Low-energy Bluetooth for Detecting Real-world Penetrance of Bystander Naloxone Kits: A Pilot Study

Opioid overdose is a growing public health emergency in the United States. The antidote naloxone must be administered rapidly after opioid overdose to prevent death. Bystander or take-home naloxone programs distribute naloxone to opioid users and other community members to increase naloxone availability at the time of overdose. However, data describing the natural history of take- home naloxone in the hands of at-risk individuals is lacking. To understand patterns of naloxone uptake in at-risk users, we developed a smart naloxone kit that uses low-energy Bluetooth (BLE) to unobtrusively detect the transit of naloxone through a hospital campus. In this paper, we describe development of the smart naloxone kit and results from the first 10 participants in our pilot study

A Model-Based Analysis of GC-Biased Gene Conversion in the Human and Chimpanzee Genomes

GC-biased gene conversion (gBGC) is a recombination-associated process that favors the fixation of G/C alleles over A/T alleles. In mammals, gBGC is hypothesized to contribute to variation in GC content, rapidly evolving sequences, and the fixation of deleterious mutations, but its prevalence and general functional consequences remain poorly understood. gBGC is difficult to incorporate into models of molecular evolution and so far has primarily been studied using summary statistics from genomic comparisons. Here, we introduce a new probabilistic model that captures the joint effects of natural selection and gBGC on nucleotide substitution patterns, while allowing for correlations along the genome in these effects. We implemented our model in a computer program, called phastBias, that can accurately detect gBGC tracts about 1 kilobase or longer in simulated sequence alignments. When applied to real primate genome sequences, phastBias predicts gBGC tracts that cover roughly 0.3% of the human and chimpanzee genomes and account for 1.2% of human-chimpanzee nucleotide differences. These tracts fall in clusters, particularly in subtelomeric regions; they are enriched for recombination hotspots and fast-evolving sequences; and they display an ongoing fixation preference for G and C alleles. They are also significantly enriched for disease-associated polymorphisms, suggesting that they contribute to the fixation of deleterious alleles. The gBGC tracts provide a unique window into historical recombination processes along the human and chimpanzee lineages. They supply additional evidence of long-term conservation of megabase-scale recombination rates accompanied by rapid turnover of hotspots. Together, these findings shed new light on the evolutionary, functional, and disease implications of gBGC. The phastBias program and our predicted tracts are freely available. © 2013 Capra et al

Open Science principles for accelerating trait-based science across the Tree of Life.

Synthesizing trait observations and knowledge across the Tree of Life remains a grand challenge for biodiversity science. Species traits are widely used in ecological and evolutionary science, and new data and methods have proliferated rapidly. Yet accessing and integrating disparate data sources remains a considerable challenge, slowing progress toward a global synthesis to integrate trait data across organisms. Trait science needs a vision for achieving global integration across all organisms. Here, we outline how the adoption of key Open Science principles-open data, open source and open methods-is transforming trait science, increasing transparency, democratizing access and accelerating global synthesis. To enhance widespread adoption of these principles, we introduce the Open Traits Network (OTN), a global, decentralized community welcoming all researchers and institutions pursuing the collaborative goal of standardizing and integrating trait data across organisms. We demonstrate how adherence to Open Science principles is key to the OTN community and outline five activities that can accelerate the synthesis of trait data across the Tree of Life, thereby facilitating rapid advances to address scientific inquiries and environmental issues. Lessons learned along the path to a global synthesis of trait data will provide a framework for addressing similarly complex data science and informatics challenges

