Small-molecule inhibitors that target bromodomains outside of the bromodomain and extra-terminal (BET) sub-family are lacking. Here, we describe highly potent and selective ligands for the ...bromodomain module of the human lysine acetyl transferase CBP/p300, developed from a series of 5-isoxazolyl-benzimidazoles. Our starting point was a fragment hit, which was optimized into a more potent and selective lead using parallel synthesis employing Suzuki couplings, benzimidazole-forming reactions, and reductive aminations. The selectivity of the lead compound against other bromodomain family members was investigated using a thermal stability assay, which revealed some inhibition of the structurally related BET family members. To address the BET selectivity issue, X-ray crystal structures of the lead compound bound to the CREB binding protein (CBP) and the first bromodomain of BRD4 (BRD4(1)) were used to guide the design of more selective compounds. The crystal structures obtained revealed two distinct binding modes. By varying the aryl substitution pattern and developing conformationally constrained analogues, selectivity for CBP over BRD4(1) was increased. The optimized compound is highly potent (K d = 21 nM) and selective, displaying 40-fold selectivity over BRD4(1). Cellular activity was demonstrated using fluorescence recovery after photo-bleaching (FRAP) and a p53 reporter assay. The optimized compounds are cell-active and have nanomolar affinity for CBP/p300; therefore, they should be useful in studies investigating the biological roles of CBP and p300 and to validate the CBP and p300 bromodomains as therapeutic targets.
•The Dark Triad and self-objectification predict men’s social networking site use.•Trait self-objectification and narcissism predicted time spent on SNSs.•Narcissism and psychopathy predicted the ...number of selfies posted on SNSs.•Narcissism and trait self-objectification predicted editing photos posted on SNSs.
An online survey of a nationally representative sample of U.S. men aged 18–40 assessed trait predictors of social networking site use as well as two forms of visual self-presentation: editing one’s image in photographs posted on social networking sites (SNSs) and posting “selfies,” or pictures users take of themselves. We examined the Dark Triad (i.e., narcissism, Machiavellianism, and psychopathy) and trait self-objectification as predictors. Self-objectification and narcissism predicted time spent on SNSs. Narcissism and psychopathy predicted the number of selfies posted, whereas narcissism and self-objectification predicted editing photographs of oneself posted on SNSs. We discuss selective self-presentation processes on social media and how these traits may influence interpersonal relationship development in computer-mediated communication.
T lymphocytes expressing a chimeric antigen receptor (CAR) targeting the CD19 antigen (CAR.19) may be of value for the therapy of B-cell malignancies. Because the in vivo survival, expansion and ...anti-lymphoma activity of CAR.19(+) T cells remain suboptimal even when the CAR contains a CD28 costimulatory endodomain, we generated a novel construct that also incorporates the interleukin-15 (IL-15) gene and an inducible caspase-9-based suicide gene (iC9/CAR.19/IL-15). We found that compared with CAR.19(+) T cells, iC9/CAR.19/IL-15(+) T cells had: (1) greater numeric expansion upon antigen stimulation (10-fold greater expansion in vitro, and 3- to 15-fold greater expansion in vivo) and reduced cell death rate (Annexin-V(+)/7-AAD(+) cells 10+/-6% for iC9/CAR.19/IL-15(+) T cells and 32+/-19% for CAR.19(+) T cells); (2) reduced expression of the programmed death 1 (PD-1) receptor upon antigen stimulation (PD-1(+) cells <15% for iC9/CAR.19/IL-15(+) T cells versus >40% for CAR.19(+) T cells); and (3) improved antitumor effects in vivo (from 4.7- to 5.4-fold reduced tumor growth). In addition, iC9/CAR.19/IL-15(+) T cells were efficiently eliminated upon pharmacologic activation of the suicide gene. In summary, this strategy safely increases the anti-lymphoma/leukemia effects of CAR.19-redirected T lymphocytes and may be a useful approach for treatment of patients with B-cell malignancies.
We quantified the wholesale transformation of the boreal landscape by open-pit oil sands mining in Alberta, Canada to evaluate its effect on carbon storage and sequestration. Contrary to claims made ...in the media, peatland destroyed by open-pit mining will not be restored. Current plans dictate its replacement with upland forest and tailings storage lakes, amounting to the destruction of over 29,500 ha of peatland habitat. Landscape changes caused by currently approved mines will release between 11.4 and 47.3 million metric tons of stored carbon and will reduce carbon sequestration potential by 5,734–7,241 metric tons C/y. These losses have not previously been quantified, and should be included with the already high estimates of carbon emissions from oil sands mining and bitumen upgrading. A fair evaluation of the costs and benefits of oil sands mining requires a rigorous assessment of impacts on natural capital and ecosystem services.
