Concept: Mixture model
The ecological impacts of emerging pollutants such as pharmaceuticals are not well understood. The lack of experimental approaches for the identification of pollutant effects in realistic settings (that is, low doses, complex mixtures, and variable environmental conditions) supports the widespread perception that these effects are often unpredictable. To address this, we developed a novel screening method (GSA-QHTS) that couples the computational power of global sensitivity analysis (GSA) with the experimental efficiency of quantitative high-throughput screening (QHTS). We present a case study where GSA-QHTS allowed for the identification of the main pharmaceutical pollutants (and their interactions), driving biological effects of low-dose complex mixtures at the microbial population level. The QHTS experiments involved the integrated analysis of nearly 2700 observations from an array of 180 unique low-dose mixtures, representing the most complex and data-rich experimental mixture effect assessment of main pharmaceutical pollutants to date. An ecological scaling-up experiment confirmed that this subset of pollutants also affects typical freshwater microbial community assemblages. Contrary to our expectations and challenging established scientific opinion, the bioactivity of the mixtures was not predicted by the null mixture models, and the main drivers that were identified by GSA-QHTS were overlooked by the current effect assessment scheme. Our results suggest that current chemical effect assessment methods overlook a substantial number of ecologically dangerous chemical pollutants and introduce a new operational framework for their systematic identification.
A mixed halide perovskite of CH3NH3PbI3-xClx is synthesized via two-step sequential solution deposition by using a mixture of PbCl2 and PbI2 as the precursor to overcome the low solubility of pure PbCl2 with easy morphology control. 11.7% power conversion efficiency is achieved for the mesoscopic cell, much higher than the cell constructed via a spin-coating process.
The diffusion of New Psychoactive Substances (NPS) in the illicit drug market is a worldwide problem. The aim of the study is to describe the qualitative distribution of drugs of abuse in seized materials confiscated in the Italian territory over the last two years. Between 2013 and 2015 162 seizures of substances purchased through the Internet and confiscated by police authorities were analyzed: 35 seizures (22%) were crystals of 3-methylmethcathinone (3-MMC). Although 3-MMC is subject to the relevant legislation in Italy, it is not controlled in other countries such as the Netherlands, from which the shipments originated. 33 seizures (20%) were crystals of 4-methylethcathinone (4-MEC), 19 seizures (12%) were powders containing methylenedioxypyrovalerone (MDPV). N,N-diallyl-5-methoxytryptamine (5-MeO-DALT) was identified in 5 powders, whereas ethylphenidate in six and pyrrolidinophenones in fourteen seized powders: 6 α-PVP (alpha-pyrrolidinovalerophenone), 6 α-PHP (alpha-pyrrolidinohexiophenone) and 1 α-PVT (alpha-pyrrolidinopentiothiophenone). Other substances identified were cathinones such as pentedrone, methylone, buthylone, ethylone, methedrone, 3-CMC (3-chloromethcathinone), 3,4-dimethylmethcathinone (3,4-DMMC), flephedrone (4-fluoromethcathinone or 4-FMC), 2-FMC and 3-FMC (2- and 3-fluoromethcathinone), MPPP (4-methyl-alpha-pyrrolidinopropiophenone), bk-2C-B (2-amino-1-(4-bromo-2,5-dimethoxyphenyl)ethan-1-one). Other compounds were NM2AI (N-methyl-2-aminoindane), MPA (1-(thiophen-2-yl)-2-methylaminopropane), MTTA (mephtetramine), 4-APB and 6-APB (4- and 6- (2-aminopropyl)benzofuran), 2-fluoromethamphetamine, 1mCPP (1-meta-chlorophenylpiperazine) and diphenidine, detected for the first time in Europe. Only three seizures contained synthetic cannabinoids, consisting of herbal blends soaked in N-(1-adamantyl)-1-pentyl-1H-indazole-3-carboxamide (AKB48), or a mixture of 5-F-AKB48 and BB-22 (1-(cyclohexylmethyl)-8-quinolinyl ester-1H-indole-3-carboxylic acid). In some mixtures of drugs - such as granules - 4-MEC and pentedrone were detected, also with traces of diphenidine on one occasion. In other cases 5-MeO-DALT, ethylphenidate and caffeine were mixed together. In one batch, the mixture was flephedrone and methoxethamine, whereas in another one the sample contained methylone, ethylone, methedrone, 4-fluoroamphetamine, 5-MeO-DALT and 5MeO-MiPT (N-methyl-N-isopropyl-5-methoxytryptamine). In 9 seizures, tablets shipped together with NPS were also found to contain sildenafil. The analyses performed on these seizures showed the presence of a wide number of NPS within the Italian boundaries coming from abroad, therefore this study confirms the threat for the public health, especially when the content of NPS being sold is not reported on the label or misleading.
In this study, antimicrobial activities of ZnO of three different particle sizes, of citric acid (CA), and of mixtures of ZnO and CA were confirmed against Propionibacterium acnes.
The solubility of lignin in a mixture of γ-valerolactone (GVL) and water at different weight ratios was measured using the Hildebrand solubility parameters. Based on the molecular structure of lignin, its solubility parameter (δ-value) was calculated as 25.5 MPa(½) . The δ-value for aqueous GVL solvent increased from 23.1 MPa(½) for pure GVL to 45.6 MPa(½) for pure water. Therefore, the lignin solubility was predicted to increase with increasing GVL concentration in the aqueous mixture up to approximately 92-96 wt % of GVL. A ternary diagram describing the phase behavior of water-GVL-lignin mixtures at room temperature was constructed based on the experimental results. The three-component system exhibited a complex behavior with a liquid-liquid and solid-liquid-liquid phase split. The efficiency of the selected fractionation trials in a previous work was validated using the ternary solubility diagram. A promising recovery pathway and lignin isolation method were deduced from the results of this work.
