Iron, Ferritin, Hereditary Ferritinopathy, and Neurodegeneration

Cellular growth, function, and protection require proper iron management, and ferritin plays a crucial role as the major iron sequestration and storage protein. Ferritin is a 24 subunit spherical shell protein composed of both light (FTL) and heavy chain (FTH1) subunits, possessing complimentary iron-handling functions and forming three-fold and four-fold pores. Iron uptake through the three-fold pores is well-defined, but the unloading process somewhat less and generally focuses on lysosomal ferritin degradation although it may have an additional, energetically efficient pore mechanism. Hereditary Ferritinopathy (HF) or neuroferritinopathy is an autosomal dominant neurodegenerative disease caused by mutations in the FTL C-terminal sequence, which in turn cause disorder and unraveling at the four-fold pores allowing iron leakage and enhanced formation of toxic, improperly coordinated iron (ICI). Histopathologically, HF is characterized by iron deposition and formation of ferritin inclusion bodies (IBs) as the cells overexpress ferritin in an attempt to address iron accumulation while lacking the ability to clear ferritin and its aggregates. Overexpression and IB formation tax cells materially and energetically, i.e., their synthesis and disposal systems, and may hinder cellular transport and other spatially dependent functions. ICI causes cellular damage to proteins and lipids through reactive oxygen species (ROS) formation because of high levels of brain oxygen, reductants and metabolism, taxing cellular repair. Iron can cause protein aggregation both indirectly by ROS-induced protein modification and destabilization, and directly as with mutant ferritin through C-terminal bridging. Iron release and ferritin degradation are also linked to cellular misfunction through ferritinophagy, which can release sufficient iron to initiate the unique programmed cell death process ferroptosis causing ROS formation and lipid peroxidation. But IB buildup suggests suppressed ferritinophagy, with elevated iron from four-fold pore leakage together with ROS damage and stress leading to a long-term ferroptotic-like state in HF. Several of these processes have parallels in cell line and mouse models. This review addresses the roles of ferritin structure and function within the above-mentioned framework, as they relate to HF and associated disorders characterized by abnormal iron accumulation, protein aggregation, oxidative damage, and the resulting contributions to cumulative cellular stress and death

What Can Cellular Redox, Iron, and Reactive Oxygen Species Suggest About the Mechanisms and Potential Therapy of COVID-19?

Accumulating evidence suggests that there are important contributions to coronavirus disease (COVID-19) from redox imbalance and improperly coordinated iron, which cause cellular oxidative damage and stress. Cells have developed elaborate redox-dependent processes to handle and store iron, and their disfunction leads to several serious diseases. Cellular reductants are important as reactive oxygen species (ROS) scavengers and to power enzymatic repair mechanisms, but they also may help generate toxic ROS. These complicated interrelationships are presented in terms of a cellular redox/iron/ROS triad, including ROS generation both at improperly coordinated iron and enzymatically, ROS interconvertibility, cellular signaling and damage, and reductant and iron chelator concentration-dependent effects. This perspective provides the rational necessary to strongly suggest that COVID-19 disrupts this interdependent triad, producing a substantial contribution to the ROS load, which causes direct ROS-induced protein and phospholipid damage, taxes cellular resources and repair mechanisms, and alters cellular signaling, especially in the more critical acute respiratory distress syndrome (ARDS) phase of the infection. Specific suggestions for therapeutic interventions using reductants and chelators that may help treat COVID-19 are discussed

Programmable Colloidal Approach to Hierarchical Structures of Methylammonium Lead Bromide Perovskite Nanocrystals with Bright Photoluminescent Properties

