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At least 559 records · Page 31

Cell division control by the Chromosomal Passenger Complex

The Chromosomal Passenger Complex (CPC) consisting of Aurora B kinase, INCENP, Survivin and Borealin, is essential for genomic stability by controlling multiple processes during both nuclear and cytoplasmic division. In mitosis it ensures accurate segregation of the duplicated chromosomes by regulating the mitotic checkpoint, destabilizing incorrectly attached spindle microtubules and by promoting the axial shortening of chromosomal arms in anaphase. During cytokinesis the CPC most likely prevents chromosome damage by imposing an abscission delay when a chromosome bridge connects the two daughter cells. Moreover, by controlling proper cytoplasmic division, the CPC averts tetraploidization. This review describes recent insights on how the CPC is capable of conducting its various functions in the dividing cell to ensure chromosomal stability.

60 APPLIED LIFE SCIENCES↗

Glycogen synthase kinase 3 regulates expression of nuclear factor-erythroid-2 related transcription factor-1 (Nrf1) and inhibits pro-survival function of Nrf1

Nuclear factor E2-related factor-1 (Nrf1) is a basic leucine zipper transcription factor that is known to regulate antioxidant and cytoprotective gene expression. It was recently shown that Nrf1 is regulated by SCF–Fbw7 ubiquitin ligase. However our knowledge of upstream signals that targets Nrf1 for degradation by the UPS is not known. We report here that Nrf1 expression is negatively regulated by glycogen synthase kinase 3 (GSK3) in Fbw7-dependent manner. We show that GSK3 interacts with Nrf1 and phosphorylates the Cdc4 phosphodegron domain (CPD) in Nrf1. Mutation of serine residue in the CPD of Nrf1 to alanine (S350A), blocks Nrf1 from phosphorylation by GSK3, and stabilizes Nrf1. Knockdown of Nrf1 and expression of a constitutively active form of GSK3 results in increased apoptosis in neuronal cells in response to ER stress, while expression of the GSK3 phosphorylation resistant S350A–Nrf1 attenuates apoptotic cell death. Together these data suggest that GSK3 regulates Nrf1 expression and cell survival function in response to stress activation. Highlights: • The effect of GSK3 on Nrf1 expression was examined. • GSK3 destabilizes Nrf1 protein via Fbw7 ubiquitin ligase. • GSK3 binds and phosphorylates Nrf1. • Protection from stress-induced apoptosis by Nrf1 is inhibited by GSK3.

60 APPLIED LIFE SCIENCES↗

The LMNA mutation p.Arg321Ter associated with dilated cardiomyopathy leads to reduced expression and a skewed ratio of lamin A and lamin C proteins

Dilated cardiomyopathy (DCM) is a disease of the heart muscle characterized by cardiac chamber enlargement and reduced systolic function of the left ventricle. Mutations in the LMNA gene represent the most frequent known genetic cause of DCM associated with disease of the conduction systems. The LMNA gene generates two major transcripts encoding the nuclear lamina major components lamin A and lamin C by alternative splicing. Both haploinsuffiency and dominant negative effects have been proposed as disease mechanism for premature termination codon (PTC) mutations in LMNA. These mechanisms however are still not clearly established. In this study, we used a representative LMNA nonsense mutation, p.Arg321Ter, to shed light on the molecular disease mechanisms. Cultured fibroblasts from three DCM patients carrying this mutation were analyzed. Quantitative reverse transcriptase PCR and sequencing of these PCR products indicated that transcripts from the mutant allele were degraded by the nonsense-mediated mRNA decay (NMD) mechanism. The fact that no truncated mutant protein was detectable in western blot (WB) analysis strengthens the notion that the mutant transcript is efficiently degraded. Furthermore, WB analysis showed that the expression of lamin C protein was reduced by the expected approximately 50%. Clearly decreased lamin A and lamin C levels were also observed by immunofluorescence microscopy analysis. However, results from both WB and nano-liquid chromatography/mass spectrometry demonstrated that the levels of lamin A protein were more reduced suggesting an effect on expression of lamin A from the wild type allele. PCR analysis of the ratio of lamin A to lamin C transcripts showed unchanged relative amounts of lamin A transcript suggesting that the effect on the wild type allele was operative at the protein level. Immunofluorescence microscopy analysis showed no abnormal nuclear morphology of patient fibroblast cells. Based on these data, we propose that heterozygosity for the nonsense mutation causes NMD degradation of the mutant transcripts blocking expression of the truncated mutant protein and an additional trans effect on lamin A protein levels expressed from the wild type allele. We discuss the possibility that skewing of the lamin A to lamin C ratio may contribute to ensuing processes that destabilize cardiomyocytes and trigger cardiomyopathy - Highlights: • We study disease mechanisms in DCM patients carrying PTC mutations in the LMNA gene. • The mutant transcript is degraded by the nonsense mediated mRNA decay system. • Skewed lamin A to lamin C protein ratio expressed from the wild type allele. • We suggest a combined pathomechanism: haploinsuffiency plus lamin A/C imbalance.

