Nanoscale Titanium Surface Engineering via Low-Temperature Hydrothermal Etching for Enhanced Antimicrobial Properties.

Bioinspired nanotopography artificially fabricated on titanium surfaces offers a solution for the rising issue of postoperative infections within orthopedics. On a small scale, hydrothermal etching has proven to deliver an effective antimicrobial nanospike surface. However, translation to an industrial setting is limited by the elevated synthesis temperature (150 °C) and associated equipment requirements. Here, for the first time, we fabricate surface nanostructures using comparatively milder synthesis temperatures (75 °C), which deliver physicochemical properties and antimicrobial capability comparable to the high-temperature surface. Using a KOH etchant, the simultaneous formation of titania and titanate crystals at both temperatures produces a one-dimensional nanostructure array. Analysis indicated that the formation mechanism comprises dissolution and reprecipitation processes, identifying the deposited titanates as hydrated layered tetra-titanates (K2Ti4O9·nH2O). A proposed nanospike formation mechanism was confirmed through the identification of a core and outer shell for individual nanostructures, primarily comprised of titanates and titania, respectively. Etching conditions dictated crystalline formation, favoring a thicker titanate core for nanorods under higher synthesis temperatures and etchant concentrations. A bactericidal investigation showed the efficacy against Gram-negative bacteria for a representative low-temperature nanosurface (34.4 ± 14.4%) was comparable to the higher temperature nanosurface (34.0 ± 17.0%), illustrating the potential of low-temperature hydrothermal synthesis. Our results provide valuable insight into the applicability of low-temperature etching protocols that are more favorable in large-scale manufacturing settings.

Defect-Promoted Ni-Based Layer Double Hydroxides with Enhanced Deprotonation Capability for Efficient Biomass Electrooxidation.

Ni-based hydroxides are promising electrocatalysts for biomass oxidation reactions, supplanting the oxygen evolution reaction (OER) due to lower overpotentials while producing value-added chemicals. The identification and subsequent engineering of their catalytically active sites are essential to facilitate these anodic reactions. Herein, the proportional relationship between catalysts' deprotonation propensity and Faradic efficiency of 5-hydroxymethylfurfural (5-HMF)-to-2,5 furandicarboxylic acid (FDCA, FEFDCA ) is revealed by thorough density functional theory (DFT) simulations and atomic-scale characterizations, including in situ synchrotron diffraction and spectroscopy methods. The deprotonation capability of ultrathin layer-double hydroxides (UT-LDHs) is regulated by tuning the covalency of metal (M)-oxygen (O) motifs through defect site engineering and selection of M3+ co-chemistry. NiMn UT-LDHs show an ultrahigh FEFDCA of 99% at 1.37 V versus reversible hydrogen electrode (RHE) and retain a high FEFDCA of 92.7% in the OER-operating window at 1.52 V, about 2× that of NiFe UT-LDHs (49.5%) at 1.52 V. Ni-O and Mn-O motifs function as dual active sites for HMF electrooxidation, where the continuous deprotonation of Mn-OH sites plays a dominant role in achieving high selectivity while suppressing OER at high potentials. The results showcase a universal concept of modulating competing anodic reactions in aqueous biomass electrolysis by electronically engineering the deprotonation behavior of metal hydroxides, anticipated to be translatable across various biomass substrates.

Locking the Ultrasound-Induced Active Conformation of Metalloenzymes in Metal-Organic Frameworks.

Enhancing the enzymatic activity inside metal-organic frameworks (MOFs) is a critical challenge in chemical technology and bio-technology, which, if addressed, will broaden their scope in energy, food, environmental, and pharmaceutical industries. Here, we report a simple yet versatile and effective strategy to optimize biocatalytic activity by using MOFs to rapidly "lock" the ultrasound (US)-activated but more fragile conformation of metalloenzymes. The results demonstrate that up to 5.3-fold and 9.3-fold biocatalytic activity enhancement of the free and MOF-immobilized enzymes could be achieved compared to those without US pretreatment, respectively. Using horseradish peroxidase as a model, molecular dynamics simulation demonstrates that the improved activity of the enzyme is driven by an opened gate conformation of the heme active site, which allows more efficient substrate binding to the enzyme. The intact heme active site is confirmed by solid-state UV-vis and electron paramagnetic resonance, while the US-induced enzyme conformation change is confirmed by circular dichroism spectroscopy and Fourier-transform infrared spectroscopy. In addition, the improved activity of the biocomposites does not compromise their stability upon heating or exposure to organic solvent and a digestion cocktail. This rapid locking and immobilization strategy of the US-induced active enzyme conformation in MOFs gives rise to new possibilities for the exploitation of highly efficient biocatalysts for diverse applications.

