The Deepwater Horizon oil spill has led to the use of >1 M gallons of oil spill dispersants, which are mixtures of surfactants and solvents. Because of this large scale use there is a critical need to understand the potential for toxicity of the currently used dispersant and potential alternatives, especially given the limited toxicity testing information that is available. In particular, some dispersants contain nonylphenol ethoxylates (NPEs), which can degrade to nonylphenol (NP), a known endocrine disruptor. Given the urgent need to generate toxicity data, we carried out a series of in vitro high-throughput assays on eight commercial dispersants. These assays focused on the estrogen and androgen receptors (ER and AR), but also included a larger battery of assays probing other biological pathways. Cytotoxicity in mammalian cells was also quantified. No activity was seen in any AR assay. Two dispersants showed a weak ER signal in one assay (EC50 of 16 ppm for Nokomis 3-F4 and 25 ppm for ZI-400). NPs and NPEs also had a weak signal in this same ER assay. Note that Corexit 9500, the currently used product, does not contain NPEs and did not show any ER activity. Cytotoxicity values for six of the dispersants were statistically indistinguishable, with median LC50 values approximately 100 ppm. Two dispersants, JD 2000 and SAF-RON GOLD, were significantly less cytotoxic than the others with LC50 values approaching or exceeding 1000 ppm.

Changes in psychiatric symptoms related to specific stages of dementia were investigated in 224 adults 45 years of age or older with Down syndrome. Findings indicate that psychiatric symptoms are a prevalent feature of dementia in the population with Down syndrome and that clinical presentation is qualitatively similar to that seen in Alzheimer's disease within the general population. Psychiatric symptoms related to Alzheimer's disease vary by the type of behavior and stage of dementia, but do not seem to be influenced by sex or level of premorbid intellectual impairment. Some psychiatric symptoms may be early indicators of Alzheimer's disease and may appear prior to substantial changes in daily functioning. Improvements in understanding the progression of dementia in individuals with Down syndrome may lead to improved diagnosis and treatment.

BACKGROUND: QSAR is a widely used method to relate chemical structures to responses or properties based on experimental observations. Much effort has been made to evaluate and validate the statistical modeling in QSAR, but these analyses treat the dataset as fixed. An overlooked but highly important issue is the validation of the setup of the dataset, which comprises addition of chemical structures as well as selection of descriptors and software implementations prior to calculations. This process is hampered by the lack of standards and exchange formats in the field, making it virtually impossible to reproduce and validate analyses and drastically constrain collaborations and re-use of data. RESULTS: We present a step towards standardizing QSAR analyses by defining interoperable and reproducible QSAR datasets, consisting of an open XML format (QSAR-ML) which builds on an open and extensible descriptor ontology. The ontology provides an extensible way of uniquely defining descriptors for use in QSAR experiments, and the exchange format supports multiple versioned implementations of these descriptors. Hence, a dataset described by QSAR-ML makes its setup completely reproducible. We also provide a reference implementation as a set of plugins for Bioclipse which simplifies setup of QSAR datasets, and allows for exporting in QSAR-ML as well as old-fashioned CSV formats. The implementation facilitates addition of new descriptor implementations from locally installed software and remote Web services; the latter is demonstrated with REST and XMPP Web services. CONCLUSIONS: Standardized QSAR datasets open up new ways to store, query, and exchange data for subsequent analyses. QSAR-ML supports completely reproducible creation of datasets, solving the problems of defining which software components were used and their versions, and the descriptor ontology eliminates confusions regarding descriptors by defining them crisply. This makes is easy to join, extend, combine datasets and hence work collectively, but also allows for analyzing the effect descriptors have on the statistical model's performance. The presented Bioclipse plugins equip scientists with graphical tools that make QSAR-ML easily accessible for the community.

Methylation of lysine residues, catalyzed by histone methyltransferase (HMT) enzymes, is one of many modifications of core histone proteins that regulate transcription and chromatin structure. G9a is the predominant HMT in mammalian euchromatin and recent data suggest that it is required to perpetuate a malignant phenotype in cancer cells and is implicated in metastasis, supporting this HMT as a therapeutic target for cancer and other diseases associated with epigenetic regulation. Of the methods currently used to measure methyltransferase activity, many involve a separation step or utilize coupling enzymes complicating implementation and data interpretation. Here we describe a homogeneous assay to measure G9a HMT activity using the chemiluminescence-based AlphaScreen immunoassay technology. Methylation of biotinylated-histone peptide is measured through specific antibody-based detection, in conjunction with streptavidin-coated donor and secondary antibody-coated acceptor beads. The method is particularly well suited for detection of inhibitors acting by the desired histone peptide competitive mechanism and is applicable to testing other HMTs, demonstrated here with the G9a homolog EHMT1, also known as GLP.

OBJECTIVES: We assessed whether local health departments (LHDs) were conducting obesity prevention programs and diabetes screening programs, and we examined associations between LHD characteristics and whether they conducted these programs. METHODS: We used the 2005 National Profile of Local Health Departments to conduct a cross-sectional analysis of 2300 LHDs nationwide. We used multivariate logistic regressions to calculate odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: Approximately 56% of LHDs had obesity prevention programs, 51% had diabetes screening programs, and 34% had both. After controlling for other factors, we found that employing health educators was significantly associated with LHDs conducting obesity prevention programs (OR = 2.08; 95% CI = 1.54, 2.81) and diabetes screening programs (OR = 1.63; 95% CI = 1.23, 2.17). We also found that conducting chronic disease surveillance was significantly associated with LHDs conducting obesity prevention programs (OR = 1.66; 95% CI = 1.26, 2.20) and diabetes screening programs (OR = 2.44; 95% CI = 1.90, 3.15). LHDs with a higher burden of diabetes prevalence were more likely to conduct diabetes screening programs (OR = 1.20; 95% CI = 1.11, 1.31) but not obesity prevention programs. CONCLUSIONS: The presence of obesity prevention and diabetes screening programs was significantly associated with LHD structural capacity and general performance. However, the effectiveness and cost-effectiveness of both types of programs remain unknown.

