Daptomycin Pore Formation Is Restricted by Lipid Acyl Chain Composition

Daptomycin is a calcium-dependent lipopeptide antibiotic that is used clinically against various Gram-positive pathogens. It acts on bacterial cell membranes, whose susceptibility varies with the content of phosphatidylglycerol (PG). Some studies have reported that daptomycin permeabilizes and depolarizes bacterial cell membranes, while others have found no evidence of membrane permeabilization and thus proposed different mechanisms of antibacterial action. Divergent observations have also been reported regarding the effect of daptomycin on model membranes, which were found to be permeabilized nonselectively, selectively for small cations, or not at all. While these diverging model studies did consider the functional roles of different lipid head groups, they assumed that the acyl chains were interchangeable. We here show this assumption to be erroneous. In equimolar mixtures of PG and phosphatidylcholine (PC), dimyristoyl lipids support membrane permeabilization, whereas dioleyl and palmitoleyl lipids do not, even though daptomycin does bind to and form oligomers on all of these membranes. These observations help reconcile some of the discrepant findings in the literature

Increased Electromer Formation and Charge Trapping in Solution-Processed versus Vacuum-Deposited Small Molecule Host Materials of Organic Light-Emitting Devices

We investigate and compare between organic light-emitting devices (OLEDs) fabricated by solution-coating versus vacuum-deposition. Electroluminescence, photoluminescence, and chromatographic measurements on typical OLED host materials reveal significant electromer formation in layers fabricated by solution-processing, pointing to stronger intermolecular interactions in these systems. Delayed electroluminescence measurements reveal that solution-processed layers also have increased charge traps. The findings provide insights on the morphological differences between solution-processed and vacuum-deposited materials and shed light on the root causes behind the lower electroluminescence stability of solution-processed OLEDs

ASME V&V40 Industry Day 2018 -- Industry and FDA Slides for Public Distribution

<p>The upcoming publication of the new ASME Standard V&V 40 -- Assessing Credibility of Computational Modeling and Simulation Results through Verification and Validation: Application to Medical Devices was a key topic at the 2018 V&V Symposium. Developed through close collaboration between device developers, regulatory agencies, and other device industry stakeholders, the ASME V&V 40 standard provides modelers in the medical device industry with a framework for establishing model credibility requirements. The anticipated publication date is July 2018.</p> <p> </p> <div>The ASME V&V 40 Subcommittee leadership coordinated an “Industry Day” event focused on the current regulatory pathway for computer models in medical device submissions and the role the ASME V&V40 standard can play in supporting computer modeling for regulatory decision-making. As such, we have garnered participation from computer modelers and regulatory affairs personnel to engage with the FDA Center for Devices and Radiological Health staff from both the Office of Device Evaluation (ODE) and the Office of Science and Engineering Laboratories (OSEL), along with members of the ASME V&V 40 Subcommittee. <br></div><div><br></div><div>Attached is the slide deck with the presentations from our industry and FDA representatives.<br></div><div></div

Interaction of a Cationic Porphyrin and Its Metal Derivatives with G‑Quadruplex DNA

G-quadruplex (GQ) structures formed from guanine-rich sequences are found throughout the genome and are overrepresented in the promoter regions of some oncogenes, at the telomeric ends of eukaryotic chromosomes, and at the 5′-untranslated regions of mRNA. Interaction of small molecule ligands with GQ DNA is an area of great research interest to develop novel anticancer therapeutics and GQ sensors. In this paper we examine the interactions of TMPyP4, its isomer TMPyP2 (containing <i>N</i>-methyl-2-pyridyl substituents, N-Me-2Py) as well as two metal derivatives ZnTMPyP4 and CuTMPyP4 with GQs formed by dT₄G₄ and dT₄G₄T in 100 mM K⁺ or Na⁺ conditions. The DNA sequences were chosen to elucidate the effect of the 3′-T on the stabilization effect of porphyrins, binding modes, affinities, and stoichiometries determined via circular dichroism melting studies, UV–vis titrations, continuous variation analysis, and fluorescence studies. Our findings demonstrate that the stabilizing abilities of porphyrins are stronger toward (dT₄G₄)₄ as compared to (dT₄G₄T)₄ (Δ<i>T</i>_m is 4.4 vs −6.4 for TMPyP4; 12.7 vs 5.7 for TMPyP2; 16.4 vs 12.1 for ZnTMPyP4; and 1.9 vs −8.4 °C for CuTMPyP4) suggesting that the 3′G-tetrad presents at least one of the binding sites. The binding affinity was determined to be moderate (<i>K</i>_a ∼ 10⁶–10⁷ μM^–1) with a typical binding stoichiometry of 1:1 or 2:1 porphyrin-to-GQ. In all studies, ZnTMPyP4 emerged as a ligand superior to TMPyP4. Overall, our work contributes to clearer understanding of interactions between porphyrins and GQ DNA

From Rain Tanks to Catchments: Use of Low-Impact Development To Address Hydrologic Symptoms of the Urban Stream Syndrome

Catchment urbanization perturbs the water and sediment budgets of streams, degrades stream health and function, and causes a constellation of flow, water quality, and ecological symptoms collectively known as the urban stream syndrome. Low-impact development (LID) technologies address the hydrologic symptoms of the urban stream syndrome by mimicking natural flow paths and restoring a natural water balance. Over annual time scales, the volumes of stormwater that should be infiltrated and harvested can be estimated from a catchment-scale water-balance given local climate conditions and preurban land cover. For all but the wettest regions of the world, a much larger volume of stormwater runoff should be harvested than infiltrated to maintain stream hydrology in a preurban state. Efforts to prevent or reverse hydrologic symptoms associated with the urban stream syndrome will therefore require: (1) selecting the right mix of LID technologies that provide regionally tailored ratios of stormwater harvesting and infiltration; (2) integrating these LID technologies into next-generation drainage systems; (3) maximizing potential cobenefits including water supply augmentation, flood protection, improved water quality, and urban amenities; and (4) long-term hydrologic monitoring to evaluate the efficacy of LID interventions

Design, Synthesis, and Biological Activity of 1,2,3-Triazolobenzodiazepine BET Bromodomain Inhibitors

A number of diazepines are known to inhibit bromo- and extra-terminal domain (BET) proteins. Their BET inhibitory activity derives from the fusion of an acetyl-lysine mimetic heterocycle onto the diazepine framework. Herein we describe a straightforward, modular synthesis of novel 1,2,3-triazolobenzodiazepines and show that the 1,2,3-triazole acts as an effective acetyl-lysine mimetic heterocycle. Structure-based optimization of this series of compounds led to the development of potent BET bromodomain inhibitors with excellent activity against leukemic cells, concomitant with a reduction in c-<i>MYC</i> expression. These novel benzodiazepines therefore represent a promising class of therapeutic BET inhibitors