The Hybrid Antibiotic Thiomarinol A Overcomes Intrinsic Resistance in Using a Privileged Dithiolopyrrolone Moiety.

An impermeable outer membrane and multidrug efflux pumps work in concert to provide Gram-negative bacteria with intrinsic resistance against many antibiotics. These resistance mechanisms reduce the intracellular concentrations of antibiotics and render them ineffective. The natural product thiomarinol A combines holothin, a dithiolopyrrolone antibiotic, with marinolic acid A, a close analogue of mupirocin.

Screen for New Antimicrobial Natural Products from the NCI Program for Natural Product Discovery Prefractionated Extract Library.

The continuing emergence of antibiotic-resistant microbes highlights the need for the identification of new chemotypes with antimicrobial activity. One of the most prolific sources of antimicrobial molecules has been the systematic screening of natural product samples. The National Institute of Allergy and Infectious Diseases and the National Cancer Institute here report a large screen of 326,656 partially purified natural product fractions against a panel of four microbial pathogens, resulting in the identification of >3000 fractions with antifungal and/or antibacterial activity.

Impact of Neuroeffector Adrenergic Receptor Polymorphisms on Incident Ventricular Fibrillation During Acute Myocardial Ischemia.

Background Cardiac adrenergic receptor gene polymorphisms have the potential to influence risk of developing ventricular fibrillation (VF) during ST-segment-elevation myocardial infarction, but no previous study has comprehensively investigated those most likely to alter norepinephrine release, signal transduction, or biased signaling. Methods and Results In a case-control study, we recruited 953 patients with ST-segment-elevation myocardial infarction without previous cardiac history, 477 with primary VF, and 476 controls without VF, and genotyped them for Arg389Gly and Ser49Gly, Gln27Glu and Gly16Arg, and Ins322-325Del. Within each minor allele-containing genotype, haplotype, or 2-genotype combination, patients with incident VF were compared with non-VF controls by odds ratios (OR) of variant frequencies referenced against major allele homozygotes.

Enzymatic Synthesis of Diverse Heterocycles by a Noncanonical Nonribosomal Peptide Synthetase.

Nonribosomal peptide synthetases (NRPSs) are typically multimodular enzymes that assemble amino acids or carboxylic acids into complex natural products. Here, we characterize a monomodular NRPS, PvfC, encoded by the () gene cluster that is essential for virulence and signaling in different bacterial species. PvfC exhibits a unique adenylation-thiolation-reductase (ATR) domain architecture that is understudied in bacteria.

Pseudomonas Virulence Factor Pathway Synthesizes Autoinducers That Regulate the Secretome of a Pathogen.

Cell-to-cell communication via chemical signals is an essential mechanism that pathogenic bacteria use to coordinate group behaviors and promote virulence. The () gene cluster is distributed in more than 500 strains of proteobacteria including both plant and human pathogens. The cluster has been implicated in the production of signaling molecules important for virulence; however, the regulatory impact of these signaling molecules on virulence had not been elucidated.

Magnetic Resonance Imaging of Contracting Ultrathin Cardiac Tissue.

Objective: Integrating cardiac-tissue patches into the beating heart and evaluating the long-term effects of such integration on cardiac contractility are two challenges in an emerging field of regenerative medicine. This pilot study presents tools for the imaging of contracting multicellular cardiac tissue constructs (MTCs) and demonstrates the feasibility of tracking the early development of strand geometry and contractions in ultrathin strands and layers of cardiac tissue using CINE MRI.

Approach: Cultured, ultrathin (~50-100-micron) MTCs of rat neonatal cardiomyocytes were plated in rectangular cell chambers (4.

In Vitro Reconstitution Reveals a Central Role for the N-Oxygenase PvfB in (Dihydro)pyrazine-N-oxide and Valdiazen Biosynthesis.

The Pseudomonas virulence factor (pvf) operon is essential for the biosynthesis of two very different natural product scaffolds: the (dihydro)pyrazine-N-oxides and the diazeniumdiolate, valdiazen. PvfB is a member of the non-heme diiron N-oxygenase enzyme family that commonly convert anilines to their nitroaromatic counterparts. In contrast, we show that PvfB catalyzes N-oxygenation of the α-amine of valine, first to the hydroxylamine and then the nitroso, while linked to the carrier protein of PvfC.

Modulation of the cardiac sodium channel Na1.5 peak and late currents by NAD precursors.

Rationale: The cardiac sodium channel Na1.5, encoded by SCN5A, produces the rapidly inactivating depolarizing current I that is responsible for the initiation and propagation of the cardiac action potential. Acquired and inherited dysfunction of Na1.

Specificity of Nonribosomal Peptide Synthetases in the Biosynthesis of the .

The () biosynthetic operon has been implicated in bacterial virulence and signaling. We identified 308 bacterial strains containing homologues that likely produce signaling molecules with distinct structures and biological activities. Several homologues of the nonribosomal peptide synthetase (NRPS), PvfC, were biochemically characterized and shown to activate l-Val or l-Leu.

