•Reductions in carbon footprint of concrete are discussed.•Extending service life by design for durability are discussed.•We discuss the processes required to make performance specifications work.
...There are many ways to reduce the carbon footprint of concrete including reduction in its portland cement clinker content by methods including: (a) optimization of total aggregate gradations, (b) use of water-reducing admixtures, (c) intergrinding clinker with limestone, and (d) use of supplementary cementing materials (SCMs). However, the most effective way to improve sustainability of concrete structures is by making them last longer through design for durability, and by minimization of construction defects. In almost every case, durable concretes will include all of the above listed aspects, but from a design approach, the emphasis needs to be on durability. Durability design includes more than the selection of concrete materials and mix proportions. It also requires that construction detailing, temperature control, adequate compaction, protection of fresh concrete, and curing be detailed in the specification and that inspection and testing be carried out to ensure that the specifications are being followed. The performance requirements need to be stated explicitly, and the objectives made clear. In addition to discussing various aspects of concrete durability, this contribution will discuss the merits of performance and objective-based specifications as well as the processes required to make them work.
Diclofenac is one of the most widely prescribed nonsteroidal anti-inflammatory drugs worldwide. It is frequently detected in surface waters; however, whether this pharmaceutical poses a risk to ...aquatic organisms is debated. Here we quantified the uptake of diclofenac by the fathead minnow (Pimephales promelas) following aqueous exposure (0.2–25.0 μg L–1) for 21 days, and evaluated the tissue and biomolecular responses in the kidney. Diclofenac accumulated in a concentration- and time-dependent manner in the plasma of exposed fish. The highest plasma concentration observed (for fish exposed to 25 μg L–1 diclofenac) was within the therapeutic range for humans. There was a strong positive correlation between exposure concentration and the number of developing nephrons observed in the posterior kidney. Diclofenac was not found to modulate the expression of genes in the kidney associated with its primary mode of action in mammals (prostaglandin-endoperoxide synthases) but modulated genes associated with kidney repair and regeneration. There were no significant adverse effects following 21 days exposure to concentrations typical of surface waters. The combination of diclofenac’s uptake potential, effects on kidney nephrons and relatively small safety margin for some surface waters may warrant a longer term chronic health effects analysis for diclofenac in fish.
The Drosophila melanogaster MD-RR strain contains an Rdl mutation (A301S) resulting in resistance to several insecticide classes viz. phenyl pyrazoles (e.g., fipronil), cyclodienes (e.g., dieldrin), ...and chlorinated aliphatic hydrocarbons (e.g., lindane). Fitness costs are commonly observed with resistant insect populations as side effects of the genetic change conferring the resistant phenotype. Because of fitness costs, reversion from the resistant to susceptible genotype and phenotype is common. However, the Rdl genotype in D. melanogaster appears to allow the flies to maintain the resistant genotype/phenotype without selective pressure and with minimal fitness costs. We provide evidence that compensation for the Rdl mutation influences the cholinergic system, where an increase in acetylcholinesterase gene expression and enzyme activity results in neurophysiological changes and cross resistance to a carbamate insecticide (propoxur oral resistance ratio (RR) of 63) and an organophosphate insecticide (dichlorvos oral RR of 7). Such cross resistance was not previously reported with the initial collection and testing of this strain. In addition to acetylcholinesterase, the Rdl mutation influences the expression of the muscarinic acetylcholine receptor subtype-B, resulting in resistance to non-selective muscarinic compounds (pilocarpine and atropine). Collectively, these results indicate that the Rdl mutation (A301S) at GABA-gated ionophore complex influences the physiology of the cholinergic system, leading to resistance to established insecticide classes. Additionally, this mutation may impact the effectiveness of insecticides targeting novel sites, like muscarinic receptors.
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•Several insecticide influence receptors/enzymes within the nervous system.•Target-site modification of neuronal receptors/enzymes impacts the function of this vital tissue.•Compensation for point mutations influences gene expression not directly related to the target.•Compensation impedes resistance management to established and yet-to-be developed insecticides.