60 APPLIED LIFE SCIENCES↗

LncRBA GSA5, up-regulated by ox-LDL, aggravates inflammatory response and MMP expression in THP-1 macrophages by acting like a sponge for miR-221

Highlights: • Expression of GAS5 is elevated in AS and in ox-LDL-stimulated macrophages. • GAS5 elevation aggravates and its silence antagonizes ox-LDL-induced inflammatory. • GAS5 enhances MMP expression in ox-LDL-stimulated macrophages. • GAS5 directly interacts with miR-221 and regulate its expression. • miR-221 reveres GAS5-mediated inflammation and MMPs in ox-LDL-treated macrophages. Atherosclerosis is a chronic inflammatory process, plaque rupture and subsequent thrombosis underline the major causes of acute cardio-cerebral vascular diseases. Long non-coding RNAs (lncRNAs) participate in diverse pathologic processes, including inflammation and myocardial infarction. Recent study confirmed the elevation of lncRNA growth arrest-specific 5 (GAS5) in atherosclerotic rats. In this study, we aimed to explore the role and mechanism of GAS5 in the progression of atherosclerotic plaque. Here, expression of GAS5 was enriched in atherosclerotic plaques and THP-1 macrophage exposed to oxidized low-density lipoprotein (ox-LDL). Furthermore, overexpression of GAS5 aggravated ox-LDL-induced pro-inflammatory cytokines (IL-6, IL-1β, TNF-α) and chemokine MCP-1 secretion in macrophages, which were reversed after GAS5 cessation. Additionally, high expression and secretion of MMP-2 and MMP-9 were increased in ox-LDL-stimulated macrophages following GAS5 elevation, but these increases were inhibited in GAS5-silenced group. Mechanism analysis identified GAS5 as a endogenous sponge to directly bind and suppress miR-221 expression. Notably, miR-221 elevation antagonized GAS5-enhanced inflammatory response and MMPs in macrophages upon ox-LDL. These results suggest that GAS5 can trigger inflammatory response and MMP expression by acting as a sponge of miR-221, which may facilitate fibrous cap degradation and aggravate atherosclerotic plaque destabilization, supporting a promising therapeutic agent against atherosclerosis.

60 APPLIED LIFE SCIENCES↗

IL-1β promotes transendothelial migration of PBMCs by upregulation of the FN/α5β1 signalling pathway in immortalised human brain microvascular endothelial cells

