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Light-activable spatiotemporal control of PROTAC-induced protein degradation was achieved with novel arylazopyrazole photoswitchable PROTACs (AP-PROTACs). The use of a promiscuous kinase inhibitor in the design enables this unique photoswitchable PROTAC to selectively degrade four protein kinases together with on/off optical control using different wavelengths of light.

Herein we report a thiol-labile cysteine protecting group based on an unsaturated pyridazinedione (PD) scaffold. We establish compatibility of the PD in conventional solid phase peptide synthesis (SPPS), showcasing this in the on-resin synthesis of biologically relevant oxytocin. Furthermore, we establish the applicability of the PD protecting group towards both microwave-assisted SPPS and native chemical ligation (NCL) in a model system.

Plasmonic Au nanoparticle photoelectrodes were fabricated and characterized with ultrafast transient absorption (TA) and photomodulated cyclic voltammetry (CV) to determine whether the plasmonic ph...

The self-assembly of inorganic nanoparticles to larger structures is of great research interest as it allows the fabrication of novel materials with collective properties correlated to the nanoparticles’ individual characteristics. Recently developed methods for controlling nanoparticle organisation have enabled the fabrication of a range of new materials. Amongst these, the assembly of nanoparticles using DNA has attracted significant attention due to the highly selective recognition between complementary DNA strands, DNA nanostructure versatility, and ease of DNA chemical modification. In this review we discuss the application of various chemical DNA modifications and molecular intercalators as tools for the manipulation of DNA-nanoparticle structures. In detail, we discuss how DNA modifications and small molecule intercalators have been employed in the chemical and photochemical DNA ligation in nanostructures; DNA rotaxanes and catenanes associated with reconfigurable nanoparticle assemblies; and DNA backbone modifications including locked nucleic acids, peptide nucleic acids and borane nucleic acids, which affect the stability of nanostructures in complex environments. We conclude by highlighting the importance of maximising the synergy between the communities of DNA chemistry and nanoparticle self-assembly with the aim to enrich the library of tools available for the manipulation of nanostructures., The chemical manipulation of DNA offers new tools to tune the properties of nanoparticle self assemblies.

Air pollutant accumulations during wintertime persistent cold air pool (PCAP) events in mountain valleys are of great concern for public health worldwide. Uncertainties associated with the simulated meteorology under stable conditions over complex terrain hinder realistic simulations of air quality using chemical transport models. We use the Community Multiscale Air Quality (CMAQ) model to simulate the gaseous and particulate species for one-month in January 2011 during the Persistent Cold Air Pool Study (PCAPS) in the Salt Lake Valley (SLV), Utah (USA). Results indicate that the temporal variability associated with the elevated NO(x) and PM(2.5) concentrations during PCAP events were captured by the model (r=0.20 for NO(x) and r=0.49 for PM(2.5)). However, concentrations were not at the correct magnitude (NMB= −35%/12% for PM(2.5) during PCAPs/non-PCAPs) where PM(2.5) was underestimated during PCAP events and overestimated during non-PCAP periods. The underestimated PCAP strength is represented by valley heat deficit, which contributed to the underestimated PM(2.5) concentrations compared with observations due to the model simulating more vertical mixing and less stable stratification than what was observed. Based on observations, the dominant PM(2.5) species were ammonium and nitrate. We provide a discussion that aims to investigate the emissions and chemistry model uncertainties using the nitrogen ratio method and the thermodynamic ammonium nitrate regime method.

Rolling circle amplification (RCA) is a powerful tool for the construction of DNA nanomaterials such as hydrogels, high-performance scaffolds and DNA nanoflowers (DNFs), hybrid materials formed of DNA and magnesium pyrophosphate. Such DNA nanomaterials have great potential in therapeutics, imaging, protein immobilisation, and drug delivery, yet limited chemistry is available to expand their functionality. Here, we present orthogonal strategies to produce densely modified RCA products and DNFs. We provide methods to selectively modify the DNA component and/or the protein cargo of these materials, thereby greatly expanding the range of chemical functionalities available to these systems. We have used our methodology to construct DNFs bearing multiple surface aptamers and peptides capable of binding to cancer cells that overexpress the HER2 oncobiomarker, demonstrating their potential for diagnostic and therapeutic applications., Graphical Abstract Graphical AbstractCombining modified dNTPs with rolling circle amplification to expand the functionality of DNA nanomaterials.

Magmatic systems are dominated by five volatiles, namely H2O, CO2, F, Cl, and S (the igneous quintet). Multiple studies have measured partitioning of four out of these five volatiles (H2O, CO2, F, and Cl) between nominally volatile-free minerals and melts, whereas the partitioning of sulfur is poorly known. To better constrain the behavior of sulfur in igneous systems we measured the partitioning of sulfur between clinopyroxene and silicate melts over a range of pressure, temperature, and melt composition from 0.8 to 1.2 GPa, 1000 to 1240 °C, and 49 to 66 wt% SiO2 (13 measurements). Additionally, we determined the crystal-melt partitioning of sulfur for plagioclase (6 measurements), orthopyroxene (2 measurements), amphibole (2 measurements), and olivine (1 measurement) in some of these same run products. Experiments were performed at high and low oxygen fugacities, where sulfur in the melt is expected to be dominantly present as an S6+ or an S2– species, respectively. When the partition coefficient is calculated as the total sulfur in the crystal divided by the total sulfur in the melt, the partition coefficient varies from 0.017 to 0.075 for clinopyroxene, from 0.036 to 0.229 for plagioclase, and is a maximum of 0.001 for olivine and of 0.003 for orthopyroxene. The variation in the total sulfur partition coefficient positively correlates with cation-oxygen bond lengths in the crystals; the measured partition coefficients increase in the order: olivine < orthopyroxene < clinopyroxene ≤ amphibole and plagioclase. At high oxygen fugacities in hydrous experiments, the clinopyroxene/melt partition coefficients for total sulfur are only approximately one-third of those measured in low oxygen fugacity, anhydrous experiments. However when the partition coefficient is calculated as total sulfur in the crystal divided by S2– in the melt, the clinopyroxene/melt partition coefficients for experiments with melts between ~51 and 66 wt% SiO2 can be described by a single mean value of 0.063 ± 0.010 (1σ standard deviation about the mean). These two observations support the hypothesis that sulfur, as S2–, replaces oxygen in the crystal structure. The results of hydrous experiments at low oxygen fugacity and anhydrous experiments at high oxygen fugacity suggest that oxygen fugacity has a greater effect on sulfur partitioning than water. Although the total sulfur clinopyroxene-melt partition coefficients are affected by the Mg/(Mg+Fe) ratio of the crystal, partition coefficients calculated using S2– in the melt display no clear dependence upon the Mg# of the clinopyroxene. Both the bulk and the S 2– partition coefficients appear unaffected by IVAl in the clinopyroxene structure. No effect of anorthite content nor of iron concentration in the crystal was seen in the data for plagioclase-melt partitioning. The data obtained for orthopyroxene and olivine were too few to establish any trends. The partition coefficients of total sulfur and S 2– between the crystals studied and silicate melts are typically lower than those of fluorine, higher than those of carbon, and similar to those of chlorine and hydrogen. These sulfur partition coefficients can be combined with analyses of volatiles in nominally volatile-free minerals and previously published partition coefficients of H2O, C, F, and Cl to constrain the concentration of the igneous quintet, the five major volatiles in magmatic systems.