The Rho GTPases Rac (Ras-related C3 botulinum toxin substrate) and Cdc42 (cell division control protein 42 homolog) regulate cell functions governing cancer malignancy, including cell polarity, ...migration, and cell-cycle progression. Accordingly, our recently developed Rac inhibitor EHop-016 (IC
, 1,100 nmol/L) inhibits cancer cell migration and viability and reduces tumor growth, metastasis, and angiogenesis
Herein, we describe MBQ-167, which inhibits Rac and Cdc42 with IC
values of 103 and 78 nmol/L, respectively, in metastatic breast cancer cells. Consequently, MBQ-167 significantly decreases Rac and Cdc42 downstream effector p21-activated kinase (PAK) signaling and the activity of STAT3, without affecting Rho, MAPK, or Akt activities. MBQ-167 also inhibits breast cancer cell migration, viability, and mammosphere formation. Moreover, MBQ-167 affects cancer cells that have undergone epithelial-to-mesenchymal transition by a loss of cell polarity and inhibition of cell surface actin-based extensions to ultimately result in detachment from the substratum. Prolonged incubation (120 hours) in MBQ-167 decreases metastatic cancer cell viability with a GI
of approximately 130 nmol/L, without affecting noncancer mammary epithelial cells. The loss in cancer cell viability is due to MBQ-167-mediated G
-M cell-cycle arrest and subsequent apoptosis, especially of the detached cells.
, MBQ-167 inhibits mammary tumor growth and metastasis in immunocompromised mice by approximately 90%. In conclusion, MBQ-167 is 10× more potent than other currently available Rac/Cdc42 inhibitors and has the potential to be developed as an anticancer drug, as well as a dual inhibitory probe for the study of Rac and Cdc42.
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The presence of endocrine disrupting chemicals (EDCs) in the environment has driven the development of screening and testing assays to both identify chemicals with hormonal activity and evaluate ...their potential to cause adverse effects. As the number of animals used for research and regulatory purposes rises, and set against a desire to reduce animal testing, there is increased emphasis on the development and application of
in vitro techniques to evaluate chemical risks to the environment. Induction of vitellogenin (VTG) in isolated fish liver cells has been used successfully to identify a wide range of EDCs, including both natural and synthetic oestrogens and a variety of other xenoestrogens. However, the vitellogenic response reported for hepatocytes in culture has been shown to vary widely, making comparisons between studies difficult. The work presented in this paper explored the variability of the vitellogenic response in primary cultures of common carp (
Cyprinus carpio) hepatocytes following exposure to the model oestrogenic compound, 17β-oestradiol (E2). As expected, variability in the vitellogenic response was observed, both in terms of the sensitivity and magnitude of VTG induction, for hepatocytes isolated from different fish. An apparent difference was observed in the response of isolated hepatocytes based on the sex of the donor fish; maximum levels of E2-stimulated VTG synthesis in hepatocytes derived from females appeared higher (1962
ng
mL
−1
±
487
n
=
9 compared with 1194
ng
mL
−1
±
223 for hepatocytes from males
n
=
9) and EC
50 values lower (1.61
±
0.4
μM E2 for females and 2.12
±
0.2
μM E2 for males). However, these differences were not statistically significant, likely in part due to the variation observed in the vitellogenic response. In particular, hepatocytes derived from female fish showed more variation than their male counterparts (the co-efficient of variation for females was 77% compared to 28% for males). Despite the variation observed in the vitellogenic response between different cultures, data from the different donor fish could be compared by standardising responses relative to the maximum VTG induction in each culture following exposure to E2. Adopting this approach in the future will allow for data from different hepatocyte cultures and from donor fish of different sexes, age and stage of maturity to be compared with greater consistency. Measurement of
vtg mRNA expression was relatively more sensitive to the oestrogenic effects of E2 exposure than measurement of VTG protein (the LOEC at the transcriptome level was 10-fold lower 0.01
μM E2 than at the protein level 0.1
μM E2) and changes in
vtg mRNA expression showed less variation between individual hepatocyte isolations. Measurement of
vtg mRNA in the hepatocyte culture system therefore may offer the most sensitive and consistent option for the screening of chemicals with oestrogenic activity in fish primary hepatocyte cultures.