Highlights: • IL-1β-induced inflammation of THBMECs increases cell-matrix adhesion. • Active β{sub 1} integrins are redistributed under inflammatory conditions. • IL-1β activates the FN/α{sub 5}β{sub 1} integrin/FAK/Src-signalling pathway. • Blocking the α{sub 5} integrin subunit reduces IL-1β-induced transendothelial migration. Neuroinflammation is often associated with pathological changes in the function of the blood-brain barrier (BBB) caused by disassembly of tight and adherens junctions that under physiological conditions are important for the maintenance of the BBB integrity. Consequently, in inflammation the BBB becomes dysfunctional, facilitating leukocyte traversal of the barrier and accumulation of immune cells within the brain. The extracellular matrix (ECM) also contributes to BBB integrity but the significance of the main ECM receptors, the β{sub 1} integrins also expressed on endothelial cells, is less well understood. To evaluate whether β{sub 1} integrin function is affected during inflammation and impacts barrier function, we used a transformed human brain microvascular endothelial cell (THBMEC)-based Interleukin 1β (IL-1β)-induced inflammatory in vitro BBB model. We demonstrate that IL-1β increases cell-matrix adhesion and induces a redistribution of active β{sub 1} integrins to the basal surface. In particular, binding of α{sub 5}β{sub 1} integrin to its ligand fibronectin is enhanced and α{sub 5}β{sub 1} integrin-dependent signalling is upregulated. Additionally, localisation of the tight junction protein claudin-5 is altered. Blockade of the α{sub 5}β{sub 1} integrin reduces the IL-1β-induced transendothelial migration of peripheral blood mononuclear cells (PBMCs). These data imply that IL-1β-induced inflammation not only destabilizes tight junctions but also increases α{sub 5}β{sub 1} integrin-dependent cell-matrix adhesion to fibronectin.

60 APPLIED LIFE SCIENCES↗

Vortex bursting and associated twist dynamics on helical vortex tubes and vortex rings

The interaction of opposite-signed twist waves on vortex tubes can lead to vortex bursting, a process where the core expands into a double ring-like structure with strong swirling flows. Previous works have studied vortex bursting on rectilinear vortices by axially perturbing the initial core size to generate the twist waves, and observed largely axisymmetric bursting dynamics. In this work, we numerically study bursting on vortical structures with curved centrelines, analysing the interaction between the centreline dynamics, twist wave generation and propagation, and vortex bursting. We focus on axially perturbed helical vortex tubes with small radius-to-pitch ratios up to$0.0625$, as well as vortex rings with a large radius-to-core size ratio$10$, both at a circulation-based Reynolds number$5000$. The results show that though the initial twist wave propagation speeds are relatively unaffected by the curvature and torsion of the centreline, the bursting process is altered significantly compared with rectilinear vortices. The self-induced rotation of the centreline of the helical tube induces a non-axisymmetric distortion of the bursting structure, which rapidly breaks up the vortex core into small-scale helical structures. A similar destabilization of the bursting structure also occurs on vortex rings. The enstrophy increase and accelerated energy decay associated with bursting are predominantly determined by the twist wave strength, rather than the curvature and torsion of the centreline. Combined, our findings imply that bursting could play an important role in transferring and dissipating energy of vortical structures in wakes, and turbulent flows in general.

Mechanics↗

Antarctic ice sheet response to sudden and sustained ice-shelf collapse (ABUMIP)

Antarctica's ice shelves modulate the grounded ice flow, and weakening of ice shelves due to climate forcing will decrease their ‘buttressing’ effect, causing a response in the grounded ice. While the processes governing ice-shelf weakening are complex, uncertainties in the response of the grounded ice sheet are also difficult to assess. The Antarctic BUttressing Model Intercomparison Project (ABUMIP) compares ice-sheet model responses to decrease in buttressing by investigating the ‘end-member’ scenario of total and sustained loss of ice shelves. Although unrealistic, this scenario enables gauging the sensitivity of an ensemble of 15 ice-sheet models to a total loss of buttressing, hence exhibiting the full potential of marine ice-sheet instability. All models predict that this scenario leads to multi-metre (1–12 m) sea-level rise over 500 years from present day. West Antarctic ice sheet collapse alone leads to a 1.91–5.08 m sea-level rise due to the marine ice-sheet instability. Mass loss rates are a strong function of the sliding/friction law, with plastic laws cause a further destabilization of the Aurora and Wilkes Subglacial Basins, East Antarctica. Improvements to marine ice-sheet models have greatly reduced variability between modelled ice-sheet responses to extreme ice-shelf loss, e.g. compared to the SeaRISE assessments.

