Signaling pathways responsible for virus-triggered IFN induction have been extensively investigated during the past decade. In limited types of cells, viral RNA is detected by certain membrane-bound Toll-like receptors (TLRs). However, in most cell types, viral RNA is recognized by cytoplasmic pattern recognition receptors (PRRs) RIG-I and MDA5. Both RIG-I and MDA5 contain two CARD modules at their N terminus and a DexD/H-box RNA helicase domain at their C terminus. Upon viral infection, the RNA helicase domains of RIG-I and MDA5 serve as intracellular viral RNA receptors. The recognition of viral RNA by RIG-I and MDA5 leads to their recruitment to the downstream mitochondrion-located CARD-containing adapter protein VISA (also known as MAVS, IPS-1, and Cardif) (6 -10). VISA is constitutively associated with another mitochondrion-associated adapter protein MITA/STING (11,12).Various studies have demonstrated that VISA plays a central role in assembling a complex that activates distinct signaling pathways leading to NF-B and IRF3 activation, respectively. VISA is associated with TRAF2 and TRAF6 through its TRAFinteraction motifs. It has been shown that TRAF2 and TRAF6 facilitate Lys-63-linked polyubiquitination of RIP and NEMO/ IKK␥, respectively, and these processes cause activation of IKK and subsequent NF-B (13-15). VISA is also associated with TRAF3, another member of the TRAF protein family (16). Gene knock-out studies have demonstrated that TRAF3 is essential in virus-triggered IRF3 activation and type I IFN induction (17, 18). However, how TRAF3 is regulated in virus-triggered signaling pathways is still enigmatic.Several studies have suggested that ubiquitination is a central rhythm of regulation of the virus-triggered IFN induction pathways. It has been shown that the E3 ubiquitin ligase TRIM25 catalyzes Lys-63-linked ubiquitination of RIG-I, and this ubiquitination is essential for the interaction of RIG-I with VISA as well as for its ability to signal (19). The Riplet/REUL E3 ubiquitin ligase also targets RIG-I for ubiquitination, which positively regulates RIG-I-mediated signaling (20,21). In contrast, the E3 ubiquitin ligase RNF125 catalyzes Lys-48-linked ubiquitination of RIG-I and negatively regulates RIG-I-mediated signaling (22). MITA and IRF3 are ubiquitinated by RNF5 and RBCK1, respectively, and subsequently degraded by proteasome-dependent processes (23,24). The E3 ubiquitin ligase Nrdp1 catalyzes the ubiquitination of TBK1, leading to its activation (25). cIAP1 and cIAP2 are E3 ubiquitin ligases that were firstly identified as signaling components associated with TRAF1 and TRAF2 and recruited to the TNF receptors TNFR1 and TNFR2 upon ligand stimulation (26,27). Recently, it has been demonstrated that in unstimulated cells, TRAF2/3 and cIAP1/2 form a cytoplasmic complex, which constitutively ubiquitinates NIK and promotes its proteasome-dependent degradation (28,29). Upon stimulation by TNF family members, such as BAFF and CD40L, the TRAF2/3-cIAP1/2 complex is recruited to the receptors, where ...

We report the synthesis and controlled radical homo- and block copolymerization of 3-guanidinopropyl methacrylamide (GPMA) utilizing aqueous reversible addition-fragmentation chain transfer (aRAFT) polymerization. The resulting homopolymer and block copolymer with N-(2-hydroxypropyl) methacrylamide (HPMA) were prepared to mimic the behavior of cell penetrating peptides (CPPs) and poly(arginine) (> 6 units) which have been shown to cross cell membranes. The homopolymerization mediated by 4-cyano-4-(ethylsulfanylthiocarbonylsulfanyl)pentanoic acid (CEP) in aqueous buffer exhibited pseudo-first-order kinetics and linear growth of molecular weight with conversion. Retention of the “living” thiocarbonylthio ω-end-group was demonstrated through successful chain extension of the GPMA macroCTA yielding GPMA37-b-GPMA61 (Mw/Mn =1.05). Block copolymers of GPMA with the non-immunogenic, biocompatible HPMA were synthesized yielding HPMA271-b-GPMA13 (Mw/Mn = 1.15). Notably, intracellular uptake was confirmed by fluorescence microscopy, confocal laser scanning microscopy, and flow cytometry experiments after 2.5 h incubation with KB cells at 4 °C and at 37 °C utilizing FITC-labeled, GPMA-containing copolymers. The observed facility of cellular uptake and the structural control afforded by aRAFT polymerization suggest significant potential for these synthetic (co)polymers as drug delivery vehicles in targeted therapies.

