The Role of High Reliability Organization Foundational Practices in Building a Culture of Safety.

Background: High reliability organizations are designed to operate under complex conditions for extended periods by strengthening systems that help serious adverse events for patients. The US Department of Veterans Affairs formally began its enterprise-wide journey to high reliability in 2019. Four foundational practices were identified to advance a culture of safety across all Veterans Health Administration facilities.

Further Probing the Properties of a Unique Sponge-derived Alkaloid Through the Isolation of a New (-)-(5)-(8)-(14)-Mycothiazole Analogue.

Scale-up isolation of (+)-(5)-(8)-(14)-mycothiazole () from Vanuatu specimens of to semisynthesize (+)-(5)-(8)-8--acetyl-(14)-mycothiazole () revealed a new diastereomer, (-)-(5)-(8)-(14)-mycothiazole (). The structure of was determined using HRMS, NMR, and comparing optical rotation to (-)-(5)-(8)-(14)-mycothiazole () and . The maximum tolerated dose of in mice was 0.

Investigating impacts of the mycothiazole chemotype as a chemical probe for the study of mitochondrial function and aging.

Small molecule inhibitors of the mitochondrial electron transport chain (ETC) hold significant promise to provide valuable insights to the field of mitochondrial research and aging biology. In this study, we investigated two molecules: mycothiazole (MTZ) - from the marine sponge C. mycofijiensis and its more stable semisynthetic analog 8-O-acetylmycothiazole (8-OAc) as potent and selective chemical probes based on their high efficiency to inhibit ETC complex I function.

Enzymatic Benzofuranoindoline Formation in the Biosynthesis of the Strained Bridgehead Bicyclic Dipeptide (+)-Azonazine A.

We uncovered and reconstituted a concise biosynthetic pathway of the strained dipeptide (+)-azonazine A from marine-derived Aspergillus insulicola. Formation of the hexacyclic benzofuranoindoline ring system from cyclo-(l-Trp-N-methyl-l-Tyr) is catalyzed by a P450 enzyme through an oxidative cyclization. Supplementing the producing strain with various indole-substituted tryptophan derivatives resulted in the generation of a series of azonazine A analogs.

Distribution and diversity of 'Tectomicrobia', a deep-branching uncultivated bacterial lineage harboring rich producers of bioactive metabolites.

Genomic and functional analyses of bacterial sponge symbionts belonging to the uncultivated candidate genus 'Entotheonella' has revealed them as the prolific producers of bioactive compounds previously identified from their invertebrate hosts. These studies also suggested 'Entotheonella' as the first members of a new candidate phylum, 'Tectomicrobia'. Here we analyzed the phylogenetic structure and environmental distribution of this as-yet sparsely populated phylum-like lineage.

Suppression of MAPK/NF-kB and activation of Nrf2 signaling by Ajugarin-I in EAE model of multiple sclerosis.

Multiple sclerosis (MS) is a debilitating neurodegenerative autoimmune disease of the central nervous system (CNS). The current study aimed to investigate the neuroprotective properties of Ajugarin-I (Aju-I) against the experimental autoimmune encephalomyelitis (EAE) model of MS and explored the underlying mechanism involved. The protective potential of Aju-I was first confirmed against glutamate-induced HT22 cells and hydrogen peroxide (H O )-induced BV2 cells.

Reevaluation of a Bicyclic Pyrazoline as a Selective 15-Lipoxygenase V-Type Activator Possessing Fatty Acid Specificity.

Regulation of lipoxygenase (LOX) activity is of great interest due to the involvement of the various LOX isoforms in the inflammatory process and hence many diseases. The bulk of investigations have centered around the discovery and design of inhibitors. However, the emerging understanding of the role of h15-LOX-1 in the resolution of inflammation provides a rationale for the development of activators as well.

Appraising California Zinfandel Exposure to Wildfire Smoke Using Natural Product Phenolic Diglycoside Biomarkers.

Zinfandel grapes are ubiquitous in California and its wine quality could be negatively impacted from wildfire smoke. Thus, the occurrence of fires prior to grape harvest presents a persistent problem to both viticulture and enology processes. This is the first broad study on Zinfandel to investigate wine quality defects produced by natural wildfires.

