A Dual-Enzyme Amplification Loop for the Sensitive Biosensing of Endopeptidases.

A rapid and sensitive approach for the detection of endopeptidases via a new analyte-triggered mutual emancipation of linker-immobilized enzymes (AMELIE) mechanism has been developed and demonstrated using a matrix metallopeptidase, a collagenase, as the model endopeptidase analyte. AMELIE involves an autocatalytic loop created by a pair of selected enzymes immobilized on solid substrates via linkers with specific sites that can be proteolyzed by one another. These bound enzymes are spatially separated so that they cannot act upon their corresponding substrates until the introduction of the target endopeptidase analyte that can also cleave one of the linkers. This triggers the self-sustained loop of enzymatic activities to emancipate all the immobilized enzymes. In this proof of concept, signal transduction was achieved by a colorimetric horseradish peroxidase-tetramethylbenzidine (HRP-TMB-H2O2) reaction with HRP that are also being immobilized by one of the linkers. The pair of immobilized enzymes were collagenase and alginate lyase, and they were immobilized by an alginate linker and a short peptide chain containing the amino acid sequence of Leu-Gly-Pro-Ala for collagenase. A detection limit of 2.5 pg collagenase mL-1 with a wide linear range up to 4 orders of magnitude was achieved. The AMELIE biosensor can detect extracellular collagenase in the supernatant of various bacteria cultures, with a sensitivity as low as 103 cfu mL-1 of E. coli. AMELIE can readily be adapted to provide the sensitive detection of other endopeptidases.

Portable molecularly imprinted polymer-based platform for detection of histamine in aqueous solutions.

Histamine, which is a naturally occurring chemical in seafood, is known to cause undesirable inflammatory response when consumed in large amounts. Histamine is produced in unsafe amounts in colored seafood when improperly stored for just a few hours. Food and health regulatory bodies across the world have guidelines limiting the amount of histamine in fresh as well as processed seafood. Conventional histamine detection is performed in testing labs, which is a slow process and results in bottlenecks in the seafood supply-chain system. A system to rapidly detect the seafood histamine levels on site is very desirable for seafood suppliers. Herein, we describe an impedance-based histamine detection sensor built on a flexible substrate that can detect histamine in the range of 100-500 ppm. Moreover, our sensor discriminates histamine in the presence of DL-histidine and other biogenic amines, with the selectivity provided by molecular imprinting technology. As a proof of concept, a smartphone controlled, portable semi-quantitative histamine sensing device was fabricated that gave out reliable testing results for histamine in different test solutions as well as for real seafood. We believe this technology can be extended towards determination of other food contaminants in aqueous solutions.

Anaesthesia use in catheter ablation for atrial fibrillation: a systematic review and meta-analysis of observational studies.

OBJECTIVES: This meta-analysis and systematic review seeks to compare both characteristic parameters and procedural outcomes of atrial fibrillation (AF) catheter ablation in patients under general anaesthesia (GA)/deep sedation and mild/moderate sedation. BACKGROUND: Catheter ablation has become a widely applied intervention for treating symptomatic AF and arrhythmias that are refractory to medical therapy. It can be conducted through from mild sedation to GA. METHODS: PubMed and Embase were searched up to July 2018 for randomised controlled trials, cohort and observational studies that assessed the outcomes of catheter ablation under GA/deep sedation or mild/moderate sedation. Nine studies were included in this meta-analysis after screening with the inclusion and exclusion criteria. Heterogeneity between studies and publication bias was evaluated by I2 index and Egger's regression, respectively. RESULTS: Our meta-analysis found catheter AF ablation with GA/deep sedation to be associated with reduced risk of recurrence (RR: 0.79, 95% CI 0.56 to 1.13, p=0.20) and complications (RR: 0.95, 95% CI 0.64 to 1.42, p=0.82), though statistically insignificant. In terms of procedural parameters, there was no significant difference between the two groups for both procedural time (SMD: -0.13, 95% CI -0.90 to 0.63, p=0.74) and fluoroscopy time (SMD: -0.41, 95% CI -1.40 to 0.58, p=0.41). Univariate meta-regression did not reveal any covariates as a moderating factor for complication and recurrence risk. CONCLUSION: Apart from an increased likelihood of procedural success, ablation by GA/deep sedation was found to be non-significantly different from the mild/moderate sedation approach in both procedural parameters and outcome measures.

