Interdisciplinary Quality Improvement Project Increases Vitamin D Supplementation in Infants.

Background: American Academy of Pediatrics guidelines recommend 400 IU of vitamin D supplementation daily for certain infants <1 year of age. We aimed to increase the proportion of reported appropriate vitamin D supplementation for infants born at our institution and those who followed up in our resident clinic through 6 months from 49% to 80% over 24 months.

Methods: Our interdisciplinary quality improvement effort included vitamin D medication delivery before nursery discharge and family and staff education.

A Case of Fastidious Mycobacterium chelonae-Causative Cellulitis: Clinical Manifestations of a Rare Bacterial Infection.

Cellulitis is rarely caused by the organism (). In this case report, we detail the clinical course of a 43-year-old female with persistent cellulitis in her right lower extremity despite intensive empiric therapy. The patient was formally diagnosed with -causative cellulitis after an extensive workup including a prolonged hospital stay involving surgical biopsy and a delayed result of an acid-fast bacilli stain.

Evidence for ligandable sites in structured RNA throughout the Protein Data Bank.

RNA has attracted considerable attention as a target for small molecules. However, methods to identify, study, and characterize suitable RNA targets have lagged behind strategies for protein targets. One approach that has received considerable attention for protein targets has been to utilize computational analysis to investigate ligandable "pockets" on proteins that are amenable to small molecule binding.

Chemical and structural studies provide a mechanistic basis for recognition of the MYC G-quadruplex.

G-quadruplexes (G4s) are noncanonical DNA structures that frequently occur in the promoter regions of oncogenes, such as MYC, and regulate gene expression. Although G4s are attractive therapeutic targets, ligands capable of discriminating between different G4 structures are rare. Here, we describe DC-34, a small molecule that potently downregulates MYC transcription in cancer cells by a G4-dependent mechanism.

Characterization of clinically used oral antiseptics as quadruplex-binding ligands.

Approaches to characterize the nucleic acid-binding properties of drugs and druglike small molecules are crucial to understanding the behavior of these compounds in cellular systems. Here, we use a Small Molecule Microarray (SMM) profiling approach to identify the preferential interaction between chlorhexidine, a widely used oral antiseptic, and the G-quadruplex (G4) structure in the KRAS oncogene promoter. The interaction of chlorhexidine and related drugs to the KRAS G4 is evaluated using multiple biophysical methods, including thermal melt, fluorescence titration and surface plasmon resonance (SPR) assays.

Macrophilone A: Structure Elucidation, Total Synthesis, and Functional Evaluation of a Biologically Active Iminoquinone from the Marine Hydroid Macrorhynchia philippina.

A previously uncharacterized pyrroloiminoquinone natural product, macrophilone A, was isolated from the stinging hydroid Macrorhynchia philippina. The structure was assigned utilizing long-range NMR couplings and DFT calculations and proved by a concise, five-step total synthesis. Macrophilone A and a synthetic analogue displayed potent biological activity, including increased intracellular reactive oxygen species levels and submicromolar cytotoxicity toward lung adenocarcinoma cells.

Nonclassical Size Dependence of Permeation Defines Bounds for Passive Adsorption of Large Drug Molecules.

Macrocyclic peptides are considered large enough to inhibit "undruggable" targets, but the design of passively cell-permeable molecules in this space remains a challenge due to the poorly understood role of molecular size on passive membrane permeability. Using split-pool combinatorial synthesis, we constructed a library of cyclic, per-N-methlyated peptides spanning a wide range of calculated lipohilicities (0 < AlogP < 8) and molecular weights (∼800 Da < MW < ∼1200 Da). Analysis by the parallel artificial membrane permeability assay revealed a steep drop-off in apparent passive permeability with increasing size in stark disagreement with current permeation models.

Insights Into the Allosteric Inhibition of the SUMO E2 Enzyme Ubc9.

Conjugation of the small ubiquitin-like modifier (SUMO) to protein substrates is an important disease-associated posttranslational modification, although few inhibitors of this process are known. Herein, we report the discovery of an allosteric small-molecule binding site on Ubc9, the sole SUMO E2 enzyme. An X-ray crystallographic screen was used to identify two distinct small-molecule fragments that bind to Ubc9 at a site distal to its catalytic cysteine.

Probing the Physicochemical Boundaries of Cell Permeability and Oral Bioavailability in Lipophilic Macrocycles Inspired by Natural Products.

Cyclic peptide natural products contain a variety of conserved, nonproteinogenic structural elements such as d-amino acids and amide N-methylation. In addition, many cyclic peptides incorporate γ-amino acids and other elements derived from polyketide synthases. We hypothesized that the position and orientation of these extended backbone elements impact the ADME properties of these hybrid molecules, especially their ability to cross cell membranes and avoid metabolic degradation.

Cell-permeable cyclic peptides from synthetic libraries inspired by natural products.

Drug design efforts are turning to a new generation of therapeutic targets, such as protein-protein interactions (PPIs), that had previously been considered "undruggable" by typical small molecules. There is an emerging view that accessing these targets will require molecules that are larger and more complex than typical small molecule drugs. Here, we present a methodology for the discovery of geometrically diverse, membrane permeable cyclic peptide scaffolds based on the synthesis and permeability screening of a combinatorial library, followed by deconvolution of membrane-permeable scaffolds to identify cyclic peptides with good to excellent passive cell permeabilities.

Manipulation of intraparticle charge delocalization by selective complexation of transition-metal ions with histidine moieties.

Ruthenium nanoparticles were cofunctionalized with pyrene and histidine moieties through Ru═carbene π bonds. The selective complexation of the histidine moiety with transition-metal ions led to a marked diminishment of the emission peak at 490 nm which arose from the nanoparticle-bridged pyrene moieties that behaved analogously to pyrene dimers with a conjugated spacer. This is accounted for by the polarization of the core electrons by the added positive charge that impacted the intraparticle charge delocalization between the particle-bound pyrene moieties.