54 ENVIRONMENTAL SCIENCES↗

On non-local energy transfer via zonal flow in the Dimits shift

The two-dimensional Terry–Horton equation is shown to exhibit the Dimits shift when suitably modified to capture both the nonlinear enhancement of zonal/drift-wave interactions and the existence of residual Rosenbluth–Hinton states. This phenomenon persists through numerous simplifications of the equation, including a quasilinear approximation as well as a four-mode truncation. It is shown that the use of an appropriate adiabatic electron response, for which the electrons are not affected by the flux-averaged potential, results in an $\boldsymbol{E}\times \boldsymbol{B}$ nonlinearity that can efficiently transfer energy non-locally to length scales of the order of the sound radius. The size of the shift for the nonlinear system is heuristically calculated and found to be in excellent agreement with numerical solutions. The existence of the Dimits shift for this system is then understood as an ability of the unstable primary modes to efficiently couple to stable modes at smaller scales, and the shift ends when these stable modes eventually destabilize as the density gradient is increased. This non-local mechanism of energy transfer is argued to be generically important even for more physically complete systems.

70 PLASMA PHYSICS AND FUSION TECHNOLOGY↗

Electron phase-space hole transverse instability at high magnetic field

Analytic treatment is presented of the electrostatic instability of an initially planar electron hole in a plasma of effectively infinite particle magnetization. It is shown that there is an unstable mode consisting of a rigid shift of the hole in the trapping direction. Its low frequency is determined by the real part of the force balance between the Maxwell stress arising from the transverse wavenumber $k$ and the kinematic jetting from the hole’s acceleration. The very low growth rate arises from a delicate balance in the imaginary part of the force between the passing-particle jetting, which is destabilizing, and the resonant response of the trapped particles, which is stabilizing. Nearly universal scalings of the complex frequency and $k$ with hole depth are derived. Particle in cell simulations show that the slow-growing instabilities previously investigated as coupled hole–wave phenomena occur at the predicted frequency, but with growth rates 2 to 4 times greater than the analytic prediction. This higher rate may be caused by a reduced resonant stabilization because of numerical phase-space diffusion in the simulations.

Physics↗

Stability of a tokamak plasma with diffuse toroidal rotation

The present work considers the stability of a high- $\beta$ , large aspect ratio, circular plasma with diffuse profiles for the safety factor and the angular toroidal frequency (López & Guazzotto, Phys. Plasmas , vol. 24, 032501). An application of the Frieman–Rotenberg formalism results in a system of scalar eigenmode equations whose coupling is retained at the plasma–vacuum transition but is disregarded across the plasma column, which is a standard practice. The solution technique consists of a multidimensional shooting method for the poloidal harmonics; robust initial guesses are constructed by solving the dispersion relation in the static scenario with vanishing magnetic shear. Flow shear appears as a high- $\beta$ toroidal contribution, and we illustrate its destabilizing influence on $n=1$ external kink modes in the presence of ideal and resistive walls. Internal resonances are avoided by means of the selection of appropriate equilibrium parameters. The stabilizing influence of a finite positive average magnetic shear is also exemplified.