Nanoparticles with high reactivity can be applied as amendments to remediate soil metal contaminations by immobilizing toxic elements. Nano-oxides of Fe have been studied but Al and Ti nano-oxides have not been tested for their remediation capacity of toxic metals. The potential of synthesized iron (Fe-O), aluminum (Al-O), and titanium (Ti-O) nano-oxides for stabilizing Cd, Pb, and Zn in mine spoil (Chat) and contaminated soil was compared using adsorption studies and a greenhouse experiment. Chat and soil were amended with nano-oxides at two rates (25 and 50 g·kg−1) and a pot experiment was conducted with sorghum (Sorghum bicolor L. Moench). Leachates were collected twice per week from plant emergence to harvest at maturity and metals were compared against an unamended control. Chat was contaminated with Cd, Pb, and Zn at 84, 1583, and 6154 mg·kg−1, and soil at 15, 1260, and 3082 mg·kg−1, respectively. Adsorption conformed to the Langmuir linear isotherm and adsorption maxima of metals were in the order of Al-O > Ti-O ≥ Fe-O. Nano-oxides reduced Cd concentration by 28% (Fe-O) to 87% (Ti-O) and Zn concentration by 14% (Fe-O) to 85% (Al-O) in plant tissues compared with unamended Chat. Nano-oxides significantly reduced Cd, Pb, and Zn in leachates and available Cd and Zn in Chat/soil relative to the respective unamended controls. Nano-oxides can be used to remediate heavy metal contaminated Chat and soil and facilitate plant growth under proper nutrient supplements. Nano-oxides of Al-O and Ti-O remediated metals more effectively than Fe-O.

Introduction\ud \ud Coronary artery disease is associated with impaired clot structure. The aim of this study was to investigate acute phase myocardial infarction (AMI) and provide detailed quantitative analysis of clot ultrastructure.\ud \ud Materials and methods\ud \ud Clot formation and breakdown, pore size, fiber density, fiber radius and protofibril packing were investigated in plasma clots from AMI patients. These data were compared to those from healthy controls.\ud \ud Results\ud \ud Analysis on clot formation using turbidity showed increased lag time, suggesting changes in protofibril packing and increased fiber size for AMI patients compared to healthy controls. Additionally, increased average rate of clotting and decreased time to maximum absorbance in AMI patients suggest that clots formed more quickly. Moreover, we observed increased time from max OD to max rate of lysis. Increased fibrinogen and decreased plasminogen in AMI patients were accounted for in represented significant differences. AMI samples showed increased time to 25% and 50% lysis, but no change in 75% lysis, representative of delayed lysis onset, but expediated lysis once initiated. These data suggest that AMI patients formed less porous clots made from more densely packed fibers with decreased numbers of protofibrils, which was confirmed using decreased permeation and increased fiber density, and decreased turbidimetry.\ud \ud Conclusions\ud \ud AMI plasma formed clots that were denser, less permeable, and lysed more slowly than healthy controls. These findings were confirmed by detailed analysis of clot ultrastructure, fiber size, and protofibril packing. Dense clot structures that are resistant to lysis may contribute to a prothrombotic milieu in AMI.

Triazole linkages (TLs) are mimics of the phosphodiester bond in oligonucleotides with applications in synthetic biology and biotechnology. Here we report the RuAAC-catalyzed synthesis of a novel 1,5-disubstituted triazole (TL2) dinucleoside phosphoramidite as well as its incorporation into oligonucleotides and compare its DNA polymerase replication competency with other TL analogues. We demonstrate that TL2 has superior replication kinetics to these analogues and is accurately replicated by polymerases. Derived structure-biocompatibility relationships show that linker length and the orientation of a hydrogen bond acceptor are critical and provide further guidance for the rational design of artificial biocompatible nucleic acid backbones.

In silico approaches identified 1, N-(6-((4-bromo- benzyl)amino)hexyl)-3,5-bis(trifluoromethyl)benzene sulfonamide, as a potential inhibitor of the S100A2-p53 protein-protein interaction, a validated pancreatic cancer drug target. Subsequent cytotoxicity screening revealed it to be a 2.97 μM cell growth inhibitor of the MiaPaCa-2 pancreatic cell line. This is in keeping with our hypothesis that inhibiting this interaction would have an anti-pancreatic cancer effect with S100A2, the validated PC drug target. A combination of focused library synthesis (three libraries, 24 compounds total) and cytotoxicity screening identified a propyl alkyl diamine spacer as optimal; the nature of the terminal phenyl substituent had limited impact on observed cytotoxicity, whereas N-methylation was detrimental to activity. In total 15 human cancer cell lines were examined, with most analogues showing broad-spectrum activity. Near uniform activity was observed against a panel of six pancreatic cancer cell lines: MiaPaCa-2, BxPC-3, AsPC-1, Capan-2, HPAC and PANC-1. In all cases there was good to excellent correlation between the predicted docking pose in the S100A2-p53 binding groove and the observed cytotoxicity, especially in the pancreatic cancer cell line with high endogenous S100A2 expression. This supports S100A2 as a pancreatic cancer drug target.