Low Temperature Nano Mechano-electrocatalytic CH4 Conversion.

Transforming natural resources to energy sources, such as converting CH4 to H2 and carbon, at high efficiency and low cost is crucial for many industries and environmental sustainability. The high temperature requirement of CH4 conversion regarding many of the current methods remains a critical bottleneck for their practical uptake. Here we report an approach based on gallium (Ga) liquid metal droplets, Ni(OH)2 cocatalysts, and mechanical energy input that offers low-temperature and scalable CH4 conversion into H2 and carbon. Mainly driven by the triboelectric voltage, originating from the joint contributions of the cocatalysts during agitation, CH4 is converted at the Ga and Ni(OH)2 interface through nanotribo-electrochemical reaction pathways. The efficiency of the system is enhanced when the reaction is performed at an increased pressure. The dehydrogenation of other nongaseous hydrocarbons using this approach is also demonstrated. This technology presents a possible low energy route for CH4 conversion without involving high temperature and harsh operating conditions.

Optimization of a Pyrimidinone Series for Selective Inhibition of Ca2+/Calmodulin-Stimulated Adenylyl Cyclase 1 Activity for the Treatment of Chronic Pain.

Adenylyl cyclase type 1 (AC1) is involved in signaling for chronic pain sensitization in the central nervous system and is an emerging target for the treatment of chronic pain. AC1 and a closely related isoform AC8 are also implicated to have roles in learning and memory signaling processes. Our team has carried out cellular screening for inhibitors of AC1 yielding a pyrazolyl-pyrimidinone scaffold with low micromolar potency against AC1 and selectivity versus AC8. Structure-activity relationship (SAR) studies led to analogues with cellular IC50 values as low as 0.25 µM, selectivity versus AC8 and other AC isoforms as well as other common neurological targets. A representative analogue displayed modest antiallodynic effects in a mouse model of inflammatory pain. This series represents the most potent and selective inhibitors of Ca2+/calmodulin-stimulated AC1 activity to date with improved drug-like physicochemical properties making them potential lead compounds for the treatment of inflammatory pain.

Valence Alignment of Mixed Ni-Fe Hydroxide Electrocatalysts through Preferential Templating on Graphene Edges for Enhanced Oxygen Evolution.

Engineering the metal-carbon heterointerface has become an increasingly important route toward achieving cost-effective and high-performing electrocatalysts. The specific properties of graphene edge sites, such as the high available density of states and extended unpaired π-bonding, make it a promising candidate to tune the electronic properties of metal catalysts. However, to date, understanding and leveraging graphene edge-metal catalysts for improved electrocatalytic performance remains largely elusive. Herein, edge-rich vertical graphene (er-VG) was synthesized and used as a catalyst support for Ni-Fe hydroxides for the oxygen evolution reaction (OER). The hybrid Ni-Fe/er-VG catalyst exhibits excellent OER performance with a mass current of 4051 A g-1 (at overpotential η = 300 mV) and turnover frequency (TOF) of 4.8 s-1 (η = 400 mV), outperforming Ni-Fe deposited on pristine VG and other metal foam supports. Angle-dependent X-ray absorption spectroscopy shows that the edge-rich VG support can preferentially template Fe-O units with a specific valence orbital alignment interacting with the unoccupied density of states on the graphene edges. This graphene edge-metal interaction was shown to facilitate the formation of undersaturated and strained Fe-sites with high valence states, while promoting the formation of redox-activated Ni species, thus improving OER performance. These findings demonstrate rational design of the graphene edge-metal interface in electrocatalysts which can be used for various energy conversion and chemical synthesis reactions.

