Metal and metal oxide nanoparticles are among the most commonly used nanomaterials and their potential for adversely affecting environmental systems raises concern. Complex microbial consortia ...underlie environmental processes, and the potential toxicity of nanoparticles to microbial systems, and the consequent impacts on trophic balances, is particularly worrisome. The diverse array of metal and metal oxides, the different sizes and shapes that can be prepared and the variety of possible surface coatings complicate assessments of toxicity. Further muddling biocidal interpretations are the diversity of microbes and their intrinsic tolerances to stresses. Here, we review a range of studies focused on nanoparticle-microbial interactions in an effort to correlate the physical-chemical properties of engineered metal and metal oxide nanoparticles to their biological response. General conclusions regarding the parent material of the nanoparticle and the nanoparticle's size and shape on potential toxicity can be made. However, the surface coating of the material, which can be altered significantly by environmental conditions, can ameliorate or promote microbial toxicity. Understanding nanoparticle transformations and how the nanoparticle surface can be designed to control toxicity represents a key area for further study. Additionally, the vast array of microbial species and the structuring of these species within communities complicate extrapolations of nanoparticle toxicity in real world settings. Ultimately, to interpret the effect and eventual fate of engineered materials in the environment, an understanding of the relationship between nanoparticle properties and responses at the molecular, cellular and community levels will be essential.
Relating microbial responses to the chemical-physical properties of nanomaterials is essential to understanding the impact of nanomaterials on natural systems.
Maintenance of membrane function is essential and regulated at the genomic, transcriptional, and translational levels. Bacterial pathogens have a variety of mechanisms to adapt their membrane in ...response to transmission between environment vector, and human host. Using a well-characterized model of lipid A diversification (Francisella), we demonstrate temperature-regulated membrane remodeling directed by multiple alleles of the lipid A-modifying N- acyltransferase enzyme, LpxD. Structural analysis of the lipid A at environmental and host temperatures revealed that the LpxD1 enzyme added a 3-OH C18 acyl group at 37 °C (host), whereas the LpxD2 enzyme added a 3-OH C16 acyl group at 18 °C (environment). Mutational analysis of either of the individual Francisella IpxD genes altered outer membrane (OM) permeability, antimicrobial peptide, and antibiotic susceptibility, whereas only the IpxD1-null mutant was attenuated in mice and subsequently exhibited protection against a lethal WT challenge. Additionally, growth-temperature analysis revealed transcriptional control of the IpxD genes and posttranslational control of the LpxD1 and LpxD2 enzymatic activities. These results suggest a direct mechanism for LPS/lipid A-level modifications resulting in alterations of membrane fluidity, as well as integrity and may represent a general paradigm for bacterial membrane adaptation and virulence-state adaptation.
We profiled soybean and Arabidopsis methylomes from the globular stage through dormancy and germination to understand the role of methylation in seed formation. CHH methylation increases ...significantly during development throughout the entire seed, targets primarily transposable elements (TEs), is maintained during endoreduplication, and drops precipitously within the germinating seedling. By contrast, no significant global changes in CG- and CHG-context methylation occur during the same developmental period. An Arabidopsis ddcc mutant lacking CHH and CHG methylation does not affect seed development, germination, or major patterns of gene expression, implying that CHH and CHG methylation does not play a significant role in seed development or in regulating seed gene activity. By contrast, over 100 TEs are transcriptionally de-repressed in ddcc seeds, suggesting that the increase in CHH-context methylation may be a failsafe mechanism to reinforce transposon silencing. Many genes encoding important classes of seed proteins, such as storage proteins, oil biosynthesis enzymes, and transcription factors, reside in genomic regions devoid of methylation at any stage of seed development. Many other genes in these classes have similar methylation patterns, whether the genes are active or repressed. Our results suggest that methylation does not play a significant role in regulating large numbers of genes important for programming seed development in both soybean and Arabidopsis. We conclude that understanding the mechanisms controlling seed development will require determining how cis-regulatory elements and their cognate transcription factors are organized in genetic regulatory networks.
Targeting translation initiation is an emerging anti-neoplastic strategy that capitalizes on de-regulated upstream MAPK and PI3K-mTOR signaling pathways in cancers. A key regulator of translation ...that controls ribosome recruitment flux is eukaryotic initiation factor (eIF) 4F, a hetero-trimeric complex composed of the cap binding protein eIF4E, the scaffolding protein eIF4G, and the RNA helicase eIF4A. Small molecule inhibitors targeting eIF4F display promising anti-neoplastic activity in preclinical settings. Among these are some rocaglate family members that are well tolerated in vivo, deplete eIF4F of its eIF4A helicase subunit, have shown activity as single agents in several xenograft models, and can reverse acquired resistance to MAPK and PI3K-mTOR targeted therapies. Herein, we highlight the power of using genetic complementation approaches and CRISPR/Cas9-mediated editing for drug-target validation ex vivo and in vivo, linking the anti-tumor properties of rocaglates to eIF4A inhibition.
