Oral Carbon Monoxide Enhances Autophagy Modulation in Prostate, Pancreatic, and Lung Cancers.

Modulation of autophagy, specifically its inhibition, stands to transform the capacity to effectively treat a broad range of cancers. However, the clinical efficacy of autophagy inhibitors has been inconsistent. To delineate clinical and epidemiological features associated with autophagy inhibition and a positive oncological clinical response, a retrospective analysis of patients is conducted treated with hydroxychloroquine, a known autophagy inhibitor. A direct correlation between smoking status and inhibition of autophagy with hydroxychloroquine is identified. Recognizing that smoking is associated with elevated circulating levels of carbon monoxide (CO), it is hypothesized that supplemental CO can amplify autophagy inhibition. A novel, gas-entrapping material containing CO in a pre-clinical model is applied and demonstrated that CO can dramatically increase the cytotoxicity of autophagy inhibitors and significantly inhibit the growth of tumors when used in combination. These data support the notion that safe, therapeutic levels of CO can markedly enhance the efficacy of autophagy inhibitors, opening a promising new frontier in the quest to improve cancer therapies.

Host surface orientation impacts environmental film accumulations.

Two environmental films were passively collected in different orientations (vertical or horizontal) at the same location over two months. We characterized these films using bright field microscopy, total dissolved species analysis, pH analysis, vibrational interfacial spectroscopy, and contact angle goniometry. Results show that horizontal films have significantly higher surface coverage than the vertical samples (+50%). The vertical and horizontal films also show different particle morphologies but the particle size distributions are not statistically different. Vertical surfaces have smaller, less compact particulate suggesting particle adsorption depends on the surface area in contact with the parent substrate. Horizontal surfaces also generate more total dissolved solid material per unit area when washed with water (+61%). The dissolved solids from the vertical substrate are more acidic per unit mass, suggesting increased pH active species like nitrate, sulfate, or organic acids. Vibrational spectroscopy provides evidence of nitrates and sulfates in both films, but spectroscopic profiles show these ions are present in different forms. Contact angle goniometry measurements show horizontal films are more hydrophilic than vertical films, despite being deposited on the same substrate material. We also report significantly different hydrogen bonding environments for condensed water between the two films. Our results suggest that environmental films deposited on vertical vs horizontal surfaces will have significantly different characteristics, informing models for deposition and impacts to human and environmental health.

Solvents and Stabilization in Ionic Liquid Films.

We report the interfacial structures and chemical environments of ionic liquid films as a function of dilution with molecular solvents and over a range of film thicknesses (a few micrometers). Data from spectroscopic ellipsometry and infrared spectroscopy measurements show differences between films comprised of neat ionic liquids, as well as films comprised of ionic liquids diluted with two molecular solvents (water and acetonitrile). While the water-diluted IL films follow thickness trends predicted by the Landau-Levich model, neat IL and IL/MeCN films deviate significantly from predicted behaviors. Specifically, these film thicknesses are far greater than the predicted values, suggesting enhanced intermolecular interactions or other non-Newtonian behaviors not captured by the theory. We correlate film thicknesses with trends in the infrared intensity profiles across film thicknesses and IL-solvent dilution conditions and interpret the changes from expected behaviors as varying amounts of the film volume existing in isotropic (bulk) vs anisotropic (interfacial) states. The hydrogen bonding network of water-diluted ionic liquids is implicated in the agreement of this system with the Landau-Levich model's thickness predictions.

Quantifying Variations in Metal-Ligand Cooperative Binding Strength with Cyclic Voltammetry and Redox-Active Ligands.

