Excitation landscape of the CP43 photosynthetic antenna complex from multiscale simulations.

Photosystem II (PSII), the principal enzyme of oxygenic photosynthesis, contains two integral light harvesting proteins (CP43 and CP47) that bind chlorophylls and carotenoids. The two intrinsic antennae play crucial roles in excitation energy transfer and photoprotection. CP43 interacts most closely with the reaction center of PSII, specifically with the branch of the reaction center (D1) that is responsible for primary charge separation and electron transfer. Deciphering the function of CP43 requires detailed atomic-level insights into the properties of the embedded pigments. To advance this goal, we employ a range of multiscale computational approaches to determine the site energies and excitonic profile of CP43 chlorophylls, using large all-atom models of a membrane-bound PSII monomer. In addition to time-dependent density functional theory (TD-DFT) used in the context of a quantum-mechanics/molecular-mechanics setup (QM/MM), we present a thorough analysis using the perturbed matrix method (PMM), which enables us to utilize information from long-timescale molecular dynamics simulations of native PSII-complexed CP43. The excited state energetics and excitonic couplings have both similarities and differences compared with previous experimental fits and theoretical calculations. Both static TD-DFT and dynamic PMM results indicate a layered distribution of site energies and reveal specific groups of chlorophylls that have shared contributions to low-energy excitations. Importantly, the contribution to the lowest energy exciton does not arise from the same chlorophylls at each system configuration, but rather changes as a function of conformational dynamics. An unexpected finding is the identification of a low-energy charge-transfer excited state within CP43 that involves a lumenal (C2) and the central (C10) chlorophyll of the complex. The results provide a refined basis for structure-based interpretation of spectroscopic observations and for further deciphering excitation energy transfer in oxygenic photosynthesis.

Correlating Structure with Spectroscopy in Ascorbate Peroxidase Compound II.

Structural and spectroscopic investigations of compound II in ascorbate peroxidase (APX) have yielded conflicting conclusions regarding the protonation state of the crucial Fe(IV) intermediate. Neutron diffraction and crystallographic data support an iron(IV)-hydroxo formulation, whereas Mössbauer, X-ray absorption (XAS), and nuclear resonance vibrational spectroscopy (NRVS) studies appear consistent with an iron(IV)-oxo species. Here we examine APX with spectroscopy-oriented QM/MM calculations and extensive exploration of the conformational space for both possible formulations of compound II. We establish that irrespective of variations in the orientation of a vicinal arginine residue and potential reorganization of proximal water molecules and hydrogen bonding, the Fe-O distances for the oxo and hydroxo forms consistently fall within distinct, narrow, and nonoverlapping ranges. The accuracy of geometric parameters is validated by coupled-cluster calculations with the domain-based local pair natural orbital approach, DLPNO-CCSD(T). QM/MM calculations of spectroscopic properties are conducted for all structural variants, encompassing Mössbauer, optical, X-ray absorption, and X-ray emission spectroscopies and NRVS. All spectroscopic observations can be assigned uniquely to an Fe(IV)═O form. A terminal hydroxy group cannot be reconciled with the spectroscopic data. Under no conditions can the Fe(IV)═O distance be sufficiently elongated to approach the crystallographically reported Fe-O distance. The latter is consistent only with a hydroxo species, either Fe(IV) or Fe(III). Our findings strongly support the Fe(IV)═O formulation of APX-II and highlight unresolved discrepancies in the nature of samples used across different experimental studies.

Comprehensive Evaluation of Models for Ammonia Binding to the Oxygen Evolving Complex of Photosystem II.