Toxicities of Irgarol 1051 derivatives, M2 and M3, to two marine diatom species.

Irgarol 1051 is highly toxic to marine autotrophs and has been widely used as an antifouling booster biocide. This study tested the toxicities of two s-triazine derivatives of Irgarol, namely M2 (3-[4-tert-butylamino-6-methylthiol-s-triazin-2-ylamino]propionaldehyde) and M3 (2-methylthio-4,6-bis-tert-butylamino-s-triazine) to two marine diatom species, Skeletonema costatum and Thalassiosira pseudonana through standard acute (96h) and chronic (7d) growth inhibition tests. Results showed that both of the two chemicals significantly inhibited the growth of S. costatum (M2: 96h-EC50 = 6789.7 µg L-1, 7d-EC50 = 3503.7 µg L-1; M3: 96h-EC50 = 45193.9 µg L-1, 7d-EC50 = 5330.0 µg L-1) and T. pseudonana (M2: 96h-EC50 = 366.2 µg L-1, 7d-EC50 = 312.5 µg L-1; M3: 96h-EC50 = 2633.4 µg L-1, 7d-EC50 = 710.5 µg L-1), while their toxicity effects were much milder than Irgarol and its major degradation product M1. By comparing with previous findings, the susceptibilities of these s-triazine compounds to two tested species were ranked as: Irgarol > M1 ≫ M2 > M3. This study promotes future research efforts on better understanding of the ecotoxicities of M2 and M3, and incorporating such information to improve the current monitoring, risk assessment and regulation of the use of Irgarol.

Toxicities of the degraded mixture of Irgarol 1051 to marine organisms.

Antifoulant Irgarol 1051 (2-methythiol-4-tert-butylamino-6-cyclopropylamino-s-triazine) can be photodegraded into M1 (2-methylthio-4-tert-butylamino-6-amino-s-triazine) and M2 (3-4-tert-butylamino-6-methylthiol-s-triazin-2-ylamino]propion-aldehyde). M3 (2-methylthio-4,6-bis-tert-butylamino-s-triazine) was also detected as a side-product in Irgarol. This study aimed to investigate the combined toxicity of a mixture of these s-triazine compounds to eight marine organisms. A degraded mixture of Irgarol in artificial seawater was obtained by photolysis over 42 d and its composition was quantified by HPLC-UV analyses. Based on short-term toxicity tests on eight selected marine species, the mixture posed significant phytotoxic effects to the cyanobacteria (Chroococcus minor and Synechococcus sp.), the diatoms (Skeletonema costatum and Thalassiosira pseudonana), the macroalgae (Ulva lactuca and Caulerpa peltata) and the dinoflagellate (Prorocentrum dentatum), though the mixture was less toxic to the copepod Tigriopus japonicus. Both Independent Action and Concentration Addition models can generate reasonably satisfactory predictions on the overall mixture toxicity to the two diatoms, implying that the four compounds likely share a similar mode of action and resemble an additive effect in the mixture.

Dual-Gated Transistor Platform for On-Site Detection of Lead Ions at Trace Levels.

On-site monitoring of heavy metals in drinking water has become crucial because of several high profile instances of contamination. Presently, reliable techniques for trace level heavy metal detection are mostly laboratory based, while the detection limits of contemporary field-based methods are barely meeting the exposure limits set by regulatory bodies such as the World Health Organization (WHO). Here, we show an on-site deployable, Pb2+ sensor on a dual-gated transistor platform whose lower detection limit is 2 orders of magnitude better than the traditional sensor and 1 order of magnitude lower than the exposure limit set by WHO. The enhanced sensitivity of our design is verified by numerically solving PNP (Planck-Nernst-Poisson) model. We demonstrate that the enhanced sensitivity is due to the suppression of ionic flux. The simplicity and the robustness of the design make it applicable for on-site screening, thereby facilitating rapid response to contamination events.

A Brain Penetrant Mutant IDH1 Inhibitor Provides In Vivo Survival Benefit.