Metal-ligand cooperativity (MLC), a phenomenon that leverages reactive ligands to promote synergistic reactions with metals, has proven to be a powerful approach to achieving new and unprecedented chemical transformations with metal complexes. While many examples of MLC are known with a wide range of substrates, experimentally quantifying how ligand modifications affect MLC binding strength remains a challenge. Here we describe how cyclic voltammetry (CV) was used to quantify differences in MLC binding strength in a series of square-pyramidal Ru complexes. This method relies on using multifunctional ligands (those capable of both MLC and ligand-centered redox activity) as electrochemical reporters of MLC binding strength. The synthesis and characterization of Ru complexes with three different redox-active tetradentate ligands and two different ancillary phosphines (PPh3 and PCy3) are described. Titration CV studies conducted using BH3·THF with BH3 as a model MLC substrate allowed ΔGMLC to be quantified for each complex. Compared to our base triaryl ligand, increasing π conjugation in the backbone of the redox-active ligand enhanced MLC binding, whereas increasing π conjugation in the flanking groups decreased the MLC binding strength. Structures and spectroscopic data collected for the isolated MLC complexes are also described along with supporting DFT calculations that were used to illuminate electronic factors that likely account for the observed differences in the MLC binding strength. These results demonstrate how redox-active ligands and CV can be used to quantify subtle differences in the MLC binding strength across a series of structurally related complexes with different ligand modifications.

Association of Chemical Aggregates and Fungal Moieties Affecting Native Environmental Films.

Fungi are prevalent microorganisms in environmental films. Their impacts on the film chemical environment and morphology remains poorly defined. Here we present microscopic and chemical analyses fungi impacts to environmental films over long- and short-time scales. We report bulk properties of films accumulated for 2 months (February and March 2019) and 12 months to contrast short and longer-term effects. Bright field microscopy results show that fungi and fungal-associated aggregates cover close to 14% of the surface after 12 months and include significant numbers of large (tens to hundreds of µm in diameter) particles aggregated with fungal colonies. Data acquired for films accumulated over shorter times (2 months) suggest mechanisms that contribute to these longer-term effects. This is important because the film's exposed surface will determine what additional material will accumulate over the ensuing weeks or months. A combination of scanning electron microscopy and energy dispersive X-ray spectroscopy provides spatially resolved maps of fugal hypha and nearby elements of interest. We also identify a "nutrient pool" associated with the fungal hypha which extend orthogonally to the growth direction to ca. 50 µm distances. We conclude that fungi have both short-term and long-term effects on the chemistry and morphology of environmental film surfaces. In short, the presence (or absence) of fungi will significantly alter the films' evolution and should be considered when analyzing environmental film impacts on local processes.

Practical Online Monitoring of Ionic Liquid Fiber Welding Solvent.

Ionic liquids (ILs) are becoming important solvents in commerce, but monitoring their purity and performance in industrial applications presents new challenges. Fiber welding technology utilizes ILs to mold and shape natural fibers (cotton, hemp, flax, silk, and wool) into morphologies that are typically attained only using synthetic, petroleum-based non-biodegradable plastics. The result is an atom-efficient process that up-converts fibrous substrates to value-added products and materials. A key aspect of bringing this and other IL-enabled technologies to market relies on efficient monitoring and recycling of IL-based solvents. Implementing online IL quality monitoring enhances the unit economics of these processes. Here, we characterize and report conductivity measurements, refractometry, and ATR-FTIR spectroscopy techniques for online IL monitoring during an industrial fiber welding process. The online analysis enables more efficient recycling of the IL solvent, increasing the process efficiency and product quality.

Enabling Superhydrophobicity-Guided Superwicking in Metal Alloys via a Nanosecond Laser-Based Surface Treatment Method.

Enabling capillary wicking on bulk metal alloys is challenging due to processing complexity at different size scales. This work presents a laser-chemical surface treatment to fabricate superwicking patterns guided by a superhydrophobic region over a large-area metal alloy surface. The laser-chemical surface treatment generates surface micro/nanostructures and desirable surface chemistry simultaneously. The superhydrophobic surface was first fabricated over the whole surface by laser treatment under water confinement and fluorosilane treatment; subsequently, superwicking stripes were processed by a second laser treatment in air and cyanosilane treatment. The resultant surface shows superwicking regions surrounded by superhydrophobic regions. During the process, superwicking regions possess dual-scale structures and polar nitrile surface chemistry. In contrast, random nanoscale structures and fluorocarbon chemistry are generated on the superhydrophobic region of the aluminum alloy 6061 substrates. The resultant superwicking region demonstrates self-propelling anti-gravity liquid transport for methanol and water. The combination of the capillary effect of the dual-scale surface microgrooves and the water affinitive nitrile group contributes toward the self-propelling movement of water and methanol at the superwicking region. The initial phase of wicking followed Washburn dynamics, whereas it entered a non-linear regime in the later phase. The wicking height and rate are regulated by microgroove geometry and spacing.