Endothelial CaMKII as a regulator of eNOS activity and NO-mediated vasoreactivity.

The multifunctional Ca2+/calmodulin-dependent protein kinase II (CaMKII) is a serine/threonine kinase important in transducing intracellular Ca2+ signals. While in vitro data regarding the role of CaMKII in the regulation of endothelial nitric oxide synthase (eNOS) are contradictory, its role in endothelial function in vivo remains unknown. Using two novel transgenic models to express CaMKII inhibitor peptides selectively in endothelium, we examined the effect of CaMKII on eNOS activation, NO production, vasomotor tone and blood pressure. Under baseline conditions, CaMKII activation was low in the aortic wall. Consistently, systolic and diastolic blood pressure, heart rate and plasma NO levels were unaltered by endothelial CaMKII inhibition. Moreover, endothelial CaMKII inhibition had no significant effect on NO-dependent vasodilation. These results were confirmed in studies of aortic rings transduced with adenovirus expressing a CaMKII inhibitor peptide. In cultured endothelial cells, bradykinin treatment produced the anticipated rapid influx of Ca2+ and transient CaMKII and eNOS activation, whereas CaMKII inhibition blocked eNOS phosphorylation on Ser-1179 and dephosphorylation at Thr-497. Ca2+/CaM binding to eNOS and resultant NO production in vitro were decreased under CaMKII inhibition. Our results demonstrate that CaMKII plays an important role in transient bradykinin-driven eNOS activation in vitro, but does not regulate NO production, vasorelaxation or blood pressure in vivo under baseline conditions.

Retene causes multifunctional transcriptomic changes in the heart of rainbow trout (Oncorhynchus mykiss) embryos.

Fish are particularly sensitive to aryl hydrocarbon receptor (AhR)-mediated developmental toxicity. The molecular mechanisms behind these adverse effects have remained largely unresolved in salmonids, and for AhR-agonistic polycyclic aromatic hydrocarbons (PAHs). This study explored the cardiac transcriptome of rainbow trout (Oncorhynchus mykiss) eleuteroembryos exposed to retene, an AhR-agonistic PAH. The embryos were exposed to retene (nominal concentration 32 µg/L) and control, their hearts were collected before, at and after the onset of the visible signs of developmental toxicity, and transcriptomic changes were studied by microarray analysis. Retene up- or down-regulated 122 genes. The largest Gene Ontology groups were signal transduction, transcription, apoptosis, cell growth, cytoskeleton, cell adhesion/mobility, cardiovascular development, xenobiotic metabolism, protein metabolism, lipid metabolism and transport, and amino acid metabolism. Together these findings suggest that retene affects multiple signaling cascades in the heart of rainbow trout embryos, and potentially disturbs processes related to cardiovascular development and function.

Deletion of Methionine Sulfoxide Reductase A Does Not Affect Atherothrombosis but Promotes Neointimal Hyperplasia and Extracellular Signal-Regulated Kinase 1/2 Signaling.

OBJECTIVE: Emerging evidence suggests that methionine oxidation can directly affect protein function and may be linked to cardiovascular disease. The objective of this study was to define the role of the methionine sulfoxide reductase A (MsrA) in models of vascular disease and identify its signaling pathways. APPROACH AND RESULTS: MsrA was readily identified in all layers of the vascular wall in human and murine arteries. Deletion of the MsrA gene did not affect atherosclerotic lesion area in apolipoprotein E-deficient mice and had no significant effect on susceptibility to experimental thrombosis after photochemical injury. In contrast, the neointimal area after vascular injury caused by complete ligation of the common carotid artery was significantly greater in MsrA-deficient than in control mice. In aortic vascular smooth muscle cells lacking MsrA, cell proliferation was significantly increased because of accelerated G1/S transition. In parallel, cyclin D1 protein and cdk4/cyclin D1 complex formation and activity were increased in MsrA-deficient vascular smooth muscle cell, leading to enhanced retinoblastoma protein phosphorylation and transcription of E2F. Finally, MsrA-deficient vascular smooth muscle cell exhibited greater activation of extracellular signal-regulated kinase 1/2 that was caused by increased activity of the Ras/Raf/mitogen-activated protein kinase signaling pathway. CONCLUSIONS: Our findings implicate MsrA as a negative regulator of vascular smooth muscle cell proliferation and neointimal hyperplasia after vascular injury through control of the Ras/Raf/mitogen-activated protein kinase kinase/extracellular signal-regulated kinase 1/2 signaling pathway.

