Development and application of consensus in silico models for advancing high-throughput toxicological predictions

Computational toxicology models have been successfully implemented to prioritize and screen chemicals. There are numerous in silico (quantitative) structure–activity relationship ([Q]SAR) models for the prediction of a range of human-relevant toxicological endpoints, but for a given endpoint and chemical, not all predictions are identical due to differences in their training sets, algorithms, and methodology. This poses an issue for high-throughput screening of a large chemical inventory as it necessitates several models to cover diverse chemistries but will then generate data conflicts. To address this challenge, we developed a consensus modeling strategy to combine predictions obtained from different existing in silico (Q)SAR models into a single predictive value while also expanding chemical space coverage. This study developed consensus models for nine toxicological endpoints relating to estrogen receptor (ER) and androgen receptor (AR) interactions (i.e., binding, agonism, and antagonism) and genotoxicity (i.e., bacterial mutation, in vitro chromosomal aberration, and in vivo micronucleus). Consensus models were created by combining different (Q)SAR models using various weighting schemes. As a multi-objective optimization problem, there is no single best consensus model, and therefore, Pareto fronts were determined for each endpoint to identify the consensus models that optimize the multiple-criterion decisions simultaneously. Accordingly, this work presents sets of solutions for each endpoint that contain the optimal combination, regardless of the trade-off, with the results demonstrating that the consensus models improved both the predictive power and chemical space coverage. These solutions were further analyzed to find trends between the best consensus models and their components. Here, we demonstrate the development of a flexible and adaptable approach for in silico consensus modeling and its application across nine toxicological endpoints related to ER activity, AR activity, and genotoxicity. These consensus models are developed to be integrated into a larger multi-tier NAM-based framework to prioritize chemicals for further investigation and support the transition to a non-animal approach to risk assessment in Canada

Relative influences of human nutrient sources, the Pacific Ocean, and climate change on Salish Sea dissolved oxygen through 2070

The Department of Ecology and Pacific Northwest National Laboratory evaluated future dissolved oxygen scenarios within the Salish Sea using a circulation and water quality model of Puget Sound, the Strait of Georgia, and the Strait of Juan de Fuca. A recently published report summarizes relative contributions of human nutrient sources, the Pacific Ocean, and climate factors on dissolved oxygen both now and through 2070. Human nitrogen contributions from the U.S. and Canada to the Salish Sea have the greatest impacts on dissolved oxygen in portions of South and Central Puget Sound. Marine point sources cause greater impacts on oxygen than human influences on river inflows now and into the future. Most of the Salish Sea reflects a relatively low impact from human sources, although that will increase as loads increase. The Pacific Ocean strongly influences dissolved oxygen concentrations under both current and future conditions. If 50-year declining trends in North Pacific Ocean dissolved oxygen continue, Salish Sea dissolved oxygen would decline far more than from human nutrient loads. Climate change will alter the timing of freshwater flow reaching the Salish Sea, as provided by the University of Washington Climate Impacts Group. This would alter estuarine circulation patterns, potentially worsening impacts in some regions but lessening others. Future air temperature increases would further decrease dissolved oxygen, particularly in shallow inlets. This is the first assessment of how Salish Sea dissolved oxygen concentrations respond to population increases, ocean conditions, and climate change. Additional analyses are needed to link sediment-water interactions and increase scientific certainty

Tissue tropisms opt for transmissible reassortants during avian and swine influenza A virus co-infection in swine

Genetic reassortment between influenza A viruses (IAVs) facilitate emergence of pandemic strains, and swine are proposed as a “mixing vessel” for generating reassortants of avian and mammalian IAVs that could be of risk to mammals, including humans. However, how a transmissible reassortant emerges in swine are not well understood. Genomic analyses of 571 isolates recovered from nasal wash samples and respiratory tract tissues of a group of co-housed pigs (influenza-seronegative, avian H1N1 IAV–infected, and swine H3N2 IAV– infected pigs) identified 30 distinct genotypes of reassortants. Viruses recovered from lower respiratory tract tissues had the largest genomic diversity, and those recovered from turbinates and nasal wash fluids had the least. Reassortants from lower respiratory tracts had the largest variations in growth kinetics in respiratory tract epithelial cells, and the cold temperature in swine nasal cells seemed to select the type of reassortant viruses shed by the pigs. One reassortant in nasal wash samples was consistently identified in upper, middle, and lower respiratory tract tissues, and it was confirmed to be transmitted efficiently between pigs. Study findings suggest that, during mixed infections of avian and swine IAVs, genetic reassortments are likely to occur in the lower respiratory track, and tissue tropism is an important factor selecting for a transmissible reassortant

Modeling factors influencing the demand for emergency department services in ontario: a comparison of methods

