Surprisingly, disengaging desmosomes from IF also accelerated the expression of differentiation markers, through precocious activation of the mechanosensitive transcriptional regulator serum response factor (SRF) and downstream activation of epidermal growth factor receptor family member ErbB2 by Src family kinase (SFK)-mediated phosphorylation. This Dsg1-SFK-ErbB2 axis also helps maintain tight junctions and barrier function later in differentiation. Together, these data demonstrate that the desmosome-IF network is a critical contributor to the cytoskeletal-adhesive machinery that supports the polarized function of the epidermis.Autophagy is an essential catabolic process induced to provide cellular energy sources in response to nutrient limitation through the activation of kinases, like AMP-activated protein kinase (AMPK) and ULK1. Although glucose starvation induces autophagy, the exact mechanism underlying this signaling has yet to be elucidated.  https://www.selleckchem.com/products/pexidartinib-plx3397.html  Here, we reveal a role for ULK1 in non-canonical autophagy signaling using diverse cell lines. ULK1 activated by AMPK during glucose starvation phosphorylates the lipid kinase PIKfyve on S1548, thereby increasing its activity and the synthesis of the phospholipid PI(5)P without changing the levels of PI(3,5)P2. ULK1-mediated activation of PIKfyve enhances the formation of PI(5)P-containing autophagosomes upon glucose starvation, resulting in an increase in autophagy flux. Phospho-mimic PIKfyve S1548D drives autophagy upregulation and lowers autophagy substrate levels. Our study has identified how ULK1 upregulates autophagy upon glucose starvation and induces the formation of PI(5)P-containing autophagosomes by activating PIKfyve.Cells in tissues experience a plethora of forces that regulate their fate and modulate development and homeostasis. Cells sense mechanical cues through localized mechanoreceptors or by influencing cytoskeletal or plasma membrane organization. Cells translate force and modulate their behavior through a process termed mechanotransduction. Cells tune their tension upon exposure to chronic force by engaging cellular machinery that modulates actin tension, which in turn stimulates matrix remodeling and stiffening and alters cell-cell adhesions until cells achieve a state of tensional homeostasis. Loss of tensional homeostasis can be induced through oncogene activity and/or tissue fibrosis, accompanies tumor progression, and is associated with increased cancer risk. The mechanical stresses that develop in tumors can also foster the mesenchymal-like transdifferentiation of cells to induce a stem-like phenotype that contributes to their aggression, metastatic dissemination, and treatment resistance. Thus, strategies that ameliorate tumor mechanics may comprise an effective strategy to prevent aggressive tumor behavior.Microbe-derived acetate activates the Drosophila immunodeficiency (IMD) pathway in a subset of enteroendocrine cells (EECs) of the anterior midgut. In these cells, the IMD pathway co-regulates expression of antimicrobial and enteroendocrine peptides including tachykinin, a repressor of intestinal lipid synthesis. To determine whether acetate acts on a cell surface pattern recognition receptor or an intracellular target, we asked whether acetate import was essential for IMD signaling. Mutagenesis and RNA interference revealed that the putative monocarboxylic acid transporter Tarag was essential for enhancement of IMD signaling by dietary acetate. Interference with histone deacetylation in EECs augmented transcription of genes regulated by the steroid hormone ecdysone including IMD targets. Reduced expression of the histone acetyltransferase Tip60 decreased IMD signaling and blocked rescue by dietary acetate and other sources of intracellular acetyl-CoA. Thus, microbe-derived acetate induces chromatin remodeling within enteroendocrine cells, co-regulating host metabolism and intestinal innate immunity via a Tip60-steroid hormone axis that is conserved in mammals.The generation of a library of variant genes is a prerequisite of directed evolution, a powerful tool for biomolecular engineering. As the number of all possible sequences often far exceeds the diversity of a practical library, methods that allow efficient library diversification in living cells are essential for in vivo directed evolution technologies to effectively sample the sequence space and allow hits to emerge. While traditional whole-genome mutagenesis often results in toxicity and the emergence of "cheater" mutations, recent developments that exploit the targeting and editing abilities of genome editors to facilitate in vivo library diversification have allowed for precise mutagenesis focused on specific genes of interest, higher mutational density, and reduced the occurrence of cheater mutations. This minireview summarizes recent advances in genome editor-directed in vivo library diversification and provides an outlook on their future applications in chemical biology.
  To prospectively determine the feasibility, safety, and efficacy of stereotactic body radiation therapy (SBRT) to primary and secondary liver tumors with MR-guided radiation therapy (MRgRT).
 
  Treatment plans with a conventional CT-guided linear accelerator and a MRI-guided tri-
  Co teletherapy unit (MR-Co) were generated and compared for patients undergoing liver-directed SBRT from 2015 to 2017. If dosimetric parameters were met on MR-Co, patients were treated with MRgRT. The highest priority constraint was >1000 cc or >800 cc of normal liver receiving <15 Gy for single- or multiple-lesion treatments, respectively. Treatment was delivered every other day.
 
  Of 23 patients screened, 20 patients (8 primary, 12 secondary) and 25 liver tumors underwent MR-guided SBRT to a median dose of 54 Gy (range 11.5-60) in a median of 3 fractions (range 1-5). With a median follow up of 18.9 months, the 1- and 2-year estimate of local control were 94.7% and 79.6%, respectively. A difference in local control between single and multiple lesions or BED ≥100Gy
  and BED <100Gy
  , respectively, was observed. The 2-year estimate of overall survival (OS) was 50.7% with a median OS of 29 months. There were no acute grade ≥3 toxicities and one late grade 3/4 toxicity from a single patient whose plan exceeded an unrecognized dose constraint at the time.
 
  MR-guided SBRT is a viable and safe option in the delivery of ultrahypofractionated ablative radiation treatment to primary and secondary liver tumors resulting in high rates of local control and very favorable toxicity profiles.
 MR-guided SBRT is a viable and safe option in the delivery of ultrahypofractionated ablative radiation treatment to primary and secondary liver tumors resulting in high rates of local control and very favorable toxicity profiles.