A multiscale ion diffusion framework sheds light on the diffusion-stability-hysteresis nexus in metal halide perovskites.

Stability and current-voltage hysteresis stand as major obstacles to the commercialization of metal halide perovskites. Both phenomena have been associated with ion migration, with anecdotal evidence that stable devices yield low hysteresis. However, the underlying mechanisms of the complex stability-hysteresis link remain elusive. Here we present a multiscale diffusion framework that describes vacancy-mediated halide diffusion in polycrystalline metal halide perovskites, differentiating fast grain boundary diffusivity from volume diffusivity that is two to four orders of magnitude slower. Our results reveal an inverse relationship between the activation energies of grain boundary and volume diffusions, such that stable metal halide perovskites exhibiting smaller volume diffusivities are associated with larger grain boundary diffusivities and reduced hysteresis. The elucidation of multiscale halide diffusion in metal halide perovskites reveals complex inner couplings between ion migration in the volume of grains versus grain boundaries, which in turn can predict the stability and hysteresis of metal halide perovskites, providing a clearer path to addressing the outstanding challenges of the field.

Biophysical mechanisms underlying tefluthrin-induced modulation of gating changes and resurgent current generation in the human Nav1.4 channel.

Human skeletal muscle contraction is triggered by activation of Nav1.4 channels. Nav1.4 channels can generate resurgent currents by channel reopening at hyperpolarized potentials through a gating transition dependent on the intracellular Navß4 peptide in the physiological conditions. Tefluthrin (TEF) is a pyrethroid insecticide that can disrupt electrical signaling in nerves and skeletal muscle, resulting in seizures, muscle spasms, fasciculations, and mental confusion. TEF can also induce tail currents through other voltage-gated sodium channels in the absence of Navß4 peptide, suggesting that muscle spasms may be caused by resurgent currents. Further, intracellular Navß4 peptide and extracellular TEF may show competitive or synergistic effects; however, their binding sites are still unknown. To address these issues, electrophysiological recordings were performed on CHO-K1 cells expressing Nav1.4 channels with intracellular Navß4 peptide, extracellular TEF, or both. TEF and Navß4 peptide induced a hyperpolarizing shift of activation and inactivation curves in the Nav1.4 channel. TEF also substantially prolonged the inactivation time constants, while simultaneous application of Navß4 peptide partially reversed this effect. Resurgent currents were enhanced by TEF and Navß4 peptide at negative potentials, but TEF more potently enhances resurgent currents and dampens decay of resurgent currents. With longer depolarization, peak resurgent currents decay was fastest with the TEF alone. Molecular docking suggested that TEF and Navß4 peptide binding site(s) are not in the narrowest part of the channel pore, but rather in the bundle-crossing regions and in the domain linkers, respectively. TEF can induce resurgent currents independently and synergistically with Navß4 peptide, which may explain the muscle spasms observed in TEF intoxication.

Lasting consequences of concussion on the aging brain: Findings from the Baltimore Longitudinal Study of Aging.

Studies suggest that concussions may be related to increased risk of neurodegenerative diseases, such as Chronic Traumatic Encephalopathy and Alzheimer's Disease. Most neuroimaging studies show effects of concussions in frontal and temporal lobes of the brain, yet the long-term impacts of concussions on the aging brain have not been well studied. We examined neuroimaging data from 51 participants (mean age at first imaging visit=65.1 ± 11.23) in the Baltimore Longitudinal Study of Aging (BLSA) who reported a concussion in their medical history an average of 23 years prior to the first imaging visit, and compared them to 150 participants (mean age at first imaging visit=66.6 ± 10.97) with no history of concussion. Participants underwent serial structural MRI over a mean of 5.17±6.14 years and DTI over a mean of 2.92±2.22 years to measure brain structure, as well as 15O-water PET over a mean of 5.33±2.19 years to measure brain function. A battery of neuropsychological tests was also administered over a mean of 11.62±7.41 years. Analyses of frontal and temporal lobe regions were performed to examine differences in these measures between the concussion and control groups at first imaging visit and in change over time. Compared to those without concussion, participants with a prior concussion had greater brain atrophy in temporal lobe white matter and hippocampus at first imaging visit, which remained stable throughout the follow-up visits. Those with prior concussion also showed differences in white matter microstructure using DTI, including increased radial and axial diffusivity in the fornix/stria terminalis, anterior corona radiata, and superior longitudinal fasciculus at first imaging visit. In 15O-water PET, higher resting cerebral blood flow was seen at first imaging visit in orbitofrontal and lateral temporal regions, and both increases and decreases were seen in prefrontal, cingulate, insular, hippocampal, and ventral temporal regions with longitudinal follow-up. There were no significant differences in neuropsychological performance between groups. Most of the differences observed between the concussed and non-concussed groups were seen at the first imaging visit, suggesting that concussions can produce long-lasting structural and functional alterations in temporal and frontal regions of the brain in older individuals. These results also suggest that many of the reported short-term effects of concussion may still be apparent later in life.

