Paclitaxel is an antineoplastic drug extracted from the Taxus species, and peripheral neuropathy is a common side effect. Paclitaxel-induced peripheral neuropathy (PIPN) seriously affects patient quality of life. Currently, the mechanism of PIPN is still unknown, and few treatments are recognized clinically. Duloxetine is recommend as the only potential treatment for chemotherapy-induced peripheral neuropathy (CIPN) by the American Society of Clinical Oncology (ASCO). However, this guidance lacks a theoretical basis and experimental evidence. Our study suggested that duloxetine could improve PIPN and provide neuroprotection. We explored the potential mechanisms of duloxetine on PIPN. As a result, duloxetine acts by inhibiting PARP cleavage and p53 activation and regulating the Bcl2 family to reverse paclitaxel(PTX)-induced oxidative stress and apoptosis. Taken together, the present study shows that using duloxetine to attenuate PTX-induced peripheral nerve injury and peripheral pain may lead to new clinical targets for CIPN. SIGNIFICANCE STATEMENT This study reported duloxetine markedly reduces neuropathic pain evoked by Paclitaxel (PTX), and related to PARP, p53 and the Bcl2 family. Our findings thus not only provide an important guidance to support duloxetine to become the first standard chemotherapy-induced peripheral neuropathy (CIPN) drug, but also will find potential new targets and positive control for new CIPN drug development. The American Society for Pharmacology and Experimental Therapeutics.RNA polymerase II (Pol II) transcribes all protein-coding genes and many noncoding RNAs in eukaryotic genomes. Although Pol II is a complex, 12-subunit enzyme, it lacks the ability to initiate transcription and cannot consistently transcribe through long DNA sequences. To execute these essential functions, an array of proteins and protein complexes interact with Pol II to regulate its activity. Selleckchem ZINC05007751 In this review, we detail the structure and mechanism of over a dozen factors that govern Pol II initiation (e.g., TFIID, TFIIH, and Mediator), pausing, and elongation (e.g., DSIF, NELF, PAF, and P-TEFb). The structural basis for Pol II transcription regulation has advanced rapidly in the past decade, largely due to technological innovations in cryoelectron microscopy. Here, we summarize a wealth of structural and functional data that have enabled a deeper understanding of Pol II transcription mechanisms; we also highlight mechanistic questions that remain unanswered or controversial. © 2020 Schier and Taatjes; Published by Cold Spring Harbor Laboratory Press.The mammalian liver possesses a unique capacity for regeneration. However, this regenerative potential declines with age due to unknown mechanisms. In this issue of Genes & Development, Ritschka and colleagues (pp. 489-494). compare liver regeneration upon partial hepatectomy in young and adult mice. Partial hepatectomy causes a transient increase in p21 in a subpopulation of hepatocytes that persists in adult mice. Remarkably, treatment with the BCL-2 family inhibitor ABT-737 blunts p21 expression, enhancing liver regeneration. © 2020 Birch and Gil; Published by Cold Spring Harbor Laboratory Press.OBJECTIVES To describe (1) the developmental trajectories of peer victimization from 6 to 17 years of age and (2) the early childhood behaviors and family characteristics associated with the trajectories. METHODS We used data from 1760 children enrolled in the Quebec Longitudinal Study of Child Development, a population-based birth cohort. Participants self-reported peer victimization at ages 6, 7, 8, 10, 12, 13, 15, and 17 years. Participants' behavior and family characteristics were measured repeatedly between ages 5 months and 5 years. RESULTS We identified 4 trajectories of peer victimization from 6 to 17 years of age low (32.9%), moderate-emerging (29.8%), childhood-limited (26.2%), and high-chronic (11.1%). Compared with children in the low peer victimization trajectory, children in the other 3 trajectories were more likely to exhibit externalizing behaviors in early childhood, and those in the high-chronic and moderate-emerging trajectories were more likely to be male. Paternal history of antisocial behavior was associated with moderate-emerging (odds ratio [OR] = 1.54; 95% confidence interval [CI] = 1.09-2.19) and high-chronic (OR = 1.93; 95% CI = 1.25-2.99) relative to low peer victimization. Living in a nonintact family in early childhood was associated with childhood-limited (OR = 1.48; 95% CI = 1.11-1.97) and high-chronic (OR = 1.59; 95% CI = 1.09-2.31) relative to low peer victimization. CONCLUSIONS Early childhood externalizing behaviors and family vulnerabilities were associated with the development of peer victimization. Some children entered the cascade of persistent peer victimization at the beginning of primary school. Support to these children and their families early in life should be an important component of peer victimization preventive interventions. Copyright © 2020 by the American Academy of Pediatrics.SUMMARYWhile flagella have been studied extensively as motility organelles, with a focus on internal structures such as the axoneme, more recent research has illuminated the roles of the flagellar surface in a variety of biological processes. Parasitic protists of the order Kinetoplastida, which include trypanosomes and Leishmania species, provide a paradigm for probing the role of flagella in host-microbe interactions and illustrate that this interface between the flagellar surface and the host is of paramount importance. An increasing body of knowledge indicates that the flagellar membrane serves a multitude of functions at this interface attachment of parasites to tissues within insect vectors, close interactions with intracellular organelles of vertebrate cells, transactions between flagella from different parasites, junctions between the flagella and the parasite cell body, emergence of nanotubes and exosomes from the parasite directed to either host or microbial targets, immune evasion, and sensing of the extracellular milieu. Recent whole-organelle or genome-wide studies have begun to identify protein components of the flagellar surface that must mediate these diverse host-parasite interactions. The increasing corpus of knowledge on kinetoplastid flagella will likely prove illuminating for other flagellated or ciliated pathogens as well. Copyright © 2020 American Society for Microbiology.