactivation of p19(Arf). iHep cells show typical epithelial morphology, express hepatic genes and acquire hepatocyte functions. Notably, transplanted iHep cells repopulate the livers of fumarylacetoacetate-hydrolase-deficient (Fah(-/-)) mice and rescue almost half of recipients from death by restoring liver functions. Our study provides a novel strategy to generate functional hepatocyte-like cells for the purpose of liver engineering and regenerative medicine.

In this paper, we systematically study the echo-enabled harmonic generation (EEHG) free electron laser (FEL). The EEHG FEL uses two modulators in combination with two dispersion sections that allow one to generate in the beam a high harmonic density modulation starting with a relatively small initial energy modulation of the beam. After presenting an analytical theory of the phenomenon, we address several practically important issues, such as the effect of incoherent synchrotron radiation in the dispersion sections, and the beam transverse size effect in the modulator. Using a representative realistic set of beam parameters, we show how the EEHG scheme enhances the FEL performance and allows one to generate a fully (both longitudinally and transversely) coherent radiation. As an example, we demonstrate that 5 nm coherent soft x rays with GW peak power can be generated directly from the 240 nm seeding laser using the proposed EEHG scheme.

Recent studies have demonstrated direct reprogramming of fibroblasts into a range of somatic cell types, but to date stem or progenitor cells have only been reprogrammed for the blood and neuronal lineages. We previously reported generation of induced hepatocyte-like (iHep) cells by transduction of Gata4, Hnf1α, and Foxa3 in p19 Arf null mouse embryonic fibroblasts (MEFs). Here, we show that Hnf1β and Foxa3, liver organogenesis transcription factors, are sufficient to reprogram MEFs into induced hepatic stem cells (iHepSCs). iHepSCs can be stably expanded in vitro and possess the potential of bidirectional differentiation into both hepatocytic and cholangiocytic lineages. In the injured liver of fumarylacetoacetate hydrolase (Fah)-deficient mice, repopulating iHepSCs become hepatocyte-like cells. They also engraft as cholangiocytes into bile ducts of mice with DDC-induced bile ductular injury. Lineage conversion into bipotential expandable iHepSCs provides a strategy to enable efficient derivation of both hepatocytes and cholangiocytes for use in disease modeling and tissue engineering.

Recent advances in the production and control of high-brightness electron beams (e-beams) have enabled a new class of intense light sources based on the free electron laser (FEL) that can examine matter atÅngstrom length and femtosecond time scales. The free, or unbound, electrons act as the lasing medium, which provides unique opportunities to exquisitely control the spatial and temporal structure of the emitted light through precision manipulation of the electron distribution. We present an experimental demonstration of light with orbital angular momentum (OAM) generated from a relativistic e-beam rearranged into an optical scale helix by a laser. With this technique, we show that a Gaussian laser mode can be effectively up-converted to an OAM mode in an FEL using only the e-beam as a mode-convertor. Results confirm theoretical predictions, and pave the way for the production of coherent OAM light with unprecedented brightness down to hard x-ray wavelengths for wide ranging applications in modern light sources.

Accelerator-based light sources such as storage rings and free-electron lasers use relativistic electron beams to produce intense radiation over a wide spectral range for fundamental research in physics, chemistry, materials science, biology and medicine. More than a dozen such sources operate worldwide, and new sources are being built to deliver radiation that meets with the ever increasing sophistication and depth of new research. Even so, conventional accelerator techniques often cannot keep pace with new demands and, thus, new approaches continue to emerge. In this article, we review a variety of recently developed and promising techniques that rely on lasers to manipulate and rearrange the electron distribution in order to tailor the properties of the radiation. Basic theories of electron-laser interactions, techniques to create micro-and nano-structures in electron beams, and techniques to produce radiation with customizable waveforms are reviewed. We overview laser-based techniques for the generation of fully coherent x-rays, mode-locked x-ray pulse trains, light with orbital angular momentum, and attosecond or even zeptosecond long coherent pulses in free-electron lasers. Several methods to generate femtosecond pulses in storage rings are also discussed. Additionally, we describe various schemes designed to enhance the performance of light sources through precision beam preparation including beam conditioning, laser heating, emittance exchange, and various laser-based diagnostics. Together these techniques represent a new emerging concept of "beam by design" in modern accelerators, which is the primary focus of this article CONTENTS