Systematic tailoring of nanocrystal architecture could provide unprecedented control over their electronic, photophysical, and charge transport properties for a variety of applications. However, at present, manipulation of the shape of perovskite nanocrystals is done mostly by trial-and-error-based experimental approaches. Here, we report systematic colloidal synthetic strategies to prepare methylammonium lead bromide quantum platelets and quantum cubes. In order to control the nucleation and growth processes of these nanocrystals, we appropriately manipulate the solvent system, surface ligand chemistry, and reaction temperature causing syntheses into anisotropic shapes. We demonstrate that both the presence of chlorinated solvent and a long chain aliphatic amine in the reaction mixture are crucial for the formation of ultrathin quantum platelets (∼2.5 nm in thickness), which is driven by mesoscale-assisted growth of spherical seed nanocrystals (∼1.6 nm in diameter) through attachment of monomers onto selective crystal facets. A combined surface and structural characterization, along with small-angle X-ray scattering analysis, confirm that the long hydrocarbon of the aliphatic amine is responsible for the well ordered hierarchical stacking of the quantum platelets of 3.5 nm separation. In contrast, the formation of ∼12 nm edge-length quantum cubes is a kinetically driven process in which a high flux of monomers is achieved by supplying thermal energy. The photoluminescence quantum yield of our quantum platelets (∼52%) is nearly 2-fold higher than quantum cubes. Moreover, the quantum platelets display a lower nonradiative rate constant than that found with quantum cubes, which suggests less surface trap states. Together, our research has the potential both to improve the design of synthetic methods for programmable control of shape and assembly and to provide insight into optoelectronic properties of these materials for solid-state device fabrication, e.g., light-emitting diodes, solar cells, and lasing materials

Mechanistic Study of the Formation of Bright White Light-Emitting Ultrasmall CdSe Nanocrystals: Role of Phosphine Free Selenium Precursors

We have designed a new nonphosphinated reaction pathway, which includes synthesis of a new, highly reactive Se-bridged organic species (chalcogenide precursor), to produce bright white light-emitting ultrasmall CdSe nanocrystals of high quality under mild reaction conditions. The detailed characterization of structural properties of the selenium precursor through combined 77Se NMR and laser desorption ionization–mass spectrometry (LDI-MS) provided valuable insights into Se release and delineated the nanocrystal formation mechanism at the molecular level. The 1H NMR study showed that the rate of disappearance of Se precursor maintained a single-exponential decay with a rate constant of 2.3 × 10–4 s–1 at room temperature. Furthermore, the combination of LDI-MS and optical spectroscopy was used for the first time to deconvolute the formation mechanism of our bright white light-emitting nanocrystals, which demonstrated initial formation of a smaller key nanocrystal intermediate (CdSe)19. Application of thermal driving force for destabilization resulted in (CdSe)n nanocrystal generation with n = 29–36 through continuous dissolution and addition of monomer onto existing nanocrystals while maintaining a living-polymerization type growth mode. Importantly, our ultrasmall CdSe nanocrystals displayed an unprecedentedly large fluorescence quantum yield of ∼27% for this size regime (<2.0 nm diameter). These mixed oleylamine and cadmium benzoate ligand-coated CdSe nanocrystals showed a fluorescence lifetime of ∼90 ns, a significantly large value for such small nanocrystals, which was due to delocalization of the exciton wave function into the ligand monolayer. We believe our findings will be relevant to formation of other metal chalcogenide nanocrystals through expansion of the understanding and manipulation of surface ligand chemistry, which together will allow the preparation of “artificial solids” with high charge conductivity and mobility for advanced solid-state device applications

Unraveling the Mechanism Underlying Surface Ligand Passivation of Colloidal Semiconductor Nanocrystals: A Route for Preparing Advanced Hybrid Nanomaterials

Optically bright colloidal semiconductor nanocrystals (CSNCs) are important nanomaterials because of their potential applications such as cellular imaging and solid-state lighting. The optoelectronic properties of CSNCs are strongly controlled by the chemical nature of the surface passivating ligands that are introduced during their synthesis. However, the existing LaMer growth model does not provide a clear understanding of the stage when ligands become attached onto the CSNC surface. Herein, apart from the three stage formation mechanism of CSNCs (supersaturation, nucleation, and growth), an entirely new stage—solely involving surface ligand attachment onto fully grown CSNCs—is now reported that controls their photoluminescence properties. Furthermore, we also demonstrate a fundamentally new surface modification approach using partially passivated CSNCs to introduce a variety of functional groups (azide, alkene, and siloxane), including photoisomerizable molecular machines (e.g., azobenzene), without the use of “state-of-the art” ligand exchange chemistry. Knowledge of the ligand adsorption phenomena and resulting adsorption time dependence expands our fundamental understanding of structure–property relationships while allowing us to engineer novel hybrid functional nanomaterials with both previously unknown optoelectronic properties and supermolecular assembly options for various applications