Physics↗

Self-sustaining sound in collisionless, high- β plasma

Using analytical theory and hybrid-kinetic numerical simulations, we demonstrate that, in a collisionless plasma, long-wavelength ion-acoustic waves (IAWs) with amplitudes $δn/n_0≳2/β$ (where $β\gg1$ is the ratio of thermal to magnetic pressure) generate sufficient pressure anisotropy to destabilize the plasma to firehose and mirror instabilities. These kinetic instabilities grow rapidly to reduce the pressure anisotropy by pitch-angle scattering and trapping particles, respectively, thereby impeding the maintenance of Landau resonances that enable such waves’ otherwise potent collisionless damping. The result is wave dynamics that evince a weakly collisional plasma: the ion distribution function is near-Maxwellian, the field-parallel flow of heat resembles its Braginskii form (except in regions where large-amplitude magnetic mirrors strongly suppress particle transport), and the relations between various thermodynamic quantities are more ‘fluid-like’ than kinetic. A nonlinear fluctuation–dissipation relation for self-sustaining IAWs is obtained by solving a plasma-kinetic Langevin problem, which demonstrates suppressed damping, enhanced fluctuation levels and weakly collisional thermodynamics when IAWs with $δn/n_0≳2/β$ are stochastically driven. We investigate how our results depend upon the scale separation between the wavelength of the IAW and the Larmor radius of the ions, and discuss briefly their implications for our understanding of turbulence and transport in the solar wind and the intracluster medium of galaxy clusters.

70 PLASMA PHYSICS AND FUSION TECHNOLOGY↗

Kinetic-ballooning-mode turbulence in low-average-magnetic-shear equilibria

In this work, kinetic-ballooning-mode (KBM) turbulence is studied via gyrokinetic flux-tube simulations in three magnetic equilibria that exhibit small average magnetic shear: the Helically Symmetric eXperiment (HSX), the helical-axis Heliotron-J and a circular tokamak geometry. For HSX, the onset of KBM being the dominant instability at low wavenumber occurs at a critical value of normalized plasma pressure $\beta ^{\rm KBM}_{\rm crit}$ that is an order of magnitude smaller than the magnetohydrodynamic (MHD) ballooning limit $\beta ^{\rm MHD}_{\rm crit}$ when a strong ion temperature gradient (ITG) is present. However, $\beta ^{\rm KBM}_{\rm crit}$ increases and approaches the MHD ballooning limit as the ITG tends to zero. For these configurations, $\beta ^{\rm KBM}_{\rm crit}$ also increases as the magnitude of the average magnetic shear increases, regardless of the sign of the normalized magnetic shear. Simulations of Heliotron-J and a circular axisymmetric geometry display behaviour similar to HSX with respect to $\beta ^{\rm KBM}_{\rm crit}$ . Despite large KBM growth rates at long wavelengths in HSX, saturation of KBM turbulence with $\beta > \beta _{\rm crit}^{\rm KBM}$ is achievable in HSX and results in lower heat transport relative to the electrostatic limit by a factor of roughly five. Nonlinear simulations also show that KBM transport dominates the dynamics when KBMs are destabilized linearly, even if KBM growth rates are subdominant to ITG growth rates.

70 PLASMA PHYSICS AND FUSION TECHNOLOGY↗

Collisional broadening of nonlinear resonant wave–particle interactions

A general procedure for understanding plasma behaviour when resonant wave–particle interactions are the sole destabilizing and transport mechanism or only heating and/or current drive source is highlighted without recourse to involved numerical or analytical treatments. These phenomena are characterized by transport that appears to be collisionless even though collisions play a central role in narrow collisional boundary layers. The order of magnitude estimates, which include nonlinear effects, are shown to provide expressions in agreement with the principal results of recent toroidal Alfvén eigenmode (TAE), toroidal magnetic field ripple, and heating and current drive treatments. More importantly, the retention of nonlinearities leads to new estimates of the alpha particle energy diffusivity at saturation for TAE modes, and the ripple threshold at which superbanana plateau evaluations of alpha particle transport are modified by nonlinear radial drift effects. In addition, the estimates indicate when quasilinear descriptions for heating and current drive will begin to fail. The phenomenological procedure demonstrates that in magnetic fusion relevant plasmas, narrow collisional boundary layers must be retained for resonant wave–particle interactions as they enhance the role of collisions, and make stochastic particle motion unlikely to be more important than other nonlinear processes.