Factors influencing terrestriality in primates of the Americas and Madagascar

Among mammals, the order Primates is exceptional in having a high taxonomic richness in which the taxa are arboreal, semiterrestrial, or terrestrial. Although habitual terrestriality is pervasive among the apes and African and Asian monkeys (catarrhines), it is largely absent among monkeys of the Americas (platyrrhines), as well as galagos, lemurs, and lorises (strepsirrhines), which are mostly arboreal. Numerous ecological drivers and species-specific factors are suggested to set the conditions for an evolutionary shift from arboreality to terrestriality, and current environmental conditions may provide analogous scenarios to those transitional periods. Therefore, we investigated predominantly arboreal, diurnal primate genera from the Americas and Madagascar that lack fully terrestrial taxa, to determine whether ecological drivers (habitat canopy cover, predation risk, maximum temperature, precipitation, primate species richness, human population density, and distance to roads) or species-specific traits (body mass, group size, and degree of frugivory) associate with increased terrestriality. We collated 150,961 observation hours across 2,227 months from 47 species at 20 sites in Madagascar and 48 sites in the Americas. Multiple factors were associated with ground use in these otherwise arboreal species, including increased temperature, a decrease in canopy cover, a dietary shift away from frugivory, and larger group size. These factors mostly explain intraspecific differences in terrestriality. As humanity modifies habitats and causes climate change, our results suggest that species already inhabiting hot, sparsely canopied sites, and exhibiting more generalized diets, are more likely to shift toward greater ground use.Fil: Eppley, Timothy M.. San Diego Zoo Wildlife Alliance; Estados Unidos. Portland State University; Estados UnidosFil: Hoeks, Selwyn. Radboud Universiteit Nijmegen; Países BajosFil: Chapman, Colin A.. University of KwaZulu-Natal; Sudáfrica. Wilson Center; Estados Unidos. Northwest University; China. The George Washington University; Estados UnidosFil: Ganzhorn, Jörg U.. Universitat Hamburg; AlemaniaFil: Hall, Katie. Sedgwick County Zoo; Estados UnidosFil: Owen, Megan A.. San Diego Zoo Wildlife Alliance; Estados UnidosFil: Adams, Dara B.. Humboldt State University; Estados Unidos. Ohio State University; Estados UnidosFil: Allgas, Néstor. Asociación Neotropical Primate Conservation Perú; PerúFil: Amato, Katherine R.. Northwestern University; Estados UnidosFil: Andriamahaihavana, McAntonin. Université D'antananarivo; MadagascarFil: Aristizabal, John F.. Universidad Autónoma de Ciudad Juárez; México. Universidad de los Andes; ColombiaFil: Baden, Andrea L.. City University of New York; Estados Unidos. New York Consortium In Evolutionary Primatology; Estados UnidosFil: Balestri, Michela. Oxford Brookes University (oxford Brookes University);Fil: Barnett, Adrian A.. University Of Roehampton; Reino Unido. Universidade Federal de Pernambuco; BrasilFil: Bicca Marques, Júlio César. Pontificia Universidade Católica do Rio Grande do Sul; BrasilFil: Bowler, Mark. University Of Suffolk; Reino Unido. San Diego Zoo Wildlife Alliance; Estados UnidosFil: Boyle, Sarah A.. Rhodes College; Estados UnidosFil: Brown, Meredith. University of Calgary; CanadáFil: Caillaud, Damien. University of California at Davis; Estados UnidosFil: Calegaro Marques, Cláudia. Universidade Federal do Rio Grande do Sul; BrasilFil: Campbell, Christina J.. California State University Northridge (calif. State Univ. Northridge);Fil: Campera, Marco. Oxford Brookes University (oxford Brookes University);Fil: Campos, Fernando A.. University of Texas at San Antonio; Estados UnidosFil: Cardoso, Tatiane S.. Museu Paraense Emílio Goeldi; BrasilFil: Carretero Pinzón, Xyomara. Proyecto Zocay; ColombiaFil: Champion, Jane. University of Calgary; CanadáFil: Chaves, Óscar M.. Universidad de Costa Rica; Costa RicaFil: Chen Kraus, Chloe. University of Yale; Estados UnidosFil: Colquhoun, Ian C.. Western University; CanadáFil: Dean, Brittany. University of Calgary; CanadáFil: Kowalewski, Miguel Martin. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Nordeste. Centro de Ecología Aplicada del Litoral. Universidad Nacional del Nordeste. Centro de Ecología Aplicada del Litoral; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Museo Argentino de Ciencias Naturales "Bernardino Rivadavia". Estación Biológica de Usos Múltiples (Sede Corrientes); Argentin

Claudin 4 Is Differentially Expressed between Ovarian Cancer Subtypes and Plays a Role in Spheroid Formation