In Vivo Evaluation of (-)-Zampanolide Demonstrates Potent and Persistent Antitumor Efficacy When Targeted to the Tumor Site.

Microtubule-stabilizing agents (MSAs) are a class of compounds used in the treatment of triple-negative breast cancer (TNBC), a subtype of breast cancer where chemotherapy remains the standard-of-care for patients. Taxanes like paclitaxel and docetaxel have demonstrated efficacy against TNBC in the clinic, however new classes of MSAs need to be identified due to the rise of taxane resistance in patients. (-)-Zampanolide is a covalent microtubule stabilizer that can circumvent taxane resistance in vitro but has not been evaluated for in vivo antitumor efficacy.

Tandem high resolution mass spectrometry based phytochemical composition of Sauromatum guttatum tubers and its enzyme inhibitory potential with molecular docking.

Sauromatum guttatum has been traditionally used in the treatment of snakebite and tumors in India, Pakistan, and China. However, it lacks detailed phytochemical composition like other members of the family Araceae. Therefore, the aim of the present study was to investigate the phytochemical composition of crude methanolic extract and subsequent fractions from S.

Re-evaluation of the Fijianolide/Laulimalide Chemotype Suggests an Alternate Mechanism of Action for C-15/C-20 Analogs.

Herein, we report on naturally derived microtubule stabilizers with activity against triple negative breast cancer (TNBC) cell lines, including paclitaxel, fijianolide B/laulimalide (), fijianolide B di-acetate (), and two new semisynthetic analogs of , which include fijianolide J () and fijianolide L (). Similar to paclitaxel, compound demonstrated classic microtubule stabilizing activity with potent (GI = 0.7-17 nM) antiproliferative efficacy among the five molecularly distinct TNBC cell lines.

Natural Product Phenolic Diglycosides Created from Wildfires, Defining Their Impact on California and Oregon Grapes and Wines.

Forest fires produce malodorous phenols, bioaccumulated in grapes as odorless phenol glycosides (mono- to tri-), and produce unpleasant wines when these complexes are transformed by glycosidases in saliva. Metabolomic analyses were used to further understand by quantitating marker phenolic diglycosides via UHPLC separations and MS/MS multiple reaction monitoring. A collection of grapes and wines provided data to forecast wine quality of grapes subjected to wildfire smoke infestations; the analytics used a panel of reference compounds (-).

Kinetic and structural investigations of novel inhibitors of human epithelial 15-lipoxygenase-2.

Human epithelial 15-lipoxygenase-2 (h15-LOX-2, ALOX15B) is expressed in many tissues and has been implicated in atherosclerosis, cystic fibrosis and ferroptosis. However, there are few reported potent/selective inhibitors that are active ex vivo. In the current work, we report newly discovered molecules that are more potent and structurally distinct from our previous inhibitors, MLS000545091 and MLS000536924 (Jameson et al, PLoS One, 2014, 9, e104094), in that they contain a central imidazole ring, which is substituted at the 1-position with a phenyl moiety and with a benzylthio moiety at the 2-position.

Assessing the ethnobotanical potential of Carissa opaca berries by merging outcomes from metabolomics profiling, enzyme assays, and in silico docking studies.

The phytochemical profile of Carissa opaca fruit extract and fractions was established through dereplication strategies employing LC-MS/MS and global natural product social molecular networking (GNPS). Crude extract and fractions were evaluated for their potential to inhibit α-glucosidase and urease in vitro. Flavonoid-O-glycosides, flavonoid-C-glycosides, flavonoids, proanthocyanidin B2, phenolics, and triterpenoids were annotated as the major classes of secondary metabolites present in the extract and fractions.

Highlights of marine natural products having parallel scaffolds found from marine-derived bacteria, sponges, and tunicates.

Marine-derived bacteria are a prolific source of a wide range of structurally diverse natural products. This review, dedicated to Professor William Fenical, begins by showcasing many seminal discoveries made at the University of California San Diego from marine-derived actinomycetes. Discussed early on is the 20-year journey of discovery and advancement of the seminal actinomycetes natural product salinosporamide A into Phase III anticancer clinical trials.