Effect of silver electrode wetting state on oxygen reduction electrochemistry.

Surface wettability plays an important role in heterogeneous electrocatalysis. Here we report a facile laser ablation strategy to directly modify the wettability of the silver catalyst surface and investigate its effect on oxygen reduction reaction (ORR). A broad range tuning of 2e-/4e- ORR pathways was achieved, with hydrophilic silver surfaces (contact angle (θw) 31.1°± 0.6°) showing high activity and selectivity towards 4e- reduction of oxygen to water.

Imidazolium Triflate Ionic Liquids' Capacitance-Potential Relationships and Transport Properties Affected by Cation Chain Lengths.

In this paper we report the effects of five imidazolium cations with varying alkyl chain lengths to study the effects of cation size on capacitance versus voltage behavior. The cations include ethyl-, butyl-, hexyl-, octyl-, and decyl-3-methylimidazolium, all paired with a triflate anion. We analyze the capacitance with respect to the cation alkyl chain length qualitatively and quantitatively by analyzing changes in the capacitance-potential curvature shape and magnitude across several standard scanning protocols and electrochemical techniques. Further, three transport properties (viscosity, diffusion coefficient, and electrical conductivity) are experimentally determined and integrated into the outcomes. Ultimately, we find higher viscosities, lower diffusion coefficients, and lower electrical conductivities when the alkyl chain length is increased. Also, capacitance values increase with cation size, except 1-octyl-3-methylimidazolium, which does not follow an otherwise linear trend. This capacitive increase is most pronounced when sweeping the potential in the cathodic direction. These findings challenge the conventional hypothesis that increasing the length of the alkyl chain of imidazolium cations diminishes the capacitance and ionic liquid performance in charge storage.

Influence of Multisite Metal-Ligand Cooperativity on the Redox Activity of Noninnocent N2S2 Ligands.

Metal-ligand cooperativity (MLC) relies on chemically reactive ligands to assist metals with small-molecule binding and activation, and it has facilitated unprecedented examples of catalysis with metal complexes. Despite growing interest in combining ligand-centered chemical and redox reactions for chemical transformations, there are few studies demonstrating how chemically engaging redox active ligands in MLC affects their electrochemical properties when bound to metals. Here we report stepwise changes in the redox activity of model Ru complexes as zero, one, and two BH3 molecules undergo MLC binding with a triaryl noninnocent N2S2 ligand derived from o-phenylenediamine (L1). A similar series of Ru complexes with a diaryl N2S2 ligand with ethylene substituted in place of phenylene (L2) is also described to evaluate the influence of the o-phenylenediamine subunit on redox activity and MLC. Cyclic voltammetry (CV) studies and density functional theory (DFT) calculations show that MLC attenuates ligand-centered redox activity in both series of complexes, but electron transfer is still achieved when only one of the two redox-active sites on the ligands is chemically engaged. The results demonstrate how incorporating more than one multifunctional reactive site could be an effective strategy for maintaining redox noninnocence in ligands that are also chemically reactive and competent for MLC.

Design of Chemical Surface Treatment for Laser-Textured Metal Alloys to Achieve Extreme Wetting Behavior.

