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NiFe oxyhydroxide materials are highly active electrocatalysts for the oxygen evolution reaction (OER), an important process for carbon-neutral energy storage. Recent spectroscopic and computational studies increasingly support iron as the site of catalytic activity but differ with respect to the relevant iron redox state. A combination of hybrid periodic density functional theory calculations and spectroelectrochemical experiments elucidate the electronic structure and redox thermodynamics of Ni-only and mixed NiFe oxyhydroxide thin-film electrocatalysts. The UV/visible light absorbance of the Ni-only catalyst depends on the applied potential as metal ions in the film are oxidized before the onset of OER activity. In contrast, absorbance changes are negligible in a 25% Fe-doped catalyst up to the onset of OER activity. First-principles calculations of proton-coupled redox potentials and magnetizations reveal that the Ni-only system features oxidation of Ni2+ to Ni3+, followed by oxidation to a mixed Ni3+/4+ state at a potential coincident with the onset of OER activity. Calculations on the 25% Fe-doped system show the catalyst is redox inert before the onset of catalysis, which coincides with the formation of Fe4+ and mixed Ni oxidation states. The calculations indicate that introduction of Fe dopants changes the character of the conduction band minimum from Ni-oxide in the Ni-only to predominantly Fe-oxide in the NiFe electrocatalyst. These findings provide a unified experimental and theoretical description of the electrochemical and optical properties of Ni and NiFe oxyhydroxide electrocatalysts and serve as an important benchmark for computational characterization of mixed-metal oxidation states in heterogeneous catalysts.

The electrical double layer (EDL) at metal oxide-electrolyte interfaces critically affects fundamental processes in water splitting, batteries, and corrosion. However, limitations in the microscopic-level understanding of the EDL have been a major bottleneck in controlling these interfacial processes. Herein, we use ab initio-based machine learning potential simulations incorporating long-range electrostatics to unravel the molecular-scale picture of the EDL at the prototypical anatase TiO 2 -electrolyte interface under various pH conditions. Our large-scale simulations, capable of capturing interfacial water dissociation/recombination reactions and electrolytic proton transport, provide unprecedented insights into the detailed structure of the EDL. Moreover, the larger capacitance of the EDL under basic relative to acidic conditions, originating from the higher affinity of the cations for the oxide surface, is found to give rise to distinct charging mechanisms on negative and positive surfaces. Our results are validated by the agreement between the computed EDL capacitance and experimental data. Microscopic understanding of the electrical double layer (EDL) is key to optimizing interfacial processes in water splitting and batteries. Here, the authors report the insight of EDL at oxide-electrolyte interfaces with ab initio machine learning simulations that agrees with available experiments.

Electron transfer reactions slow down when they become very thermodynamically favorable, a counterintuitive interplay of kinetics and thermodynamics termed the inverted region in Marcus theory. Here we report inverted region behavior for proton-coupled electron transfer (PCET). Photochemical studies of anthracene-phenol-pyridine triads give rate constants for PCET charge recombination that are slower for the more thermodynamically favorable reactions. Photoexcitation forms an anthracene excited state that undergoes PCET to create a charge-separated state. The rate constants for return charge recombination show an inverted dependence on the driving force upon changing pyridine substituents and the solvent. Calculations using vibronically nonadiabatic PCET theory yield rate constants for simultaneous tunneling of the electron and proton that account for the results.