The identity and insertion pathway of the substrate oxygen atoms that are coupled to dioxygen by the oxygen-evolving complex (OEC) remains a central question toward understanding Nature's water oxidation mechanism. In several studies, ammonia has been used as a small "water analogue" to elucidate the pathway of substrate access to the OEC and to aid in determining which of the oxygen ligands of the tetramanganese cluster are substrates for O-O bond formation. On the basis of structural and spectroscopic investigations, five first-sphere binding modes of ammonia have been suggested, involving either substitution of an existing H2O/OH-/O2- group or addition as an extra ligand to a metal ion of the Mn4CaO5 cluster. Some of these modes, specifically the ones involving substitution, have already been subject to spectroscopy-oriented quantum chemical investigations, whereas more recent suggestions that postulate the addition of ammonia have not been examined so far with quantum chemistry for their agreement with spectroscopic data. Herein, we use a common structural framework and theoretical methodology to evaluate structural models of the OEC that represent all proposed modes of first-sphere ammonia interaction with the OEC in its S2 state. Criteria include energetic, magnetic, kinetic, and spectroscopic properties compared against available experimental EPR, ENDOR, ESEEM, and EDNMR data. Our results show that models featuring ammonia replacing one of the two terminal water ligands on Mn4 align best with experimental data, while they definitively exclude substitution of a bridging µ-oxo ligand as well as incorporation of ammonia as a sixth ligand on Mn1 or Mn4.

Localization of Brain Signals by Alternating Projection.

A popular approach for modeling brain activity in MEG and EEG is based on a small set of current dipoles, where each dipole represents the combined activation of a local area of the brain. Here, we address the problem of multiple dipole localization with a novel solution called Alternating Projection (AP). The AP solution is based on minimizing the least-squares (LS) criterion by transforming the multi-dimensional optimization required for direct LS solution, to a sequential and iterative solution in which one source at a time is localized, while keeping the other sources fixed. Results from simulated, phantom, and human MEG data demonstrated the high accuracy of the AP method, with superior localization results than popular scanning methods from the multiple-signal classification (MUSIC) and beamformer families. In addition, the AP method was more robust to forward model errors resulting from head rotations and translations, as well as different cortex tessellation grids for the forward and inverse solutions, with consistently higher localization accuracy in low SNR and highly correlated sources.

Exploring Electrophilic Hydrophosphination via Metal Phosphenium Intermediates.

Two Mo(0) phosphenium complexes containing ancillary secondary phosphine ligands have been investigated with respect to their ability to participate in electrophilic addition at unsaturated substrates and subsequent P-H hydride transfer to "quench" the resulting carbocations. These studies provide stoichiometric "proof of concept" for a proposed new metal-catalyzed electrophilic hydrophosphination mechanism. The more strongly Lewis acidic phosphenium complex, [Mo(CO)4(PR2H)(PR2)]+ (R=Ph, Tolp), cleanly hydrophosphinates 1,1-diphenylethylene, benzophenone, and ethylene, while other substrates react rapidly to give products resulting from competing electrophilic processes. A less Lewis acidic complex, [Mo(CO)3(PR2H)2(PR2)]+, generally reacts more slowly but participates in clean hydrophosphination of a wider range of unsaturated substrates, including styrene, indene, 1-hexene, and cyclohexanone, in addition to 1,1-diphenylethylene, benzophenone, and ethylene. Mechanistic studies are described, including stoichiometric control reactions and computational and kinetic analyses, which probe whether the observed P-H addition actually does occur by the proposed electrophilic mechanism, and whether hydridic P-H transfer in this system is intra- or intermolecular. Preliminary reactivity studies indicate challenges that must be addressed to exploit these promising results in catalysis.

Reactive high-spin iron(IV)-oxo sites through dioxygen activation in a metal-organic framework.

In nature, nonheme iron enzymes use dioxygen to generate high-spin iron(IV)=O species for a variety of oxygenation reactions. Although synthetic chemists have long sought to mimic this reactivity, the enzyme-like activation of O2 to form high-spin iron(IV) = O species remains an unrealized goal. Here, we report a metal-organic framework featuring iron(II) sites with a local structure similar to that in α-ketoglutarate-dependent dioxygenases. The framework reacts with O2 at low temperatures to form high-spin iron(IV) = O species that are characterized using in situ diffuse reflectance infrared Fourier transform, in situ and variable-field Mössbauer, Fe Kß x-ray emission, and nuclear resonance vibrational spectroscopies. In the presence of O2, the framework is competent for catalytic oxygenation of cyclohexane and the stoichiometric conversion of ethane to ethanol.