<p>Abstract</p> <p>Background</p> <p>Emergency departments are medical treatment facilities, designed to provide episodic care to patients suffering from acute injuries and illnesses as well as patients who are experiencing sporadic flare-ups of underlying chronic medical conditions which require immediate attention. Supply and demand for emergency department services varies across geographic regions and time. Some persons do not rely on the service at all whereas; others use the service on repeated occasions. Issues regarding increased wait times for services and crowding illustrate the need to investigate which factors are associated with increased frequency of emergency department utilization. The evidence from this study can help inform policy makers on the appropriate mix of supply and demand targeted health care policies necessary to ensure that patients receive appropriate health care delivery in an efficient and cost-effective manner. The purpose of this report is to assess those factors resulting in increased demand for emergency department services in Ontario. We assess how utilization rates vary according to the severity of patient presentation in the emergency department. We are specifically interested in the impact that access to primary care physicians has on the demand for emergency department services. Additionally, we wish to investigate these trends using a series of novel regression models for count outcomes which have yet to be employed in the domain of emergency medical research.</p> <p>Methods</p> <p>Data regarding the frequency of emergency department visits for the respondents of Canadian Community Health Survey (CCHS) during our study interval (2003-2005) are obtained from the National Ambulatory Care Reporting System (NACRS). Patients' emergency department utilizations were linked with information from the Canadian Community Health Survey (CCHS) which provides individual level medical, socio-demographic, psychological and behavioral information for investigating predictors of increased emergency department utilization. Six different multiple regression models for count data were fitted to assess the influence of predictors on demand for emergency department services, including: Poisson, Negative Binomial, Zero-Inflated Poisson, Zero-Inflated Negative Binomial, Hurdle Poisson, and Hurdle Negative Binomial. Comparison of competing models was assessed by the Vuong test statistic.</p> <p>Results</p> <p>The CCHS cycle 2.1 respondents were a roughly equal mix of males (50.4%) and females (49.6%). The majority (86.2%) were young-middle aged adults between the ages of 20-64, living in predominantly urban environments (85.9%), with mid-high household incomes (92.2%) and well-educated, receiving at least a high-school diploma (84.1%). Many participants reported no chronic disease (51.9%), fell into a small number (0-5) of ambulatory diagnostic groups (62.3%), and perceived their health status as good/excellent (88.1%); however, were projected to have high Resource Utilization Band levels of health resource utilization (68.2%). These factors were largely stable for CCHS cycle 3.1 respondents. Factors influencing demand for emergency department services varied according to the severity of triage scores at initial presentation. For example, although a non-significant predictor of the odds of emergency department utilization in high severity cases, access to a primary care physician was a statistically significant predictor of the likelihood of emergency department utilization (OR: 0.69; 95% CI OR: 0.63-0.75) and the rate of emergency department utilization (RR: 0.57; 95% CI RR: 0.50-0.66) in low severity cases.</p> <p>Conclusion</p> <p>Using a theoretically appropriate hurdle negative binomial regression model this unique study illustrates that access to a primary care physician is an important predictor of both the odds and rate of emergency department utilization in Ontario. Restructuring primary care services, with aims of increasing access to undersupplied populations may result in decreased emergency department utilization rates by approximately 43% for low severity triage level cases.</p

Inflammatory Genital Infections Mitigate a Severe Genetic Bottleneck in Heterosexual Transmission of Subtype A and C HIV-1

The HIV-1 epidemic in sub-Saharan Africa is driven largely by heterosexual transmission of non-subtype B viruses, of which subtypes C and A are predominant. Previous studies of subtype B and subtype C transmission pairs have suggested that a single variant from the chronically infected partner can establish infection in their newly infected partner. However, in subtype A infected individuals from a sex worker cohort and subtype B individuals from STD clinics, infection was frequently established by multiple variants. This study examined over 1750 single-genome amplified viral sequences derived from epidemiologically linked subtype C and subtype A transmission pairs very early after infection. In 90% (18/20) of the pairs, HIV-1 infection is initiated by a single viral variant that is derived from the quasispecies of the transmitting partner. In addition, the virus initiating infection in individuals who were infected by someone other than their spouse was characterized to determine if genital infections mitigated the severe genetic bottleneck observed in a majority of epidemiologically linked heterosexual HIV-1 transmission events. In nearly 50% (3/7) of individuals infected by someone other than their spouse, multiple genetic variants from a single individual established infection. A statistically significant association was observed between infection by multiple genetic variants and an inflammatory genital infection in the newly infected individual. Thus, in the vast majority of HIV-1 transmission events in cohabiting heterosexual couples, a single genetic variant establishes infection. Nevertheless, this severe genetic bottleneck can be mitigated by the presence of inflammatory genital infections in the at risk partner, suggesting that this restriction on genetic diversity is imposed in large part by the mucosal barrier

Low-dose rectal inoculation of rhesus macaques by SIVsmE660 or SIVmac251 recapitulates human mucosal infection by HIV-1