Summary Background Research investigating which aspects of mental health service provision are most effective in prevention of suicide is scarce. We aimed to examine the uptake of key mental health ...service recommendations over time and to investigate the association between their implementation and suicide rates. Methods We did a descriptive, cross-sectional, and before-and-after analysis of national suicide data in England and Wales. We collected data for individuals who died by suicide between 1997 and 2006 who were in contact with mental health services in the 12 months before death. Data were obtained as part of the National Confidential Inquiry into Suicide and Homicide by People with Mental Illness. When denominator data were missing, we used information from the Mental Health Minimum Data Set. We compared suicide rates for services implementing most of the recommendations with those implementing fewer recommendations and examined rates before and after implementation. We stratified results for level of socioeconomic deprivation and size of service provider. Findings The average number of recommendations implemented increased from 0·3 per service in 1998 to 7·2 in 2006. Implementation of recommendations was associated with lower suicide rates in both cross-sectional and before-and-after analyses. The provision of 24 h crisis care was associated with the biggest fall in suicide rates: from 11·44 per 10 000 patient contacts per year (95% CI 11·12–11·77) before to 9·32 (8·99–9·67) after (p<0·0001). Local policies on patients with dual diagnosis (10·55; 10·23–10·89 before vs 9·61; 9·18–10·05 after, p=0·0007) and multidisciplinary review after suicide (11·59; 11·31–11·88 before vs 10·48; 10·13–10·84 after, p<0·0001) were also associated with falling rates. Services that did not implement recommendations had little reduction in suicide. The biggest falls in suicide seemed to be in services with the most deprived catchment areas (incidence rate ratio 0·90; 95% CI 0·88–0·92) and the most patients (0·86; 0·84–0·88). Interpretation Our findings suggest that aspects of provision of mental health services can affect suicide rates in clinical populations. Investigation of the relation between new initiatives and suicide could help to inform future suicide prevention efforts and improve safety for patients receiving mental health care. Funding National Patient Safety Agency, UK.
Physiologically stable multimodality imaging probes for positron emission tomography/single-photon emission computed tomography (PET/SPECT)-magnetic resonance imaging (MRI) were synthesized using the ...superparamagnetic maghemite iron oxide (γ-Fe
O
) nanoparticles (SPIONs). The SPIONs were sterically stabilized with a finely tuned mixture of diblock copolymers with either methoxypolyethylene glycol (MPEG) or primary amine NH
end groups. The radioisotope for PET or SPECT imaging was incorporated with the SPIONs at high temperature.
Co
ions with a long half-life of 270.9 days were used as a model for the radiotracer to study the kinetics of radiolabeling, characterization, and the stability of the radiolabeled SPIONs. Radioactive
Ga
and Cu
-labeled SPIONs were also produced successfully using the optimized conditions from the
Co
-labeling process. No free radioisotopes were detected in the aqueous phase for the radiolabeled SPIONs 1 week after dispersion in phosphate-buffered saline (PBS). All labeled SPIONs were not only well dispersed and stable under physiological conditions but also noncytotoxic in vitro. The ability to design and produce physiologically stable radiolabeled magnetic nanoparticles with a finely controlled number of functionalizable end groups on the SPIONs enables the generation of a desirable and biologically compatible multimodality PET/SPECT-MRI agent on a single T2 contrast MRI probe.
All decapod crustaceans are considered potentially susceptible to White Spot Syndrome Virus (WSSV) infection, but the degree of White Spot Disease (WSD) susceptibility varies widely between species. ...The European shore crab
can be infected with the virus for long periods of time without signs of disease. Given the high mortality rate of susceptible species, the differential susceptibility of these resistant hosts offers an opportunity to investigate mechanisms of disease resistance.
Here, the temporal transcriptional responses (mRNA and miRNA) of
following WSSV injection were analysed and compared to a previously published dataset for the highly WSSV susceptible
to identify key genes, processes and pathways contributing to increased WSD resistance.
We show that, in contrast to
, the transcriptional response during the first 2 days following WSSV injection in
is limited. During the later time points (7 days onwards), two groups of crabs were identified, a recalcitrant group where no replication of the virus occurred, and a group where significant viral replication occurred, with the transcriptional profiles of the latter group resembling those of WSSV-susceptible species. We identify key differences in the molecular responses of these groups to WSSV injection.