LOCALIZATION OF SPATIALLY EXTENDED BRAIN SOURCES BY FLEXIBLE ALTERNATING PROJECTION (FLEX-AP).

Magnetoencephalography (MEG) and electroencephalography (EEG) are widely employed techniques for the in-vivo measurement of neural activity with exceptional temporal resolution. Modeling the neural sources underlying these signals is of high interest for both neuroscience research and pathology. The method of Alternating Projection (AP) was recently shown to outperform the well-established recursively applied and projected multiple signal classification (RAP-MUSIC) algorithm. In this work, we further enhanced AP to allow for source extent estimation, a novel approach termed flexible extent AP (FLEX-AP). We found that FLEX-AP achieves significantly lower errors for spatially coherent sources compared to AP, RAP-MUSIC, and the corresponding extension, FLEX-RAP-MUSIC. We also found an advantage for discrete dipoles under forward modeling errors encountered in real-world scenarios. Together, our results indicate that the FLEX-AP method can unify dipole fitting and distributed source imaging into a single algorithm with promising accuracy.

Hyperbolic graph embedding of MEG brain networks to study brain alterations in individuals with subjective cognitive decline.

An expansive area of research focuses on discerning patterns of alterations in functional brain networks from the early stages of Alzheimer's disease, even at the subjective cognitive decline (SCD) stage. Here, we developed a novel hyperbolic MEG brain network embedding framework for transforming high-dimensional complex MEG brain networks into lower-dimensional hyperbolic representations. Using this model, we computed hyperbolic embeddings of the MEG brain networks of two distinct participant groups: individuals with SCD and healthy controls. We demonstrated that these embeddings preserve both local and global geometric information, presenting reduced distortion compared to rival models, even when brain networks are mapped into low-dimensional spaces. In addition, our findings showed that the hyperbolic embeddings encompass unique SCD-related information that improves the discriminatory power above and beyond that of connectivity features alone. Notably, we introduced a unique metric-the radius of the node embeddings-which effectively proxies the hierarchical organization of the brain. Using this metric, we identified subtle hierarchy organizational differences between the two participant groups, suggesting increased hierarchy in the dorsal attention, frontoparietal, and ventral attention subnetworks among the SCD group. Last, we assessed the correlation between these hierarchical variations and cognitive assessment scores, revealing associations with diminished performance across multiple cognitive evaluations in the SCD group. Overall, this study presents the first evaluation of hyperbolic embeddings of MEG brain networks, offering novel insights into brain organization, cognitive decline, and potential diagnostic avenues of Alzheimer's disease.

The dual-path hypothesis for the emergence of anosognosia in Alzheimer's disease.

Although neurocognitive models have been proposed to explain anosognosia in Alzheimer's disease (AD), the neural cascade responsible for its origin in the human brain remains unknown. Here, we build on a mechanistic dual-path hypothesis that brings error-monitoring and emotional processing systems as key elements for self-awareness, with distinct impacts on the emergence of anosognosia in AD. Proceeding from the notion of anosognosia as a dimensional syndrome, varying between a lack of concern about one's own deficits (i.e., anosodiaphoria) and a complete lack of awareness of deficits, our hypothesis states that (i) unawareness of deficits would result from primary damage to the error-monitoring system, whereas (ii) anosodiaphoria would more likely result from an imbalance between emotional processing and error-monitoring. In the first case, a synaptic failure in the error-monitoring system, in which the anterior and posterior cingulate cortices play a major role, would have a negative impact on error (or deficits) awareness, preventing patients from becoming aware of their condition. In the second case, an impairment in the emotional processing system, in which the amygdala and the orbitofrontal cortex play a major role, would prevent patients from monitoring the internal milieu for relevant errors (or deficits) and assigning appropriate value to them, thus biasing their impact on the error-monitoring system. Our hypothesis stems on two scientific premises. One comes from preliminary results in AD patients showing a synaptic failure in the error-monitoring system along with a decline of awareness for cognitive difficulties at the time of diagnosis. Another comes from the somatic marker hypothesis, which proposes that emotional signals are critical to adaptive behavior. Further exploration of these premises will be of great interest to illuminate the foundations of self-awareness and improve our knowledge of the underlying paths of anosognosia in AD and other brain disorders.