Mutations in IDH1 are highly prevalent in human glioma. First line treatment is radiotherapy, which many patients often forego to avoid treatment-associated morbidities. The high prevalence of IDH1 mutations in glioma highlights the need for brain-penetrant IDH1 mutant-selective inhibitors as an alternative therapeutic option. Here, we have explored the utility of such an inhibitor in IDH1 mutant patient-derived models to assess the potential therapeutic benefits associated with intracranial 2-HG inhibition. Treatment of mutant IDH1 cell line models led to a decrease in intracellular 2-HG levels both in vitro and in vivo. Interestingly, inhibition of 2-HG production had no effect on in vitro IDH1 mutant glioma cell proliferation. In contrast, IDH1 mutant-selective inhibitors provided considerable survival benefit in vivo. However, even with near complete inhibition of intratumoral 2-HG production, not all mutant glioma models responded to treatment. The results suggest that disruption of 2-HG production with brain-penetrant inhibitors in IDH1 mutant gliomas may have substantial patient benefit.

Glucuronide and Sulfate Conjugates of Bisphenol A: Chemical Synthesis and Correlation Between Their Urinary Levels and Plasma Bisphenol A Content in Voluntary Human Donors.

Bisphenol A (BPA) glucuronide and sulfate conjugates are major products of Phase II metabolism of BPA in humans. In the past, their determination in body fluids usually involves tedious enzymatic hydrolysis and multiresidual analysis. The recent availability of authentic standards of these conjugates enables our better understand of the human metabolism of BPA and the distribution of their metabolites in body fluids. In this work, we report the chemical synthesis and purification of BPA mono- and di-glucuronide and BPA mono- and di-sulfate. Their levels, as well as that of BPA, in 140 paired human plasma and urine samples collected randomly from voluntary donors in Hong Kong SAR, China, were determined by solid-phase extraction and liquid chromatography-tandem mass spectrometry (LC-MS/MS). BPA was found in more than 135 human plasma and urine samples. Its Phase II metabolites, ranging from N.D. to 36.7 µg g-1-creatinine, also were detected in 139 of the 140 urine samples. Good correlation (r = 0.911) between molar concentration of BPA in the plasma and that of "total urinary BPA" (i.e., ln [(BPA + ∑ BPA phase II conjugate)molar concentration]) was observed. Direct quantification of Phase II metabolites of BPA in human urine can be a useful assessment tool for population exposure to this potent endocrine disrupting chemical.

Uptake and biotransformation of 2,2',4,4'-tetrabromodiphenyl ether (BDE-47) in four marine microalgae species.

Hydroxylated- and methoxylated- polybrominated diphenyl ethers (OH-PBDEs and MeO-PBDEs) are more toxic than PBDEs and occur widely in the marine environment, and yet their origins remain controversial. In this study, four species of microalgae (Isochrysis galbana, Prorocentrum minimum, Skeletonema grethae and Thalassiosira pseudonana) were exposed to BDE-47, which is synthetic and is the predominant congener of PBDEs in the environment. By chemical analysis after incubation of 2 to 6 days, the efficiency of uptake of BDE-47 and, more importantly, the potential of undergoing biotransformation to form OH-PBDEs and MeO-PBDEs by the microalgae were investigated. Growth rates of these axenic microalgae were not affected upon exposure to environmentally relevant concentrations (0.2-20 µg BDE-47 L-1), and accumulation ranged from 0.772 ± 0.092 µg BDE-47 g-1 lipid to 215 ± 54 µg BDE-47 g-1 lipid within 2 days. Debromination of BDE-47 and formation of BDE-28 occurred in all microalgae species (0.01 to 0.87%), but biotransformation to OH-PBDEs was only found in I. galbana upon exposure to extremely high concentration. The results of this study showed that biotransformation of microalgae species is unlikely an explanation for the OH-PBDEs and MeO-PBDEs found in the marine environment.

Glucuronide and sulfate conjugates of tetrabromobisphenol A (TBBPA): Chemical synthesis and correlation between their urinary levels and plasma TBBPA content in voluntary human donors.

3,3',5,5'-Tetrabromobisphenol-A (TBBPA) is an important brominated flame retardant in epoxy, vinyl esters and polycarbonate resins. Previous studies have already shown the occurrence of its Phase II metabolites, TBBPA-glucuronide and sulfate conjugates, in human urine, after oral administration of TBBPA. The main objective of this work is to examine correlations among level of TBBPA in human blood and those of its Phase II metabolites in human urine. Four water-soluble TBBPA conjugates were synthesized, purified and characterized. An analytical protocol using solid-phase extraction and liquid chromatography-electrospray tandem mass spectrometry (SPE-LC-MS/MS) quantification was developed for the simultaneous analysis of these glucuronide and sulfate conjugates in human urine samples. TBBPA and its Phase II metabolites in paired human plasma and urine samples collected randomly from 140 voluntary donors in Hong Kong SAR, China, were determined. One or more TBBPA conjugates were detected in all of the urine samples, with concentration ranging from 0.19 to 127.24µgg-1-creatinine. TBBPA was also quantified in >85% of the plasma and urine samples. Strong correlations were observed between TBBPA content in plasma and the total amount of TBBPA-related compounds in urine.