Physics↗

Evolution of an arched magnetized laboratory plasma in a sheared magnetic field

Arched magnetized structures are a common occurrence in space and laboratory plasmas. Results from a laboratory experiment on spatio-temporal evolution of an arched magnetized plasma ( $\beta \approx 10^{-3}$ , Lundquist number $\approx 10^{4}$ , plasma radius/ion gyroradius $\approx 20$ ) in a sheared magnetic configuration are presented. The experiment is designed to model conditions relevant to the formation and destabilization of similar structures in the solar atmosphere. The magnitude of a nearly horizontal overlying magnetic field was varied to study its effects on the writhe and twist of the arched plasma. In addition, the direction of the guiding magnetic field along the arch was varied to investigate its role in the formation of either forward- or reverse-S shaped plasma structures. The electrical current in the arched plasma was well below the current required to make it kink unstable. A significant increase in the writhe of the arched plasma was observed with larger magnitudes of overlying magnetic field. A forward-S shaped arched plasma was observed for a guiding magnetic field oriented nearly antiparallel to the initial arched plasma current, while the parallel orientation yielded the reverse-S shaped arched plasma.

70 PLASMA PHYSICS AND FUSION TECHNOLOGY↗

Biomimetic Metal-Free Hydride Donor Catalysts for CO 2 Reduction

The catalytic reduction of carbon dioxide to fuels and value-added chemicals is of significance for the development of carbon recycling technologies. One of the main challenges associated with catalytic CO 2 reduction is product selectivity: the formation of carbon monoxide, molecular hydrogen, formate, methanol, and other products occurs with similar thermodynamic driving forces, making it difficult to selectively reduce CO 2 to the target product. Significant scientific effort has been aimed at the development of catalysts that can suppress the undesired hydrogen evolution reaction and direct the reaction toward the selective formation of the desired products, which are easy to handle and store. Inspired by natural photosynthesis, where the CO 2 reduction is achieved using NADPH cofactors in the Calvin cycle, in this study we explore biomimetic metal-free hydride donors as catalysts for the selective reduction of CO 2 to formate. Here, we outline our recent findings on the thermodynamic and kinetic parameters that control the hydride transfer from metal-free hydrides to CO 2 . By experimentally measuring and theoretically calculating the thermodynamic hydricities of a range of metal-free hydride donors, we derive structural and electronic factors that affect their hydride-donating abilities. Two dominant factors that contribute to the stronger hydride donors are identified to be (i) the stabilization of the positive charge formed upon HT via aromatization or by the presence of electron-donating groups and (ii) the destabilization of hydride donors through the anomeric effect or in the presence of significant structural constrains in the hydride molecule. Hydride donors with appropriate thermodynamic hydricities were reacted with CO 2 , and the formation of the formate ion (the first reduction step in CO 2 reduction to methanol) was confirmed experimentally, providing an important proof of principle that organocatalytic CO 2 reduction is feasible. The kinetics of hydride transfer to CO 2 were found to be slow, and the sluggish kinetics were assigned in part to the large self-exchange reorganization energy associated with the organic hydrides in the DMSO solvent. Finally, we outline our approaches to the closure of the catalytic cycle via the electrochemical and photochemical regeneration of the hydride (R–H) from the conjugate hydride acceptors (R + ). We illustrate how proton-coupled electron transfer can be efficiently utilized not only to lower the electrochemical potential at which the hydride regeneration takes place but also to suppress the unwanted dimerization that neutral radical intermediates tend to undergo. Overall, this account provides a summary of important milestones achieved in organocatalytic CO 2 reduction and provides insights into the future research directions needed for the discovery of inexpensive catalysts for carbon recycling.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗

Light-Driven C(sp 3 )–C(sp 3 ) Bond Functionalizations Enabled by the PCET Activation of Alcohol O–H Bonds

Methods that enable the selective functionalization of C–C bonds offer unique opportunities for the skeletal diversification of complex molecules and provide access to unique structures without the need for de novo synthesis. While considerable advances have been made in transition-metal-based approaches, much recent work has focused on alternative strategies for C–C bond cleavage enabled by transient free radicals. In particular, alkoxy radicals derived from simple alcohols are known to significantly destabilize adjacent C–C bonds, enabling spontaneous cleavage to eject a carbon-centered radical and afford carbonyl products via β-fragmentation. Here, while this reactivity has long been recognized, its applications in synthesis have been limited, in part, by the challenges associated with generating the key alkoxy radical intermediates.