Extreme wetting activities of laser-textured metal alloys have received significant interest due to their superior performance in a wide range of commercial applications and fundamental research studies. Fundamentally, extreme wettability of structured metal alloys depends on both the surface structure and surface chemistry. However, compared with the generation of physical topology on the surface, the role of surface chemistry is less explored for the laser texturing processes of metal alloys to tune the wettability. This work introduces a systematic design approach to modify the surface chemistry of laser textured metal alloys to achieve various extreme wettabilities, including superhydrophobicity/superoleophobicity, superhydrophilicity/superoleophilicity, and coexistence of superoleophobicity and superhydrophilicity. Microscale trenches are first created on the aluminum alloy 6061 surfaces by nanosecond pulse laser surface texturing. Subsequently, the textured surface is immersion-treated in several chemical solutions to attach target functional groups on the surface to achieve the final extreme wettability. Anchoring fluorinated groups (-CF2- and -CF3) with very low dispersive and nondispersive surface energy leads to superoleophobicity and superhydrophobicity, resulting in repelling both water and diiodomethane. Attachment of the polar nitrile (-C≡N) group with very high nondispersive and high dispersive surface energy achieves superhydrophilicity and superoleophilicity by drawing water and diiodomethane molecules in the laser-textured capillaries. At last, anchoring fluorinated groups (-CF2- and -CF3) and polar sodium carboxylate (-COONa) together leads to very low dispersive and very high nondispersive surface energy components. It results in the coexistence of superoleophobicity and superhydrophilicity, where the treated surface attracts water but repels diiodomethane.

Cambiarenes: Single-Step Synthesis and Selective Zwitterion Binding of a Clip-Shaped Macrocycle with a Redox-Active Core.

A novel macrocyclic host molecule was synthesized that forms in a single step from commercially available starting materials. The core of the macrocycle backbone possesses two quinone rings and, thus, it is redox-active. Host-guest binding involving the clip-shaped cavity indicates selective binding of pyridine N-oxides based on the electron density of and steric bulk around the anionic oxygen.

The Influence of Redox-Innocent Donor Groups in Tetradentate Ligands Derived from o-Phenylenediamine: Electronic Structure Investigations with Nickel.

The continued development of redox-active ligands requires an understanding as to how ligand modifications and related factors affect the locus of redox activity and spin density in metal complexes. Here we describe the synthesis, characterization, and electronic structure of nickel complexes containing triaryl NNNN (1) and SNNS (2) ligands derived from o-phenylenediamine. The tetradentate ligands in 1 and 2 were investigated and compared to those in metal complexes with compositionally similar ligands to determine how ligand-centered redox properties change when redox-active flanking groups are replaced with redox-innocent NMe2 or SMe. A derivative of 2 in which the phenylene backbone was replaced with ethylene (3) was also prepared to interrogate the importance of o-phenylenediamine for ligand-centered redox activity. Cyclic voltammograms collected for 1 and 2 revealed two fully reversible ligand-centered redox events. Remarkably, several quasi-reversible ligand-centered redox waves were also observed for 3 despite the absence of the o-phenylenediamine subunit. Oxidizing 1 and 2 with silver salts containing different counteranions (BF4-, OTf-, NTf2-) allowed the electrochemically generated complexes to be analyzed as a function of different oxidation states using single-crystal X-ray diffraction (XRD), EPR spectroscopy, and S K-edge X-ray absorption spectroscopy. The experimental data are corroborated by DFT calculations, and together, they reveal how the location of unpaired spin density and electronic structure in singly and doubly oxidized salts of 1 and 2 varies depending on the coordinating ability of the counteranions and exogenous ligands such as pyridine.

Thermotropic Phase Transitions in Butyltrimethylammonium Bis(trifluoromethylsulfonyl)imide Ionic Liquids are Dependent on Heat Flux.

Transmission infrared spectroscopy (IR) and differential scanning calorimetry are used to identify and characterize multiple phase transitions of butyltrimethylammonium bis(trifluoromethylsulfonyl)imide ([N1114] [TFSI]). Phase-dependent properties are analyzed using temperature-controlled transmission IR, in which we identify changes in the molecular arrangements at and around phase transition temperatures between -80 and 30 °C, which span crystallization and melting phase transitions. Our data report the dependence of phase transition behavior across multiple heat flow rates and the resulting molecular organizations that are formed. This is significant as temperature-specific organizations and properties of ionic liquids (ILs) contribute significantly to their application in separations and in devices. We also identify and discuss the relationship between phase transition temperatures and classes of those transitions when various temperature ramp rates are applied. Our analysis indicates that these relationships of IL thermochemistry could be developed as a diagnostic for assigning phase transition types.