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•CRISPR/Cas9 gene editing is a powerful approach for in vivo drug-target validation•Rocaglates interact with eIF4A1 in vitro and in vivo•Anti-neoplastic activity of rocaglates is a consequence of eIF4A1 inhibition
Rocaglates are anti-neoplastic agents that are thought to inhibit the RNA helicase eIF4A, although alternative targets have also been proposed. Using a series of biochemical assays and CRISPR/Cas9 genome editing, Chu et al. provide genetic evidence that the anti-neoplastic activities of rocaglates are a consequence of eIF4A1 inhibition.
•Random forest model provides variable importance for predicting algal biomass.•Bayesian regression model was used to predict trophic state classes in US estuaries.•Bayesian updating provides ...framework to build on prior ecological knowledge.•Model places changes at one site into national-scale comparative context.
One of the goals of coastal ecological research is to describe, quantify and predict human effects on coastal ecosystems. Broad cross-systems assessments to classify ecosystem status or condition have been developed, but are not updated frequently, likely because a lot of information and effort is needed to implement them. Such assessments could be more useful if the probability of being in a class indicating status or condition could be predicted using widely available data and information, providing a useful way to interpret changes in underlying predictors by considering their expected impact on ecosystem condition. To illustrate a possible approach, we used chlorophyll-a as an indicator of condition, in place of the intended comprehensive condition assessment. We demonstrated a predictive approach starting with a random forest model to inform variable selection, then used a Bayesian multilevel ordered categorical regression to quantify a coastal trophic state index and predict system status. We initially fit the model using non-informative priors to water quality data (total nitrogen and phosphorus, dissolved inorganic nitrogen and phosphorus, secchi depth) from 2010 and a regional factor. We then updated the model using prior distributions based on posterior parameter distributions from the initial fit and data from 2015. The Bayesian model demonstrates an intuitive way to update a model or analysis with new data while retaining the benefit of prior knowledge and maintaining flexibility to consider new kinds of information. To illustrate how the model could be used, we applied our developed trophic state index and classification to a time series of water quality data from Boston Harbor, a coastal ecosystem that has undergone significant changes in nutrient inputs. The analysis shows how water quality status and trends in Boston Harbor can be understood in the comparative ecological context provided by data from estuaries around the continental US and illustrates how the analytical approach could be used as an interpretive tool by non-practitioners of Bayesian statistics as well as a framework for further model development and analysis.
The diversity of MTOR-regulated mRNA translation remains unresolved. Whereas ribosome-profiling suggested that MTOR almost exclusively stimulates translation of the TOP (terminal oligopyrimidine ...motif) and TOP-like mRNAs, polysome-profiling indicated that MTOR also modulates translation of mRNAs without the 5' TOP motif (non-TOP mRNAs). We demonstrate that in ribosome-profiling studies, detection of MTOR-dependent changes in non-TOP mRNA translation was obscured by low sensitivity and methodology biases. Transcription start site profiling using nano-cap analysis of gene expression (nanoCAGE) revealed that not only do many MTOR-sensitive mRNAs lack the 5' TOP motif but that 5' UTR features distinguish two functionally and translationally distinct subsets of MTOR-sensitive mRNAs: (1) mRNAs with short 5' UTRs enriched for mitochondrial functions, which require EIF4E but are less EIF4A1-sensitive; and (2) long 5' UTR mRNAs encoding proliferation- and survival-promoting proteins, which are both EIF4E- and EIF4A1-sensitive. Selective inhibition of translation of mRNAs harboring long 5' UTRs via EIF4A1 suppression leads to sustained expression of proteins involved in respiration but concomitant loss of those protecting mitochondrial structural integrity, resulting in apoptosis. Conversely, simultaneous suppression of translation of both long and short 5' UTR mRNAs by MTOR inhibitors results in metabolic dormancy and a predominantly cytostatic effect. Thus, 5' UTR features define different modes of MTOR-sensitive translation of functionally distinct subsets of mRNAs, which may explain the diverse impact of MTOR and EIF4A inhibitors on neoplastic cells.
Double skin facades are a popular research area but by no means a completed one. This review highlights the reasons why perhaps research topic popularity and flexibility does not always yield ...commercial results in industry. It is intended to be used as a tool for researchers to access a synopsis of double skin façade research as it currently stands in the 21st century and differentiates itself from other review articles by exploring the nexus of factors affecting ventilation and thermal performance and building integration of double skin façade systems. A sample of over 100 papers dated between 2000 and 2021 were selected through the identification, screening, and refinement stages of the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) method to organise the research into a systematic categorisation dependent on a range of parameters affecting double skin façade performance. This meta-analysis resulted in tabular summaries in each relevant section to provide an overview of the specific design factors affecting ventilation and thermal performance or building integration. Additionally, key trends in methodology, climate, and operation conditions were identified resulting in original graphical figures. The predominant closing remark of this review is that there is no singular definition, design or configuration of a double skin façade, there are multiple methodologies for assessing its performance as a heating, cooling, fresh air or energy generation technology and it is highly dependent on changing climate, geometry, building application and materials. As a result, there is presently no standardised way of assessing the viability of a double skin façade system from a technical, economic, and environmental perspective, and therefore could be the missing link between this popular research area, and greater real-world application in the global built environment.