Oxidative activation of the Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) regulates vascular smooth muscle migration and apoptosis.

Activation of the Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) and reactive oxygen species (ROS) promote neointimal hyperplasia after vascular injury. CaMKII can be directly activated by ROS through oxidation. In this study, we determined whether abolishing the oxidative activation site of CaMKII alters vascular smooth muscle cell (VCMC) proliferation, migration and apoptosis in vitro and neointimal formation in vivo. VSMC isolated from a knock-in mouse with oxidation-resistant CaMKIIδ (CaMKII M2V) displayed similar proliferation but decreased migration and apoptosis. Surprisingly, ROS production and expression of the NADPH oxidase subunits p47 and p22 were decreased in M2V VSMC, whereas superoxide dismutase 2 protein expression was upregulated. In vivo, after carotid artery ligation, no differences in neointimal size or remodeling were observed. In contrast to VSMC, CaMKII expression and autonomous activity were significantly higher in M2V compared to WT carotid arteries, suggesting that an autoregulatory mechanism determines CaMKII activity in vivo. Our findings demonstrate that preventing oxidative activation of CaMKII decreases migration and apoptosis in vitro and suggest that CaMKII regulates ROS production. Our study presents novel evidence that CaMKII expression in vivo is regulated by a negative feedback loop following oxidative activation.

Stimuli-responsive functionalized mesoporous silica nanoparticles for drug release in response to various biological stimuli.

A silica-based mesoporous nanosphere (MSN) controlled-release drug delivery system has been synthesized and characterized. The system uses l-cysteine derivatized gold nanoparticles (AuNPs), bound to the MSNs using Cu2+ as a bridging ion. The AuNPs serve as removable caps that hinder the release of drug molecules inside the amino functionalized MSN mesoporous framework. The modified MSNs themselves exhibit negligible cytotoxicity to living cells, as revealed using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The drug delivery system requires one of two biological stimuli to trigger drug release. These stimuli are either: low pH (pH < 5); or elevated levels of adenosine triphosphate (ATP) (concentration > 4 mM). The feasibility of biologically controlled release was demonstrated through the stimuli-induced removal of the AuNP caps over the MSN releasing the anticancer drug doxorubicin. We envisage that this MSN system could play a significant role in developing new generations of controlled-release delivery vehicles.

The multifunctional Ca²âº/calmodulin-dependent kinase IIδ (CaMKIIδ) regulates arteriogenesis in a mouse model of flow-mediated remodeling.

OBJECTIVE: Sustained hemodynamic stress mediated by high blood flow promotes arteriogenesis, the outward remodeling of existing arteries. Here, we examined whether Ca²âº/calmodulin-dependent kinase II (CaMKII) regulates arteriogenesis. METHODS AND RESULTS: Ligation of the left common carotid led to an increase in vessel diameter and perimeter of internal and external elastic lamina in the contralateral, right common carotid. Deletion of CaMKIIδ (CaMKIIδ-/-) abolished this outward remodeling. Carotid ligation increased CaMKII expression and was associated with oxidative activation of CaMKII in the adventitia and endothelium. Remodeling was abrogated in a knock-in model in which oxidative activation of CaMKII is abolished. Early after ligation, matrix metalloproteinase 9 (MMP9) was robustly expressed in the adventitia of right carotid arteries of WT but not CaMKIIδ-/- mice. MMP9 mainly colocalized with adventitial macrophages. In contrast, we did not observe an effect of CaMKIIδ deficiency on other proposed mediators of arteriogenesis such as expression of adhesion molecules or smooth muscle proliferation. Transplantation of WT bone marrow into CaMKIIδ-/- mice normalized flow-mediated remodeling. CONCLUSION: CaMKIIδ is activated by oxidation under high blood flow conditions and is required for flow-mediated remodeling through a mechanism that includes increased MMP9 expression in bone marrow-derived cells invading the arterial wall.