Nature of S-States in the Oxygen-Evolving Complex Resolved by High-Energy Resolution Fluorescence Detected X-ray Absorption Spectroscopy.

Photosystem II, the water splitting enzyme of photosynthesis, utilizes the energy of sunlight to drive the four-electron oxidation of water to dioxygen at the oxygen-evolving complex (OEC). The OEC harbors a Mn4CaO5 cluster that cycles through five oxidation states Si (i = 0-4). The S3 state is the last metastable state before the O2 evolution. Its electronic structure and nature of the S2 → S3 transition are key topics of persisting controversy. Most spectroscopic studies suggest that the S3 state consists of four Mn(IV) ions, compared to the Mn(III)Mn(IV)3 of the S2 state. However, recent crystallographic data have received conflicting interpretations, suggesting either metal- or ligand-based oxidation, the latter leading to an oxyl radical or a peroxo moiety in the S3 state. Herein, we utilize high-energy resolution fluorescence detected (HERFD) X-ray absorption spectroscopy to obtain a highly resolved description of the Mn K pre-edge region for all S-states, paying special attention to use chemically unperturbed S3 state samples. In combination with quantum chemical calculations, we achieve assignment of specific spectroscopic features to geometric and electronic structures for all S-states. These data are used to confidently discriminate between the various suggestions concerning the electronic structure and the nature of oxidation events in all observable catalytic intermediates of the OEC. Our results do not support the presence of either peroxo or oxyl in the active configuration of the S3 state. This establishes Mn-centered storage of oxidative equivalents in all observable catalytic transitions and constrains the onset of the O-O bond formation until after the final light-driven oxidation event.

An F-ratio-based method for estimating the number of active sources in MEG.

Introduction: Magnetoencephalography (MEG) is a powerful technique for studying the human brain function. However, accurately estimating the number of sources that contribute to the MEG recordings remains a challenging problem due to the low signal-to-noise ratio (SNR), the presence of correlated sources, inaccuracies in head modeling, and variations in individual anatomy. Methods: To address these issues, our study introduces a robust method for accurately estimating the number of active sources in the brain based on the F-ratio statistical approach, which allows for a comparison between a full model with a higher number of sources and a reduced model with fewer sources. Using this approach, we developed a formal statistical procedure that sequentially increases the number of sources in the multiple dipole localization problem until all sources are found. Results: Our results revealed that the selection of thresholds plays a critical role in determining the method's overall performance, and appropriate thresholds needed to be adjusted for the number of sources and SNR levels, while they remained largely invariant to different inter-source correlations, translational modeling inaccuracies, and different cortical anatomies. By identifying optimal thresholds and validating our F-ratio-based method in simulated, real phantom, and human MEG data, we demonstrated the superiority of our F-ratio-based method over existing state-of-the-art statistical approaches, such as the Akaike Information Criterion (AIC) and Minimum Description Length (MDL). Discussion: Overall, when tuned for optimal selection of thresholds, our method offers researchers a precise tool to estimate the true number of active brain sources and accurately model brain function.

Reaction Center Excitation in Photosystem II: From Multiscale Modeling to Functional Principles.