In silico screening predicted 1 (N-(4-((4-(3-(4-(3-methoxyphenyl)-1H-1,2,3-triazol-1-yl)propyl)piperazin-1-yl) sulfonyl)-phenyl)acetamide) as an inhibitor of the S100A2-p53 protein-protein interaction. S100A2 is a validated pancreatic cancer drug target. In the MiaPaCa-2 pancreatic cell line, 1 was a ∼50 μM growth inhibitor. Synthesis of five focused compound libraries and cytotoxicity screening revealed increased activity from the presence of electron withdrawing moieties on the sulfonamide aromatic ring, with the 3,5-bis-CF3 Library 3 analogues the most active, with GI50 values of 0.91 (3-ClPh; 13 i; BxPC-3, Pancreas) to 9.0 μM (4-CH3 ; 13 d; PANC-1, Pancreas). Activity was retained against an expanded pancreatic cancer cell line panel (MiaPaCa-2, BxPC-3, AsPC-1, Capan-2, PANC-1 and HPAC) and the normal cell line MCF10A (breast). Bulky 4-disposed substituents on the terminal phenyl ring enhanced broad spectrum activity with growth inhibition values spanning 1.1 to 3.1 μM (4-C(CH3 )3 ; 13 e; BxPC-3 and AsPC-1 (pancreas), respectively). Central alkyl spacer contraction from propyl to ethyl proved detrimental to activity with Library 4 and 5.5- to 10-fold less cytotoxic than the propyl linked Library 2 and Library 3. The data herein was consistent with the predicted binding poses of the compounds evaluated. The highest levels of cytotoxicity were observed with those analogues best capable of adopting a near identical pose to the p53-peptide in the S100A2-p53 binding groove.

One of the most vital elements of management for patients with inborn errors of intermediary metabolism is the promotion of anabolism, the state in which the body builds new components, and avoidance of catabolism, the state in which the body breaks down its own stores for energy. Anabolism is maintained through the provision of a sufficient supply of substrates for energy, as well as critical building blocks of essential amino acids, essential fatty acids, and vitamins for synthetic function and growth. Patients with metabolic diseases are at risk for decompensation during prolonged fasting, which often occurs during illnesses in which enteral intake is compromised. During these times, intravenous nutrition must be supplied to fully meet the specific nutritional needs of the patient. We detail our approach to intravenous management for metabolic patients and its underlying rationale. This generally entails a combination of intravenous glucose and lipid as well as early introduction of protein and essential vitamins. We exemplify the utility of our approach in case studies, as well as scenarios and specific disorders which require a more careful administration of nutritional substrates or a modification of macronutrient ratios.

Background Obesity is among the most serious public health problems worldwide, with few safe pharmaceutical interventions. Natural products have become an important source of potential anti-obesity therapeutics. Dihydromyricetin (DHM) exerts antidiabetic effects. The biochemical target of DHM, however, has been unknown. It is crucial to identify the biochemical target of DHM for elucidating its physiological function and therapeutic value. Objectives The objective of this study was to identify the biochemical target of DHM. Methods An abundant antiadipogenic flavanonol was extracted from the herbal plant Ampelopsis grossedentata through bioassay-guided fractionation and characterized with high-resolution LC-MS and 1H and 13C nuclear magnetic resonance. Antiadipogenic experiments were done with mouse 3T3-L1 preadipocytes. A biochemical target of the chemical of interest was identified with drug affinity responsive target stability assay. Direct interactions between the chemical of interest and the protein target in vitro were predicted with molecular docking and subsequently confirmed with surface plasmon resonance. Expression levels of peroxisome proliferator-activated receptor γ (PPARγ), which is associated with 78-kDa glucose-regulated protein (GRP78), were measured with real-time qPCR. Results DHM was isolated, purified, and structurally characterized. Cellular studies showed that DHM notably reduced intracellular oil droplet formation in 3T3-L1 cells with a median effective concentration of 294 μM (i.e., 94 μg/mL). DHM targeted the ATP binding site of GRP78, which is associated with adipogenesis. An equilibrium dissociation constant between DHM and GRP78 was 21.8 μM. In 3T3-L1 cells upon treatment with DHM at 50 μM (i.e., 16 μg/mL), the expression level of PPARγ was downregulated to 53.9% of the solvent vehicle control's level. Conclusions DHM targets GRP78 in vitro. DHM is able to reduce lipid droplet formation in 3T3-L1 cells through a mode of action that is plausibly associated with direct interactions between GRP78 and DHM, which is a step forward in determining potential applications of DHM as an anti-obesity agent.

Acute kidney injury (AKI) is a complex disease associated with increased mortality that may be due to deleterious distant organ effects. AKI associated with respiratory complications, in particular, has a poor outcome. In murine models, AKI is characterized by increased circulating cytokines, lung chemokine upregulation, and neutrophilic infiltration, similar to other causes of indirect acute lung injury (ALI; e.g., sepsis). Many causes of lung inflammation are associated with a lung metabolic profile characterized by increased oxidative stress, a shift toward the use of other forms of energy production, and/or a depleted energy state. To our knowledge, there are no studies that have evaluated pulmonary energy production and metabolism after AKI. We hypothesized that based on the parallels between inflammatory acute lung injury and AKI-mediated lung injury, a similar metabolic profile would be observed. Lung metabolomics and ATP levels were assessed 4 h, 24 h, and 7 days after ischemic AKI in mice. Numerous novel findings regarding the effect of AKI on the lung were observed including 1) increased oxidative stress, 2) a shift toward alternate methods of energy production, and 3) depleted levels of ATP. The findings in this report bring to light novel characteristics of AKI-mediated lung injury and provide new leads into the mechanisms by which AKI in patients predisposes to pulmonary complications.

Aqueous rechargeable zinc metal batteries promise attractive advantages including safety, high volumetric energy density, and low cost; however, such benefits cannot be unlocked unless Zn reversibility meets stringent commercial viability. Herein, we report remarkable improvements on Zn reversibility in aqueous electrolytes when phosphonium-based cations are used to reshape interfacial structures and interphasial chemistries, particularly when their ligands contain an ether linkage. This novel aqueous electrolyte supports unprecedented Zn reversibility by showing dendrite-free Zn plating/stripping for over 6400 h at 0.5 mA cm-2 , or over 280 h at 2.5 mA cm-2 , with coulombic efficiency above 99 % even with 20 % Zn utilization per cycle. Excellent full cell performance is demonstrated with Na2 V6 O16 ⋅1.63 H2 O cathode, which cycles for 2000 times at 300 mA g-1 . The microscopic characterization and modeling identify the mechanism of unique interphase chemistry from phosphonium and its functionalities as the key factors responsible for dictating reversible Zn chemistry.