Dual Role of Electron-Accepting Metal-Carboxylate Ligands: Reversible Expansion of Exciton Delocalization and Passivation of Nonradiative Trap-States in Molecule-like CdSe Nanocrystals

This paper reports large bathochromic shifts of up to 260 meV in both the excitonic absorption and emission peaks of oleylamine (OLA)-passivated molecule-like (CdSe)34 nanocrystals caused by postsynthetic treatment with the electron accepting Cd(O2CPh)2 complex at room temperature. These shifts are found to be reversible upon removal of Cd(O2CPh)2 by N,N,N′,N′-tetramethylethylene-1,2-diamine. 1H NMR and FTIR characterizations of the nanocrystals demonstrate that the OLA remained attached to the surface of the nanocrystals during the reversible removal of Cd(O2CPh)2. On the basis of surface ligand characterization, X-ray powder diffraction measurements, and additional control experiments, we propose that these peak red shifts are a consequence of the delocalization of confined exciton wave functions into the interfacial electronic states that are formed from interaction of the LUMO of the nanocrystals and the LUMO of Cd(O2CPh)2, as opposed to originating from a change in size or reorganization of the inorganic core. Furthermore, attachment of Cd(O2CPh)2 to the OLA-passivated (CdSe)34 nanocrystal surface increases the photoluminescence quantum yield from 5% to an unprecedentedly high 70% and causes a 3-fold increase of the photoluminescence lifetime, which are attributed to a combination of passivation of nonradiative surface trap states and relaxation of exciton confinement. Taken together, our work demonstrates the unique aspects of surface ligand chemistry in controlling the excitonic absorption and emission properties of ultrasmall (CdSe)34 nanocrystals, which could expedite their potential applications in solid-state device fabrication

Elucidating the role of surface passivating ligand structural parameters in hole wave function delocalization in semiconductor cluster molecules

This article describes the mechanisms underlying electronic interactions between surface passivating ligands and (CdSe)34 semiconductor cluster molecules (SCMs) that facilitate band-gap engineering through the delocalization of hole wave functions without altering their inorganic core. We show here both experimentally and through density functional theory calculations that the expansion of the hole wave function beyond the SCM boundary into the ligand monolayer depends not only on the pre-binding energetic alignment of interfacial orbitals between the SCM and surface passivating ligands but is also strongly influenced by definable ligand structural parameters such as the extent of their π-conjugation [π-delocalization energy; pyrene (Py), anthracene (Anth), naphthalene (Naph), and phenyl (Ph)], binding mode [dithiocarbamate (DTC, –NH–CS2−), carboxylate (–COO−), and amine (–NH2)], and binding head group [–SH, –SeH, and –TeH]. We observe an unprecedentedly large ∼650 meV red-shift in the lowest energy optical absorption band of (CdSe)34 SCMs upon passivating their surface with Py-DTC ligands and the trend is found to be Ph- < Naph- < Anth- < Py-DTC. This shift is reversible upon removal of Py-DTC by triethylphosphine gold(I) chloride treatment at room temperature. Furthermore, we performed temperature-dependent (80–300 K) photoluminescence lifetime measurements, which show longer lifetime at lower temperature, suggesting a strong influence of hole wave function delocalization rather than carrier trapping and/or phonon-mediated relaxation. Taken together, knowledge of how ligands electronically interact with the SCM surface is crucial to semiconductor nanomaterial research in general because it allows the tuning of electronic properties of nanomaterials for better charge separation and enhanced charge transfer, which in turn will increase optoelectronic device and photocatalytic efficiencies