Oxygenic photosynthesis is the fundamental energy-converting process that utilizes sunlight to generate molecular oxygen and the organic compounds that sustain life. Protein-pigment complexes harvest light and transfer excitation energy to specialized pigment assemblies, reaction centers (RC), where electron transfer cascades are initiated. A molecular-level understanding of the primary events is indispensable for elucidating the principles of natural photosynthesis and enabling development of bioinspired technologies. The primary enzyme in oxygenic photosynthesis is Photosystem II (PSII), a membrane-embedded multisubunit complex, that catalyzes the light-driven oxidation of water. The RC of PSII consists of four chlorophyll a and two pheophytin a pigments symmetrically arranged along two core polypeptides; only one branch participates in electron transfer. Despite decades of research, fundamental questions remain, including the origin of this functional asymmetry, the nature of primary charge-transfer states and the identity of the initial electron donor, the origin of the capability of PSII to enact charge separation with far-red photons, i.e., beyond the "red limit" where individual chlorophylls absorb, and the role of protein conformational dynamics in modulating charge-separation pathways.In this Account, we highlight developments in quantum-chemistry based excited-state computations for multipigment assemblies and the refinement of protocols for computing protein-induced electrochromic shifts and charge-transfer excitations calibrated with modern local correlation coupled cluster methods. We emphasize the importance of multiscale atomistic quantum-mechanics/molecular-mechanics and large-scale molecular dynamics simulations, which enabled direct and accurate modeling of primary processes in RC excitation at the quantum mechanical level.Our findings show how differential protein electrostatics enable spectral tuning of RC pigments and generate functional asymmetry in PSII. A chlorophyll pigment on the active branch (ChlD1) has the lowest site energy in PSII and is the primary electron donor. The complete absence of low-lying charge-transfer states within the central pair of chlorophylls excludes a long-held assumption about the initial charge separation. Instead, we identify two primary charge separation pathways, both with the same pheophytin acceptor (PheoD1): a fast pathway with ChlD1 as the primary electron donor (short-range charge-separation) and a slow pathway with PD1PD2 as the initial donor (long-range charge separation). The low-energy spectrum is dominated by two states with significant charge-transfer character, ChlD1δ+PheoD1δ- and PD1δ+PheoD1δ-. The conformational dynamics of PSII allows these charge-transfer states to span wide energy ranges, pushing oxygenic photosynthesis beyond the "red limit". These results provide a quantum mechanical picture of the primary events in the RC of oxygenic photosynthesis, forming a solid basis for interpreting experimental observations and for extending photosynthesis research in new directions.

Detecting Anosognosia from the Prodromal Stage of Alzheimer's Disease.

BACKGROUND: Though not originally developed for this purpose, the Healthy Aging Brain Care Monitor (HABC-M) seems a valuable instrument for assessing anosognosia in Alzheimer's disease (AD). OBJECTIVES: Our study aimed at 1) investigating the validity of the HABC-M (31 items), and its cognitive, psychological, and functional subscales, in discriminating AD patients from controls; 2) exploring whether the HABC-M discrepancy scores between the self-reports of patients/controls in these different domains and the respective ratings provided by their caregivers/informants correlate with an online measure of self-awareness; 3) determining whether the caregiver burden level, also derived from the HABC-M, could add additional support for detecting anosognosia. METHODS: The HABC-M was administered to 30 AD patients and 30 healthy controls, and to their caregivers/informants. A measure of online awareness was established from subjects' estimation of their performances in a computerized experiment. RESULTS: The HABC-M discrepancy scores distinguished AD patients from controls. The cognitive subscale discriminated the two groups from the prodromal AD stage, with an AUC of 0.88 [95% CI: 0.78;0.97]. Adding the caregiver burden level raised it to 0.94 [0.86;0.99]. Significant correlations between the HABC-M and online discrepancy scores were observed in the patients group, providing convergent validity of these methods. CONCLUSIONS: The cognitive HABC-M (six items) can detect anosognosia across the AD spectrum. The caregiver burden (four items) may corroborate the suspicion of anosognosia. The short-hybrid scale, built from these 10 items instead of the usual 31, showed the highest sensitivity for detecting anosognosia from the prodromal AD stage, which may further help with timely diagnosis.

Triplet states in the reaction center of Photosystem II.