We propose that increased WSD resistance in
may result from impaired WSSV endocytosis due to the inhibition of internal vesicle budding by dynamin-1, and a delay in movement to the nucleus caused by the downregulation of cytoskeletal transcripts required for WSSV cytoskeleton docking, during early stages of the infection. This response allows resistant hosts greater time to fine-tune immune responses associated with miRNA expression, apoptosis and the melanisation cascade to defend against, and clear, invading WSSV. These findings suggest that the initial stages of infection are key to resistance to WSSV in the crab and highlight possible pathways that could be targeted in farmed crustacean to enhance resistance to WSD.
The Rho GTPase Rac regulates actin cytoskeleton reorganization to form cell surface extensions (lamellipodia) required for cell migration/invasion during cancer metastasis. Rac hyperactivation and ...overexpression are associated with aggressive cancers; thus, interference of the interaction of Rac with its direct upstream activators, guanine nucleotide exchange factors (GEFs), is a viable strategy for inhibiting Rac activity. We synthesized EHop-016, a novel inhibitor of Rac activity, based on the structure of the established Rac/Rac GEF inhibitor NSC23766. Herein, we demonstrate that EHop-016 inhibits Rac activity in the MDA-MB-435 metastatic cancer cells that overexpress Rac and exhibits high endogenous Rac activity. The IC50 of 1.1 μm for Rac inhibition by EHop-016 is ∼100-fold lower than for NSC23766. EHop-016 is specific for Rac1 and Rac3 at concentrations of ≤5 μm. At higher concentrations, EHop-016 inhibits the close homolog Cdc42. In MDA-MB-435 cells that demonstrate high active levels of the Rac GEF Vav2, EHop-016 inhibits the association of Vav2 with a nucleotide-free Rac1(G15A), which has a high affinity for activated GEFs. EHop-016 also inhibits the Rac activity of MDA-MB-231 metastatic breast cancer cells and reduces Rac-directed lamellipodia formation in both cell lines. EHop-016 decreases Rac downstream effects of PAK1 (p21-activated kinase 1) activity and directed migration of metastatic cancer cells. Moreover, at effective concentrations (<5 μm), EHop-016 does not affect the viability of transformed mammary epithelial cells (MCF-10A) and reduces viability of MDA-MB-435 cells by only 20%. Therefore, EHop-016 holds promise as a targeted therapeutic agent for the treatment of metastatic cancers with high Rac activity.
Background: Rac is a central regulator of cancer cell migration/invasion and metastasis.
Results: EHop-016 inhibits Rac activity with an IC50 of 1 μm. EHop-016 blocks Rac interaction with the Rac exchange factor Vav2, lamellipodia extension, and cell migration.
Conclusion: EHop-016 is an effective Rac inhibitor.
Significance: EHop-016 has potential as a metastasis therapeutic and for investigations of Rac-regulated cellular responses.
This article describes the nuclear data covariance analysis of an experimental design for a neutron energy-tuning assembly (ETA) created to shape a 14-MeV neutron point source to an objective ...spectrum. Underlying nuclear data uncertainties play a large role in the radiation transport and reaction rates for the range of responses to be expected from an experiment. The methodology leveraged the Standardized Computer Analysis for Licensing Evaluation (SCALE) Sampler module to determine the uncertainty in the neutron transport. The reaction uncertainty was perturbed with the International Reactor Dosimetry and Fusion File v.1.05 uncertainty, correlation matrix, and reaction cross section through multivariate normal distribution sampling to provide a final response metric. The resultant neutron fluence uncertainty for the ETA ranged from 2.7% to 6.2% in the energy range from 1.28 keV to 14.1 MeV, which contains 99.99% of the neutron fluence. The integrated uncertainties, including statistical and systematic nuclear data uncertainties, for the reaction products analyzed were 2.33% to 4.84% for most reactions, but 55Mn(n, γ), a less well-characterized reaction occurring in an energy domain with high flux uncertainty, was 19.7%. The mean of the reaction distributions was within 1.1% of the unperturbed nuclear data simulation. The experiment is planned for late 2019, where the predicted results will be compared against the experimental outcomes. The methodology presented can be utilized with alternate nuclear libraries in SCALE to develop uncertainty bounds and neutron flux spectra for many radiation-transport problems.
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