Discovery of (Dihydro)pyrazine N-Oxides via Genome Mining in Pseudomonas.

Overexpression of the Pseudomonas virulence factor ( pvf) biosynthetic operon led to the identification of a family of pyrazine N-oxides (PNOs), including a novel dihydropyrazine N,N'-dioxide (dPNO) metabolite. The nonribosomal peptide synthetase responsible for production of (d)PNOs was characterized, and a biosynthetic pathway for (d)PNOs was proposed. This work highlights the unique chemistry catalyzed by pvf-encoded enzymes and sets the stage for bioactivity studies of the metabolites produced by the virulence pathway.

Sirtuin 1 regulates cardiac electrical activity by deacetylating the cardiac sodium channel.

The voltage-gated cardiac Na channel (Na1.5), encoded by the SCN5A gene, conducts the inward depolarizing cardiac Na current (I) and is vital for normal cardiac electrical activity. Inherited loss-of-function mutations in SCN5A lead to defects in the generation and conduction of the cardiac electrical impulse and are associated with various arrhythmia phenotypes.

Elevated neonatal insulin-like growth factor I is associated with fetal hypertrophic cardiomyopathy in diabetic women.

Objective: We sought to determine if fetal hypertrophic cardiomyopathy (HCM) or cardiac dysfunction is associated with elevated maternal or neonatal insulin-like growth factor (IGF)-I levels in women with diabetes.

Study Design: In a prospective cohort study, fetal echocardiogram findings at 36 weeks' gestation in women with pregestational diabetes mellitus were compared to those in women without diabetes mellitus. HCM was defined as septal or free wall thickness ≥5 mm and cardiac dysfunction as a modified myocardial performance index ≥0.

Periprostatic adipose tissue from obese prostate cancer patients promotes tumor and endothelial cell proliferation: a functional and MR imaging pilot study.

Background: Obesity, particularly visceral adiposity, confers a worse prognosis for prostate cancer (PCa) patients, and increasing periprostatic adipose (PPA) tissue thickness or density is positively associated with more aggressive disease. However, the cellular mechanism of this activity remains unclear. Therefore, in this pilot study, we assessed the functional activity of PPA tissue secretions and established a biochemical profile of PPA as compared to subcutaneous adipose (SQA) tissues from lean, overweight and obese PCa patients.

A study of best practices for clinical documentation system implementation.

Nurses are key leaders and team members for the implementation of clinical documentation systems. This paper reviews key success factors during implementation of clinical documentation systems to overcome traditional barriers, ensure commitment to universal goals and facilitate the use of technology for patient safety and continuous quality improvement efforts. Top level management support, particularly from nursing executives, is vital.

2008 HIMSS Survey results: best practices in implementing nursing/interdisciplinary documentation systems.

Health care organizations are increasingly using computer systems to support nursing care documentation; however, processes used to deploy such systems are widely varied. The purpose of this survey was to understand current practices related to implementation of computerized nursing and interdisciplinary documentation systems with the goal to establish best practice guidelines. In Spring 2007, members from the Healthcare Information Management and Systems Society Nursing Informatics Working Group interviewed a sample of 15 hospitals to solicit information regarding the following processes: leadership activities, clinical transformation processes, project management activities, implementation processes, evaluation metrics, terminology and other standards used, and methods used to facilitate end-user adoption.

Corticosterone administration does not affect timing of breeding in Florida scrub-jays (Aphelocoma coerulescens).

Providing supplemental food to Florida scrub-jays (Aphelocoma coerulescens) causes a reliable advance in clutch initiation of 1 to 2 weeks. In some years, supplemental food appeared to not only advance laying date but also decrease baseline concentrations of corticosterone (CORT) relative to controls. The coincidence of low CORT levels and early breeding led us to hypothesize that CORT serves to communicate information about environmental conditions to the hypothalamic-pituitary-gonadal (HPG) axis, which ultimately influences the timing of breeding.

Role of selective leptin resistance in diet-induced obesity hypertension.

Leptin is an adipocyte-derived hormone that plays a key role in the regulation of body weight through its actions on appetite and metabolism. Leptin also increases sympathetic nerve activity (SNA) and blood pressure. We tested the hypothesis that diet-induced obesity is associated with resistance to the metabolic actions of leptin but preservation of its renal SNA and arterial pressure effects, leading to hypertension.

Hypothalamic PI3K and MAPK differentially mediate regional sympathetic activation to insulin.

The action of insulin in the central nervous system produces sympathetic nervous system activation (also called sympathoactivation), although the neuronal intracellular mechanisms that mediate this are unclear. We hypothesized that PI3K and MAPK, the major pathways involved in insulin receptor signaling, mediate sympathetic nerve responses to insulin. Intracerebroventricular administration of insulin in rat increased multifiber sympathetic nerve activity to the hindlimb, brown adipose tissue (BAT), adrenal gland, and kidney.