Force-transducing molecular ensembles at growing microtubule tips control mitotic spindle size.

Correct mitotic spindle size is required for accurate chromosome segregation during cell division. It is controlled by mechanical forces generated by molecular motors and non-motor proteins acting on spindle microtubules. However, how forces generated by individual proteins enable bipolar spindle organization is not well understood.

Inhibition of Acetyl-CoA Carboxylase Causes Malformations in Rats and Rabbits: Comparison of Mammalian Findings and Alternative Assays.

Acetyl-CoA carboxylase (ACC) is an enzyme within the de novo lipogenesis (DNL) pathway and plays a role in regulating lipid metabolism. Pharmacologic ACC inhibition has been an area of interest for multiple potential indications including oncology, acne vulgaris, metabolic diseases such as type 2 diabetes mellitus, and nonalcoholic fatty liver disease/nonalcoholic steatohepatitis. A critical role for ACC in de novo synthesis of long-chain fatty acids during fetal development has been demonstrated in studies in mice lacking Acc1, where the absence of Acc1 results in early embryonic lethality.

A multi-institutional study benchmarking the zebrafish developmental assay for prediction of embryotoxic plasma concentrations from rat embryo-fetal development studies.

Predicting embryotoxicity of pharmaceutical compounds or industrial chemicals is crucial for public safety. Conventional studies which monitor embryo-fetal development in rats and rabbits are costly and time consuming. Alternative assays which are simpler and less costly are being pursued.

Characterizing sources of variability in zebrafish embryo screening protocols.

There is a need for fast, efficient, and cost-effective hazard identification and characterization of chemical hazards. This need is generating increased interest in the use of zebrafish embryos as both a screening tool and an alternative to mammalian test methods. A Collaborative Workshop on Aquatic Models and 21st Century Toxicology identified the lack of appropriate and consistent testing protocols as a challenge to the broader application of the zebrafish embryo model.

Including the 'Spiritual' Within Mental Health Care in the UK, from the Experiences of People with Mental Health Problems.

Spirituality as a dimension of quality of life and well-being has recently begun to be more valued within person-centred treatment approaches to mental health in the UK. The aim of this paper is to provide indicators of the extent to which accessing a spiritual support group may be useful within mental health recovery from the view point of those in receipt of it. The study design was a small-scale exploratory study utilising mixed methods.

High-Mileage Light-Duty Fleet Vehicle Emissions: Their Potentially Overlooked Importance.

State and local agencies in the United States use activity-based computer models to estimate mobile source emissions for inventories. These models generally assume that vehicle activity levels are uniform across all of the vehicle emission level classifications using the same age-adjusted travel fractions. Recent fuel-specific emission measurements from the SeaTac Airport, Los Angeles, and multi-year measurements in the Chicago area suggest that some high-mileage fleets are responsible for a disproportionate share of the fleet's emissions.

Reactive Nitrogen Species Emission Trends in Three Light-/Medium-Duty United States Fleets.

Repeated, fuel-specific, emission measurements in Denver (2005/2013), Los Angeles (LA) (2008/2013), and Tulsa (2005/2013) provide long-term trends in on-road reactive nitrogen emissions from three light-/medium-duty U.S. fleets.

Stem cell-derived systems in toxicology assessment.

Industrial sectors perform toxicological assessments of their potential products to ensure human safety and to fulfill regulatory requirements. These assessments often involve animal testing, but ethical, cost, and time concerns, together with a ban on it in specific sectors, make appropriate in vitro systems indispensable in toxicology. In this study, we summarize the outcome of an EPAA (European Partnership of Alternatives to Animal Testing)-organized workshop on the use of stem cell-derived (SCD) systems in toxicology, with a focus on industrial applications.

On-road heavy-duty vehicle emissions monitoring system.

The introduction of particulate and oxides of nitrogen (NOx) after-treatment controls on heavy-duty vehicles has spurred the need for fleet emissions data to monitor their reliability and effectiveness. The University of Denver has developed a new method for rapidly measuring heavy-duty vehicles for gaseous and particulate fuel specific emissions. The method was recently used to collect 3088 measurements at a Port of Los Angeles location and a weigh station on I-5 in northern California.

The recession of 2008 and its impact on light-duty vehicle emissions in three western United States cities.

