The Retinoic acid-Inducible Gene I (RIG-I) like receptors (RLRs) are the major viral RNA sensors essential for the initiation of antiviral immune responses. RLRs are subjected to stringent ...transcriptional and posttranslational regulations, of which ubiquitination is one of the most important. However, the role of ubiquitination in RLR transcription is unknown. Here, we screen 375 definite ubiquitin ligase knockout cell lines and identify Ubiquitin Protein Ligase E3 Component N-Recognin 5 (UBR5) as a positive regulator of RLR transcription. UBR5 deficiency reduces antiviral immune responses to RNA viruses, while increases viral replication in primary cells and mice. Ubr5 knockout mice are more susceptible to lethal RNA virus infection than wild type littermates. Mechanistically, UBR5 mediates the Lysine 63-linked ubiquitination of Tripartite Motif Protein 28 (TRIM28), an epigenetic repressor of RLRs. This modification prevents intramolecular SUMOylation of TRIM28, thus disengages the TRIM28-imposed brake on RLR transcription. In sum, UBR5 enables rapid upregulation of RLR expression to boost antiviral immune responses by ubiquitinating and de-SUMOylating TRIM28.
Possible mechanisms for Rh-promoted indole formation from vinyl/azidoarenes were examined computationally, and a mechanism is proposed in which the Rh catalyst promotes generation of a nitrene but is ...not directly involved in cyclization.
Several small molecule species formally known primarily as toxic gases have, over the past 20 years, been shown to be endogenously generated signaling molecules. The biological signaling associated ...with the small molecules NO, CO, H2S (and the nonendogenously generated O2), and their derived species have become a topic of extreme interest. It has become increasingly clear that these small molecule signaling agents form an integrated signaling web that affects/regulates numerous physiological processes. The chemical interactions between these species and each other or biological targets is an important factor in their roles as signaling agents. Thus, a fundamental understanding of the chemistry of these molecules is essential to understanding their biological/physiological utility. This review focuses on this chemistry and attempts to establish the chemical basis for their signaling functions.
Summary
What candidates say in an interview is important—but so is how they say it. We draw on dual‐process theory to explain why interviewers rely on individuals' dynamic and static nonverbal cues ...to evaluate performance with quick, implicit inferences (System 1 processing). Yet, it remains unclear which cues most influence interviewers' judgments and whether moderators affecting interviewers' reliance on System 1 thinking (e.g., interview structure, modality, duration, and interviewee gender) impact the relationship between nonverbal cues and interview ratings. We performed the first meta‐analysis to address these questions, integrating findings across 63 studies (N = 4868). The nonverbal cues demonstrating the strongest association with interview performance were professional appearance (ρ = .62), eye contact (ρ = .45), and head movement (ρ = .43). Moderator analyses highlight the persistent power of nonverbal cues, as the results were largely unaffected by interview structure, modality, or duration. Experimental design did play a role, as did interviewees' gender, with stronger effects for certain nonverbal cues (e.g., facial expressions and professional appearance) for women than men, conveying interviewers' reliance on gender‐based stereotypes when judging their performance. Overall, these results suggest nonverbal cues and characteristics are an important influence on job applicants' success in employment interviews.
Is Al2Cl6 Aromatic? Cautions in Superficial NICS Interpretation Torres, Juan José; Islas, Rafael; Osorio, Edison ...
The journal of physical chemistry. A, Molecules, spectroscopy, kinetics, environment, & general theory,
07/2013, Letnik:
117, Številka:
26
Journal Article
Recenzirano
In this article, we employed the induced magnetic field method to show that the Al2X6 (X = F, Cl, Br, I) clusters cannot be classified as aromatic systems. Interestingly, even nucleus independent ...chemical shift (NICS) reveals the same conclusion when analyzed in greater detail, showing that a superficial analysis of this index can easily lead to incorrect interpretations. In view of the fact that the NICS index is extensively used by computational and theoretically oriented experimental chemists, this is an important warning against superficial analyses, as it can lead to erroneous chemical interpretation.
