Chemistry domain of applicability evaluation against existing estrogen receptor high-throughput assay-based activity models.

Introduction: The U. S. Environmental Protection Agency's Endocrine Disruptor Screening Program (EDSP) Tier 1 assays are used to screen for potential endocrine system-disrupting chemicals.

Optimizing androgen receptor prioritization using high-throughput assay-based activity models.

Computational models using data from high-throughput screening assays have promise for prioritizing and screening chemicals for testing under the U.S. Environmental Protection Agency's Endocrine Disruptor Screening Program (EDSP).

A Framework for the Interoperability of Cloud Platforms: Towards FAIR Data in SAFE Environments.

As the number of cloud platforms supporting scientific research grows, there is an increasing need to support interoperability between two or more cloud platforms. A well accepted core concept is to make data in cloud platforms Findable, Accessible, Interoperable and Reusable (FAIR). We introduce a companion concept that applies to cloud-based computing environments that we call a ecure and uthorized AIR nvironment (SAFE).

Development of the InTelligence And Machine LEarning (TAME) Toolkit for Introductory Data Science, Chemical-Biological Analyses, Predictive Modeling, and Database Mining for Environmental Health Research.

Research in environmental health is becoming increasingly reliant upon data science and computational methods that can more efficiently extract information from complex datasets. Data science and computational methods can be leveraged to better identify relationships between exposures to stressors in the environment and human disease outcomes, representing critical information needed to protect and improve global public health. Still, there remains a critical gap surrounding the training of researchers on these methods.

Dug: a semantic search engine leveraging peer-reviewed knowledge to query biomedical data repositories.

Motivation: As the number of public data resources continues to proliferate, identifying relevant datasets across heterogenous repositories is becoming critical to answering scientific questions. To help researchers navigate this data landscape, we developed Dug: a semantic search tool for biomedical datasets utilizing evidence-based relationships from curated knowledge graphs to find relevant datasets and explain why those results are returned.

Results: Developed through the National Heart, Lung and Blood Institute's (NHLBI) BioData Catalyst ecosystem, Dug has indexed more than 15 911 study variables from public datasets.

The Data Use Ontology to streamline responsible access to human biomedical datasets.

Human biomedical datasets that are critical for research and clinical studies to benefit human health also often contain sensitive or potentially identifying information of individual participants. Thus, care must be taken when they are processed and made available to comply with ethical and regulatory frameworks and informed consent data conditions. To enable and streamline data access for these biomedical datasets, the Global Alliance for Genomics and Health (GA4GH) Data Use and Researcher Identities (DURI) work stream developed and approved the Data Use Ontology (DUO) standard.

Catalyzing Knowledge-Driven Discovery in Environmental Health Sciences through a Community-Driven Harmonized Language.

Harmonized language is critical for helping researchers to find data, collecting scientific data to facilitate comparison, and performing pooled and meta-analyses. Using standard terms to link data to knowledge systems facilitates knowledge-driven analysis, allows for the use of biomedical knowledge bases for scientific interpretation and hypothesis generation, and increasingly supports artificial intelligence (AI) and machine learning. Due to the breadth of environmental health sciences (EHS) research and the continuous evolution in scientific methods, the gaps in standard terminologies, vocabularies, ontologies, and related tools hamper the capabilities to address large-scale, complex EHS research questions that require the integration of disparate data and knowledge sources.

Identifying and Prioritizing Chemicals with Uncertain Burden of Exposure: Opportunities for Biomonitoring and Health-Related Research.

Background: The National Institutes of Health's Environmental influences on Child Health Outcomes (ECHO) initiative aims to understand the impact of environmental factors on childhood disease. Over 40,000 chemicals are approved for commercial use. The challenge is to prioritize chemicals for biomonitoring that may present health risk concerns.

Laying a Community-Based Foundation for Data-Driven Semantic Standards in Environmental Health Sciences.

Background: Despite increasing availability of environmental health science (EHS) data, development, and implementation of relevant semantic standards, such as ontologies or hierarchical vocabularies, has lagged. Consequently, integration and analysis of information needed to better model environmental influences on human health remains a significant challenge.

Objectives: We aimed to identify a committed community and mechanisms needed to develop EHS semantic standards that will advance understanding about the impacts of environmental exposures on human disease.

Workshop report: Identifying opportunities for global integration of toxicogenomics databases, 26-27 June 2013, Research Triangle Park, NC, USA.

A joint US-EU workshop on enhancing data sharing and exchange in toxicogenomics was held at the National Institute for Environmental Health Sciences. Currently, efficient reuse of data is hampered by problems related to public data availability, data quality, database interoperability (the ability to exchange information), standardization and sustainability. At the workshop, experts from universities and research institutes presented databases, studies, organizations and tools that attempt to deal with these problems.