Microbial taxonomic assignment based on 16S marker gene amplification requires multiple data transformations, often encompassing the use of a variety of computational platforms. Bioinformatics ...analysis may represent a bottleneck for researchers as many tools require programmatic access in order to implement the software. Here we describe a step-by-step approach for taxonomic assignment using QIIME2 and highlight the utility of graphical-based microbiome tools for further analysis and identification of biological relevant taxa with reference to an outcome of interest.
A major focus in community ecology is understanding how biological interactions and environmental conditions shape horizontal communities. However, few studies have explored whether cross-community ...interactions are consistent or non-stationary across environmental gradients. Using the relative abundance of birds, aquatic macroinvertebrates and plants, we examined how cross-community congruence varied between short and long-hydroperiod prairie pothole wetlands in southern Alberta. These wetlands are structured by their hydroperiod: the length of time that ponded water is present in the wetland. We compared the strength of cross-community congruence and the strength of congruence between each horizontal community and wetland hydroperiod in wetlands that typically contain ponded water throughout the year to wetlands that dry up every summer. The strength of cross-community relationships was similar between more permanent and more ephemeral wetland classes, suggesting that biological interactions have a near equivalent role in shaping community composition, regardless of hydroperiod. However, because cross-community congruence, measured as the Procrustes pseudo-R value, was, on average, 77% ± SE 12% greater than that between each horizontal community and measures of wetland hydroperiod, we concluded that community structure is not shaped by hydroperiod alone. We attribute the observed cross-community congruence to (1) plants and aquatic macroinvertebrates influence birds through habitat and food provisioning, and (2) birds influence plants and aquatic macroinvertebrates by dispersing their propagules.
Bromodomains, protein modules that recognize and bind to acetylated lysine, are emerging as important components of cellular machinery. These acetyl-lysine (KAc) “reader” domains are part of the ...write–read–erase concept that has been linked with the transfer of epigenetic information. By reading KAc marks on histones, bromodomains mediate protein–protein interactions between a diverse array of partners. There has been intense activity in developing potent and selective small molecule probes that disrupt the interaction between a given bromodomain and KAc. Rapid success has been achieved with the BET family of bromodomains, and a number of potent and selective probes have been reported. These compounds have enabled linking of the BET bromodomains with diseases, including cancer and inflammation, suggesting that bromodomains are druggable targets. Herein, we review the biology of the bromodomains and discuss the SAR for the existing small molecule probes. The biology that has been enabled by these compounds is summarized.
Bromodomains are protein modules that bind to acetylated lysine residues. Their interaction with histone proteins suggests that they function as “readers” of histone lysine acetylation, a component ...of the proposed “histone code”. Bromodomain-containing proteins are often found as components of larger protein complexes with roles in fundamental cellular process including transcription. The publication of two potent ligands for the BET bromodomains in 2010 demonstrated that small molecules can inhibit the bromodomain–acetyl-lysine protein–protein interaction. These molecules display strong phenotypic effects in a number of cell lines and affect a range of cancers in vivo. This work stimulated intense interest in developing further ligands for the BET bromodomains and the design of ligands for non-BET bromodomains. Here we review the recent progress in the field with particular attention paid to ligand design, the assays employed in early ligand discovery, and the use of computational approaches to inform ligand design.
The nitrogen-to-oxygen (N/O) abundance ratio is an important diagnostic of galaxy evolution because the ratio is closely tied to the growth of metallicity and the star formation history in galaxies. ...Estimates for the N/O are traditionally made with optical lines that could suffer from extinction and excitation effects, so the N/O is arguably measured better through far-infrared (far-IR) fine-structure lines. Here we show that the N iii57 m/O iii52 m line ratio, denoted N3O3, is a physically robust probe of N/O. This parameter is insensitive to gas temperature and only weakly dependent on electron density. Although it has a dependence on the hardness of the ionizing radiation field, we show that it is well corrected when the Ne iii15.5 m/Ne ii12.8 m line ratio is included. We verify the method, and characterize its intrinsic uncertainties by comparing the results to photoionization models. We then apply our method to a sample of nearby galaxies using new observations obtained with SOFIA/FIFI-LS in combination with available Herschel/PACS data, and the results are compared with optical N/O estimates. We find evidence for a systematic offset between the far-IR and optically derived N/O. We argue that the likely reason is that our far-IR method is biased toward younger and denser H ii regions, while the optical methods are biased toward older H ii regions as well as diffuse ionized gas. This work provides a local template for studies of the abundance of interstellar medium in the early Universe.
Protecting the Microbiota Rooney, C M; Ahmed, S; Wilcox, M H
The Journal of infectious diseases,
06/2021, Volume:
223, Issue:
Supplement_3
Journal Article
Peer reviewed
Abstract
We examine 3 different approaches to protecting the gut microbiome: highly targeted antibiotics, antibiotic destruction, and antibiotic binding. Each approach shows promise to prevent the ...off-target effects of antibiotics on the gut microbiome.
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