In oxygenic photosynthesis sunlight is harvested and funneled as excitation energy into the reaction center (RC) of Photosystem II (PSII), the site of primary charge separation that initiates the photosynthetic electron transfer chain. The chlorophyll ChlD1 pigment of the RC is the primary electron donor, forming a charge-separated radical pair with the vicinal pheophytin PheoD1 (ChlD1+PheoD1-). To avert charge recombination, the electron is further transferred to plastoquinone QA, whereas the hole relaxes to a central pair of chlorophylls (PD1PD2), subsequently driving water oxidation. Spin-triplet states can form within the RC when forward electron transfer is inhibited or back reactions are favored. This can lead to formation of singlet dioxygen, with potential deleterious effects. Here we investigate the nature and properties of triplet states within the PSII RC using a multiscale quantum-mechanics/molecular-mechanics (QM/MM) approach. The low-energy spectrum of excited singlet and triplet states, of both local and charge-transfer nature, is compared using range-separated time-dependent density functional theory (TD-DFT). We further compute electron paramagnetic resonance properties (zero-field splitting parameters and hyperfine coupling constants) of relaxed triplet states and compare them with available experimental data. Moreover, the electrostatic modulation of excited state energetics and redox properties of RC pigments by the semiquinone QA- is described. The results provide a detailed electronic-level understanding of triplet states within the PSII RC and form a refined basis for discussing primary and secondary electron transfer, charge recombination pathways, and possible photoprotection mechanisms in PSII.

Structure and Flexibility of Copper-Modified DNA G-Quadruplexes Investigated by 19 F ENDOR Experiments at 34†GHz.

DNA G-quadruplexes (GQs) are of great interest due to their involvement in crucial biological processes such as telomerase maintenance and gene expression. Furthermore, they are reported as catalytically active DNAzymes and building blocks in bio-nanotechnology. GQs exhibit remarkable structural diversity and conformational heterogeneity, necessitating precise and reliable tools to unravel their structure-function relationships. Here, we present insights into the structure and conformational flexibility of a unimolecular GQ with high spatial resolution via electron-nuclear double resonance (ENDOR) experiments combined with Cu(II) and fluorine labeling. These findings showcase the successful application of the 19 F-ENDOR methodology at 34 GHz, overcoming the limitations posed by the complexity and scarcity of higher-frequency spectrometers. Importantly, our approach retains both sensitivity and orientational resolution. This integrated study not only enhances our understanding of GQs but also expands the methodological toolbox for studying other macromolecules.

Conformational energies of reference organic molecules: benchmarking of common efficient computational methods against coupled cluster theory.

We selected 145 reference organic molecules that include model fragments used in computer-aided drug design. We calculated 158 conformational energies and barriers using force fields, with wide applicability in commercial and free softwares and extensive application on the calculation of conformational energies of organic molecules, e.g. the UFF and DREIDING force fields, the Allinger's force fields MM3-96, MM3-00, MM4-8, the MM2-91 clones MMX and MM+, the MMFF94 force field, MM4, ab initio Hartree-Fock (HF) theory with different basis sets, the standard density functional theory B3LYP, the second-order post-HF MP2 theory and the Domain-based Local Pair Natural Orbital Coupled Cluster DLPNO-CCSD(T) theory, with the latter used for accurate reference values. The data set of the organic molecules includes hydrocarbons, haloalkanes, conjugated compounds, and oxygen-, nitrogen-, phosphorus- and sulphur-containing compounds. We reviewed in detail the conformational aspects of these model organic molecules providing the current understanding of the steric and electronic factors that determine the stability of low energy conformers and the literature including previous experimental observations and calculated findings. While progress on the computer hardware allows the calculations of thousands of conformations for later use in drug design projects, this study is an update from previous classical studies that used, as reference values, experimental ones using a variety of methods and different environments. The lowest mean error against the DLPNO-CCSD(T) reference was calculated for MP2 (0.35 kcal mol-1), followed by B3LYP (0.69 kcal mol-1) and the HF theories (0.81-1.0 kcal mol-1). As regards the force fields, the lowest errors were observed for the Allinger's force fields MM3-00 (1.28 kcal mol-1), ΜΜ3-96 (1.40 kcal mol-1) and the Halgren's MMFF94 force field (1.30 kcal mol-1) and then for the MM2-91 clones MMX (1.77 kcal mol-1) and MM+ (2.01 kcal mol-1) and MM4 (2.05 kcal mol-1). The DREIDING (3.63 kcal mol-1) and UFF (3.77 kcal mol-1) force fields have the lowest performance. These model organic molecules we used are often present as fragments in drug-like molecules. The values calculated using DLPNO-CCSD(T) make up a valuable data set for further comparisons and for improved force field parameterization.