Decision trees for evaluating skin and respiratory sensitizing potential of chemicals in accordance with European regulations.

Guidance for determining the sensitizing potential of chemicals is available in EC Regulation No. 1272/2008 Classification, Labeling, and Packaging of Substances; REACH guidance from the European Chemicals Agency; and the United Nations Globally Harmonized System (GHS). We created decision trees for evaluating potential skin and respiratory sensitizers.

Phosphorylation of STIM1 underlies suppression of store-operated calcium entry during mitosis.

Store-operated Ca(2+) entry (SOCE) and Ca(2+) release-activated Ca(2+) currents (I(crac)) are strongly suppressed during cell division, the only known physiological situation in which Ca(2+) store depletion is uncoupled from the activation of Ca(2+) influx [corrected]. We found that the endoplasmic reticulum (ER) Ca(2+) sensor STIM1 failed to rearrange into near-plasma membrane puncta in mitotic cells, a critical step in the SOCE-activation pathway. We also found that STIM1 from mitotic cells is recognized by the phospho-specific MPM-2 antibody, suggesting that STIM1 is phosphorylated during mitosis.

STIM1 is a calcium sensor specialized for digital signaling.

When cells are activated by calcium-mobilizing agonists at low, physiological concentrations, the resulting calcium signals generally take the form of repetitive regenerative discharges of stored calcium, termed calcium oscillations [1]. These intracellular calcium oscillations have long fascinated biologists as a mode of digitized intracellular signaling. Recent work has highlighted the role of calcium influx as an essential component of calcium oscillations [2].

Calcium influx mechanisms underlying calcium oscillations in rat hepatocytes.

Unlabelled: The process of capacitative or store-operated Ca(2+) entry has been extensively investigated, and recently two major molecular players in this process have been described. Stromal interacting molecule (STIM) 1 acts as a sensor for the level of Ca(2+) stored in the endoplasmic reticulum, and Orai proteins constitute pore-forming subunits of the store-operated channels. Store-operated Ca(2+) entry is readily demonstrated with protocols that provide extensive Ca(2+) store depletion; however, the role of store-operated entry with modest and more physiological cell stimuli is less certain.

Complex actions of 2-aminoethyldiphenyl borate on store-operated calcium entry.

Store-operated Ca2+ entry (SOCE) is likely the most common mode of regulated influx of Ca2+ into cells. However, only a limited number of pharmacological agents have been shown to modulate this process. 2-Aminoethyldiphenyl borate (2-APB) is a widely used experimental tool that activates and then inhibits SOCE and the underlying calcium release-activated Ca2+ current (I CRAC).

Calcium inhibition and calcium potentiation of Orai1, Orai2, and Orai3 calcium release-activated calcium channels.

The recent discoveries of Stim1 and Orai proteins have shed light on the molecular makeup of both the endoplasmic reticulum Ca(2+) sensor and the calcium release-activated calcium (CRAC) channel, respectively. In this study, we investigated the regulation of CRAC channel function by extracellular Ca(2+) for channels composed primarily of Orai1, Orai2, and Orai3, by co-expressing these proteins together with Stim1, as well as the endogenous channels in HEK293 cells. As reported previously, Orai1 or Orai2 resulted in a substantial increase in CRAC current (I(crac)), but Orai3 failed to produce any detectable Ca(2+)-selective currents.

Role of the store-operated calcium entry proteins Stim1 and Orai1 in muscarinic cholinergic receptor-stimulated calcium oscillations in human embryonic kidney cells.

We have investigated the nature of the Ca2+ entry supporting [Ca2+]i oscillations in human embryonic kidney (HEK293) cells by examining the roles of recently described store-operated Ca2+ entry proteins, Stim1 and Orai1. Knockdown of Stim1 by RNA interference (RNAi) reduced the frequency of [Ca2+]i oscillations in response to a low concentration of methacholine to the level seen in the absence of external Ca2+. However, knockdown of Stim1 did not block oscillations in canomical transient receptor potential 3 channel (TRPC3)-expressing cells and did not affect Ca2+ entry in response to arachidonic acid.

Large store-operated calcium selective currents due to co-expression of Orai1 or Orai2 with the intracellular calcium sensor, Stim1.

The molecular nature of store-operated Ca(2+)-selective channels has remained an enigma, due largely to the continued inability to convincingly demonstrate Ca(2+)-selective store-operated currents resulting from exogenous expression of known genes. Recent findings have implicated two proteins, Stim1 and Orai1, as having essential roles in store-operated Ca(2+) entry across the plasma membrane. However, transient overexpression of these proteins on their own results in little or no increase in store-operated entry.