A Photo-Triggered Traceless Staudinger-Bertozzi Ligation Reaction.

The use of light to control the course of a chemical/biochemical reaction is an attractive idea because of its ease of administration with high precision and fine spatial resolution. Staudinger ligation is one of the commonly adopted conjugation processes that involve a spontaneous reaction between azides and arylphosphines to form iminophosphoranes, which further hydrolyze to give stable amides. We designed an anthracenylmethyl diphenylphosphinothioester (1) that showed promising Staudinger ligation reactivity upon photo-excitation. Broadband photolysis at 360-400 nm in aqueous organic solvents induced heterolytic cleavage of its anthracenylmethyl-phosphorus bond, releasing a diphenylphosphinothioester (2) as an efficient traceless Staudinger-Bertozzi ligation reagent. The quantum yield of such a photo-induced heterolytic bond-cleavage at the optimal wavelength of photolysis (376 nm) at room temperature is ≥0.07. This work demonstrated the feasibility of photocaging arylphosphines to realize the photo-triggering of the Staudinger ligation reaction.

The effects of bupropion on hybrid striped bass brain chemistry and predatory behavior.

Increased use of antidepressants has led to an increase in their detection in final treated wastewater effluents and receiving streams. Antidepressants are intended to modify human behavior by altering brain chemistry, and because of the high functional conservation of antidepressant target receptors in vertebrates, aquatic organisms may be at risk. The antidepressant bupropion is designed to alter brain norepinephrine and dopamine concentrations in humans. The objective of the present study was to understand if alteration of dopaminergic neurotransmitter concentrations in the hybrid striped bass (Morone saxatilis × Morone chrysops) brain by bupropion would alter this predator's ability to capture prey. The authors exposed hybrid striped bass to bupropion in a static system for 6 d, followed by a 6-d recovery period. During the present study's 12-d experiment, each hybrid striped bass was fed 4 unexposed fathead minnows every 3 d, and the time it took the hybrid striped bass to consume each of those 4 fathead minnows was quantified. After each feeding event, hybrid striped bass brains were harvested and analyzed for changes in several brain neurotransmitter concentrations, including serotonin, norepinephrine, dopamine, and many of their metabolites. Although bupropion altered the concentration of dopamine and many of the dopaminergic neurotransmitter metabolite concentrations in the brains on day 3 of the exposure, it did not alter the time to capture prey. This suggests that alteration of dopaminergic neurotransmitter concentrations in the hybrid striped bass brain does not alter a predator's ability to capture prey. Environ Toxicol Chem 2016;35:2058-2065. © 2016 SETAC.

Organobromine compound profiling in human adipose: Assessment of sources of bromophenol.

Bromophenols (BRPs) have been widely detected in human tissues, however, relative proportions from natural products and/or anthropogenic flame retardants are not clear. 21 polybrominated diphenyl ethers (PBDEs), 15 MeO/OH-PBDEs, and 10 BRPs were simultaneously quantified in adipose collected from people from New York City, USA. An in vitro assay utilizing human liver microsomes was performed for detected predominant organobromine. High concentrations of 2,4,6-triBRP and PBDEs were observed, and extremely low concentrations of naturally occurring MeO/OH-PBDEs were detected. Similar biotransformatioin rates of BRPs and MeO/OH-PBDEs indicated that the relative high concentration of 2,4,6-triBRP in humans was not of natural origin. Significant correlation observed between concentrations of 2,4,6-triBRP and BDE-209 suggested that the two chemicals may share a common source. Both 2,4,6-triBRP and BDE-209 were detected in commercial ABS resins, suggesting that plastic products made from ABS resins could be potential sources of co-exposure of the two compounds for humans.

Urinary bromophenol glucuronide and sulfate conjugates: Potential human exposure molecular markers for polybrominated diphenyl ethers.