Background Retinoblastoma (Rb) is the most common primary intraocular tumor in children. Local treatment of the intraocular disease is usually effective if diagnosed early; however advanced Rb can metastasize through routes that involve invasion of the choroid, sclera and optic nerve or more broadly via the ocular vasculature. Metastatic Rb patients have very high mortality rates. While current therapy for Rb is directed toward blocking tumor cell division and tumor growth, there are no specific treatments targeted to block Rb metastasis. Two such targets are matrix metalloproteinases-2 and -9 (MMP-2, −9), which degrade extracellular matrix as a prerequisite for cellular invasion and have been shown to be involved in other types of cancer metastasis. Cancer Clinical Trials with an anti-MMP-9 therapeutic antibody were recently initiated, prompting us to investigate the role of MMP-2, −9 in Rb metastasis. Methods We compare MMP-2, −9 activity in two well-studied Rb cell lines: Y79, which exhibits high metastatic potential and Weri-1, which has low metastatic potential. The effects of inhibitors of MMP-2 (ARP100) and MMP-9 (AG-L-66085) on migration, angiogenesis, and production of immunomodulatory cytokines were determined in both cell lines using qPCR, and ELISA. Cellular migration and potential for invasion were evaluated by the classic wound-healing assay and a Boyden Chamber assay. Results Our results showed that both inhibitors had differential effects on the two cell lines, significantly reducing migration in the metastatic Y79 cell line and greatly affecting the viability of Weri-1 cells. The MMP-9 inhibitor (MMP9I) AG-L-66085, diminished the Y79 angiogenic response. In Weri-1 cells, VEGF was significantly reduced and cell viability was decreased by both MMP-2 and MMP-9 inhibitors. Furthermore, inhibition of MMP-2 significantly reduced secretion of TGF-β1 in both Rb models. Conclusions Collectively, our data indicates MMP-2 and MMP-9 drive metastatic pathways, including migration, viability and secretion of angiogenic factors in Rb cells. These two subtypes of matrix metalloproteinases represent new potential candidates for targeted anti-metastatic therapy for Rb.

House dust mites (HDM), common allergens that can induce atopic dermatitis (AD), are widely employed to generate mouse models of AD. In the current study, we compared the AD-like phenotypes between two mouse strains, NC/Nga, and BALB/c, in response to HDM, and performed cellular, molecular, and pharmacological characterization of HDM-induced dermatitis in NC/Nga mice. In-life endpoints included skin clinical scores, ear thickness, transepidermal water loss (TEWL), and scratching bouts. Terminal endpoints included histopathology, total serum IgE and tissue cytokines. Further phenotyping of NC/Nga was performed by flow cytometry, gene expression analysis, and pharmacology. HDM applications resulted in a more robust AD-like dermatitis in NC/Nga than BALB/c mice as evidenced by greater changes in in-life endpoints (clinical scores, ear thickness, scratching bouts, and TEWL), histological markers (overall inflammation, acanthosis, and parakeratosis), and tissue inflammatory cytokines although serum total IgE level is higher in BALB/c than NC/Nga mice. Flow cytometry analysis of skin immune cells in HDM-treated NC/Nga mice showed increased production of IL-4, IL-13, IL-17A and IFNγ, which was mainly from CD3 − cells. The immune/inflammatory responses in NC/Nga mice are supported by gene expression analysis, where multiple pathways are similar to human AD lesional skin. Treatment with JAK1 inhibitor or anti-IL-4Rα antibody attenuated multiple AD-relevant endpoints in NC/Nga mice. These data confirm NC/Nga mice are predisposed to HDM-induced dermatitis compared to BALB/c, and reveal a complex immune profile that shares several relevant pathways and pharmacological mechanisms with human AD.

The newly purified extracellular polysaccharides (exopolysaccharides) from Parachlorella kessleri (PCEPS) were evaluated on their antitumor and immunomodulatory effects in cell culture and mouse colon carcinoma peritoneal dissemination model. In two-dimensional cell culture, the PCEPS treatment inhibited cell growth of both murine and human colon carcinoma cells in a dose- and time-dependent manner. In contrast, the growth of mouse splenocytes (SPLs) and bone marrow cells (BMCs) were stimulated by the treatment with PCEPS. The treatment with PCEPS also increased specific subpopulations of the cells in BMCs: antigen presenting cells (CD19+ B cells, 33D1+ dendritic cells and CD68+ macrophage) and CD8+ cytotoxic T cells. In three-dimensional spheroid culture, spheroid growth of CT26 cells co-cultured with HL-60 human neutrophilic promyeloblasts and Jurkat cells (human lymphoblasts), but not THP-1 human monocyte/macrophage was significantly attenuated by PCEPS treatment. In a mouse CT26 colon carcinoma peritoneal dissemination model, intraperitoneal injection of PCEPS (10 mg/kg, twice per week) significantly attenuated the growth of CT26 colon carcinoma in syngeneic mice. The present study suggests that PCEPS inhibits colon carcinoma growth via direct cell growth inhibition and a stimulation of the host antitumor immune responses. Taken together, the current study suggests that exopolysaccharides derived from Parachlorella kessleri contain significant bioactive materials that inhibit colon carcinoma growth.