CaMKII is essential for the proasthmatic effects of oxidation.

Increased reactive oxygen species (ROS) contribute to asthma, but little is known about the molecular mechanisms connecting increased ROS with characteristic features of asthma. We show that enhanced oxidative activation of the Ca(2+)/calmodulin-dependent protein kinase (ox-CaMKII) in bronchial epithelium positively correlates with asthma severity and that epithelial ox-CaMKII increases in response to inhaled allergens in patients. We used mouse models of allergic airway disease induced by ovalbumin (OVA) or Aspergillus fumigatus (Asp) and found that bronchial epithelial ox-CaMKII was required to increase a ROS- and picrotoxin-sensitive Cl(-) current (ICl) and MUC5AC expression, upstream events in asthma progression. Allergen challenge increased epithelial ROS by activating NADPH oxidases. Mice lacking functional NADPH oxidases due to knockout of p47 and mice with epithelial-targeted transgenic expression of a CaMKII inhibitory peptide or wild-type mice treated with inhaled KN-93, an experimental small-molecule CaMKII antagonist, were protected against increases in ICl, MUC5AC expression, and airway hyperreactivity to inhaled methacholine. Our findings support the view that CaMKII is a ROS-responsive, pluripotent proasthmatic signal and provide proof-of-concept evidence that CaMKII is a therapeutic target in asthma.

The multifunctional Ca2+/calmodulin-dependent kinase II regulates vascular smooth muscle migration through matrix metalloproteinase 9.

The multifunctional CaMKII has been implicated in vascular smooth muscle cell (VSMC) migration, but little is known regarding its downstream targets that mediate migration. Here, we examined whether CaMKII regulates migration through modulation of matrix metalloproteinase 9 (MMP9). Using CaMKIIδ(-/-) mice as a model system, we evaluated migration and MMP9 regulation in vitro and in vivo. After ligation of the common carotid artery, CaMKII was activated in the neointima as determined by oxidation and autophosphorylation. We found that MMP9 was robustly expressed in the neointima and adventitia of carotid-ligated wild-type (WT) mice but was barely detectable in CaMKIIδ(-/-) mice. The perimeter of the external elastic lamina, a correlate of migration-related outward remodeling, was increased in WT but not in CaMKIIδ(-/-) mice. Migration induced by serum, platelet-derived growth factor, and tumor necrosis factor-α (TNF-α) was significantly decreased in CaMKIIδ(-/-) as compared with WT VSMCs, but migration was rescued with adenoviral overexpression of MMP9 in CaMKIIδ(-/-) VSMCs. Likewise, overexpression of CaMKIIδ in CaMKIIδ(-/-) VSMCs increased migration, whereas an oxidation-resistant mutant of CaMKIIδ did not. TNF-α strongly induced CaMKII oxidation and autophosphorylation as well as MMP9 activity, mRNA, and protein levels in WT, but not in CaMKIIδ(-/-) VSMC. Surprisingly, TNF-α strongly induced MMP9 promoter activity in WT and CaMKIIδ(-/-) VSMC. However, the MMP9 mRNA stability was significantly decreased in CaMKIIδ(-/-) VSMC. Our data demonstrate that CaMKII promotes VSMC migration through posttranscriptional regulation of MMP9 and suggest that CaMKII effects on MMP9 expression may be a therapeutic pathway in vascular injury.

Progress in Heterogeneous Photocatalysis: From Classical Radical Chemistry to Engineering Nanomaterials and Solar Reactors.

The field of heterogeneous photocatalysis has expanded rapidly in the last four decades, having undergone various evolutionary phases related to energy and the environment. The two most significant applications of photocatalysis are geared toward solar water splitting and the purification of air and water. Notably, the interdisciplinary nature of the field has increased significantly, incorporating semiconductor physics, surface sciences, photo and physical chemistry, materials science, and chemical engineering. Whereas this forms the basis on which the field continues to grow, adequate bridging of multidisciplinary knowledge remains essential. By recalling some of the classical fundamentals of photocatalysis, this Perspective provides contemporary views on heterogeneous photochemical conversion, encompassing charge transport characteristics, radical chemistry and organic degradation mechanisms, photocatalyst design, and photoreactor engineering.