Effects and controls of capacitive hysteresis in ionic liquid electrochemical measurements.

Capacitance vs. potential relationships help electrochemists better understand electrode-liquid interfacial behaviors. However, the current ionic liquid literature does not have a unified experimental approach, and hysteresis effects are of significant concern. Known experimental variables that can influence capacitance-potential data include electrode material and morphology, potential scan direction, equivalent circuit model applied during analysis, and, to some extent, the electrochemical technique employed. To our knowledge, the present work is the first systematic study of four major variables that are relevant to IL-based capacitance measurements, and of their effects on resulting capacitance curvature. We examine: (1) the potential range explored, (2) the potential scan direction applied, (3) the data acquisition protocol used to collect data, and (4) the electrochemical technique used to generate capacitance data. Specifically, we find that all four of these (some more than others) 'user-defined' experimental variables influence the resulting capacitance-potential curvature for a typical ionic liquid electrochemical system. In an effort to minimize bias and to permit better comparisons of data collected from different laboratories we provide guidelines to help critically assess IL capacitance-potential data.

Non-Covalently Pre-Assembled High-Performance Near-Infrared Fluorescent Molecular Probes for Cancer Imaging.

New fluorescent molecular probes, which can selectively target specific cell surface receptors, are needed for microscopy, in vivo imaging, and image guided surgery. The preparation of multivalent probes using standard synthetic chemistry can be a laborious process due to low reaction yields caused by steric effects. In this study, fluorescent molecular probes were prepared by a programmed non-covalent pre-assembly process that used a near-infrared fluorescent squaraine dye to thread a macrocycle bearing a cyclic arginine-glycine-aspartate peptide antagonist (cRGDfK) as a cancer targeting unit. Cell microscopy studies using OVCAR-4 (ovarian cancer) and A549 (lung cancer) cells that express high levels of the integrin αvß3 or αvß5 receptors, respectively, revealed a multivalent cell targeting effect. That is, there was comparatively more cell uptake of a pre-assembled probe equipped with two copies of the cRGDfK antagonist than a pre-assembled probe with only one appended cRGDfK antagonist. The remarkably high photostability and low phototoxicity of these near-infrared probes allowed for acquisition of long-term fluorescence movies showing endosome trafficking in living cells. In vivo near-infrared fluorescence imaging experiments compared the biodistribution of a targeted and untargeted probe in a xenograft mouse tumor model. The average tumor-to-muscle ratio for the pre-assembled targeted probe was 3.6 which matches the tumor targeting performance reported for analogous cRGDfK-based probes that were prepared entirely by covalent synthesis. The capability to excite these pre-assembled near-infrared fluorescent probes with blue or deep-red excitation light makes it possible to determine if a target site is located superficially or buried in tissue, a probe performance feature that is likely to be very helpful for eventual applications such as fluorescence guided surgery.

Capacitive hysteresis at the 1-ethyl-3-methylimidazolium tris(pentafluoroethyl)-trifluorophosphate-polycrystalline gold interface.

We report potential-dependent capacitance curves over a 2-V potential range for the 1-ethyl-3-methylimidazolium tris(pentafluoroethyl)-trifluorophosphate (Emim FAP)-polycrystalline gold interface, and examine the effect of potential scan direction on results. We find very small levels of capacitive hysteresis in the Emim FAP-polycrystalline Au electrochemical system, where capacitance curves show minor dependence on the potential scan direction employed. This is a considerably different response than that reported for the Emim FAP-Au(111) interface where significant hysteresis is observed based on the potential scan direction (Drüschler et al. in J Phys Chem C 115 (14):6802-6808, 2011). Hysteresis effects have previously been suggested to be a general feature of an ionic liquid (IL) at electrified interfaces due to slow interfacial processes and has been demonstrated for numerous electrochemical systems. We provide new evidence that the experimental procedure used to acquire capacitance data and data workup could also have implications on capacitance-potential relationships in ILs. This work serves to progress our understanding of the nature of capacitive hysteresis at the IL-electrode interface. Graphical abstract Subtle changes in experimental methods can lead to significantly different capacitance measurements in ionic liquids. Which is the best approach?

