Notes

SARS-CoV-2 Screening Before International Traveling by plane, 12 , 2020 in order to Might 2021.
Mechanistically, the CCR4-NOT complex targets and destabilizes mRNAs mainly through its association with Argonaute 2 (AGO2) and butyrate response factor 1 (BRF1) in the liver. Therefore, the CCR4-NOT complex contributes to liver homeostasis by modulating the liver transcriptome through mRNA deadenylation. © 2020 Takahashi et al.1-(1-propanoylpiperidin-4-yl)-3-[4-(trifluoromethoxy)phenyl]urea (TPPU) and 1-(4-trifluoro-methoxy-phenyl)-3-(1-cyclopropanecarbonyl-piperidin-4-yl)-urea (TCPU) are potent inhibitors of soluble epoxide hydrolase (sEH) which have much better efficacy in relieving nociceptive response than the FDA-approved drug, gabapentin, in a rodent model of diabetic neuropathy. Experiments conducted in sEH-knock-out mice or with coadministration of a potent sEH displacer demonstrated that the pharmacokinetics of TPPU and TCPU were influenced by the specific binding to their pharmacologic target sEH, a phenomenon known as target-mediated drug disposition phenomenon (TMDD). To quantitatively characterize the complex pharmacokinetics of TPPU and TCPU and gain better understanding on their target occupancy, population pharmacokinetics analysis using a nonlinear mixed-effect modeling approach was performed in the current study. The final model was a novel simultaneous TMDD interaction model, where TPPU and TCPU compete for sEH, wnd Experimental Therapeutics.Mononuclear macrophages derived from the bone marrow (myeloid cells) are key cellular components of the innate immune system in different organs. In this mini-review, we are focused on both brain and blood macrophages known as microglia and monocytes, respectively. We provide a succinct summary of the cells' functions under both normal and pathological conditions, with particular reference to common neurodegenerative disorders, Alzheimer's and Parkinson's disease. SIGNIFICANCE STATEMENT In this mini-review we aim to summarize available literature on microglial and myeloid involvement in CNS disease, directing the reader towards relevant and translatable interpretations of myeloid cell function in CNS health and neurodegeneration. The American Society for Pharmacology and Experimental Therapeutics.Leonurine (LEO) is a bioactive small molecular compound that has protective effects on the cardiovascular system. It prevents the early progression of atherosclerosis, however, it is not clear whether LEO is effective for plaque stability. A novel mouse atherosclerosis model involving tandem stenosis (TS) of the right carotid artery combined with western diet (WD) feeding was used. ApoE -/- mice were fed with a WD and received LEO administration daily for 13 weeks. TS was introduced 6 weeks after the onset of experiments. We found that LEO enhanced plaque stability by increasing fibrous cap thickness, and collagen content while decreasing the population of CD68 positive cells. Enhanced plaque stability by LEO was associated with the NOS-NO system. LEO restored the balance between eNOS and iNOS derived NO production; suppressed NF-κB signaling pathway; reduced the level of the inflammatory infiltration in plaque including cytokine IL-6 and downregulated the expression of adhesion moleculars molecules. These findings support the distinct role of LEO in plaque stabilization. In vitro studies with ox-LDL challenged HUVECs revealed that LEO balanced NO production and inhibited NF-κB/P65 nuclear translocation, thus mitigating inflammation. In conclusion, the restored balance of the NOS-NO syestem and mitigated inflammation contribute to the plaque stabilizing effect of LEO. SIGNIFICANCE STATEMENT LEO restored the balance between eNOS and iNOS in NO production, and inhibited excessive inflammation in atherosclerotic "unstable" and rupture-prone plaques in ApoE-/- mice. The protective effect of LEO for stabilizing atherosclerotic plaques was due to improved collagen content, increased fibrous cap thickness and decreased accumulation of macrophages/foam cells. So far, LEO has passed the safety and feasibility test of phase I clinical trial. The American Society for Pharmacology and Experimental Therapeutics.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. 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.SUMMARYCRISPR-Cas systems have been engineered as powerful tools to control gene expression in bacteria. The most common strategy relies on the use of Cas effectors modified to bind target DNA without introducing DNA breaks. These effectors can either block the RNA polymerase or recruit it through activation domains. Here, we discuss the mechanistic details of how Cas effectors can modulate gene expression by blocking transcription initiation or acting as transcription roadblocks. CRISPR-Cas tools can be further engineered to obtain fine-tuned control of gene expression or target multiple genes simultaneously. Several caveats in using these tools have also been revealed, including off-target effects and toxicity, making it important to understand the design rules of engineered CRISPR-Cas effectors in bacteria. Cobimetinib Alternatively, some types of CRISPR-Cas systems target RNA and could be used to block gene expression at the posttranscriptional level. Finally, we review applications of these tools in high-throughput screens and the progress and challenges in introducing CRISPR knockdown to other species, including nonmodel bacteria with industrial or clinical relevance.
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