One possible source of urinary bromophenol (BP) glucuronide and sulfate conjugates in mammalian animal models and humans is polybromodiphenyl ethers (PBDEs), a group of additive flame-retardants found ubiquitously in the environment. In order to study the correlation between levels of PBDEs in human blood plasma and those of the corresponding BP-conjugates in human urine, concentrations of 17 BDE congeners, 22 OH-BDE and 13 MeO-BDE metabolites, and 3 BPs in plasma collected from 100 voluntary donors in Hong Kong were measured by gas chromatograph tandem mass spectrometry (GC-MS). Geometric mean concentration of ΣPBDEs, ΣOH-BDEs, ΣMeO-BDEs and ΣBPs in human plasma were 4.45 ng g(-1) lw, 1.88 ng g(-1) lw, 0.42 ng g(-1) lw and 1.59 ng g(-1) lw respectively. Concentrations of glucuronide and sulfate conjugates of 2,4-dibromophenol (2,4-DBP) and 2,4,6-tribromophenol (2,4,6-TBP) in paired samples of urine were determined by liquid chromatography tandem triple quadrupole mass spectrometry (LC-MS/MS). BP-conjugates were found in all of the parallel urine samples, in the range of 0.08-106.49 µg g(-1)-creatinine. Correlations among plasma concentrations of ΣPBDEs/ΣOH-BDEs/ΣMeO-BDEs/ΣBPs and BP-conjugates in urine were evaluated by multivariate regression and Pearson product correlation analyses. These urinary BP-conjugates were positively correlated with ΣPBDEs in blood plasma, but were either not or negatively correlated with other organobromine compounds in blood plasma. Stronger correlations (Pearson's r as great as 0.881) were observed between concentrations of BDE congeners having the same number and pattern of bromine substitution on their phenyl rings in blood plasma and their corresponding BP-conjugates in urine.

Biomarker-driven phase 2 study of MK-2206 and selumetinib (AZD6244, ARRY-142886) in patients with colorectal cancer.

PURPOSE: PI3K/AKT/mTOR and RAS/RAF/MEK pathways are frequently dysregulated in colorectal cancer (CRC). We conducted a biomarker-driven trial of the combination of MK-2206, an allosteric AKT 1/2/3 inhibitor, and selumetinib, a MEK 1/2 inhibitor, in patients with CRC to evaluate inhibition of phosphorylated ERK (pERK) and AKT (pAKT) in paired tumor biopsies. PATIENTS AND METHODS: Adult patients with advanced CRC were enrolled in successive cohorts stratified by KRAS mutation status. Initially, 12 patients received oral MK-2206 90 mg weekly with oral selumetinib 75 mg daily in 28-day cycles. Following an interim analysis, the doses of MK-2206 and selumetinib were increased to 135 mg weekly and 100 mg daily, respectively. Paired tumor biopsies were evaluated for target modulation. RESULTS: Common toxicities were gastrointestinal, hepatic, dermatologic, and hematologic. Of 21 patients enrolled, there were no objective responses. Target modulation did not achieve the pre-specified criteria of dual 70 % inhibition of pERK and pAKT levels in paired tumor biopsies. CONCLUSION: Despite strong scientific rationale and preclinical data, clinical activity was not observed. The desired level of target inhibition was not achieved. Overlapping toxicities limited the ability to dose escalate to achieve exposures likely needed for clinical activity, highlighting the challenges in developing optimal combinations of targeted agents.

Maternal transfer, distribution, and metabolism of BDE-47 and its related hydroxylated, methoxylated analogs in zebrafish (Danio rerio).