Virtual and high-throughput screens (HTS) should have complementary strengths and weaknesses, but studies that prospectively and comprehensively compare them are rare. We undertook a parallel docking and HTS screen of 197861 compounds against cruzain, a thiol protease target for Chagas disease, looking for reversible, competitive inhibitors. On workup, 99% of the hits were eliminated as false positives, yielding 146 well-behaved, competitive ligands. These fell into five chemotypes: two were prioritized by scoring among the top 0.1% of the docking-ranked library, two were prioritized by behavior in the HTS and by clustering, and one chemotype was prioritized by both approaches. Determination of an inhibitor/cruzain crystal structure and comparison of the high-scoring docking hits to experiment illuminated the origins of docking false-negatives and false-positives. Prioritizing molecules that are both predicted by docking and are HTS-active yields well-behaved molecules, relatively unobscured by the false-positives to which both techniques are individually prone.

The events of September 11, 2001, set in motion the broadest emergency response ever conducted by the US Department of Health and Human Services. In this article, some of the nurses who deployed to New York City in the aftermath of that horrific attack on the United States offer their recollections of the events. Although Public Health Service Commissioned Corps (PHS CC) officers participated in deployments before 9/11, this particular deployment accelerated the transformation of the PHS CC, because people came to realize the tremendous potential of a uniformed service of 6,000 health care professionals. When not responding to emergencies, PHS CC nurses daily serve the mission of the PHS to protect, promote, and advance the health and safety of the nation. In times of crisis, the PHS CC nurses stand ready to deploy in support of those in need of medical assistance.

Ingenol-3-angelate (Ing3A), extracted from Euphorbia peplus, is currently in clinical trials for eradicating basal cell carcinoma, actinic keratosis, and squamous cell carcinoma (SCC) in situ by topical application. Although structurally related to phorbol esters and a protein kinase C activator, topical Ing3A, but not phorbol 12-myristate 13-acetate (PMA), inhibited the growth of subcutaneous tumors derived from PAM212 (mouse SCC) and B16 (mouse melanoma). Ing3A and PMA both induced acute neutrophilic inflammation on mouse skin, but only Ing3A caused subcutaneous hemorrhage and vascular damage. Both Ing3A and PMA activated extracellular signal-regulated kinase 1/2 (ERK1/2) in epidermis, but Ing3A also activated ERK1/2 in skin dermal fibroblasts and endothelial cells. Pretreatment with topical cyclosporin A (CsA), verapamil, or XR9576, modulators of P-glycoprotein (P-gp), prevented Ing3A-induced hemorrhage but not neutrophil infiltration. CsA also impaired the anticancer activity of Ing3A, whereas the anti-inflammatory dexamethasone did not. Ing3A, but not PMA, blocked photoaffinity labeling of human P-gp with [(125)I]iodoaryazidoprazosin and inhibited P-gp-mediated drug resistance to HCT-15 cells. The intracellular levels of Ing3A were significantly lower in P-gp-expressing cells, and treatment with XR9576 increased the levels to those of cells that do not express P-gp, showing that Ing3A binds to and is transported by P-gp. Taken together, our results suggest that P-gp-mediated absorptive transport, dermal penetration, and vascular damage contribute to the anticancer activity of Ing3A in vivo.

The Nrf2 (nuclear factor E2 p45-related factor 2) transcription factor responds to diverse oxidative and electrophilic environmental stresses by circumventing repression by Keap1, translocating to the nucleus, and activating cytoprotective genes. Nrf2 responses provide protection against chemical carcinogenesis, chronic inflammation, neurodegeneration, emphysema, asthma and sepsis in murine models. Nrf2 regulates the expression of a plethora of genes that detoxify oxidants and electrophiles and repair or remove damaged macromolecules, such as through proteasomal processing. However, many direct targets of Nrf2 remain undefined. Here, mouse embryonic fibroblasts (MEF) with either constitutive nuclear accumulation (Keap1(-/-)) or depletion (Nrf2(-/-)) of Nrf2 were utilized to perform chromatin-immunoprecipitation with parallel sequencing (ChIP-Seq) and global transcription profiling. This unique Nrf2 ChIP-Seq dataset is highly enriched for Nrf2-binding motifs. Integrating ChIP-Seq and microarray analyses, we identified 645 basal and 654 inducible direct targets of Nrf2, with 244 genes at the intersection. Modulated pathways in stress response and cell proliferation distinguish the inducible and basal programs. Results were confirmed in an in vivo stress model of cigarette smoke-exposed mice. This study reveals global circuitry of the Nrf2 stress response emphasizing Nrf2 as a central node in cell survival response.

Cancer cells have distinct metabolic needs that are different from normal cells and can be exploited for development of anti-cancer therapeutics. Activation of the tumor specific M2 form of pyruvate kinase (PKM2) is a potential strategy for returning cancer cells to a metabolic state characteristic of normal cells. Here, we describe activators of PKM2 based upon a substituted thieno[3,2-b]pyrrole[3,2-d]pyridazinone scaffold. The synthesis of these agents, structure-activity relationships, analysis of activity at related targets (PKM1, PKR and PKL) and examination of aqueous solubility are investigated. These agents represent the second reported chemotype for activation of PKM2.