Can a failure in the error-monitoring system explain unawareness of memory deficits in Alzheimer's disease?

Unawareness of memory deficits is an early manifestation in patients with Alzheimer's disease (AD), which often delays diagnosis. This intriguing behavior constitutes a form of anosognosia, whose neural mechanisms remain largely unknown. We hypothesized that anosognosia may depend on a critical synaptic failure in the error-monitoring system, which would prevent AD patients from being aware of their own memory impairment. To investigate, we measured event-related potentials (ERPs) evoked by erroneous responses during a word memory recognition task in two groups of amyloid positive individuals with only subjective memory complaints at study entry: those who progressed to AD within the five-year study period (PROG group), and those who remained cognitively normal (CTRL group). A significant reduction in the amplitude of the positivity error (Pe), an ERP related to error awareness, was observed in the PROG group at the time of AD diagnosis (vs study entry) in intra-group analysis, as well as when compared with the CTRL group in inter-group analysis, based on the last EEG acquisition for all subjects. Importantly, at the time of AD diagnosis, the PROG group exhibited clinical signs of anosognosia, overestimating their cognitive abilities, as evidenced by the discrepancy scores obtained from caregiver/informant vs participant reports on the cognitive subscale of the Healthy Aging Brain Care Monitor. To our knowledge, this is the first study to reveal the emergence of a failure in the error-monitoring system during a word memory recognition task at the early stages of AD. This finding, along with the decline of awareness for cognitive impairment observed in the PROG group, strongly suggests that a synaptic dysfunction in the error-monitoring system may be the critical neural mechanism at the origin of unawareness of deficits in AD.

Does Serial Femtosecond Crystallography Depict State-Specific Catalytic Intermediates of the Oxygen-Evolving Complex?

Recent advances in serial femtosecond crystallography (SFX) of photosystem II (PSII), enabled by X-ray free electron lasers (XFEL), provided the first geometric models of distinct intermediates in the catalytic S-state cycle of the oxygen-evolving complex (OEC). These models are obtained by flash-advancing the OEC from the dark-stable state (S1) to more oxidized intermediates (S2 and S3), eventually cycling back to the most reduced S0. However, the interpretation of these models is controversial because geometric parameters within the Mn4CaO5 cluster of the OEC do not exactly match those expected from coordination chemistry for the spectroscopically verified manganese oxidation states of the distinct S-state intermediates. Here we focus on the first catalytic transition, S1 → S2, which represents a one-electron oxidation of the OEC. Combining geometric and electronic structure criteria, including a novel effective oxidation state approach, we analyze existing 1-flash (1F) SFX-XFEL crystallographic models that should depict the S2 state of the OEC. We show that the 1F/S2 equivalence is not obvious, because the Mn oxidation states and total unpaired electron counts encoded in these models are not fully consistent with those of a pure S2 state and with the nature of the S1 → S2 transition. Furthermore, the oxidation state definition in two-flashed (2F) structural models is practically impossible to elucidate. Our results advise caution in the extraction of electronic structure information solely from the literal interpretation of crystallographic models and call for re-evaluation of structural and mechanistic interpretations that presume exact correspondence of such models to specific catalytic intermediates of the OEC.