Changes of Resurgent Na+ Currents in the Nav1.4 Channel Resulting from an SCN4A Mutation Contributing to Sodium Channel Myotonia.

Myotonia congenita (MC) is a rare disorder characterized by stiffness and weakness of the limb and trunk muscles. Mutations in the SCN4A gene encoding the alpha-subunit of the voltage-gated sodium channel Nav1.4 have been reported to be responsible for sodium channel myotonia (SCM). The Nav1.4 channel is expressed in skeletal muscles, and its related channelopathies affect skeletal muscle excitability, which can manifest as SCM, paramyotonia and periodic paralysis. In this study, the missense mutation p.V445M was identified in two individual families with MC. To determine the functional consequences of having a mutated Nav1.4 channel, whole-cell patch-clamp recording of transfected Chinese hamster ovary cells was performed. Evaluation of the transient Na+ current found that a hyperpolarizing shift occurs at both the activation and inactivation curves with an increase of the window currents in the mutant channels. The Nav1.4 channel's co-expression with the Navß4 peptide can generate resurgent Na+ currents at repolarization following a depolarization. The magnitude of the resurgent currents is higher in the mutant than in the wild-type (WT) channel. Although the decay kinetics are comparable between the mutant and WT channels, the time to the peak of resurgent Na+ currents in the mutant channel is significantly protracted compared with that in the WT channel. These findings suggest that the p.V445M mutation in the Nav1.4 channel results in an increase of both sustained and resurgent Na+ currents, which may contribute to hyperexcitability with repetitive firing and is likely to facilitate recurrent myotonia in SCM patients.

Blood Metabolite Signature of Metabolic Syndrome Implicates Alterations in Amino Acid Metabolism: Findings from the Baltimore Longitudinal Study of Aging (BLSA) and the Tsuruoka Metabolomics Cohort Study (TMCS).

Rapid lifestyle and dietary changes have contributed to a rise in the global prevalence of metabolic syndrome (MetS), which presents a potential healthcare crisis, owing to its association with an increased burden of multiple cardiovascular and neurological diseases. Prior work has identified the role that genetic, lifestyle, and environmental factors can play in the prevalence of MetS. Metabolomics is an important tool to study alterations in biochemical pathways intrinsic to the pathophysiology of MetS. We undertook a metabolomic study of MetS in serum samples from two ethnically distinct, well-characterized cohorts-the Baltimore Longitudinal Study of Aging (BLSA) from the U.S. and the Tsuruoka Metabolomics Cohort Study (TMCS) from Japan. We used multivariate logistic regression to identify metabolites that were associated with MetS in both cohorts. Among the top 25 most significant (lowest p-value) metabolite associations with MetS in each cohort, we identified 18 metabolites that were shared between TMCS and BLSA, the majority of which were classified as amino acids. These associations implicate multiple biochemical pathways in MetS, including branched-chain amino acid metabolism, glutathione production, aromatic amino acid metabolism, gluconeogenesis, and the tricarboxylic acid cycle. Our results suggest that fundamental alterations in amino acid metabolism may be central features of MetS.