Microbial transformation of arsenic species in municipal landfill leachate.

The microbial transformation of arsenic species in municipal landfill leachate (MLL) was investigated with the objective to highlight arsenic transformation in the landfill system. Across the 43 day incubation in MLL, more than 90% arsenate (iAs(V)) was found to reduce to arsenite (iAs(III)) within 20 days, while iAs(III) was comparably stable although a fraction of iAs(III) was temporarily oxidated to iAs(V) in the first 3 days. Transformation of monomethylarsonic acid (MMA(V)) to dimethylarsinic acid (DMA(V)) in MLL was slow with only 5% MMA(V) methylated to DMA(V) after 43 days incubation. A portion of DMA(V) and MMA(V) in MLL was demonstrated to transform into thiol-organoarsenic and monomethylarsonous acid (MMA(III)), which were identified to include dimethyldithioarsinic acid (DMDTA(V)), dimethylmonothioarsinic acid (DMMTA(V)) and monomethyldithioarsonic acid (MMDTA(V)) by HPLC-ICPMS and LC-ESI-MS/MS. The microbial formation of DMDTA(V), DMMTA(V) and MMDTA(V) is postulated to relate to hydrogen sulfide generated by bacteria in MLL. Differences in arsenic transformation in sterilised and non-sterilised MLLs demonstrate bacteria play a crucial role in arsenic transformation in the landfill body. This study reveals the complexity of arsenic speciation and highlights the potential risk of forming highly toxic thiol-organoarsenic and MMA(III) in the landfill environment.

AhR2-mediated, CYP1A-independent cardiovascular toxicity in zebrafish (Danio rerio) embryos exposed to retene.

In the embryo-larval stages of fish, alkylphenanthrenes such as retene (7-isopropyl-1-methylphenanthrene) produce a suite of developmental abnormalities typical of exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), including pericardial and yolk sac edema, cardiovascular dysfunction, and skeletal deformities. To investigate the mechanism and target tissue of retene toxicity, we used observational, histological, and protein knockdown techniques in zebrafish (Danio rerio) embryos. The primary overt signs of toxicity are pericardial edema and reduced blood flow, first observed at 36 h post-fertilization (hpf). The most pronounced effects at this stage are a reduced layer of cardiac jelly in the atrium and reduced diastolic filling. Conversely, an increased layer of cardiac jelly is observed at 72 hpf in retene-exposed embryos. Induction of cytochrome P4501A (CYP1A) is apparent in a subset of cardiomyocytes by 48 hpf suggesting that early cardiac effects may be due to AhR activation in the myocardium. Myocardial CYP1A induction is transient, with only endocardial induction observed at 72 hpf. Knockdown of cyp1a by morpholino oligonucleotides does not affect retene toxicity; however, ahr2 knockdown prevents toxicity. Thus, the mechanism of retene cardiotoxicity is AhR2-mediated and CYP1A-independent, similar to TCDD; however, the onset and proximate signs of retene toxicity differ from those of TCDD. Retene cardiotoxicity also differs mechanistically from the cardiac effects of non-alkylated phenanthrane, illustrating that alkyl groups can alter toxic action. These findings have implications for understanding the toxicity of complex mixtures containing alkylated and non-alkylated polycyclic aromatic hydrocarbons.

Cytochrome P4501A1 is required for vascular dysfunction and hypertension induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin.

