Genomes2Drugs: Identifies Target Proteins and Lead Drugs from Proteome Data

Background: Genome sequencing and bioinformatics have provided the full hypothetical proteome of many pathogenic organisms. Advances in microarray and mass spectrometry have also yielded large output datasets of possible target proteins/genes. However, the challenge remains to identify new targets for drug discovery from this wealth of information. Further analysis includes bioinformatics and/or molecular biology tools to validate the findings. This is time consuming and expensive, and could fail to yield novel drugs if protein purification and crystallography is impossible. To pre-empt this, a researcher may want to rapidly filter the output datasets for proteins that show good homology to proteins that have already been structurally characterised or proteins that are already targets for known drugs. Critically, those researchers developing novel antibiotics need to select out the proteins that show close homology to any human proteins, as future inhibitors are likely to cross-react with the host protein, causing off-target toxicity effects later in clinical trials. Methodology/Principal Findings: To solve many of these issues, we have developed a free online resource called Genomes2Drugs which ranks sequences to identify proteins that are (i) homologous to previously crystallized proteins or (ii) targets of known drugs, but are (iii) not homologous to human proteins. When tested using the Plasmodium falciparum malarial genome the program correctly enriched the ranked list of proteins with known drug target proteins. Conclusions/Significance: Genomes2Drugs rapidly identifies proteins that are likely to succeed in drug discovery pipelines

Thyroid hormone regulates distinct paths to maturation in pigment cell lineages

Thyroid hormone (TH) regulates diverse developmental events and can drive disparate cellular outcomes. In zebrafish, TH has opposite effects on neural crest derived pigment cells of the adult stripe pattern, limiting melanophore population expansion, yet increasing yellow/orange xanthophore numbers. To learn how TH elicits seemingly opposite responses in cells having a common embryological origin, we analyzed individual transcriptomes from thousands of neural crest-derived cells, reconstructed developmental trajectories, identified pigment cell-lineage specific responses to TH, and assessed roles for TH receptors. We show that TH promotes maturation of both cell types but in distinct ways. In melanophores, TH drives terminal differentiation, limiting final cell numbers. In xanthophores, TH promotes accumulation of orange carotenoids, making the cells visible. TH receptors act primarily to repress these programs when TH is limiting. Our findings show how a single endocrine factor integrates very different cellular activities during the generation of adult form

Optics of cone photoreceptors in the chicken (Gallus gallus domesticus)

Vision is the primary sensory modality of birds, and its importance is evident in the sophistication of their visual systems. Coloured oil droplets in the cone photoreceptors represent an adaptation in the avian retina, acting as long-pass colour filters. However, we currently lack understanding of how the optical properties and morphology of component structures (e.g. oil droplet, mitochondrial ellipsoid and outer segment) of the cone photoreceptor influence the transmission of light into the outer segment and the ultimate effect they have on receptor sensitivity. In this study, we use data from microspectrophotometry, digital holographic microscopy and electron microscopy to inform electromagnetic models of avian cone photoreceptors to quantitatively investigate the integrated optical function of the cell. We find that pigmented oil droplets primarily function as spectral filters, not light collection devices, although the mitochondrial ellipsoid improves optical coupling between the inner segment and oil droplet. In contrast, unpigmented droplets found in violet-sensitive cones double sensitivity at its peak relative to other cone types. Oil droplets and ellipsoids both narrow the angular sensitivity of single cone photoreceptors, but not as strongly as those in human cones

Complementary shifts in photoreceptor spectral tuning unlock the full adaptive potential of ultraviolet vision in birds

Color vision in birds is mediated by four types of cone photoreceptors whose maximal sensitivities (λmax) are evenly spaced across the light spectrum. In the course of avian evolution, the λmax of the most shortwave-sensitive cone, SWS1, has switched between violet (λmax > 400 nm) and ultraviolet (λmax < 380 nm) multiple times. This shift of the SWS1 opsin is accompanied by a corresponding short-wavelength shift in the spectrally adjacent SWS2 cone. Here, we show that SWS2 cone spectral tuning is mediated by modulating the ratio of two apocarotenoids, galloxanthin and 11',12'-dihydrogalloxanthin, which act as intracellular spectral filters in this cell type. We propose an enzymatic pathway that mediates the differential production of these apocarotenoids in the avian retina, and we use color vision modeling to demonstrate how correlated evolution of spectral tuning is necessary to achieve even sampling of the light spectrum and thereby maintain near-optimal color discrimination

Perceived control, locus of control and preparatory information: effects on the perception of an acute pain stimulus