Current limitations to on-demand drug manufacturing can be addressed by technologies that streamline manufacturing processes. Combining the production of two or more drugs into a single batch could not only be useful for research, clinical studies, and urgent therapies but also effective when combination therapies are needed or where resources are scarce. Here we propose strategies to concurrently produce multiple biologics from yeast in single batches by multiplexing strain development, cell culture, separation, and purification. We demonstrate proof-of-concept for three biologics co-production strategies: (i) inducible expression of multiple biologics and control over the ratio between biologic drugs produced together; (ii) consolidated bioprocessing; and (iii) co-expression and co-purification of a mixture of two monoclonal antibodies. We then use these basic strategies to produce drug mixtures as well as to separate drugs. These strategies offer a diverse array of options for on-demand, flexible, low-cost, and decentralized biomanufacturing applications without the need for specialized equipment.
In archival samples of European-ancestry subjects, light-eyed individuals have been found to consume more alcohol than dark-eyed individuals. No published population-based studies have directly tested the association between alcohol dependence (AD) and eye color. We hypothesized that light-eyed individuals have a higher prevalence of AD than dark-eyed individuals. A mixture model was used to select a homogeneous sample of 1,263 European-Americans and control for population stratification. After quality control, we conducted an association study using logistic regression, adjusting for confounders (age, sex, and genetic ancestry). We found evidence of association between AD and blue eye color (P = 0.0005 and odds ratio = 1.83 (1.31-2.57)), supporting light eye color as a risk factor relative to brown eye color. Network-based analyses revealed a statistically significant (P = 0.02) number of genetic interactions between eye color genes and AD-associated genes. We found evidence of linkage disequilibrium between an AD-associated GABA receptor gene cluster, GABRB3/GABRG3, and eye color genes, OCA2/HERC2, as well as between AD-associated GRM5 and pigmentation-associated TYR. Our population-phenotype, network, and linkage disequilibrium analyses support association between blue eye color and AD. Although we controlled for stratification we cannot exclude underlying occult stratification as a contributor to this observation. Although replication is needed, our findings suggest that eye pigmentation information may be useful in research on AD. Further characterization of this association may unravel new AD etiological factors. © 2015 Wiley Periodicals, Inc.
Group selection may be defined as selection caused by the differential extinction or proliferation of groups. The socially polymorphic spider Anelosimus studiosus exhibits a behavioural polymorphism in which females exhibit either a ‘docile’ or ‘aggressive’ behavioural phenotype. Natural colonies are composed of a mixture of related docile and aggressive individuals, and populations differ in colonies' characteristic docile:aggressive ratios. Using experimentally constructed colonies of known composition, here we demonstrate that population-level divergence in docile:aggressive ratios is driven by site-specific selection at the group level-certain ratios yield high survivorship at some sites but not others. Our data also indicate that colonies responded to the risk of extinction: perturbed colonies tended to adjust their composition over two generations to match the ratio characteristic of their native site, thus promoting their long-term survival in their natal habitat. However, colonies of displaced individuals continued to shift their compositions towards mixtures that would have promoted their survival had they remained at their home sites, regardless of their contemporary environment. Thus, the regulatory mechanisms that colonies use to adjust their composition appear to be locally adapted. Our data provide experimental evidence of group selection driving collective traits in wild populations.
Whether fungicide resistance management is optimised by spraying chemicals with different modes of action as a mixture (i.e. simultaneously) or in alternation (i.e. sequentially) has been studied by experimenters and modellers for decades. However results have been inconclusive. We use previously-parameterised and validated mathematical models of wheat septoria leaf blotch and grapevine powdery mildew to test which tactic provides better resistance management, using the total yield before resistance causes disease control to become economically-ineffective (“lifetime yield”) to measure effectiveness. We focus on tactics involving the combination of a low-risk and a high-risk fungicide, and the case in which resistance to the high-risk chemical is complete (i.e. in which there is no partial resistance). Lifetime yield is then optimised by spraying as much low-risk fungicide as is permitted, combined with slightly more high-risk fungicide than needed for acceptable initial disease control, applying these fungicides as a mixture. That mixture rather than alternation gives better performance is invariant to model parameterisation and structure, as well as the pathosystem in question. However if comparison focuses on other metrics, e.g. lifetime yield at full label dose, either mixture or alternation can be optimal. Our work shows how epidemiological principles can explain the evolution of fungicide resistance, and also highlights a theoretical framework to address the question of whether mixture or alternation provides better resistance management. It also demonstrates that precisely how spray tactics are compared must be given careful consideration.
Intraspecific variation in ploidy occurs in a wide range of species including pathogenic and nonpathogenic eukaryotes such as yeasts and oomycetes. Ploidy can be inferred indirectly - without measuring DNA content - from experiments using next-generation sequencing (NGS). We present nQuire, a statistical framework that distinguishes between diploids, triploids and tetraploids using NGS. The command-line tool models the distribution of base frequencies at variable sites using a Gaussian Mixture Model, and uses maximum likelihood to select the most plausible ploidy model. nQuire handles large genomes at high coverage efficiently and uses standard input file formats.