National Health and Nutrition Examination Survey data show an association between hypertension and exposure to dioxin-like halogenated aromatic hydrocarbons (HAHs). Furthermore, chronic exposure of mice to the prototypical HAH, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), induces reactive oxygen species (ROS), endothelial dysfunction, and hypertension. Because TCDD induces cytochrome P4501A1 (CYP1A1) and CYP1A1 can increase ROS, we tested the hypothesis that TCDD-induced endothelial dysfunction and hypertension are mediated by CYP1A1. CYP1A1 wild-type (WT) and knockout (KO) mice were fed one control or TCDD-containing pill (180 ng TCDD/kg, 5 days/week) for 35 days (n = 10-14/genotype/treatment). Blood pressure was monitored by radiotelemetry, and liver TCDD concentration, CYP1A1 induction, ROS, and aortic reactivity were measured at 35 days. TCDD accumulated to similar levels in livers of both genotypes. TCDD induced CYP1A1 in endothelium of aorta and mesentery without detectable expression in the vessel wall. TCDD also induced superoxide anion production, measured by NADPH-dependent lucigenin luminescence, in aorta, heart, and kidney of CYP1A1 WT mice but not KO mice. In contrast, TCDD induced hydrogen peroxide, measured by amplex red assay, to similar levels in aorta of CYP1A1 WT and KO mice but not in heart or kidney. TCDD reduced acetylcholine-dependent vasorelaxation in aortic rings of CYP1A1 WT mice but not in KO mice. Finally, TCDD steadily increased blood pressure after 15 days, which plateaued after 25 days (+20 mmHg) in CYP1A1 WT mice but failed to alter blood pressure in KO mice. These results demonstrate that CYP1A1 is required for TCDD-induced cardiovascular superoxide anion production, endothelial dysfunction, and hypertension.

Arsenic speciation in municipal landfill leachate.

Arsenic species in municipal landfill leachates (MLL) were investigated by HPLC-DRC-ICPMS and LC-ESI-MS/MS. Various arsenic species including arsenate (iAs(V)), arsenite (iAs(III)), monomethylarsonic acid (MMA(V)), dimethylarsinic acid (DMA(V)), as well as sulfur-containing organoarsenic species were detected. Two sulfur-containing arsenic species in a MLL were positively identified as dimethyldithioarsinic acid (DMDTA(V)) and dimethylmonothioarsinic acid (DMMTA(V)) by comparing their molecular ions, fragment patterns and sulfur/arsenic ratios with in-house synthesised thiol-organoarsenic compounds. The findings demonstrated the potential for transformation of DMA(V) to DMDTA(V) and DMMTA(V) in a DMA(V)-spiked MLL in a landfill leachate environment.

An activated renin-angiotensin system maintains normal blood pressure in aryl hydrocarbon receptor heterozygous mice but not in null mice.

It has been postulated that fetal vascular abnormalities in aryl hydrocarbon receptor null (ahr(-/-)) mice may alter cardiovascular homeostasis in adulthood. We tested the hypothesis that blood pressure regulation in adult heterozygous mice (ahr(+/-)) would be normal, compared to ahr(-/-) mice, since no vascular abnormalities have been reported in the heterozygote animals. Mean arterial blood pressure (MAP) was measured using radiotelemetry prior to and during treatment with inhibitors of the autonomic nervous system, nitric oxide synthase (NOS), angiotensin converting enzyme (ACE), or endothelin-1 A receptor (ET(A)). Also, indices of renin-angiotensin system (RAS) activation were measured. ahr(+/-) and ahr(-/-) mice were normotensive and hypotensive, respectively, compared to wild-type (ahr(+/+)) littermates. Responses of all genotypes to autonomic nervous system inhibition were normal. ahr(+/-) mice responded normally to NOS inhibition, while the responses of ahr(-/-) mice were significantly blunted. In contrast, ahr(+/-) mice were significantly more responsive to inhibition of ACE, an ET(A) antagonist, or both, while ahr(-/-) mice were significantly less responsive to ACE inhibition and more responsive to an ET(A) antagonist. ahr(+/-) mice also exhibited significant increases in plasma renin and ACE activity, plasma sodium, and urine osmolality, indicative of RAS activation. Thus, normotension in ahr(+/-) mice appears to be maintained by increased RAS and ET-1 signaling, while hypotension in ahr(-/-) mice may result from decreased RAS signaling. In conclusion, despite the lack of overt fetal vascular abnormalities in ahr(+/-) mice, the loss of a single ahr allele has a significant effect on blood pressure regulation.