Alcohols↗

Exceptionally Complex Electronic Structures of Lanthanide Oxides and Small Molecules

Lanthanide (Ln) oxide clusters and molecular systems provide a bottom-up look at the electronic structures of the bulk materials because of close parallels in the patterns of Ln 4fN subshell occupancy between the molecular and bulk Ln 2 O 3 size limits. At the same time, these clusters and molecules offer a challenge to the theory community to find appropriate and robust treatments for the 4f N patterns across the Ln series. Anion photoelectron (PE) spectroscopy provides a powerful experimental tool for studying these systems, mapping the energies of the ground and low-lying excited states of the neutral relative to the initial anion state, providing spectroscopic patterns that reflect the Ln 4f N occupancy. In this Account, we review our anion PE spectroscopic and computational studies on a range of small lanthanide molecules and cluster species. The PE spectra of LnO – (Ln = Ce, Pr, Sm, Eu) diatomic molecules show spectroscopic signatures associated with detachment of an electron from what can be described as a diffuse Ln 6s-like orbital. While the spectra of all four diatomics share this common transition, the fine structure in the transition becomes more complex with increasing 4f occupancy. This effect reflects increased coupling between the electrons occupying the corelike 4f and diffuse 6s orbitals with increasing N. Understanding the PE spectra of these diatomics sets the stage for interpreting the spectra of polyatomic molecular and cluster species. In general, the results confirm that the partial 4f N subshell occupancy is largely preserved between molecular and bulk oxides and borides. However, they also suggest that surfaces and edges of bulk materials may support a low-energy, diffuse Ln 6s band, in contrast to bulk interiors, in which the 6s band is destabilized relative to the 5d band. We also identify cases in which the molecular Ln centers have 4f N+1 occupancy rather than bulklike 4f N , which results in weaker Ln–O bonding. Specifically, Sm centers in mixed Ce–Sm oxides or in Sm x O y – (y ≤ x) clusters have this higher 4f N+1 occupancy. The PE spectra of these particular species exhibit a striking increase in the relative intensities of excited-state transitions with decreasing photon energy (resulting in lower photoelectron kinetic energy). Furthermore, this is opposite of what is expected on the basis of the threshold laws that govern photodetachment. We relate this phenomenon to strong electron–neutral interactions unique to these complex electronic structures. The time scale of the interaction, which shakes up the electronic configuration of the neutral, increases with decreasing electron momentum. From a computational standpoint, we point out that special care must be taken when considering Ln cluster and molecular systems toward the center of the Ln series (e.g., Sm, Eu), where treatment of electrons explicitly or using an effective core potential can yield conflicting results on competing subshell occupancies. However, despite the complex electronic structures associated with partially filled 4f N subshells, we demonstrate that inexpensive and tractable calculations yield useful qualitative insight into the general electronic structural features.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗

Structural Changes Associated with Transthyretin Misfolding and Amyloid Formation Revealed by Solution and Solid-State NMR

Elucidation of structural changes involved in protein misfolding and amyloid formation is crucial for unraveling the molecular basis of amyloid formation. We report structural analyses of the amyloidogenic intermediate and amyloid aggregates of transthyretin using solution and solid-state nuclear magnetic resonance (NMR) spectroscopy. These NMR solution results show that one of the two main β-sheet structures (CBEF β-sheet) is maintained in the aggregation-competent intermediate, while the other DAGH β-sheet is more flexible on millisecond time scales. Magic-angle-spinning solid-state NMR revealed that AB loop regions interacting with strand A in the DAGH β-sheet undergo conformational changes, leading to the destabilized DAGH β-sheet.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