•Synopsis of double skin façade research in the 21st century.•Key trends in methodology, climate, constructional parameters, and emerging topics.•Ventilation and thermal performance analysis of double skin facades.•Assessment of factors affecting building integration of double skin facades.•Systematic categorisation of factors affecting viability of double skin facades.
Increased use and improved methodology of carbonate clumped isotope thermometry has greatly enhanced our ability to interrogate a suite of Earth‐system processes. However, interlaboratory ...discrepancies in quantifying carbonate clumped isotope (Δ47) measurements persist, and their specific sources remain unclear. To address interlaboratory differences, we first provide consensus values from the clumped isotope community for four carbonate standards relative to heated and equilibrated gases with 1,819 individual analyses from 10 laboratories. Then we analyzed the four carbonate standards along with three additional standards, spanning a broad range of δ47 and Δ47 values, for a total of 5,329 analyses on 25 individual mass spectrometers from 22 different laboratories. Treating three of the materials as known standards and the other four as unknowns, we find that the use of carbonate reference materials is a robust method for standardization that yields interlaboratory discrepancies entirely consistent with intralaboratory analytical uncertainties. Carbonate reference materials, along with measurement and data processing practices described herein, provide the carbonate clumped isotope community with a robust approach to achieve interlaboratory agreement as we continue to use and improve this powerful geochemical tool. We propose that carbonate clumped isotope data normalized to the carbonate reference materials described in this publication should be reported as Δ47 (I‐CDES) values for Intercarb‐Carbon Dioxide Equilibrium Scale.
Key Points
The exclusive use of carbonate reference materials is a robust method for the standardization of clumped isotope measurements
Measurements using different acid temperatures, designs of preparation lines, and mass spectrometers are statistically indistinguishable
We propose new consensus values for a set of seven carbonate reference materials and updated guidelines to report clumped isotope measurements
Mammary-tissue-restricted cytochrome P450 4Z1 (CYP4Z1) has garnered interest for its potential role in breast cancer progression. CYP4Z1-dependent metabolism of arachidonic acid preferentially ...generates 14,15-epoxyeicosatrienoic acid (14,15-EET), a metabolite known to influence cellular proliferation, migration, and angiogenesis. In this study, we developed time-dependent inhibitors of CYP4Z1 designed as fatty acid mimetics linked to the bioactivatable pharmacophore, 1-aminobenzotriazole (ABT). The most potent analogue, 8-(1H-benzotriazol-1-yl)aminooctanoic acid (7), showed a 60-fold lower shifted-half-maximal inhibitory concentration (IC50) for CYP4Z1 compared to ABT, efficient mechanism-based inactivation of the enzyme evidenced by a K I = 2.2 μM and a k inact = 0.15 min–1, and a partition ratio of 14. Furthermore, 7 exhibited low off-target inhibition of other CYP isozymes. Finally, low micromolar concentrations of 7 inhibited 14,15-EET production in T47D breast cancer cells transfected with CYP4Z1. This first-generation, selective mechanism-based inhibitor (MBI) will be a useful molecular tool to probe the biochemical role of CYP4Z1 and its association with breast cancer.
Mindfulness Goes to Work Aikens, Kimberly A.; Astin, John; Pelletier, Kenneth R. ...
Journal of occupational and environmental medicine,
2014-July, Letnik:
56, Številka:
7
Journal Article
Recenzirano
OBJECTIVE:The objective of this study was to determine whether a mindfulness program, created for the workplace, was both practical and efficacious in decreasing employee stress while enhancing ...resiliency and well-being.
METHODS:Participants (89) recruited from The Dow Chemical Company were selected and randomly assigned to an online mindfulness intervention (n = 44) or wait-list control (n = 45). Participants completed the Perceived Stress Scale, the Five Facets of Mindfulness Questionnaire, the Connor-Davidson Resiliency Scale, and the Shirom Vigor Scale at pre- and postintervention and 6-month follow-up.
RESULTS:The results indicated that the mindfulness intervention group had significant decreases in perceived stress as well as increased mindfulness, resiliency, and vigor.
CONCLUSIONS:This online mindfulness intervention seems to be both practical and effective in decreasing employee stress, while improving resiliency, vigor, and work engagement, thereby enhancing overall employee well-being.
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