Skylight

Indoleamine 2,3-dioxygenase 1 (IDO1) is a moonlight protein endowed with catalytic and signaling functions. It plays a pivotal role in the immune breaking mechanism leading to immunosuppression in cancer microenvironment. Intense research efforts have been devoted to designing catalytic inhibitors for developing immunotherapies, yet neglecting the enzyme’s signaling function. A few IDO1 inhibitors have reached the clinical stage, including navoximod, epacadostat and linrodostat. Using second harmonic generation analysis (SHG) and molecular dynamics simulations, here we show that these clinical inhibitors can induce distinct allosteric motions in the enzyme that affect the stability of the transient signaling complex between IDO1 and Src tyrosine kinase. Next generation sequencing demonstrates that, despite sharing a similar ability to inhibit the enzyme’s catalytic function, all three catalytic inhibitors modulate the IDO1’s signaling function in different ways, regulating distinct transcriptomes in SKOV3 cells.

Inspiration for the Weary Therapist is a companion for the modern practitioner. Addressing a diverse audience and written by a master clinician and supervisor, Inspiration for the Weary Therapist helps modern therapists traverse the complicated landscape of practicing therapy in the age of COVID-19. Instead of a heavy, theoretical approach that can leave the already exhausted therapist feeling more overwhelmed, Inspiration for the Weary Therapist guides readers through challenging professional situations, soothes them during upsetting clinical moments, and encourages them to keep going during changing times. Rather than teaching mental health professionals how to practice, this book helps them believe in themselves again and reconnect with their confidence as clinicians through increased self-compassion and personal growth. This practical and helpful guide is essential reading for all mental health practitioners who are searching for inspiration and motivation and who want to reconnect to what it means to be a therapist.

We studied the anti-dyslipidemic effects of Petasites japonicus subsp. giganteus (PJG) in vitro and in vivo. A water extract from the leaves of PJG (PJGL-WE) markedly inhibited lipoprotein production from Caco-2 human colonic carcinoma cells differentiated into intestinal epithelium-like cells and from HepG2 human hepatoma cells. We examined the effects of PJGL-WE on the expression of lipogenic enzymes in both cells at the mRNA level. As a result, PJGL-WE suppressed gene expression involved in transacylation, such as monoacylglycerol acyltransferase 2 and diacylglycerol acyltransferase 2; however, it did not affect enzymes involved in fatty acid synthesis. PJGL-WE also attenuated the expression of microsomal triglyceride transfer protein and apolipoprotein B100, elements required for lipoprotein synthesis. Furthermore, we studied the actions of PJGL-WE on adipose tissue accumulation, intrahepatic lipid content, and plasma parameters in vivo. PJGL-WE suppressed mesenteric adipose tissue accumulation and normalized intrahepatic triglyceride content and plasma triglyceride levels in mice fed a high-fat diet. These findings suggested that PJGL-WE attenuated the expression of genes required for lipid and lipoprotein synthesis, thereby suppressing lipid absorption from the small intestine and participating in the improvement of fatty liver and normalization of plasma triglyceride levels.

This paper discusses the challenges facing the transaction processing (TP) industry from a corporate customer's perspective. It compares and contrasts the approaches taken by the TP-heavy camp (traditional TP vendors with mainframe or minicomputer background), and the TP-light industry (DOS/Windows/UNIX database and client/server tool companies). It highlights the weaknesses of TP monitors for open systems and discusses the architectural flaws of OSF's DCE technology which might prevent DCE from becoming a widely accepted standard. >