The most stable forms of E5Li7+ (E=Ge, Sn, and Pb) have been explored by means of a stochastic search of their potential‐energy surfaces by using the gradient embedded genetic algorithm (GEGA). The ...preferred isomer of the Ge5Li7+ ion is a slightly distorted analogue of the D5h three‐dimensional seven‐pointed starlike structure adopted by the lighter C5Li7+ and Si5Li7+ clusters. In contrast, the preferred structures for Sn5Li7+ and Pb5Li7+ are quite different. By starting from the starlike arrangement, corresponding lowest‐energy structures are generated by migration of one of the E atoms out of the plane with the a corresponding rearrangement of the Li atoms. To understand these structural preferences, we propose a new energy decomposition analysis based on isomerizations (isomerization energy decomposition analysis (IEDA)), which enable us to extract energetic information from isomerization between structures, mainly from highly charged fragments.
Structural analysis: The combination of lithium and Group 14 elements is shown to prefer one of two distinct E5Li7+ clusters (E = C, Si, Ge, Sn, and Pb) depending on the identity of E, and the preferences are rationalized on the basis of a simple isomerization energy decomposition scheme (see figure).
Ceftolozane/tazobactam (C/T), a cephalosporin/beta-lactamase inhibitor combination, was evaluated in vitro vs. 10 comparators against 299 pediatric extended-spectrum-cephalosporin-resistant or ...carbapenem-resistant (ESC-R/CR) Gram-negative Enterobacteriaceae from three freestanding pediatric centers. Isolates were from urine or other sterile sites of children and adolescents through 21 years of age. Susceptibilities were assayed by microbroth dilution via custom Sensititre plates (Thermo Fisher Scientific). Susceptibility was determined using the Sensititre Vizion® system (Thermo Fisher Scientific). Susceptibility breakpoint criteria were those of the Clinical and Laboratory Standards Institute (CLSI) for 2017, except for colistin (EUCAST 2019). Overall, 87.5% isolates were C/T susceptible (MIC ≤2 μg/ml; MIC
50/90,
0.25/4 μg/ml). Susceptibility to C/T was detected more frequently as compared to all other antimicrobials tested except for colistin (95.4%) and meropenem (97.4%). Percent susceptibility to C/T was high for E. coli (91%) and Klebsiella spp. (73.3%). C/T demonstrated good in-vitro activity and high potency against most beta-lactam resistant pediatric Enterobacteriaceae from three geographically diverse U.S. regions.
Short interfering RNAs (siRNAs) are promising drug candidates for a wide range of targets including those previously considered “undruggable”. However, properties associated with the native RNA ...structure limit drug development, and chemical modifications are necessary. Here we describe the structure-guided discovery of functional modifications for the guide strand 5′-end using computational screening with the high-resolution structure of human Ago2, the key nuclease on the RNA interference pathway. Our results indicate the guide strand 5′-end nucleotide need not engage in Watson–Crick (W/C) H-bonding but must fit the general shape of the 5′-end binding site in MID/PIWI domains of hAgo2 for efficient knockdown. 1,2,3-Triazol-4-yl bases formed from the CuAAC reaction of azides and 1-ethynylribose, which is readily incorporated into RNA via the phosphoramidite, perform well at the guide strand 5′-end. In contrast, purine derivatives with modified Hoogsteen faces or N2 substituents are poor choices for 5′-end modifications. Finally, we identified a 1,2,3-triazol-4-yl base incapable of W/C H-bonding that performs well at guide strand position 12, where base pairing to target was expected to be important. This work expands the repertoire of functional nucleotide analogues for siRNAs.
Results from density functional theory calculations on a proton-promoted 2+2 cycloaddition to form plumisclerin A’s cyclobutane ring are described. On the basis of these results, it is proposed that ...protonation allows for an energetically viable stepwise cycloaddition that provides an alternative to photochemical cyclobutane formation.
We describe accommodations that we have made to our applied computational–theoretical chemistry laboratory to provide access for blind and visually impaired students interested in independent ...investigation of structure–function relationships. Our approach utilizes tactile drawings, molecular model kits, existing software, Bash and Perl scripts written in-house, and three-dimensional printing in a process that allows a blind or visually impaired student to satisfy her or his curiosity about structure–function relationships with minimal assistance from sighted co-workers.
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