Drug repurposing, or identifying new uses for existing drugs, has emerged as an alternative to traditional drug discovery processes involving de novo synthesis. Drugs that are currently approved or under development for non-antibiotic indications may possess antibiotic properties, and therefore may have repurposing potential, either alone or in combination with an antibiotic. They might also serve as “antibiotic adjuvants” to enhance the activity of certain antibiotics.

Background: Second-generation antipsychotics (SGAs) are assumed to have little abuse potential. However, reports of quetiapine abuse have emerged as prescribing has increased in recent years. The US Food and Drug Administration’s (FDA) Adverse Event Reporting System (FAERS) provides postmarketing information regarding adverse drug events (ADEs). This is the first study to analyze quetiapine abuse-related ADEs reported to FAERS to determine whether a disproportionate rate of such events have been reported when compared with other commonly used SGAs. Methods: A cross-sectional analysis of FAERS data from January 1, 2015, to December 31, 2017, was performed. The total number of all-cause and abuse-related ADEs reported to FAERS regarding quetiapine, olanzapine, aripiprazole, and risperidone were identified, along with demographic and mortality data. The proportional reporting ratio (PRR) was calculated to assess disproportionate reporting of abuse-related adverse drug reactions between quetiapine and each of three alternative SGA medications. Results: Abuse-related ADEs represented 11% (3144/27 962) of total ADEs reported for quetiapine, 8% for olanzapine (1548/19 228), 5% (1380/29 699) for aripiprazole, and 3% (1168/45 518) for risperidone. The PRRs (95% confidence interval) for quetiapine versus olanzapine, aripiprazole, and risperidone were 1.40 (1.32-1.48), 2.42 (2.28-2.57), and 4.38 (4.10-4.68), respectively, indicating that abuse-related events were significantly more likely to be reported with quetiapine than each comparator drug. In addition, more deaths were reported among the abuse-related events regarding quetiapine (673) than olanzapine (200), aripiprazole (88), and risperidone (143). Conclusion: This study corroborates recent evidence indicating that quetiapine might possess a significantly higher abuse potential than other commonly used SGAs. Although prospective studies are needed to better understand the abuse potential of quetiapine, increased vigilance in monitoring for signs of substance abuse might be warranted when prescribing quetiapine.

Introduction: Antibiotic use is an important risk factor for Clostridium difficile infection (CDI). Prior meta-analyses have identified antibiotics and antibiotic classes that pose the greatest risk for CDI; however, CDI epidemiology is constantly changing and contemporary analyses are needed. Objectives: The objective of this study was to evaluate the association between CDI and important antibiotic classes in recent years using the FDA Adverse Event Report System (FAERS). Methods: FAERS reports from January 1, 2015 to December 31, 2017 were analyzed. The Medical Dictionary for Regulatory Activities (MedDRA) was used to identify CDI cases. We computed the Reporting Odds Ratios (RORs) and corresponding 95% confidence intervals (95%CI) for the association between antibiotics and CDI. An association was considered statistically significant when the lower limit of the 95%CI was greater than 1. Results: A total of 2,042,801 reports (including 5,187 CDI reports) were considered, after inclusion criteria were applied. Lincosamides (e.g., clindamycin) had the greatest proportion of CDI reports, representing 10.4% of all lincosamide reports. CDI RORs (95%CI) for the antibiotic classes were (in descending order): lincosamides 46.95 (39.49-55.82), monobactams 29.97 (14.60-61.54), penicillin combinations 20.05 (17.39-23.12), carbapenems 19.16 (15.52-23.67), cephalosporins/ monobactams/carbapenems 17.28 (14.95-19.97), cephalosporins 15.33 (12.60-18.65), tetracyclines 7.54 (5.42-10.50), macrolides 5.80 (4.48-7.51), fluoroquinolones 4.94 (4.20-5.81), and trimethoprim-sulfonamides 3.32 (2.03-5.43). Conclusion: All antibiotic classes included in the study were significantly associated with CDI. Lincosamides (e.g., clindamycin) had the highest CDI ROR among the antibiotics evaluated in this study.