The global economic recession of 2008-2010 severely depressed light-duty vehicle sales in the United States. On-road fleets observed with a remote vehicle exhaust sensor in 2013 at three historical sampling locations in Denver, Los Angeles, and Tulsa showed large reductions in the fleet fractions of 2009 model year vehicles of 40%, 38%, and 35%, respectively, when compared to prerecession 2007 levels with the light-duty truck category suffering the largest percentage declines. The fleet fraction for these ∼ 5 year old vehicles is normally reserved for vehicles more than twice their age.

Fishing for teratogens: a consortium effort for a harmonized zebrafish developmental toxicology assay.

A consortium of biopharmaceutical companies previously developed an optimized Zebrafish developmental toxicity assay (ZEDTA) where chorionated embryos were exposed to non-proprietary test compounds from 5 to 6 h post fertilization and assessed for morphological integrity at 5 days post fertilization. With the original 20 test compounds, this achieved an overall predictive value for teratogenicity of 88% of mammalian in vivo outcome [Gustafson, A. L.

Improving the odds of success in drug discovery: choosing the best compounds for in vivo toxicology studies.

A set of molecules that advanced into exploratory animal toxicology studies (two species) was examined to determine what properties contributed to success in these safety studies. Compounds were rigorously evaluated across numerous safety end points and classified as "pass" if a suitable in vivo therapeutic index (TI) was achieved for advancement into regulatory toxicology studies. The most predictive end point contributing to compound survival was a predicted human efficacious concentration (Ceff) of ≤250 nM (total drug) and ≤40 nM (free drug).

Heavy-duty truck emissions in the South Coast Air Basin of California.

California and Federal emissions regulations for 2007 and newer heavy-duty diesel engines require an order of magnitude reduction in particulate matter and oxides of nitrogen spurring the introduction of new aftertreatment systems. Since 2008, four emission measurement campaigns have been conducted at a Port of Los Angeles location and an inland weigh station in the South Coast Air Basin of California. Fuel specific oxides of nitrogen emissions at the Port have decreased 12% since 2010 while infrared opacity (a measure of particulate matter) remained low, showing no diesel particulate filter deterioration.

Toxicity assessments of nonsteroidal anti-inflammatory drugs in isolated mitochondria, rat hepatocytes, and zebrafish show good concordance across chemical classes.

To reduce costly late-stage compound attrition, there has been an increased focus on assessing compounds in in vitro assays that predict attributes of human safety liabilities, before preclinical in vivo studies are done. Relevant questions when choosing a panel of assays for predicting toxicity are (a) whether there is general concordance in the data among the assays, and (b) whether, in a retrospective analysis, the rank order of toxicity of compounds in the assays correlates with the known safety profile of the drugs in humans. The aim of our study was to answer these questions using nonsteroidal anti-inflammatory drugs (NSAIDs) as a test set since NSAIDs are generally associated with gastrointestinal injury, hepatotoxicity, and/or cardiovascular risk, with mitochondrial impairment and endoplasmic reticulum stress being possible contributing factors.

Guidelines for Biosafety Training Programs for Workers Assigned to BSL-3 Research Laboratories.

The Guidelines for Biosafety Training Programs for Workers Assigned to BSL-3 Research Laboratories were developed by biosafety professionals who oversee training programs for the 2 national biocontainment laboratories (NBLs) and the 13 regional biocontainment laboratories (RBLs) that participate in the National Institute of Allergy and Infectious Diseases (NIAID) NBL/RBL Network. These guidelines provide a general training framework for biosafety level 3 (BSL-3) high-containment laboratories, identify key training concepts, and outline training methodologies designed to standardize base knowledge, understanding, and technical competence of laboratory personnel working in high-containment laboratories. Emphasis is placed on building a culture of risk assessment-based safety through competency training designed to enhance understanding and recognition of potential biological hazards as well as methods for controlling these hazards.

Placental transfer of (125)Iodinated humanized immunoglobulin G2Δa in the Sprague Dawley rat.

Antibody-like biopharmaceuticals cross the placenta by utilizing transport pathways available for transfer of maternal antibodies to the conceptus. To characterize the timing and magnitude of this transfer in the rat, embryo/fetal biodistribution of maternally administered radiolabeled humanized IgG2 was quantified over the course of gestation using gamma counting and whole body autoradiography. The result was humanized IgG2 found in rat embryo/fetal tissues as early as gestation day 11 with a >1000-fold increase in the amount of total IgG2 by day 21.