Blood Metabolite Signatures of Metabolic Syndrome in Two Cross-Cultural Older Adult Cohorts.

Metabolic syndrome (MetS) affects an increasing number of older adults worldwide. Cross-cultural comparisons can provide insight into how factors, including genetic, environmental, and lifestyle, may influence MetS prevalence. Metabolomics, which measures the biochemical products of cell processes, can be used to enhance a mechanistic understanding of how biological factors influence metabolic outcomes. In this study we examined associations between serum metabolite concentrations, representing a range of biochemical pathways and metabolic syndrome in two older adult cohorts: The Tsuruoka Metabolomics Cohort Study (TMCS) from Japan (n = 104) and the Baltimore Longitudinal Study of Aging (BLSA) from the United States (n = 146). We used logistic regression to model associations between MetS and metabolite concentrations. We found that metabolites from the phosphatidylcholines-acyl-alkyl, sphingomyelin, and hexose classes were significantly associated with MetS and risk factor outcomes in both cohorts. In BLSA, metabolites across all classes were uniquely associated with all outcomes. In TMCS, metabolites from the amino acid, biogenic amines, and free fatty acid classes were uniquely associated with MetS, and metabolites from the sphingomyelin class were uniquely associated with elevated triglycerides. The metabolites and metabolite classes we identified may be relevant for future studies exploring disease mechanisms and identifying novel precision therapy targets for individualized medicine.

The Biophysical Basis Underlying Gating Changes in the p.V1316A Mutant Nav1.7 Channel and the Molecular Pathogenesis of Inherited Erythromelalgia.

The Nav1.7 channel critically contributes to the excitability of sensory neurons, and gain-of-function mutations of this channel have been shown to cause inherited erythromelalgia (IEM) with neuropathic pain. In this study, we report a case of a severe phenotype of IEM caused by p.V1316A mutation in the Nav1.7 channel. Mechanistically, we first demonstrate that the Navß4 peptide acts as a gating modifier rather than an open channel blocker competing with the inactivating peptide to give rise to resurgent currents in the Nav1.7 channel. Moreover, there are two distinct open and two corresponding fast inactivated states in the genesis of resurgent Na+ currents. One is responsible for the resurgent route and practically existent only in the presence of Navß4 peptide, whereas the other is responsible for the "silent" route of recovery from inactivation. In this regard, the p.V1316A mutation makes hyperpolarization shift in the activation curve, and depolarization shift in the inactivation curve, vividly uncoupling inactivation from activation. In terms of molecular gating operation, the most important changes caused by the p.V1316A mutation are both acceleration of the transition from the inactivated states to the activated states and deceleration of the reverse transition, resulting in much larger sustained as well as resurgent Na+ currents. In summary, the genesis of the resurgent currents in the Nav1.7 channel is ascribable to the transient existence of a distinct and novel open state promoted by the Navß4 peptide. In addition, S4-5 linker in domain III where V1316 is located seems to play a critical role in activation-inactivation coupling, chiefly via direct modulation of the transitional kinetics between the open and the inactivated states. The sustained and resurgent Na+ currents may therefore be correlatively enhanced by specific mutations involving this linker and relevant regions, and thus marked hyperexcitability in corresponding neural tissues as well as IEM symptomatology.

Sandensolide Induces Oxidative Stress-Mediated Apoptosis in Oral Cancer Cells and in Zebrafish Xenograft Model.

