Enzymatic Synthesis of 3'-5', 3'-5' Cyclic Dinucleotides, Their Binding Properties to the Stimulator of Interferon Genes Adaptor Protein, and Structure/Activity Correlations. | LitMetric
The 3'-5', 3'-5' cyclic dinucleotides (3'3'CDNs) are bacterial second messengers that can also bind to the stimulator of interferon genes (STING) adaptor protein in vertebrates and activate the host innate immunity. Here, we profiled the substrate specificity of four bacterial dinucleotide synthases from (DncV), (btDisA), (dgcZ), and (tDGC) using a library of 33 nucleoside-5'-triphosphate analogues and then employed these enzymes to synthesize 24 3'3'CDNs. The STING affinity of CDNs was evaluated in cell-based and biochemical assays, and their ability to induce cytokines was determined by employing human peripheral blood mononuclear cells. Interestingly, the prepared heterodimeric 3'3'CDNs bound to the STING much better than their homodimeric counterparts and showed similar or better potency than bacterial 3'3'CDNs. We also rationalized the experimental findings by in-depth STING-CDN structure-activity correlations by dissecting computed interaction free energies into a set of well-defined and intuitive terms. To this aim, we employed state-of-the-art methods of computational chemistry, such as quantum mechanics/molecular mechanics (QM/MM) calculations, and complemented the computed results with the {STING:3'3'c-di--AMP} X-ray crystallographic structure. QM/MM identified three outliers (mostly homodimers) for which we have no clear explanation of their impaired binding with respect to their heterodimeric counterparts, whereas the = 0.7 correlation between the computed Δ' and experimental Δ's for the remaining ligands has been very encouraging.
Objective(s): To identify trends in HIV diagnosis disparities among subpopulations of Black/African American and White persons by selected characteristics (i.e., sex assigned at birth, age group, and region of residence) in the United States during 2017‒2021.
Objective: Focal cortical seizures travel long distances from the onset zone, but the long-distance propagation pathways are uncertain. In vitro and in vivo imaging techniques have investigated the local spread of seizures but did not elucidate long-distance spread. Furthermore, classical studies in slices suggested seizure spread locally along deep cortical layers, whereas more recent in vivo imaging studies posit a role for superficial cortical layers in local spread.
Purpose: To assess the rate of heterotopic ossification (HO) following acetabular surgery with a standardized protocol via the Kocher-Langenbeck. Secondarily, to evaluate patient characteristics, injury variables, and perioperative data among patients with HO and no HO.
Methods: This was a retrospective case series from an academic Level I trauma center.
Objectives: Implementation of diffusion-weighted imaging (DWI) for abdominal imaging in children has challenges due to motion artifacts exacerbated by long acquisition times. We aimed to compare acquisition time and image quality between conventional DWI and multi-band (MB) DWI of the liver in children and young adults.
Methods: Clinical MRI exams from May 2023 to January 2024 were reviewed, including four DWI sequences: respiratory-triggered (RTr, clinical standard), free-breathing (FB), MB-DWI with shift factor 1 (MBsf1), and MB-DWI with shift factor 2 (MBsf2).
In the present investigation, 13% ± 0.84 of the extracted and purified phycocyanin from Phormidium versicolor was obtained, with a purity of 0.69 following dialysis.