OH-PBDEs have been reported to be more potent than the postulated precursor PBDEs or corresponding MeO-PBDEs. However, there are contradictory reports for transformation of these compounds in organisms, particularly, for biotransformation of OH-PBDEs and MeO-PBDEs, only one study reported transformation of 6-OH-BDE-47 and 6-MeO-BDE-47 in Japanese medaka. In present study zebrafish (Danio rerio) were exposed to BDE-47, 6-OH-BDE-47, 6-MeO-BDE-47, 2'-OH-BDE-28 and 2'-MeO-BDE-28 in the diet for 20 d. Concentrations of each exposed compound were measured in eggs collected on days 0, 5, 10, 15 or 20. After 20 d exposure, concentrations of precursor and biotransformation products in liver and liver-free residual carcass were measured by use of GC-MS/MS. Total mass of the five compounds in bodies of adults were: 2'-MeO-BDE-28 ∼ 6-MeO-BDE-47>BDE-47>2'-OH-BDE-28>6-OH-BDE-47. MeO-PBDEs were also accumulated more into parental fish body than in liver, while OH-PBDEs accumulated in liver more than in liver-free residual carcass. Concentrations in liver of males were greater than those of females. This result suggests sex-related differences in accumulation. Ratios between concentration in eggs and liver (E/L) were: 2.9, 1.7, 0.8, 0.4 and 0.1 for 6-MeO-BDE-47, BDE-47, 6-OH-BDE-47, 2'-MeO-BDE-28 and 2'-OH-BDE-28, respectively. This result suggests transfer from adult females to eggs. BDE-47 was not transformed into OH-PBDEs or MeO-PBDEs. Inter-conversions of 6-OH-BDE-47 and 6-MeO-BDE-47, 2'-OH-BDE-28 and 2'-MeO-BDE-28 were observed, with metabolite/precursor concentration ratios for 6-OH-BDE-47, 6-MeO-BDE-47, 2'-OH-BDE-28 and 2'-MeO-BDE-28 being 3.8%, 14.6%, 2.9% and 76.0%, respectively. Congener-specific differences were observed in distributions between liver and carcass, maternal transfer and transformation. The two MeO-PBDEs were accumulated into adults, transferred to eggs, and were transformed to the structural similar OH-PBDEs, which might be more toxic. BDE-47 was accumulated into adults and transferred from females to eggs, but not transformed to MeO-PBDEs and/or OH-PBDEs. Accumulation of OH-PBDEs into adults as well as rates of transformation of OH-PBDEs to MeO-PBDEs were all several orders of magnitude less. Thus, MeO-PBDEs are likely to present more of a risk in the environment.

Effects of an oral allosteric AKT inhibitor (MK-2206) on human nasopharyngeal cancer in vitro and in vivo.

AIM: Protein kinase B (AKT) signaling frequently is deregulated in human cancers and plays an important role in nasopharyngeal carcinoma (NPC). This preclinical study investigated the effect of MK-2206, a potent allosteric AKT inhibitor, on human NPC cells in vitro and in vivo. METHODS: The effect of MK-2206 on the growth and proliferation of CNE-1, CNE-2, HONE-1, and SUNE-1 cells was assessed by Cell Counting Kit 8 and colony formation assay. Flow cytometry was performed to analyze cell cycle and apoptosis. The effects of MK-2206 on the AKT pathway were analyzed by Western blotting. Autophagy induction was evaluated via electron microscopy and Western blot. To test the effects of MK-2206 in vivo, CNE-2 cells were subcutaneously implanted into nude mice. Tumor-bearing mice were treated orally with MK-2206 or placebo. Tumors were harvested for immunohistochemical analysis. RESULTS: In vitro, MK-2206 inhibited the four NPC cell line growths and reduced the sizes of the colonies in a dose-dependent manner. At 72 and 96 hours, the half maximal inhibitory concentration (IC50) values of MK-2206 in CNE-1, CNE-2, and HONE-1 cell lines were 3-5 µM, whereas in SUNE-1, IC50 was less than 1 µM, and MK-2206 induced cell cycle arrest at the G1 phase. However, our study found no evidence of apoptosis. MK-2206 induced autophagy in NPC cells, as evidenced by electron microscopy and Western blot, and inhibited the growth of tumors that were subcutaneously implanted in mice. Inhibition of downstream phosphorylation through the PRAS40 and S6 pathways seems to be the main mechanism for the MK-2206-induced growth inhibition. CONCLUSION: Our preclinical study suggests that MK-2206's antiproliferative effect may be useful for NPC treatment; however, strategies for reinforcing this effect are needed to maximize clinical benefit.

Mechanisms of toxicity of hydroxylated polybrominated diphenyl ethers (HO-PBDEs) determined by toxicogenomic analysis with a live cell array coupled with mutagenesis in Escherichia coli.