Claudin 4 is a cellular adhesion molecule that is frequently overexpressed in ovarian cancer and other epithelial cancers. In this study, we sought to determine whether the expression of claudin 4 is associated with outcome in ovarian cancer patients and may be involved in tumor progression. We examined claudin 4 expression in ovarian cancer tissues and cell lines, as well as by immunohistochemical staining of tissue microarrays (TMAs; n = 500), spheroids present in patients’ ascites, and spheroids formed in vitro. Claudin 4 was expressed in nearly 70% of the ovarian cancer tissues examined and was differentially expressed across ovarian cancer subtypes, with the lowest expression in clear cell subtype. No association was found between claudin 4 expression and disease-specific survival in any subtype. Claudin 4 expression was also observed in multicellular spheroids obtained from patients’ ascites. Using an in vitro spheroid formation assay, we found that NIH:OVCAR5 cells treated with shRNA against claudin 4 required a longer time to form compact spheroids compared to control NIH:OVCAR5 cells that expressed high levels of claudin 4. The inability of the NIH:OVCAR5 cells treated with claudin 4 shRNA to form compact spheroids was verified by FITC-dextran exclusion. These results demonstrate a role for claudin 4 and tight junctions in spheroid formation and integrity

ProteinHistorian: Tools for the Comparative Analysis of Eukaryote Protein Origin

The evolutionary history of a protein reflects the functional history of its ancestors. Recent phylogenetic studies identified distinct evolutionary signatures that characterize proteins involved in cancer, Mendelian disease, and different ontogenic stages. Despite the potential to yield insight into the cellular functions and interactions of proteins, such comparative phylogenetic analyses are rarely performed, because they require custom algorithms. We developed ProteinHistorian to make tools for performing analyses of protein origins widely available. Given a list of proteins of interest, ProteinHistorian estimates the phylogenetic age of each protein, quantifies enrichment for proteins of specific ages, and compares variation in protein age with other protein attributes. ProteinHistorian allows flexibility in the definition of protein age by including several algorithms for estimating ages from different databases of evolutionary relationships. We illustrate the use of ProteinHistorian with three example analyses. First, we demonstrate that proteins with high expression in human, compared to chimpanzee and rhesus macaque, are significantly younger than those with human-specific low expression. Next, we show that human proteins with annotated regulatory functions are significantly younger than proteins with catalytic functions. Finally, we compare protein length and age in many eukaryotic species and, as expected from previous studies, find a positive, though often weak, correlation between protein age and length. ProteinHistorian is available through a web server with an intuitive interface and as a set of command line tools; this allows biologists and bioinformaticians alike to integrate these approaches into their analysis pipelines. ProteinHistorian's modular, extensible design facilitates the integration of new datasets and algorithms. The ProteinHistorian web server, source code, and pre-computed ages for 32 eukaryotic genomes are freely available under the GNU public license at http://lighthouse.ucsf.edu/ProteinHistorian/

DNA Specificity Determinants Associate with Distinct Transcription Factor Functions

To elucidate how genomic sequences build transcriptional control networks, we need to understand the connection between DNA sequence and transcription factor binding and function. Binding predictions based solely on consensus predictions are limited, because a single factor can use degenerate sequence motifs and because related transcription factors often prefer identical sequences. The ETS family transcription factor, ETS1, exemplifies these challenges. Unexpected, redundant occupancy of ETS1 and other ETS proteins is observed at promoters of housekeeping genes in T cells due to common sequence preferences and the presence of strong consensus motifs. However, ETS1 exhibits a specific function in T cell activation; thus, unique transcriptional targets are predicted. To uncover the sequence motifs that mediate specific functions of ETS1, a genome-wide approach, chromatin immunoprecipitation coupled with high-throughput sequencing (ChIP-seq), identified both promoter and enhancer binding events in Jurkat T cells. A comparison with DNase I sensitivity both validated the dataset and also improved accuracy. Redundant occupancy of ETS1 with the ETS protein GABPA occurred primarily in promoters of housekeeping genes, whereas ETS1 specific occupancy occurred in the enhancers of T cell–specific genes. Two routes to ETS1 specificity were identified: an intrinsic preference of ETS1 for a variant of the ETS family consensus sequence and the presence of a composite sequence that can support cooperative binding with a RUNX transcription factor. Genome-wide occupancy of RUNX factors corroborated the importance of this partnership. Furthermore, genome-wide occupancy of co-activator CBP indicated tight co-localization with ETS1 at specific enhancers, but not redundant promoters. The distinct sequences associated with redundant versus specific ETS1 occupancy were predictive of promoter or enhancer location and the ontology of nearby genes. These findings demonstrate that diversity of DNA binding motifs may enable variable transcription factor function at different genomic sites