An exon skipping screen identifies antitumor drugs that are potent modulators of pre-mRNA splicing, suggesting new therapeutic applications.

Agents that modulate pre-mRNA splicing are of interest in multiple therapeutic areas, including cancer. We report our recent screening results with the application of a cell-based Triple Exon Skipping Luciferase Reporter (TESLR) using a library that is composed of FDA approved drugs, clinical compounds, and mechanistically characterized tool compounds. Confirmatory assays showed that three clinical antitumor therapeutic candidates (milciclib, PF-3758309 and PF-562271) are potent splicing modulators and that these drugs are, in fact, nanomolar inhibitors of multiple kinases involved in the regulation the spliceosome.

Reinvestigation of Mycothiazole Reveals the Penta-2,4-dien-1-ol Residue Imparts Picomolar Potency and 8 Configuration.

Reinvestigation of mycothiazole () revealed picomolar potency (IC = 0.00016, 0.00027, 0.

Unraveling Structures Containing Highly Conjugated Pyrrolo[4,3,2-]quinoline Cores That Are Deficient in Diagnostic Proton NMR Signals.

This study began with the goal of identifying additional constituents from extracts obtained from an Indo-Pacific sponge (coll. no. 06132).

Correction: The value of universally available raw NMR data for transparency, reproducibility, and integrity in natural product research.

Correction for 'The value of universally available raw NMR data for transparency, reproducibility, and integrity in natural product research' by James B. McAlpine et al., Nat.

The value of universally available raw NMR data for transparency, reproducibility, and integrity in natural product research.

Covering: up to 2018With contributions from the global natural product (NP) research community, and continuing the Raw Data Initiative, this review collects a comprehensive demonstration of the immense scientific value of disseminating raw nuclear magnetic resonance (NMR) data, independently of, and in parallel with, classical publishing outlets. A comprehensive compilation of historic to present-day cases as well as contemporary and future applications show that addressing the urgent need for a repository of publicly accessible raw NMR data has the potential to transform natural products (NPs) and associated fields of chemical and biomedical research. The call for advancing open sharing mechanisms for raw data is intended to enhance the transparency of experimental protocols, augment the reproducibility of reported outcomes, including biological studies, become a regular component of responsible research, and thereby enrich the integrity of NP research and related fields.

The potential of achiral sponge-derived and synthetic bromoindoles as selective cytotoxins against PANC-1 tumor cells.

Our quest to isolate and characterize natural products with in vitro solid tumor selectivity is driven by access to repositories of Indo-Pacific sponge extracts. In this project an extract of a species of Haplosclerida sponge obtained from the US NCI Natural Products Repository displayed, by in vitro disk diffusion assay (DDA) and IC determinations, selective cytotoxicity with modest potency to a human pancreatic cancer cell line (PANC-1) relative to the human lymphoblast leukemia cell line (CCRF-CEM). Two brominated indoles, the known 6-bromo conicamin () and the new derivative, 6-Br-8-keto-conicamin A (), were identified and (IC 1.

Inhibition of NF-κB-dependent HIV-1 replication by the marine natural product bengamide A.

HIV-1 inhibitors that act by mechanisms distinct from existing antiretrovirals can provide novel insights into viral replication and potentially inform development of new therapeutics. Using a multi-cycle HIV-1 replication assay, we screened 252 pure compounds derived from marine invertebrates and microorganisms and identified 6 (actinomycin Z, bastadin 6, bengamide A, haliclonacyclamine A + B, keramamine C, neopetrosiamide B) that inhibited HIV-1 with 50% effective concentrations (ECs) of 3.8 μM or less.

Bioactive Secondary Metabolites from the Marine Sponge Genus Agelas.

The marine sponge genus comprises a rich reservoir of species and natural products with diverse chemical structures and biological properties with potential application in new drug development. This review for the first time summarized secondary metabolites from sponges discovered in the past 47 years together with their bioactive effects.