Supplemental Digital Content is available in the text., Objective: GPVI (glycoprotein VI) is a key molecular player in collagen-induced platelet signaling and aggregation. Recent evidence indicates that it also plays important role in platelet aggregation and thrombus growth through interaction with fibrin(ogen). However, there are discrepancies in the literature regarding whether the monomeric or dimeric form of GPVI binds to fibrinogen at high affinity. The mechanisms of interaction are also not clear, including which region of fibrinogen is responsible for GPVI binding. We aimed to gain further understanding of the mechanisms of interaction at molecular level and to identify the regions on fibrinogen important for GPVI binding. Approach and Results: Using multiple surface- and solution-based protein-protein interaction methods, we observe that dimeric GPVI binds to fibrinogen with much higher affinity and has a slower dissociation rate constant than the monomer due to avidity effects. Moreover, our data show that the highest affinity interaction of GPVI is with the αC-region of fibrinogen. We further show that GPVI interacts with immobilized fibrinogen and fibrin variants at a similar level, including a nonpolymerizing fibrin variant, suggesting that GPVI binding is independent of fibrin polymerization. Conclusions: Based on the above findings, we conclude that the higher affinity of dimeric GPVI over the monomer for fibrinogen interaction is achieved by avidity. The αC-region of fibrinogen appears essential for GPVI binding. We propose that fibrin polymerization into fibers during coagulation will cluster GPVI through its αC-region, leading to downstream signaling, further activation of platelets, and potentially stimulating clot growth.

Ischemia-reperfusion injury (IRI) is an important risk factor for accelerated cardiac allograft rejection and graft dysfunction . Utilizing a rat heart isogeneic transplant model, we identified inflammatory pathways involved in IRI in order to identify therapeutic targets involved in disease. Pathway analyses identified several relevant targets, including cytokine signaling by the IL-1 receptor (IL-1R) pathway and inflammasome activation. To investigate the role of IL-1R signaling pathways during IRI, we treated syngeneic cardiac transplant recipients at 1-hour posttransplant with Anakinra, a US Food and Drug Administration (FDA)-approved IL-1R antagonist; or parthenolide, a caspase-1 and nuclear factor kappa-light-chain-enhancer of activated B cells inhibitor that blocks IL-1β maturation. Both Anakinra and parthenolide significantly reduced graft inflammation and cellular recruitment in the treated recipients relative to nontreated controls. Anakinra treatment administered at 1-hour posttransplant to recipients of cardiac allografts from CMV-infected donors significantly increased the time to rejection and reduced viral loads at rejection. Our results indicate that reducing IRI by blocking IL-1Rsignaling pathways with Anakinra or inflammasome activity with parthenolide provides a promising approach for extending survival of cardiac allografts from CMV-infected donors.

Site-selective protein modification is of significant interest in chemical biology research, with lysine residues representing a particularly challenging target. Whilst lysines are popular for bioconjugation, due to their nucleophilicity, solvent accessibility and the stability of the resultant conjugates, their high abundance means site-selectivity is very difficult to achieve. Antibody–drug conjugates (ADCs) present a powerful therapeutic application of protein modification, and have often relied extensively upon lysine bioconjugation for their synthesis. Here we discuss advances in methodologies for achieving site-selective lysine modification, particularly within the context of antibody conjugate construction, including the cysteine-to-lysine transfer (CLT) protocol which we have recently reported., In this feature article we discuss developments in site-selective lysine modification methodologies and their application towards the synthesis of antibody–drug conjugates; including our recent work on a cysteine-to-lysine transfer (CLT) protocol.

Leucine-rich alpha-2-glycoprotein 1 (LRG1) is present abundantly in the microenvironment of many tumours where it contributes to vascular dysfunction, which impedes the delivery of therapeutics. In this work we demonstrate that LRG1 is predominantly a non-internalising protein. We report the development of a novel antibody–drug conjugate (ADC) comprising the anti-LRG1 hinge-stabilised IgG4 monoclonal antibody Magacizumab coupled to the anti-mitotic payload monomethyl auristatin E (MMAE) via a cleavable dipeptide linker using the site-selective disulfide rebridging dibromopyridazinedione (diBrPD) scaffold. It is demonstrated that this ADC retains binding post-modification, is stable in serum and effective in in vitro cell studies. We show that the extracellular LRG1-targeting ADC provides an increase in survival in vivo when compared against antibody alone and similar anti-tumour activity when compared against standard chemotherapy, but without undesired side-effects. LRG1 targeting through this ADC presents a novel and effective proof-of-concept en route to improving the efficacy of cancer therapeutics., LRG1 is present abundantly in the microenvironment of many tumours. LRG1 targeting through the reported non-internalising ADC presents a novel and effective proof-of-concept en route to improving the efficacy of cancer therapeutics.

A robust and reliable method for enhancing the photoluminescence (PL) of multilayer MoS2 is demonstrated using an oxygen plasma treatment process followed by laser exposure. Here, the plasma and laser treatments result in an indirect-to-direct band gap transition. The oxygen plasma creates a slight decoupling of the layers and converts some of the MoS2 to MoO3. Subsequent laser irradiation further oxidizes the MoS2 to MoO3, as confirmed via X-ray photoelectron spectroscopy, and results in localized regions of brightly luminescent MoS2 monolayer triangular islands as seen in high-resolution transmission electron microscopy images. The PL lifetimes are found to decrease from 494 to 190 ps after plasma and laser treatment, reflecting the smaller size of the MoS2 grains/regions. Atomic force microscopic imaging shows a 2 nm increase in thickness of the laser-irradiated regions, which provides further evidence of the MoS2 being converted to MoO3.

There is increasing evidence that COPD is a disease of accelerated lung aging, with the accumulation of senescent cells that lose their ability to repair and secrete multiple inflammatory proteins known as the senescence-associated secretory phenotype (SASP), which mimic the profile of inflammatory mediators secreted in COPD. This review discusses novel drugs (senotherapies) that target cellular senescence and which may be a promising therapeutic approach to prevent currently unaddressed disease progression and mortality in COPD. A major pathway leading to senescence is via the activation of phosphoinositide-3-kinase/mammalian target of rapamycin signaling. Existing drugs, such as rapamycin and metformin, target this pathway. Mitochondrial oxidative stress is a key driving mechanism for this pathway, and mitochondria-targeted antioxidants are promising. A key finding in COPD is loss of antiaging molecules such as sirtuin-1 and sirtuin-6, which are reduced by phosphoinositide-3-kinase/mammalian target of rapamycin signaling through microRNA-34a. Sirtuin activators are in development, and inhibiting microRNA-34a restores sirtuin expression experimentally in COPD cells. Senolytic therapies induce apoptosis and removal of senescent cells and reduce the senescence-associated secretory phenotype response in animal models of aging and in pilot clinical studies of other age-related diseases. A combination of senolytics and senostatics (drugs that inhibit cellular senescence) may be a valuable new approach to COPD, especially if started early in the disease process. Furthermore, COPD is associated with several comorbidities that share the same aging pathways which may be spread by extracellular vesicles, and thus a single treatment for all these diseases is feasible in the future to extend health span.