We recently developed a novel strategy to identify transmitted HIV-1 genomes in acutely infected humans using single-genome amplification and a model of random virus evolution. Here, we used this approach to determine the molecular features of simian immunodeficiency virus (SIV) transmission in 18 experimentally infected Indian rhesus macaques. Animals were inoculated intrarectally (i.r.) or intravenously (i.v.) with stocks of SIVmac251 or SIVsmE660 that exhibited sequence diversity typical of early-chronic HIV-1 infection. 987 full-length SIV env sequences (median of 48 per animal) were determined from plasma virion RNA 1–5 wk after infection. i.r. inoculation was followed by productive infection by one or a few viruses (median 1; range 1–5) that diversified randomly with near starlike phylogeny and a Poisson distribution of mutations. Consensus viral sequences from ramp-up and peak viremia were identical to viruses found in the inocula or differed from them by only one or a few nucleotides, providing direct evidence that early plasma viral sequences coalesce to transmitted/founder viruses. i.v. infection was >2,000-fold more efficient than i.r. infection, and viruses transmitted by either route represented the full genetic spectra of the inocula. These findings identify key similarities in mucosal transmission and early diversification between SIV and HIV-1, and thus validate the SIV–macaque mucosal infection model for HIV-1 vaccine and microbicide research

Microplastic-Associated Biofilms: A Comparison of Freshwater and Marine Environments

Microplastics (<5 mm particles) occur within both engineered and natural freshwater ecosystems, including wastewater treatment plants, lakes, rivers, and estuaries. While a significant proportion of microplastic pollution is likely sequestered within freshwater environments, these habitats also constitute an important conduit of microscopic polymer particles to oceans worldwide. The quantity of aquatic microplastic waste is predicted to dramatically increase over the next decade, but the fate and biological implications of this pollution are still poorly understood. A growing body of research has aimed to characterize the formation, composition, and spatiotemporal distribution of microplastic-associated (“plastisphere”) microbial biofilms. Plastisphere microorganisms have been suggested to play significant roles in pathogen transfer, modulation of particle buoyancy, and biodegradation of plastic polymers and co-contaminants, yet investigation of these topics within freshwater environments is at a very early stage. Here, what is known about marine plastisphere assemblages is systematically compared with up-to-date findings from freshwater habitats. Through analysis of key differences and likely commonalities between environments, we discuss how an integrated view of these fields of research will enhance our knowledge of the complex behavior and ecological impacts of microplastic pollutants

Measurement of associated Z plus charm production in proton-proton collisions at root s=8TeV

A study of the associated production of a Z boson and a charm quark jet (Z + c), and a comparison to production with a b quark jet (Z + b), in pp collisions at a centre-of-mass energy of 8 TeV are presented. The analysis uses a data sample corresponding to an integrated luminosity of 19.7 fb(-1), collected with the CMS detector at the CERN LHC. The Z boson candidates are identified through their decays into pairs of electrons or muons. Jets originating from heavy flavour quarks are identified using semileptonic decays of c or b flavoured hadrons and hadronic decays of charm hadrons. The measurements are performed in the kinematic region with two leptons with pT(l) > 20 GeV, vertical bar eta(l)vertical bar 25 GeV and vertical bar eta(jet)vertical bar Z + c + X) B(Z -> l(+)l(-)) = 8.8 +/- 0.5 (stat)+/- 0.6 (syst) pb. The ratio of the Z+c and Z+b production cross sections is measured to be sigma(pp -> Z+c+X)/sigma (pp -> Z+b+X) = 2.0 +/- 0.2 (stat)+/- 0.2 (syst). The Z+c production cross section and the cross section ratio are also measured as a function of the transverse momentum of theZ boson and of the heavy flavour jet. The measurements are compared with theoretical predictions.Peer reviewe

Search for a singly produced third-generation scalar leptoquark decaying to a tau lepton and a bottom quark in proton-proton collisions at root s=13 TeV

A search is presented for a singly produced third-generation scalar leptoquark decaying to a tau lepton and a bottom quark. Associated production of a leptoquark and a tau lepton is considered, leading to a final state with a bottom quark and two tau leptons. The search uses proton-proton collision data at a center-of-mass energy of 13 TeV recorded with the CMS detector, corresponding to an integrated luminosity of 35.9 fb(-1). Upper limits are set at 95% confidence level on the production cross section of the third-generation scalar leptoquarks as a function of their mass. From a comparison of the results with the theoretical predictions, a third-generation scalar leptoquark decaying to a tau lepton and a bottom quark, assuming unit Yukawa coupling (lambda), is excluded for masses below 740 GeV. Limits are also set on lambda of the hypothesized leptoquark as a function of its mass. Above lambda = 1.4, this result provides the best upper limit on the mass of a third-generation scalar leptoquark decaying to a tau lepton and a bottom quark.Peer reviewe