DESIGNING EFFICIENT LOCALIZED SURFACE PLASMON RESONANCE-BASED SENSING PLATFORMS: OPTIMIZATION OF SENSOR RESPONSE BY CON-TROLLING THE EDGE LENGTH OF GOLD NANOPRISMS

poster abstractOver the last few years, the unique localized surface plasmon resonance (LSPR) properties of plasmonic nanostructures have been used to design la-bel-free biosensors. In this research, we demonstrate that it is the difference in edge length of gold nanoprisms that significantly influences their bulk re-fractive index sensitivity and local sensing efficiency. Nanoprisms with edge lengths in the range of 28-51 nm were synthesized by the chemical-reduction method and sensing platforms were fabricated by chemisorptions of these nanoprisms onto silanized glass substrates. The plasmonic nanosensors prepared from 28 nm edge length nanoprisms exhibited the largest sensitivity to change in bulk refractive index with a value of 647 nm/RIU. The refractive index sensitivity decreased with increasing edge length, with nanoprisms of 51 nm edge lengths displaying a sensitivity of 384 nm/RIU. In contrast, we found that the biosensing efficiency of sensing platforms modified with biotin increased with increasing edge length, and the sensing platforms fabricated from 51 nm edge length nanoprisms displaying the highest local sensing efficiency. The lowest concentration of streptavidin that could be measured reliably was 1.0 pM and the limit of detection for the sensing platforms fabricated from 51 nm edge length nanoprisms was 0.5 pM, which is much lower than found with gold bipyramids, nanostars, and nanorods

Ultrathin Plasmonic Tungsten Oxide Quantum Wells with Controllable Free Carrier Densities

Localized surface plasmon resonances (LSPR) of nanostructures can be tuned by controlling their morphology, local dielectric environment, and free carrier concentration. We report the colloidal synthesis of an ∼3 tungsten–oxygen (W-O) layer thick (∼1 nm), two-dimensional (2D) WO3-x nanoplatelets (NPLs) (x ≈ 0.55–1.03), which display tunable near-infrared LSPR properties and additionally high free electron density (Ne) that arises predominantly from the large shape factor of 2D NPLs. Importantly, the W to O composition ratios inferred from their LSPR measurements show much higher percentage of oxygen vacancies than those determined by X-ray diffraction analysis, suggesting that the aspect ratio of ultrathin WO3-x NPLs is the key to producing an unprecedentedly large Ne, although synthesis temperature is also an independent factor. We find that NPL formation is kinetically controlled, whereas thermodynamic parameter manipulation leads to Ne values as high as 4.13 × 1022 cm–3, which is close to that of plasmonic noble metals, and thus our oxide-based nanostructures can be considered as quasi-metallic. The unique structural properties of 2D nanomaterials along with the high Ne of WO3-x NPLs provide an attractive alternative to plasmonic noble metal nanostructures for various plasmon-driven energy conversions and design of photochromic nanodevices

Reversible Tuning of the Plasmoelectric Effect in Noble Metal Nanostructures Through Manipulation of Organic Ligand Energy Levels

Ligand-controlled tuning of localized surface plasmon resonance (LSPR) properties of noble metal nanostructures is fundamentally important for various optoelectronic applications such as photocatalysis, photovoltaics, and sensing. Here we demonstrate that the free carrier concentration of gold triangular nanoprisms (Au TNPs) can be tuned up to 12% upon functionalization of their surface with different para-substituted thiophenolate (X–Ph–S−) ligands. We achieve this unprecedentedly large optical response (plasmoelectric effect) in TNPs through the selective manipulation of electronic processes at the Au–thiolate interface. Interestingly, thiophenolates with electron withdrawing (donating) groups (X) produce λLSPR blue (red) shifts with broadening (narrowing) of localized surface plasmon resonance peak (λLSPR) line widths. Surprisingly, these experimental results are opposite to a straightforward application of the Drude model. Utilizing density functional theory calculations, we develop here a frontier molecular orbital approach of Au-thiophenolate interactions in the solid-state to delineate the observed spectral response. Importantly, all the spectroscopic properties are fully reversible by exchanging thiophenolates containing electron withdrawing groups with thiophenolates having electron donating groups, and vice versa. On the basis of the experimental data and calculations, we propose that the delocalization of electrons wave function controls the free carrier concentration of Au and thus the LSPR properties rather than simple electronic properties (inductive and/or resonance effects) of thiophenolates. This is further supported by the experimentally determined work functions, which are tunable over 1.9 eV in the X–Ph–S–passivated Au TNPs. We believe that our unexpected finding has great potential to guide in developing unique noble metal nanostructure–organic ligand hybrid nanoconjugates, which could allow us to bypass the complications associated with off-resonance LSPR activation of noble metal-doped semiconductor nanocrystals for various surface plasmon-driven applications