Tropical forests absorb large amounts of atmospheric CO2 through photosynthesis, but high surface temperatures suppress this absorption while promoting isoprene emissions. While mechanistic isoprene emission models predict a tight coupling to photosynthetic electron transport (ETR) as a function of temperature, direct field observations of this phenomenon are lacking in the tropics and are necessary to assess the impact of a warming climate on global isoprene emissions. Here we demonstrate that in the early successional species Vismia guianensis in the central Amazon, ETR rates increased with temperature in concert with isoprene emissions, even as stomatal conductance (gs ) and net photosynthetic carbon fixation (Pn ) declined. We observed the highest temperatures of continually increasing isoprene emissions yet reported (50°C). While Pn showed an optimum value of 32.6 ± 0.4°C, isoprene emissions, ETR, and the oxidation state of PSII reaction centers (qL ) increased with leaf temperature with strong linear correlations for ETR (ƿ = 0.98) and qL (ƿ = 0.99) with leaf isoprene emissions. In contrast, other photoprotective mechanisms, such as non-photochemical quenching, were not activated at elevated temperatures. Inhibition of isoprenoid biosynthesis repressed Pn at high temperatures through a mechanism that was independent of stomatal closure. While extreme warming will decrease gs and Pn in tropical species, our observations support a thermal tolerance mechanism where the maintenance of high photosynthetic capacity under extreme warming is assisted by the simultaneous stimulation of ETR and metabolic pathways that consume the direct products of ETR including photorespiration and the biosynthesis of thermoprotective isoprenoids. Our results confirm that models which link isoprene emissions to the rate of ETR hold true in tropical species and provide necessary "ground-truthing" for simulations of the large predicted increases in tropical isoprene emissions with climate warming.

Current influenza virus vaccines are focused on humoral immunity and are limited by the short duration of protection, narrow cross-strain efficacy, and suboptimal immunogenicity. Here, we combined two chemically and biologically distinct adjuvants, an oil-in-water nanoemulsion (NE) and RNA-based agonists of RIG-I, to determine whether the diverse mechanisms of these adjuvants could lead to improved immunogenicity and breadth of protection against the influenza virus. NE activates TLRs, stimulates immunogenic apoptosis, and enhances cellular antigen uptake, leading to a balanced TH1/TH2/TH17 response when administered intranasally. RIG-I agonists included RNAs derived from Sendai and influenza viral defective interfering RNAs (IVT DI, 3php, respectively) and RIG-I/TLR3 agonist, poly(I:C) (pIC), which induce IFN-Is and TH1-polarized responses. NE/RNA combined adjuvants potentially allow for costimulation of multiple innate immune receptor pathways, more closely mimicking patterns of activation occurring during natural viral infection. Mice intranasally immunized with inactivated A/Puerto Rico/8/1934 (H1N1) (PR/8) adjuvanted with NE/IVT DI or NE/3php (but not NE/pIC) showed synergistic enhancement of systemic PR/8-specific IgG with significantly greater avidity and virus neutralization activity than the individual adjuvants. Notably, NE/IVT DI induced protective neutralizing titers after a single immunization. Hemagglutinin stem-specific antibodies were also improved, allowing recognition of heterologous and heterosubtypic hemagglutinins. All NE/RNAs elicited substantial PR/8-specific sIgA. Finally, a unique cellular response with enhanced TH1/TH17 immunity was induced with the NE/RNAs. These results demonstrate that the enhanced immunogenicity of the adjuvant combinations was synergistic and not simply additive, highlighting the potential value of a combined adjuvant approach for improving the efficacy of vaccination against the influenza virus.

Targeting protein degradation with Proteolysis-Targeting Chimeras (PROTACs) is an area of great current interest in drug discovery. Nevertheless, although the high effectiveness of PROTACs against a wide variety of targets has been established, most degraders reported to date display limited intrinsic tissue selectivity and do not discriminate between cells of different types. Here, we describe a strategy for selective protein degradation in a specific cell type. We report the design and synthesis of a trastuzumab-PROTAC conjugate (Ab-PROTAC 3) in which E3 ligase-directed degrader activity is caged with an antibody linker which can be hydrolyzed following antibody–PROTAC internalization, releasing the active PROTAC and inducing catalytic protein degradation. We show that 3 selectively targets bromodomain-containing protein 4 (BRD4) for degradation only in HER2 positive breast cancer cell lines, while sparing HER2 negative cells. Using live cell confocal microscopy, we show internalization and lysosomal trafficking of the conjugate specifically in HER2 positive cells, leading to the release of active PROTAC in quantities sufficient to induce potent BRD4 degradation. These studies demonstrate proof-of-concept for tissue-specific BRD4 degradation, overcoming limitations of PROTAC selectivity, with significant potential for application to novel targets.

Lead (Z)-N-(4-(2-cyano-2-(3,4-dichlorophenyl)vinyl)phenyl)acetamide, 1 showed MCF-7 GI50 =30 nM and 400-fold selective c.f. MCF10A (normal breast tissue). Acetamide moiety modification (13 a-g) to introduce additional hydrophobicity was favoured with MCF-7 breast cancer cell activity enhanced at 1.3 nM. Other analogues were potent against the HT29 colon cancer cell line at 23 nM. Textbook SAR data was observed in the MCF-7 cell line, in an MTT assay, via the ortho (17 a), meta (17 b) and para (13 f). The amino alcohol -OH moiety was pivotal, but no stereochemical preference noted. But, these data did not fit our homology modelling expectations. Aberrant MTT ((3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl-tetrazolium bromide) screening results and metabolic interference confirmed by sulforhodamine B (SRB) screening. Interfering analogues resulted in 120 and 80-fold CYP1A1 and CYP1A2 amplification, with no upregulation of SULT1A1. This is consistent with activation of the AhR pathway. Piperidine per-deuteration reduced metabolic inactivation. 3-OH / 4-OH piperidine analogues showed differential MTT and SRB activity supporting MTT assay metabolic inactivation. Data supports piperidine 3-OH, but not the 4-OH, as a CYP substrate. This family of β-amino alcohol substituted 3,4-dichlorophenylacetonitriles show broad activity modulated via the AhR pathway. By SRB analysis the most potent analogue was 23 b, (Z)-3-(4-(3-(4-phenylpiperidin-1-yl)-2-hydroxypropoxy)phenyl)-2-(3,4-dichlorophenyl)-acrylonitrile.