Comparison of the MOVES2010a, MOBILE6.2, and EMFAC2007 mobile source emission models with on-road traffic tunnel and remote sensing measurements.

Unlabelled: The Desert Research Institute conducted an on-road mobile source emission study at a traffic tunnel in Van Nuys, California, in August 2010 to measure fleet-averaged, fuel-based emission factors. The study also included remote sensing device (RSD) measurements by the University of Denver of 13,000 vehicles near the tunnel. The tunnel and RSD fleet-averaged emission factors were compared in blind fashion with the corresponding modeled factors calculated by ENVIRON International Corporation using U.

Multispecies remote sensing measurements of vehicle emissions on Sherman Way in Van Nuys, California.

Unlabelled: As part of the 2010 Van Nuys tunnel study, researchers from the University of Denver measured on-road fuel-specific light-duty vehicle emissions from nearly 13,000 vehicles on Sherman Way (0.4 miles west of the tunnel) in Van Nuys, California, with its multispecies Fuel Efficiency Automobile Test (FEAT) remote sensor a week ahead of the tunnel measurements. The remote sensing mean gram per kilogram carbon monoxide (CO), hydrocarbon (HC), and oxide of nitrogen (NO(x)) measurements are 8.

Embryo-fetal transfer of bevacizumab (Avastin) in the rat over the course of gestation and the impact of neonatal Fc receptor (FcRn) binding.

Background: There is concern about embryo-fetal exposure to antibody-based biopharmaceuticals based on the increase of such therapies being prescribed to women of childbearing potential. Therefore, there is a desire to better characterize embryo-fetal exposure of these molecules. The pregnant rat is a standard model for evaluating the potential consequences of exposure but placental transfer of antibody-based biopharmaceuticals is not well understood in this model.

Embryo-fetal distribution of a biopharmaceutical IgG2 during rat organogenesis.

Embryo-fetal biodistribution of a maternally administered humanized IgG2 in rats was evaluated by enzyme-linked immunosorbent assay in dose response and time course studies. Fetal and maternal plasma IgG2 levels increased with dose from 10 to 300mg/kg but fetal:maternal ratio decreased with increasing dose. Plasma IgG2 levels decreased in fetal rat with increasing time post-dose but more slowly than maternal levels.

Reproductive toxicity assessment of sunitinib, a multitargeted receptor tyrosine kinase inhibitor, in male and female rats.

Background: Sunitinib (SUTENT, Pfizer Inc., New York, NY) is a multitargeted inhibitor of selected receptor tyrosine kinases, which produces an antiproliferative and antiangiogenic effect by blocking pathways fundamental to tumor growth and survival. We investigated the effects of sunitinib on male and female fertility and early embryonic development in the rat.

Inter-laboratory assessment of a harmonized zebrafish developmental toxicology assay - progress report on phase I.

This report provides a progress update of a consortium effort to develop a harmonized zebrafish developmental toxicity assay. Twenty non-proprietary compounds (10 animal teratogens and 10 animal non-teratogens) were evaluated blinded in 4 laboratories. Zebrafish embryos from pond-derived and cultivated strain wild types were exposed to the test compounds for 5 days and subsequently evaluated for lethality and morphological changes.

Emission changes resulting from the San Pedro Bay, California Ports Truck Retirement Program.

Recent U.S. Environmental Protection Agency emissions regulations have resulted in lower emissions of particulate matter and oxides of nitrogen from heavy-duty diesel trucks.

Developmental toxicity testing for safety assessment: new approaches and technologies.

The ILSI Health and Environmental Sciences Institute's Developmental and Reproductive Toxicology Technical Committee held a 2-day workshop entitled "Developmental Toxicology-New Directions" in April 2009. The fourth session of this workshop focused on new approaches and technologies for the assessment of developmental toxicology. This session provided an overview of the application of genomics technologies for developmental safety assessment, the use of mouse embryonic stem cells to capture data on developmental toxicity pathways, dynamical cell imaging of zebrafish embryos, the use of computation models of development pathways and systems, and finally, high-throughput in vitro approaches being utilized by the EPA ToxCast program.

Not a walk in the park: the ECVAM whole embryo culture model challenged with pharmaceuticals and attempted improvements with random forest design.

Background: The European Committee for the Validation of Alternative Methods (ECVAM) supported the development of a linear discriminant embryotoxicity prediction model founded on rat whole embryo culture (Piersma et al. (2004). Altern Lab Anim 32:275–307).