Liberal democracy is increasingly under threat today by radical politics of the right and left, including fanaticism. While a common feature of contemporary political discourse, the concept of fanaticism is too often invoked with little precision or awareness of its various meanings. This dissertation seeks to remedy this while also providing a critique of fanaticism as a way of doing politics. Accordingly, this dissertation explores the long history of the concept of fanaticism from ancient times through the Reformation and its later political manifestation following the French Revolution. In doing this, special attention is given to its transformation from a primarily religious to a political concept around the time of the French Revolution. In order to further examine this transition, this dissertation examines the conceptualizations of fanaticism found in the work of Immanuel Kant, Edmund Burke, and Fyodor Dostoevsky, all keen observers of fanaticism—especially its political variant. These authors provide broad insights into the concept because of their diverse geographical, political, temporal, and contextual backgrounds. While the concept of fanaticism resists easy definition and, indeed, has changed over time, this examination yields a complex and nuanced understanding of fanaticism involving irrationality, messianism, the embrace of abstraction, the desire for novelty, the pursuit of perfection, a lack of limits in politics, the embrace of violence, certainty, and passion, all the while often serving as an “opium” for intellectuals. These various elements constitute a sematic field within which the concept of fanaticism can be found. After examining the concept of fanaticism, this dissertation concludes with an argument against those who argue that fanaticism is a political virtue that ought to be adopted as well as an argument against fanaticism itself, holding that it is anti-democratic, illiberal, anti-political, and never necessary.

Renewable energy technologies, particularly solar, rely on processes that convert energy from and store energy in chemical bonds. Therefore, understanding and optimizing these reactions is critical to the efficient transduction of solar energy. Intrinsic to these technological reactions as well as those nature is the directed translocation of electrons and protons. These two fundamental chemical reagents often transfer concertedly and as such the kinetics of these reactions require special attention. In this dissertation, computational and theoretical characterizations of proton-coupled electron transfer (PCET) reactions in electro- and photochemical energy conversion processes are presented.A Co complex that performs highly selective, low-overpotential oxygen reduction to hydrogen peroxide was analyzed with density functional theory calculations. These calculations along with experimental kinetics elucidated a likely mechanism for this efficient transformation based on a rate-determining second proton transfer to a Co-hydroperoxo intermediate. In heterogeneous catalysis, a density functional theory characterization of the promising NiFe oxyhydroxide oxygen-evolving electrocatalyst is presented. Spectroelectrochemistry and calculations demonstrated the likely involvement of Fe4+ sites under catalytic current-carrying conditions. The evolution of hydrogen on Au electrodes by triethylammonium in acetonitrile solvent demonstrates a uniquely potential-dependent kinetic isotope effects. Numerical models for the nonadiabatic cathodic rate constant of proton discharge on an electrode were employed to understand this phenomenon as differing contributions of vibronic states for a transferring proton and deuteron.In addition, computational and theoretical models of anthracene-phenol-pyridine unimolecular triads complemented transient spectroscopies in an investigation of photoinduced PCET. Experiment and nonadiabatic rate theory jointly demonstrated the Marcus inverted region for the charge recombination reaction that follows photoexcitation of the triad. A model system study further described the physical criteria for observing inverted region kinetics for PCET.Computational and numerical models are very valuable to understanding experimental phenomena and elucidating molecular and materials design principles for even more efficient and selective energy transduction. This dissertation studies many aspects of energy conversion reactions including electronic structure, atomistic molecular and interfacial structures, reaction thermodynamics and mechanisms, and nonadiabatic rate theories in various limits. Theoretical understandings of each of these components of PCET reactivity, many in conjunction with or inspired by novel experiments, are presented herein.