Ecosystem Resilience and Threshold Response in the Galápagos Coastal Zone

Background: The Intergovernmental Panel on Climate Change (IPCC) provides a conservative estimate on rates of sea-level rise of 3.8 mm yr⁻¹ at the end of the 21st century, which may have a detrimental effect on ecologically important mangrove ecosystems. Understanding factors influencing the long-term resilience of these communities is critical but poorly understood. We investigate ecological resilience in a coastal mangrove community from the Galápagos Islands over the last 2700 years using three research questions: What are the 'fast and slow' processes operating in the coastal zone? Is there evidence for a threshold response? How can the past inform us about the resilience of the modern system?Methodology/Principal Findings: Palaeoecological methods (AMS radiocarbon dating, stable carbon isotopes (δ13C)) were used to reconstruct sedimentation rates and ecological change over the past 2,700 years at Diablas lagoon, Isabela, Galápagos. Bulk geochemical analysis was also used to determine local environmental changes, and salinity was reconstructed using a diatom transfer function. Changes in relative sea level (RSL) were estimated using a glacio-isostatic adjustment model. Non-linear behaviour was observed in the Diablas mangrove ecosystem as it responded to increased salinities following exposure to tidal inundations. A negative feedback was observed which enabled the mangrove canopy to accrete vertically, but disturbances may have opened up the canopy and contributed to an erosion of resilience over time. A combination of drier climatic conditions and a slight fall in RSL then resulted in a threshold response, from a mangrove community to a microbial mat.Conclusions/Significance: Palaeoecological records can provide important information on the nature of non-linear behaviour by identifying thresholds within ecological systems, and in outlining responses to 'fast and slow' environmental change between alternative stable states. This study highlights the need to incorporate a long-term ecological perspective when designing strategies for maximizing coastal resilience.</p

Integrating Diverse Datasets Improves Developmental Enhancer Prediction

Gene-regulatory enhancers have been identified using various approaches, including evolutionary conservation, regulatory protein binding, chromatin modifications, and DNA sequence motifs. To integrate these different approaches, we developed EnhancerFinder, a two-step method for distinguishing developmental enhancers from the genomic background and then predicting their tissue specificity. EnhancerFinder uses a multiple kernel learning approach to integrate DNA sequence motifs, evolutionary patterns, and diverse functional genomics datasets from a variety of cell types. In contrast with prediction approaches that define enhancers based on histone marks or p300 sites from a single cell line, we trained EnhancerFinder on hundreds of experimentally verified human developmental enhancers from the VISTA Enhancer Browser. We comprehensively evaluated EnhancerFinder using cross validation and found that our integrative method improves the identification of enhancers over approaches that consider a single type of data, such as sequence motifs, evolutionary conservation, or the binding of enhancer-associated proteins. We find that VISTA enhancers active in embryonic heart are easier to identify than enhancers active in several other embryonic tissues, likely due to their uniquely high GC content. We applied EnhancerFinder to the entire human genome and predicted 84,301 developmental enhancers and their tissue specificity. These predictions provide specific functional annotations for large amounts of human non-coding DNA, and are significantly enriched near genes with annotated roles in their predicted tissues and lead SNPs from genome-wide association studies. We demonstrate the utility of EnhancerFinder predictions through in vivo validation of novel embryonic gene regulatory enhancers from three developmental transcription factor loci. Our genome-wide developmental enhancer predictions are freely available as a UCSC Genome Browser track, which we hope will enable researchers to further investigate questions in developmental biology. © 2014 Erwin et al