Diseases are multifactorial, with redundancies and synergies between various pathways. However, most of the antibody-based therapeutics on the market interact with only one target, thus limiting their efficacy. The targeting of multiple epitopes could improve the therapeutic index of treatment and counteract mechanisms of resistance. To this effect, a new class of therapeutics has emerged: bispecific antibodies. Bispecific formation using chemical methods is rare and low-yielding and/or requires a large excess of one of the two proteins to avoid homodimerization and heterogeneity. In order for chemically prepared bispecifics to deliver their full potential, high-yielding, modular, and reliable cross-linking technologies are required. Herein, we describe a novel approach not only for the rapid and high-yielding chemical generation of bispecific antibodies from native antibody fragments, but also for the site-specific dual functionalization of the resulting bioconjugates. Based on orthogonal clickable functional groups, this strategy enables the assembly of functionalized bispecifics with controlled loading in a modular and convergent manner.

Despite its importance in the design of photocaged molecules, less attention is focused on linker chemistry than the cage itself. Here, we describe unique uncaging properties displayed by two coumarin-caged thymidine compounds, each conjugated with (2) or without (1) an extended, self-immolative spacer. Photolysis of 1 using long wavelength UVA (365 nm) or visible (420, 455 nm) light led to the release of free thymidine along with the competitive generation of a thymidine-bearing recombination product. The occurrence of this undesired side reaction, which is previously unreported, was not present with the photolysis of 2, which released thymidine exclusively with higher quantum efficiency. We propose that the spatial separation between the cage and the substrate molecule conferred by the extended linker can play a critical role in circumventing this unproductive reaction. This report reinforces the importance of linker selection in the design of coumarin-caged oligonucleosides and other conjugates.

Concentrations of fluorine and chlorine were measured in glasses (quenched melts) and coexisting clinopyroxene, orthopyroxene, olivine, and plagioclase in run products of experiments previously used to measure sulfur partitioning between these phases. The partitioning of F between clinopyroxene and silicate melt was determined in 13 experiments at a variety of pressures, temperatures, and melt compositions ranging from basaltic to dacitic (49 to 66 wt% SiO2) at 0.8 to 1.2 GPa and 1000 to 1240 °C, at hydrous and anhydrous conditions. Additionally, we determined the crystal-melt partitioning of F for 4 experiments with plagioclase, 2 with orthopyroxene, and 1 with olivine. Although Cl was also measured in the experiments, the concentrations in the crystals are close to background concentration levels. The partition coefficients of fluorine between clinopyroxene and melt varied from ~0.09 to 0.29 and were linearly dependent upon the concentration of aluminum in the octahedral M1 site of clinopyroxene. Similar relationships are seen when our results are combined with previous measurements of the fluorine partition coefficient between clinopyroxene and melt, but each study shows its own unique correlation between the F partition coefficient and AlM1. These dissimilarities in correlations with AlM1 are attributed to differing analytical protocols used in the various studies. However, the combined data set demonstrates a linear correlation with AlM1, the inverse of the NBO/T ratio of the melt (T/NBO), pressure and temperature, which can be described as: l n ⁡ ( D F C p x / L ) = ( 0.2298 ± 0.04847 ) ( T / N B O ) - ( 1.029 ± 0.8045 ) ( A l M 1 ) - ( 3889 ± 1803 ) ( 1 / T ) - ( 0.5472 ± 0.1084 ) ( P ) + 0.5871 ± 1.304 , where each uncertainty is 1 standard error in the fit (as calculated by the R-project software), T is in K, and P is in GPa. Although this relationship reproduces 81% of the partitioning data to within 25% (relative), the different linear trends of the partition coefficient, DFCpx/L vs. AlM1 from different laboratories suggest the need for additional investigations and development of clinopyroxene standards with certified fluorine compositions. Nevertheless, we conclude that the self-consistency of each study indicates that F partition coefficients determined using one protocol can be applied to minerals or glasses analyzed using the same protocol and ion microprobe to better understand the storage and transport of fluorine in magmatic systems.

We have compiled and analyzed a comprehensive dataset of field observations of iodine speciation in marine aerosol. The soluble iodine content of fine aerosol (PM1) is dominated by soluble organic ...

Fibrinogen is essential for blood coagulation. The C-terminus of the fibrinogen α-chain (αC-region) is composed of an αC-domain and αC-connector. Two recombinant fibrinogen variants (α390 and α220) were produced to investigate the role of subregions in modulating clot stability and resistance to lysis. The α390 variant, truncated before the αC-domain, produced clots with a denser structure and thinner fibres. In contrast, the α220 variant, truncated at the start of the αC-connector, produced clots that were porous with short, stunted fibres and visible fibre ends. These clots were mechanically weak and susceptible to lysis. Our data demonstrate differential effects for the αC-subregions in fibrin polymerisation, clot mechanical strength, and fibrinolytic susceptibility. Furthermore, we demonstrate that the αC-subregions are key for promoting longitudinal fibre growth. Together, these findings highlight critical functions of the αC-subregions in relation to clot structure and stability, with future implications for development of novel therapeutics for thrombosis.

Methionine synthase deficiency (cblG complementation group) is a rare inborn error of metabolism affecting the homocysteine re-methylation pathway. It leads to a biochemical phenotype of hyperhomocysteinemia and hypomethioninemia. The clinical presentation of cblG is variable, ranging from seizures, encephalopathy, macrocytic anemia, hypotonia, and feeding difficulties in the neonatal period to onset of psychiatric symptoms or acute neurologic changes in adolescence or adulthood. Given the variable and non-specific symptoms seen in cblG, the diagnosis of affected patients is often delayed. Medical management of cblG includes the use of hydroxocobalamin, betaine, folinic acid, and in some cases methionine supplementation. Treatment has been shown to lead to improvement in the biochemical profile of affected patients, with lowering of total homocysteine levels and increasing methionine levels. However, the published literature contains differing conclusions on whether treatment is effective in changing the natural history of the disease. Herein, we present 5 patients with cblG who have shown substantial clinical benefit from treatment with objective improvement in their neurologic outcomes. We demonstrate more favorable outcomes in our patients who were treated early in life, especially those who were treated before neurologic symptoms manifested. Given improved outcomes from treatment of pre-symptomatic patients, cblG warrants inclusion in newborn screening. This article is protected by copyright. All rights reserved.