Presently, natural sources and herbs are being sought for the treatment of human oral squamous cell carcinoma (OSCC) in order to alleviate the side effects of chemotherapy. This study investigates the effect of sandensolide, a cembrane isolated from Sinularia flexibilis, to inhibit human OSCC cell growth with the aim of developing a new drug for the treatment of oral cancer. In vitro cultured human OSCC models (Ca9.22, SCC9 and HSC-3 cell lines) and oral normal cells (HGF-1), as well as a zebrafish xenograft model, were used to test the cytotoxicity of sandensolide (MTT assay), as well as to perform cell cycle analysis and Western blotting. Both the in vitro bioassay and the zebrafish xenograft model demonstrated the anti-oral cancer effect of sandensolide. Moreover, sandensolide was able to significantly suppress colony formation and induce apoptosis, as well as cell cycle arrest, in OSCC by regulating multiple key proteins. Induction of reactive oxygen species (ROS) was observed in sandensolide-treated oral cancer cells. However, these apoptotic changes were rescued by NAC pretreatment. These findings contribute to the knowledge of the model of action of sandensolide, which may induce oxidative stress-mediated cell death pathways as a potential agent in oral cancer therapeutics.

Flow- and voltage-dependent blocking effect of ethosuximide on the inward rectifier K⁺ (Kir2.1) channel.

Absence seizures are manifestations of abnormal thalamocortical oscillations characterized by spike-and-wave complexes in EEG. Ethosuximide (ETX) is one of the principal medications against absence seizures. We investigate the effect of ETX on the Kir2.1 channel, a prototypical inward rectifier K(+) channel possibly playing an important role in the setting of neuronal membrane potential. We demonstrate that the outward currents of Kir2.1 channels are significantly inhibited by intracellular ETX. We further show that the movement of neutral molecule ETX in the Kir2.1 channel is accompanied by ∼1.2 K(+), giving rise to the vivid voltage dependence of ETX unbinding rate. Moreover, the apparent affinity (K d ) of ETX in the channels are decreased by single-point mutations involving M183, E224, and S165, and especially by double mutations involving T141/S165, which always also disrupt the flux-coupling feature of ETX block. Molecular dynamics simulation demonstrates narrowing of the pore at ∼D172 by binding of ETX to S165 or T141. ETX block of the Kir2.1 channels may cause a modest but critical depolarization of the relevant neurons, decreasing available T-type Ca(2+) channels and consequently lessening pathological thalamocortical burst discharges.

Gating of the kir2.1 channel at the bundle crossing region by intracellular spermine and other cations.

In the Kir2.1 channel, the flow-dependent blocking effect of intracellular spermine (SPM) strongly indicates coupled movement of ions in a segment of the pore. We have shown that the bundle crossing region of M2 constitutes this critical segment of the pore. Moreover, this segment may undergo opening/closing conformational changes mimicking channel gating. In this study, we further investigate these "gating" conformational changes and relevant controlling mechanisms at this critical segment. We demonstrate that A184R mutation in the inner end of the bundle crossing region not only abolishes the inward rectifying features of SPM block but also tends to close the channel pore, which can then only be opened by intracellular (e.g., Na(+) , or equally effectively, K(+) ) but not extracellular cations. We also found that the exit (back to the intracellular milieu) of the blocking in the deep site is facilitated rather than deterred by the presence of the other SPM in the superficial site. We conclude that intracellular SPM may bind to a deep site in the pore and serve as a flow-dependent blocker. The SPM in the superficial site, on the other hand, serves both as a docking form ready for permeation to the deep site, and as a gating particle capable of opening the bundle crossing region. This inner end of the bundle crossing region of the Kir2.1 channel pore thus constitutes a pivotal segment, which, in collaboration with intracellular SPM and K(+) ions, closely couple channel gating to (inward rectifying) ion permeation.

The bundle crossing region is responsible for the inwardly rectifying internal spermine block of the Kir2.1 channel.