Results of previous studies have indicated that 6-HO-BDE-47, the addition of the hydroxyl (HO) group to the backbone of BDE-47, significantly increased the toxicity of the chemical compared to its postulated precursor analogues, BDE-47 and 6-MeO-BDE-47. However, whether such a result is conserved across polybrominated diphenyl ether (PBDE) congeners was unknown. Here, cytotoxicity of 32 PBDE analogues (17 HO-PBDEs and 15 MeO-PBDEs) was further tested and the underlying molecular mechanism was investigated. A total of 14 of the 17 HO-PBDEs inhibited growth of Escherichia coli during 4 or 24 h durations of exposure, but none of the MeO-PBDEs was cytotoxic at the concentrations tested. 6-HO-BDE-47 and 2-HO-BDE-28 were most potent with 4 h median effect concentrations (EC50) of 12.13 and 6.25 mg/L, respectively, which trended to be lesser with a longer exposure time (24 h). Expression of 30 modulated and validated genes by 6-HO-BDE-47 in a previous study was also observed after exposure to other HO-PBDE analogues. For instance, uhpT was upregulated by 13 HO-PBDEs, and three rRNA operons (rrnA, rrnB, and rrnC) were downregulated by 8 HO-PBDEs. These unanimous responses suggested a potential common molecular signaling modulated by HO-PBDEs. To explore new information on mechanisms of action, this work was extended by testing the increased susceptibility of 182 mutations of transcriptional factors (TFs) and 22 mutations as genes modulated by 6-HO-BDE-47 after exposure to 6-HO-BDE-47 at the 4 h IC50 concentration. Although a unanimous upregulation of uhpT was observed after exposure to HO-PBDEs, no significant shift in sensitivity was observed in uhpT-defective mutants. The 54 genes, selected by cut-offs of 0.35 and 0.65, were determined to be responsible for "organic acid/oxoacid/carboxylic acid metabolic process" pathways, which supported a previous finding.

The difference between temperate and tropical saltwater species' acute sensitivity to chemicals is relatively small.

Due to a lack of saltwater toxicity data in tropical regions, toxicity data generated from temperate or cold water species endemic to North America and Europe are often adopted to derive water quality guidelines (WQG) for protecting tropical saltwater species. If chemical toxicity to most saltwater organisms increases with water temperature, the use of temperate species data and associated WQG may result in under-protection to tropical species. Given the differences in species composition and environmental attributes between tropical and temperate saltwater ecosystems, there are conceivable uncertainties in such 'temperate-to-tropic' extrapolations. This study aims to compare temperate and tropical saltwater species' acute sensitivity to 11 chemicals through a comprehensive meta-analysis, by comparing species sensitivity distributions (SSDs) between the two groups. A 10 percentile hazardous concentration (HC10) is derived from each SSD, and then a temperate-to-tropic HC10 ratio is computed for each chemical. Our results demonstrate that temperate and tropical saltwater species display significantly different sensitivity towards all test chemicals except cadmium, although such differences are small with the HC10 ratios ranging from 0.094 (un-ionised ammonia) to 2.190 (pentachlorophenol) only. Temperate species are more sensitive to un-ionised ammonia, chromium, lead, nickel and tributyltin, whereas tropical species are more sensitive to copper, mercury, zinc, phenol and pentachlorophenol. Through comparison of a limited number of taxon-specific SSDs, we observe that there is a general decline in chemical sensitivity from algae to crustaceans, molluscs and then fishes. Following a statistical analysis of the results, we recommend an extrapolation factor of two for deriving tropical WQG from temperate information.

Design and synthesis of heterobimetallic Ru(II)-Ln(III) complexes as chemodosimetric ensembles for the detection of biogenic amine odorants.

The detection of neutral biogenic amines plays a crucial role in food safety. Three new heterobimetallic Ru(II)-Ln(III) donor-acceptor complexes, KPrRu, KNdRu, and KSmRu, K{[Ru((II))((t)Bubpy)(CN)4]2-Ln((III))(H2O)4} (where (t)Bubpy = 4,4'-di-tert-butyl-2,2'-bipyridine), have been synthesized and characterized. Their photophysical and X-ray crystallographic data were reported in this study. These complexes were found to be selective for biogenic amine vapors, such as histamine, putrescine, and spermidine, with a detection limit down to the ppb level. The sensitivities of these complexes to the amines were recorded as ~log K = 3.6-5.0. Submicron rods of the complexes, with a nanoscale diameter and microscale length, were obtained through a simple precipitation process. Free-standing polymeric films with different degrees of porosity were fabricated by blending the submicron rods with polystyrene polymer. The polymer with the highest level of porosity exhibited the strongest luminescence enhancement after amine exposure. Real time monitoring of gaseous biogenic amines was applied to real fish samples (Atlantic mackerel) by studying the spectrofluorimetric responses of the Ru(II)-Ln(III) blended polymer film.