High expression of integrin αvß3 enables uptake of targeted fluorescent probes into ovarian cancer cells and tumors.

The cell line OVCAR-4 was recently ranked as one of the most representative cell lines for high grade serous ovarian cancer (HGSOC). However, little work has been done to assess the susceptibility of OVCAR-4 cells and tumors to the more common types of molecular targeting. Proteome profiles suggest OVCAR-4 express high levels of integrin αvß3 receptors. Using flow cytometry with fluorescent antibodies we determined that OVCAR-4 cells have high number of integrin αvß3 receptors ([9.8 ±â€¯2.5] × 104/cell) compared to the well-characterized cell line U87-MG ([5.2 ±â€¯1.4] × 104/cell). However, OVCAR-4 cells also have roughly three times the surface area of U87-MG cells, so the average αvß3 receptor density is actually lower (11 ±â€¯3 versus 18 ±â€¯6 receptors/µm2). A series of new fluorescent molecular probes was prepared with structures comprised of a deep-red squaraine fluorophore (∼680 nm emission) covalently attached to zero, one, or two cyclic pentapeptide cRGD sequences for integrin targeting. Microscopy studies showed that uptake of the divalent probe into cultured OVCAR-4 cells was 2.2 ±â€¯0.4 higher than the monovalent probe, which in turn was 2.2 ±â€¯0.4 higher than the untargeted probe. This probe targeting trend was also seen in OVCAR-4 mouse tumor models. The results suggest that clinically relevant OVCAR-4 cells can be targeted using molecular probes based on αvß3 integrin receptor antagonists such as the cRGD peptide. Furthermore, deep-red fluorescent cRGD-squaraine probes have potential as targeted stains of cancerous tissue associated with HGSOC in surgery and pathology settings.

Self-Organization of Ions at the Interface between Graphene and Ionic Liquid DEME-TFSI.

Electrochemical effects manifest as nonlinear responses to an applied electric field in electrochemical devices, and are linked intimately to the molecular orientation of ions in the electric double layer (EDL). Herein, we probe the origin of the electrochemical effect using a double-gate graphene field effect transistor (GFET) of ionic liquid N,N-diethyl-N-(2-methoxyethyl)-N-methylammonium bis(trifluoromethylsulfonyl)imide (DEME-TFSI) top-gate, paired with a ferroelectric Pb0.92La0.08Zr0.52Ti0.48O3 (PLZT) back-gate of compatible gating efficiency. The orientation of the interfacial molecular ions can be extracted by measuring the GFET Dirac point shift, and their dynamic response to ultraviolet-visible light and a gate electric field was quantified. We have observed that the strong electrochemical effect is due to the TFSI anions self-organizing on a treated GFET surface. Moreover, a reversible order-disorder transition of TFSI anions self-organized on the GFET surface can be triggered by illuminating the interface with ultraviolet-visible light, revealing that it is a useful method to control the surface ion configuration and the overall performance of the device.

Non-Covalent Assembly Method that Simultaneously Endows a Liposome Surface with Targeting Ligands, Protective PEG Chains, and Deep-Red Fluorescence Reporter Groups.

A new self-assembly method is used to rapidly functionalize the surface of liposomes without perturbing the membrane integrity or causing leakage of the aqueous contents. The key molecule is a cholesterol-squaraine-PEG conjugate with three important structural elements: a cholesterol membrane anchor, a fluorescent squaraine docking station that allows rapid and high-affinity macrocycle threading, and a long PEG-2000 chain to provide steric shielding of the decorated liposome. The two-step method involves spontaneous insertion of the conjugate into the outer leaflet of pre-formed liposomes followed by squaraine threading with a tetralactam macrocycle that has appended targeting ligands. A macrocycle with six carboxylates permitted immobilization of intact fluorescent liposomes on the surface of cationic polymer beads, whereas a macrocycle with six zinc(II)-dipicolylamine units enabled selective targeting of anionic membranes, including agglutination of bacteria in the presence of human cells.