Inward rectifier potassium channels conduct K(+) across the cell membrane more efficiently in the inward than outward direction in physiological conditions. Voltage-dependent and flow-dependent blocks of outward K(+) currents by intracellular polyamines (e.g., spermine (SPM)) have been proposed as the major mechanisms underlying inward rectification. In this study, we show that the SPM blocking affinity curve is shifted according to the shift in K(+) reversal potential. Moreover, the kinetics of SPM entry to and exit from the binding site are correlatively slowed by specific E224 and E299 mutations, which always also disrupt the flux coupling feature of SPM block. The entry rates carry little voltage dependence, whereas the exit rates are e-fold decelerated per ∼15 mV depolarization. Interestingly, the voltage dependence remains rather constant among WT and quite a few different mutant channels. This voltage dependence offers an unprecedented chance of mapping the location (electrical distance) of the SPM site in the pore because these kinetic data were obtained along the preponderant direction of K(+) current flow (outward currents for the entry rate and inward currents for the exit rate) and thus contamination from flow dependence should be negligible. Moreover, double mutations involving E224 and A178 or M183 seem to alter the height of the same asymmetrical barrier between the SPM binding site and the intracellular milieu. We conclude that the SPM site responsible for the inward rectifying block is located at an electrical distance of ∼0.5 from the inside and is involved in a flux coupling segment in the bundle crossing region of the pore. With preponderant outward K(+) flow, SPM is "pushed" to the outmost site of this segment (∼D172). On the other hand, the blocking SPM would be pushed to the inner end of this segment (∼M183-A184) with preponderant inward K(+) flow. Moreover, E224 and E299 very likely electrostatically interact with the other residues (e.g., R228, R260) in the cytoplasmic domain and then allosterically keep the bundle crossing region in an open conformation appropriate for the flux coupling block of SPM.

Enhanced temperature control method using ANFIS with FPGA.

Temperature control in etching process is important for semiconductor manufacturing technology. However, pressure variations in vacuum chamber results in a change in temperature, worsening the accuracy of the temperature of the wafer and the speed and quality of the etching process. This work develops an adaptive network-based fuzzy inference system (ANFIS) using a field-programmable gate array (FPGA) to improve the effectiveness. The proposed method adjusts every membership function to keep the temperature in the chamber stable. The improvement of the proposed algorithm is confirmed using a medium vacuum (MV) inductively-coupled plasma- (ICP-) type etcher.

Kinetic Alterations in Resurgent Sodium Currents of Mutant Nav1.4 Channel in Two Patients Affected by Paramyotonia Congenita.

Paramyotonia congenita (PMC) is a rare skeletal muscle disorder characterized by muscle stiffness upon repetitive exercise and cold exposure. PMC was reported to be caused by dominant mutations in the SCN4A gene encoding the α subunit of the Nav1.4 channel. Recently, we identified two missense mutations of the SCN4A gene, p.V781I and p.A1737T, in two PMC families. To evaluate the changes in electrophysiological properties caused by the mutations, both mutant and wild-type (WT) SCN4A genes were expressed in CHO-K1 and HEK-293T cells. Then, whole-cell patch-clamp recording was employed to study the altered gating of mutant channels. The activation curve of transient current showed a hyperpolarizing shift in both mutant Nav1.4 channels as compared to the WT channel, whereas there was a depolarizing shift in the fast inactivation curve. These changes confer to an increase in window current in the mutant channels. Further investigations demonstrated that the mutated channel proteins generate significantly larger resurgent currents as compared to the WT channel and take longer to attain the peak of resurgent current than the WT channel. In conclusion, the current study demonstrates that p.V781I and p.A1737T mutations in the Nav1.4 channel increase both the sustained and the resurgent Na+ current, leading to membrane hyperexcitability with a lower firing threshold, which may influence the clinical phenotype.

Disease Burden Affects Aging Brain Function.

BACKGROUND: Most older adults live with multiple chronic disease conditions, yet the effect of multiple diseases on brain function remains unclear. METHODS: We examine the relationship between disease multimorbidity and brain activity using regional cerebral blood flow (rCBF) 15O-water PET scans from 97 cognitively normal participants (mean baseline age 76.5) in the Baltimore Longitudinal Study of Aging (BLSA). Multimorbidity index scores, generated from the presence of 13 health conditions, were correlated with PET data at baseline and in longitudinal change (n = 74) over 5.05 (2.74 SD) years. RESULTS: At baseline, voxel-based analysis showed that higher multimorbidity scores were associated with lower relative activity in orbitofrontal, superior frontal, temporal pole and parahippocampal regions, and greater activity in lateral temporal, occipital, and cerebellar regions. Examination of the individual health conditions comprising the index score showed hypertension and chronic kidney disease individually contributed to the overall multimorbidity pattern of altered activity. Longitudinally, both increases and decreases in activity were seen in relation to increasing multimorbidity over time. These associations were identified in orbitofrontal, lateral temporal, brainstem, and cerebellar areas. CONCLUSION: Together, these results show that greater multimorbidity is associated with widespread areas of altered brain activity, supporting a link between health and changes in aging brain function.