Focal cortical dysplasia (FCD) is one of the most common malformations causing refractory epilepsy. Dysregulation of glutamatergic systems plays a critical role in the hyperexcitability of dysplastic neurons in FCD lesions. The pharmacoresistant nature of epilepsy associated with FCD may be due to a lack of well tolerated and precise antiepileptic drugs that can target glutamate receptors. Here, for the first time in human FCD brain slices, we show that the established, non-competitive α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist, perampanel has potent antiepileptic action. Moreover, we demonstrate that this effect is due to a reduction in burst firing behavior in human FCD microcircuits. These data support a potential role for the treatment of refractory epilepsy associated with FCD in human patients.

Conditions related to cardiometabolic disease, including metabolic syndrome and type 2 diabetes, are common among men with Klinefelter syndrome (KS).The molecular mechanisms underlying this aberrant metabolism in KS are largely unknown, although there is an assumption that chronic testosterone deficiency plays a role. This cross-sectional study compared plasma metabolites in 31 pubertal adolescent males with KS to 32 controls of similar age (14 ± 2 yrs), pubertal stage, and body mass index z-score (0.1 ± 1.2), and then between testosterone treated (n=16) and untreated males with KS. The plasma metabolome in males with KS was distinctly different from controls, with 22% of measured metabolites having a differential abundance and seven metabolites nearly completely separating KS from controls (AUC>0.9, p

A double-exchange interaction (DEI) was demonstrated to boost the oxygen evolution reaction (OER) in spinel oxides. DEI was ignited by synergistic actions of constructing nanoheterojunctions and creating oxygen vacancy (V

Breast cancer is the most common cancer in women, with more than 1.7 million diagnoses worldwide per annum. Metastatic breast cancer remains incurable, and the presence of triple-negative phenotypes makes targeted treatment impossible. The aryl hydrocarbon receptor (AhR), most commonly associated with the metabolism of xenobiotic ligands, has emerged as a promising biological target for the treatment of this deadly disease. Ligands for the AhR can be classed as exogenous or endogenous and may have agonistic or antagonistic activity. It has been well reported that agonistic ligands may have potent and selective growth inhibition activity in a number of oncogenic cell lines, and one (aminoflavone) has progressed to phase I clinical trials for breast cancer sufferers. In this study, we examine the current state of the literature in this area and elucidate the promising advances that are being made in hijacking the cytosolic-to-nuclear pathway of the AhR for the possible future treatment of breast cancer.

The Au-rich polymetallic massive sulfide orebodies of the Kassandra mining district belong to the intrusion-related carbonate-hosted replacement deposit class. Marble lenses contained within the Stratoni fault zone host the Madem Lakkos and Mavres Petres deposits at the eastern end of the fault system, where paragenetically early skarn and massive sulfide are spatially associated with late Oligocene aplitic and porphyritic dikes. Skarn transitions into predominant massive and banded replacement sulfide bodies, which are overprinted by a younger assemblage of boulangerite-bearing, quartz-rich sulfide and late quartz-rhodochrosite vein breccias. The latter style of mineralization is most abundant at the Piavitsa prospect at the western end of the exposed fault system. The sulfide orebodies at the Olympias deposit are hosted by marble in association with the Kassandra fault, where textural and mineralogical similarities to the sulfide bodies within the Stratoni fault zone suggest a genetic relationship. Estimated trapping temperatures and pressures based on fluid inclusion data indicate that carbonate replacement mineralization took place at depths less than about 5.9 km. Carbon and oxygen isotope patterns in carbonate from the Stratoni fault zone support isotopic exchange principally through fluid–wall-rock interaction, whereas decarbonation and fluid-rock exchange reactions were important at the Olympias deposit. Carbonate minerals associated with skarn and replacement sulfide throughout the district have isotopic compositions that are consistent with formation from a hydrothermal fluid of magmatic origin. Lower homogenization temperatures and salinities in the younger quartz-rich sulfide assemblage and quartz-rhodochrosite vein breccias, together with low δ18O values of gangue carbonate, suggest dilution of a primary magmatic fluid with meteoric water late in the evolution of the hydrothermal system in both the Olympias area and the Stratoni fault zone. The replacement sulfide orebodies in the district likely inherited their uniform Pb isotope composition from a late Oligocene igneous source and the isotopically heterogeneous metamorphic basement units. Metal distribution patterns at the scale of the Stratoni fault zone show diminishing Cu concentration with decreasing Pb/Zn and Ag/Au ratios from Madem Lakkos to Mavres Petres and the Piavitsa prospect in the west. The sulfide orebodies at the Olympias deposit exhibit elevated Cu values in the east with increasing Pb/Zn and Ag/Au ratios down-plunge to the south-southwest. Metal concentration and ratios support zoning related to temperature and solubility changes with increasing distance from a probable magmatic source. Structural and igneous relationships, together with fluid inclusion microthermometric and carbon-oxygen isotope data and metal distribution patterns, are supportive of a zoned hydrothermal system that exceeded 12 km along the Stratoni fault zone, sourced by an igneous intrusion to the southeast of the Madem Lakkos deposit. The Olympias replacement sulfide orebodies, associated with the Kassandra fault, resulted from a local hydrothermal system that was likely derived from a concealed igneous intrusion to the east of the deposit.

Introduction The Tethyan mountain ranges stretch from northwestern Africa and western Europe to the southwest Pacific Ocean and constitute the longest continuous orogenic belt on Earth. It is an extremely fertile metallogenic belt, which includes a wide diversity of ore deposit types formed in very different geodynamic settings, which are the source of a wide range of commodities mined for the benefit of society (Janković, 1977, 1997; Richards, 2015, 2016). There are other ore deposit types in this segment of the Tethyan metallogenic belt that are not covered in this special issue, such as bauxite and Ni laterite deposits (Herrington et al., 2016), ophiolite-related chromite deposits (Çiftçi et al., 2019), sedimentary exhalative and Mississippi Valley-type deposits (Palinkaš et al., 2008; Hanilçi et al., 2019), or deposits related to surficial brine processes (Helvacı, 2019).