Retinoblastoma (Rb) is the most common intraocular malignancy in children comprising 4% of all pediatric tumors. Early intervention increases survival rates up to 95% in developed countries; being survival rates associated to socio-economic status. Despite the high survival rates in developed countries, preservation of the eye and vision are continuing challenges in the management of Rb. Vitreous seeds constitute the greatest challenge in treatment of Rb. The unique location of these seeds within the vitreous makes them difficult to treat. Viable seeds showed reduced proliferative capacity and metabolism. making the majority refractory to current chemotherapeutics. This prompted the development of new delivery routes for chemotherapeutics, such as intra-ophthalmic artery, intravitreal, and subconjunctival administration. Still ocular salvage rates have not exceeded 70% in over two decades. Novel, safer therapies are required but there is a fundamental lack of knowledge about the biology of the tumor for the development of targeted therapies; the vitreous, as it surrounds the seeds; and the interactions between the vitreous and the seeds. Despite the current understanding of how cancer is a multifaceted disease full of complex cellular and protein interactions (commonly referred to as the tumor microenvironment, TME), the immunology of the vitreous microenvironment and the role it plays in the sustainment of seeds in Rb disease is poorly understood. In this study, we begin investigating Rb tumor cells and how they alter the TME by examination of matrix metalloproteinases, a family of enzymes involved in degradation of the extracellular matrix and tissue remodeling heavily implicated in tumor migration and survival. We identified two gelatinases, MMP-2 and MMP-9, to be expressed in Rb cell lines and demonstrated by pharmacological inhibition and genetic knockdown, a role for these gelatinases in Rb cell migration, invasion, and survival. Additionally, we demonstrated how secretion of VEGF, involved in angiogenesis, and TGFbeta, involved in metastasis, were altered by MMP-2 and MMP-9 pharmacological inhibition. As MMPs are pivotal for the tumor and extracellular matrix interactions within the TME leading to tissue invasion, we then transitioned to the vitreous, investigating the vitreous as a TME and how it sustains Rb. Multiple proteins are found within the soluble phase of the vitreous that are associated with ocular pathological processes, including diabetes retinopathy and proliferative vitreoretinopathy. Therefore, we compared the presence of a small cohort of proteins associated to ocular pathologies, to healthy vitreous and to Rb patients’ vitreous samples, identifying high expression of Platelet-Derived Growth Factor Receptor beta (PDGFRbeta) and its ligand PDGFBB in the Rb samples. Additional studies of ex vivo healthy human vitreous, murine Rb xenografts, and patient-derived Rb xenograft tissues, measured high activity of the PDGF-PDGFRbeta signaling pathway in diseased, but not healthy tissue. We focused the next part of this work on the role PDGFRbeta plays in vitreous seeds. To investigate this pathway in depth we used established Rb cell lines, namely Y79-the metastatic and aggressive model, and Weri-1 Rb, the non-metastatic model. Our work demonstrated PDGFRbeta was overexpressed in Y79 cells, the metastatic model of Rb, in vitro. To provide mechanistic insight, we utilized the tyrosine kinase inhibitor imatinib mesylate (IM), and demonstrated PDGF-PDGFRbeta signaling pathway regulates Rb cell proliferation, invasion, and survival. We found increased PDGF-PDGFRbeta signaling resulted in higher activity of the p53-inactivator, MDM2, as well as the pro-inflammatory NFkappaB pathway, both of which are involved in tumor survival. As there is a lack of models for vitreous seeding, we utilized magnetic nanoparticles to generate the first in vitro vitreous seed model and demonstrated similar features between an ex vivo seed and one of our in vitro magnet-generated 3D tumor spheroids, validating our system. Using this novel technology, we recapitulated our in vitro 2D work and demonstrated that inhibition of the PDGF-PDGFRbeta signaling pathway results in decreased spheroid size. PDGFRB gene knockdown by siRNA confirmed the results with the pharmacological agent showing these results were PDGF-PDGFRbeta signaling-specific. Next, we tested the effects of IM, as a potential Rb therapy, in retinal endothelial cells h(RECs) as retinal endothelial cell-associated toxicities are one of the challenges with conventional chemotherapies in Rb. We measured the capacity of hREC to proliferate and for tube formation in the presence of the therapy. Our results demonstrated neither proliferation nor tube formation of hRECs changed when exposed to IM. Upon further examination, we demonstrated the absence of PDGFRB mRNA expression in hRECs. Taken together these results illustrate the potential use of anti-PDGFRbeta therapy as a targeted therapy in Rb. (Abstract shortened by ProQuest.)