Hippo-Lats-Yorkie signaling regulates tissue overgrowth and tumorigenesis in Drosophila. We show that the Mst1 and Mst2 protein kinases, the mammalian Hippo orthologs, are cleaved and constitutively activated in the mouse liver. Combined Mst1/2 deficiency in the liver results in loss of inhibitory Ser127 phosphorylation of the Yorkie ortholog, Yap1, massive overgrowth, and hepatocellular carcinoma (HCC). Reexpression of Mst1 in HCC-derived cell lines promotes Yap1 Ser127 phosphorylation and inactivation, and abrogates their tumorigenicity. Notably, Mst1/2 inactivates Yap1 in liver through an intermediary kinase distinct from Lats1/2. Approximately 30% of human HCCs show low Yap1(Ser127) phosphorylation and a majority exhibit loss of cleaved, activated Mst1. Mst1/2 inhibition of Yap1 is an important pathway for tumor suppression in liver relevant to human HCC. Significance The pathways that regulate quiescence and tumor suppression in the liver have not been fully elucidated. We show that the Mst1 and Mst2 kinases are tumor suppressors and regulators of liver size in adults and that negative regulation of the transcriptional coactivator, Yap1, is central to Mst1/2 tumor suppressor function. Loss of both Mst1 and Mst2 is sufficient to initiate hepatocyte proliferation, resulting in dramatic liver overgrowth, resistance to pro-apoptotic stimuli, and the development of HCC. Mst1 and Mst2 promote phosphorylation of Yap1 and thereby suppress its oncogenic activity. Mst1/2 regulation of Yap1 is tissue-specific and, in the liver, involves an Mst1/2-regulated Yap1 kinase distinct from Lats1/2. Significantly, the Mst-Yap1 pathway is disrupted in a substantial fraction of human HCCs.

Summary Replenishing insulin-producing pancreatic β cell mass will benefit both type I and type II diabetics. In adults, pancreatic β cells are generated primarily by self duplication. We report on a novel mouse model of insulin resistance that induces dramatic pancreatic β cell proliferation and β cell mass expansion. Using this model we identify a new hormone, betatrophin, that is primarily expressed in liver and fat. Expression of betatrophin correlates with β cell proliferation in other mouse models of insulin resistance and during gestation. Transient expression of betatrophin in mouse liver significantly and specifically promotes pancreatic β cell proliferation, expands β cell mass, and improves glucose tolerance. Thus, betatrophin treatment could augment or replace insulin injections by increasing the number of endogenous insulin-producing cells in diabetics.

The controllable assembly behavior of diphenylalanine molecules to form nanowires (NWs) and nanotubes (NTs) and their structural details are presented (see figure). The nanoscale morphologies are closely related to molecular arrangements of diphenylalanine as revealed by Rietveld refinement of powder X‐ray diffraction patterns and electron‐density distributions in NTs and NWs via the maximum entropy method analysis.

A facile in situ supramolecular assembly and modular modification of biocompatible hydrogels were demonstrated using cucurbit[6]uril-conjugated hyaluronic acid (CB[6]-HA), diaminohexane-conjugated HA (DAH-HA), and tags-CB[6] for cellular engineering applications. The strong and selective host-guest interaction between CB[6] and DAH made possible the supramolecular assembly of CB[6]/DAH-HA hydrogels in the presence of cells. Then, the 3D environment of CB[6]/DAH-HA hydrogels was modularly modified by the simple treatment with various multifunctional tags-CB[6]. Furthermore, we could confirm in situ formation of CB[6]/DAH-HA hydrogels under the skin of nude mice by sequential subcutaneous injections of CB[6]-HA and DAH-HA solutions. The fluorescence of modularly modified fluorescein isothiocyanate (FITC)-CB[6] in the hydrogels was maintained for up to 11 days, reflecting the feasibility to deliver the proper cues for cellular proliferation and differentiation in the body. Taken together, CB[6]/DAH-HA hydrogels might be successfully exploited as a 3D artificial extracellular matrix for various tissue engineering applications.

Graphene is a promising candidate to complement brittle and expensive transparent conducting oxides. Nevertheless, previous research efforts have paid little attention to reduced graphene, which can be of great benefit due to low-cost solution processing without substrate transfer. Here we demonstrate workfunction-tunable, highly conductive, N-doped reduced graphene film, which is obtainable from the spin-casting of graphene oxide dispersion and can be successfully employed as a transparent cathode for high-performance polymer light-emitting diodes (PLEDs) as an alternative to fluorine-doped tin oxide (FTO). The sheet resistance of N-doped reduced graphene attained 300 Ω/□ at 80% transmittance, one of the lowest values ever reported from the reduction of graphene oxide films. The optimal doping of quaternary nitrogen and the effective removal of oxygen functionalities via sequential hydrazine treatment and thermal reduction accomplished the low resistance. The PLEDs employing N-doped reduced graphene cathodes exhibited a maximum electroluminescence efficiency higher than those of FTO-based devices (4.0 cd/A for FTO and 7.0 cd/A for N-doped graphene at 17,000 cd/m(2)). The reduced barrier for electron injection from a workfunction-tunable, N-doped reduced graphene cathode offered this remarkable device performance.

SignificanceDelivery remains a significant challenge for robust implementation of CRISPR/Cas9. We report an efficient CRISPR/Cas9 delivery system comprising PEGylated nanoparticles based on the α-helical polypeptide PPABLG. Assisted by the high membrane-penetrating ability of the polypeptide, P-HNPs achieved efficient cellular internalization and endosomal escape. The CRISPR/Cas9 delivery system could reach 47.3% gene editing in cells, 35% gene deletion in vivo, and HeLa tumor growth suppression >71%, demonstrating an advantage over the existing conventional polycationic transfection reagents. Efficient also in knock-in and gene activation, the reported CRISPR/Cas9 delivery system serves to advance gene editing in vitro and in vivo.

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