This study investigated the effects of differences in a pre-procedure briefing (providing or withholding preparatory information and explicit control) on the perception of the second of two identical acute pain stimuli. 61 healthy participants were allocated to one of three conditions: Information + Control (I+C), Information - No Control (I-NC) or No information - No Control (NINC). Baseline measures of Pressure Pain Threshold (PPT) and pain rating using Visual Analogue Scales (VAS) were taken, as was a measure of general internal/external Locus of Control (LOC). Participants were read the briefing and subjected to a second pain stimulus of identical intensity to their baseline measures. Participants rated the second stimulus using the VASs, and compared it to the first using comparison scales. Results show that differences in a pre-procedure briefing significantly altered participants' perception of the pain stimulus. Participants in the I-NC group rated the second stimulus more painful than the first, and participants in the NI-NC group rated the second stimulus as less painful than the first. There is also suggestive evidence that these differences may relate to individual LOC style. We recommend encouragement of patient participation to engender at least the perception of control in clinical situations involving acutely painful procedures

Prioritising Informed Health Choices Key Concepts for those impacted by cancer: a protocol [version 1; peer review: 2 approved]

Background: Few areas of health have been as insidiously influenced by misinformation as cancer. Thus, interventions that can help people impacted by cancer reduce the extent to which they are victims of misinformation are necessary. The Informed Health Choices (IHC) initiative has developed Key Concepts that can be used in the development of interventions for evaluating the trustworthiness of claims about the effects of health treatments. We are developing an online education programme called Informed Health Choices-Cancer (IHC-C) based on the IHC Key Concepts. We will provide those impacted by cancer with the knowledge and skills necessary to think critically about the reliability of health information and claims and make informed choices. Methods: We will establish a steering group (SG) of 12 key stakeholders, including oncology specialists and academics. In addition, we will establish a patient and public involvement (PPI) panel of 20 people impacted by cancer. After training the members on the Key Concepts and the prioritisation process, we will conduct a two-round prioritisation process. In the first round, 12 SG members and four PPI panel members will prioritise Key Concepts for inclusion. In the second round, the remaining 16 PPI members will undertake the prioritisation based on the prioritised Key Concepts from the first round. Participants in both rounds will use a structured judgement form to rate the importance of the Key Concepts for inclusion in the online IHC-C programme. A consensus meeting will be held, where members will reach a consensus on the Key Concepts to be included and rank the order in which the prioritised Key Concepts will be addressed in the IHC-C programme. Conclusions: At the end of this process, we will identify which Key Concepts should be included and the order in which they should be addressed in the IHC-C programme

Application of handheld devices to field research among underserved construction worker populations: a workplace health assessment pilot study

This is the final version of the article. Available from BioMed Central via the DOI in this record.BACKGROUND: Novel low-cost approaches for conducting rapid health assessments and health promotion interventions among underserved worker groups are needed. Recruitment and participation of construction workers is particularly challenging due to their often transient periods of work at any one construction site, and their limited time during work to participate in such studies. In the present methodology report, we discuss the experience, advantages and disadvantages of using touch screen handheld devices for the collection of field data from a largely underserved worker population. METHODS: In March 2010, a workplace-centered pilot study to examine the feasibility of using a handheld personal device for the rapid health assessment of construction workers in two South Florida Construction sites was undertaken. A 45-item survey instrument, including health-related questions on tobacco exposure, workplace safety practices, musculoskeletal disorders and health symptoms, was programmed onto Apple iPod Touch® devices. Language sensitive (English and Spanish) recruitment scripts, verbal consent forms, and survey questions were all preloaded onto the handheld devices. The experience (time to survey administration and capital cost) of the handheld administration method was recorded and compared to approaches available in the extant literature. RESULTS: Construction workers were very receptive to the recruitment, interview and assessment processes conducted through the handheld devices. Some workers even welcomed the opportunity to complete the questionnaire themselves using the touch screen handheld device. A list of advantages and disadvantages emerged from this experience that may be useful in the rapid health assessment of underserved populations working in a variety of environmental and occupational health settings. CONCLUSIONS: Handheld devices, which are relatively inexpensive, minimize survey response error, and allow for easy storage of data. These technological research modalities are useful in the collection and assessment of environmental and occupational research data.This study was supported in part by the National Institute for Occupational Safety and Health (NIOSH)'s Deep South Educational Research Center at the University of Alabama (sub-contract: 288477-10) as a Graduate Student Pilot Grant Award; the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) grant F31AR057687 and the National Institute for Occupational Safety and Health (NIOSH) grant R01 OH003915