Sluggish water dissociation kinetics on nonprecious metal oxide electrocatalysts is considered as the rate-limiting step for the development of hydrogen evolution in alkaline media. A unique hetero...

Photosynthetic organisms use nonphotochemical quenching (NPQ) mechanisms to dissipate excess absorbed light energy and protect themselves from photooxidation. In the model green alga Chlamydomonas reinhardtii , the capacity for rapidly reversible NPQ (qE) is induced by high light, blue light, and UV light via increased expression of LHCSR and PSBS genes that are necessary for qE. Here, we used a forward genetics approach to identify SPA1 and CUL4, components of a putative green algal E3 ubiquitin ligase complex, as critical factors in a signaling pathway that controls light-regulated expression of the LHCSR and PSBS genes in C. reinhardtii . The spa1 and cul4 mutants accumulate increased levels of LHCSR1 and PSBS proteins in high light, and unlike the wild type, they express LHCSR1 and exhibit qE capacity even when grown in low light. The spa1-1 mutation resulted in constitutively high expression of LHCSR and PSBS RNAs in both low light and high light. The qE and gene expression phenotypes of spa1-1 are blocked by mutation of CrCO, a B-box Zn-finger transcription factor that is a homolog of CONSTANS, which controls flowering time in plants. CONSTANS-like cis -regulatory sequences were identified proximal to the qE genes, consistent with CrCO acting as a direct activator of qE gene expression. We conclude that SPA1 and CUL4 are components of a conserved E3 ubiquitin ligase that acts upstream of CrCO, whose regulatory function is wired differently in C. reinhardtii to control qE capacity via cis -regulatory CrCO-binding sites at key photoprotection genes.

Alternative medical therapy with multiple intravenous colloidal silver infusions may cause severe illness, including profound copper deficiency‐induced anemia and hepatic toxicity. No chelating agent for silver poisoning exists and effective therapy requires apheresis in combination with continuous administration of oral copper.

We conducted a series of monazite and xenotime dissolution experiments in a boron-bearing silicic melt at 1000–1400 °C and 800 MPa in a piston-cylinder apparatus. We present new measurements of monazite and xenotime solubility in hydrous (~3 wt% water), boron-bearing rhyolitic melts, as well as the diffusivities of the essential structural constituents of those minerals (LREE, P, and Y). We compare our results to the previous studies and discuss the implications of this study on the understanding of natural, silicic (granitic/rhyolitic) systems. We propose one equation describing the relationship between the solubility of xenotime and temperature in hydrous rhyolitic melts: ln ⁡ Y = 18.3 ± 0.3 − 125499 ± 3356 R T and another for monazite: ln ⁡ Σ LREE = 18.6 ± 1.5 − 129307 ± 18163 R T . In the presence of sufficient phosphorous, the concentration of LREE needed for monazite saturation is within the uncertainty of the Y concentration needed from xenotime saturation and indicates that in the case of equilibrium crystallization the mineral that forms will only depend on the availability of LREE and Y and HREE. Given the similarity of the solubility of xenotime to that of monazite, we propose that previously published models of monazite solubility in silicic melts can potentially be applied to xenotime, and could, like monazite, serve as a geothermometer. In the case of disequilibrium crystallization in front of rapidly growing crystals, Y will diffuse faster than LREE and xenotime will only crystallize when LREE are depleted. We also found that the diffusion of Y is greater than the diffusion of P from dissolving xenotime, unlike the similar diffusivities of LREE and P during monazite dissolution. The significant difference between Y and P diffusivities suggests that the components forming xenotime diffuse as separate entities rather than molecular complexes. The dissolution of phosphates (monazite, xenotime, apatite) in hydrous, silicic melts with the addition of boron leads to liquid-liquid immiscibility at high temperatures where the saturation values of P and either light rare earth elements or Y are in the weight percent range. Immiscibility is not observable at low, magmatic temperatures, most probably due to the lower concentrations of P2O5 necessary for phosphate saturation at these conditions; however addition of other components, notably F, may result in liquid-liquid immiscibility at magmatic temperatures.

Uranium (U) contamination is a major environmental problem associated with the mining and processing of nuclear materials for both weapons and power production. When possible, in situ soil remediation techniques are preferable for reducing the risk associated with diffuse low-level U contamination. Uranium is known to form sparingly soluble phosphate compounds that persist in the environment. Therefore, batch experiments were performed to evaluate the efficacy of three phosphate amendments, hydroxyapatite (HA), sodium phytate (IP6) and sodium tripolyphosphate (TPP), to immobilize U in contaminated sediments. The amendments were added at equivalent phosphorus (P) concentrations and then equilibrated under a range of test conditions, with changes in soluble U and Ptotal monitored at pre-set time intervals. Only HA was effective at reducing the soluble U soil fraction when compared to the control, with IP6 and TPP increasing the soluble U soil fraction. After equilibration, changes in contaminant partitioning in the amended sediments were evaluated using operational extraction methods. Sequential extraction results for HA generally indicated a transfer of U from labile to more recalcitrant phases, while the results for IP6 and TPP were more ambiguous. Keywords: Soil contamination, Uranium, Uranyl, Phytate, Hydroxyapatite, Phosphate, Autunite, Batch experiment, Immobilization, Sequential extraction

The electrocatalytic oxidation of urea using Ni-based catalysts is able to oxidize urea at high rates, reaching hundreds of mA cm−2 depending on electrode and solution properties. Most of the demonstrated systems, however, report a drop-off in current ~ 0.3 V positive of the Ni2+/Ni3+ redox transition resulting in a dramatic decrease of activity. The drop-off limits the electrochemical window available for urea decomposition. To overcome this narrow window, Ni2+ ions are herein adsorbed onto carbon black electrodes cohesively bound with Nafion. The resulting electrodes are electrochemically tested for urea electro-oxidation activity whereby their cyclic voltammograms display no drop-off in activity up to 1.5 V positive of the Ni2+/Ni3+ transition. The oxidation currents of the adsorbed Ni2+ electrodes demonstrate urea decomposition rates nearly identical to Ni-metal films, and impedance measurements show similar charge transfer limitations. Electrodes are monitored after electrochemical cycling with atomic force microscopy to reveal that adsorbed species coalesce into surface particles, which behave like bulk Ni(OH)2, implying that the commonly observed drop-off in current may be due to structural characteristics of Ni(OH)2 and NiOOH. The simplicity of the adsorption process and its ability to widen the electrochemical window for urea oxidation allows new substrates to be incorporated into urea degradation systems without sacrificing high urea oxidation rates.