Changes in Resurgent Sodium Current Contribute to the Hyperexcitability of Muscles in Patients with Paramyotonia Congenita.

Paramyotonia congenita (PMC) is a rare hereditary skeletal muscle disorder. The major symptom, muscle stiffness, is frequently induced by cold exposure and repetitive exercise. Mutations in human SCN4A gene, which encodes the α-subunit of Nav1.4 channel, are responsible for PMC. Mutation screening of SCN4A gene from two PMC families identified two missense mutations, p.T1313M and p.R1448H. To elucidate the electrophysiological abnormalities caused by the mutations, the p.T1313M, p.R1448H, and wild-type (WT) SCN4A genes were transient expressed on Chinese hamster ovary (CHO-K1) cells. The detailed study on the gating defects of the mutant channels using the whole-cell patch clamping technique was performed. The mutant Nav1.4 channels impaired the basic gating properties with increasing sustained and window currents during membrane depolarization and facilitated the genesis of resurgent currents during repolarization. The mutations caused a hyperpolarization shift in the fast inactivation and slightly enhanced the slow inactivation with an increase in half-maximal inactivation voltage. No differences were found in the decay kinetics of the tail current between mutant and WT channels. In addition to generating the larger resurgent sodium current, the time to peak in the mutant channels was longer than that in the WT channels. In conclusion, our results demonstrated that the mutations p.T1313M and p.R1448H in Nav1.4 channels can enhance fast inactivation, slow inactivation, and resurgent current, revealing that subtle changes in gating processes can influence the clinical phenotype.

Cannabidiol Selectively Binds to the Voltage-Gated Sodium Channel Nav1.4 in Its Slow-Inactivated State and Inhibits Sodium Current.

Cannabidiol (CBD), one of the cannabinoids from the cannabis plant, can relieve the myotonia resulting from sodium channelopathy, which manifests as repetitive discharges of muscle membrane. We investigated the binding kinetics of CBD to Nav1.4 channels on the muscle membrane. The binding affinity of CBD to the channel was evaluated using whole-cell recording. The CDOCKER program was employed to model CBD docking onto the Nav1.4 channel to determine its binding sites. Our results revealed no differential inhibition of sodium current by CBD when the channels were in activation or fast inactivation status. However, differential inhibition was observed with a dose-dependent manner after a prolonged period of depolarization, leaving the channel in a slow-inactivated state. Moreover, CBD binds selectively to the slow-inactivated state with a significantly faster binding kinetics (>64,000 M-1 s-1) and a higher affinity (Kd of fast inactivation vs. slow-inactivation: >117.42 µM vs. 51.48 µM), compared to the fast inactivation state. Five proposed CBD binding sites in a bundle crossing region of the Nav1.4 channels pore was identified as Val793, Leu794, Phe797, and Cys759 in domain I/S6, and Ile1279 in domain II/S6. Our findings imply that CBD favorably binds to the Nav1.4 channel in its slow-inactivated state.

Diminished cage effect in solid p-H2: infrared spectra of ClSCS, ClCS, and ClSC in an irradiated p-H2 matrix containing Cl2 and CS2.

Irradiation of a p-H(2) matrix containing Cl(2) and CS(2) at 3.3 K with laser emission at 340 nm followed by annealing of the matrix produced main features at 1479.5 and 1480.8 cm(-1). These lines are attributed to nu(1) (SCS antisymmetric stretching) mode of ClSCS. Irradiation of the matrix at 355 nm decomposes ClSCS. Products CS (1272.2 and 1271.1 cm(-1)), ClCS (1193.9/1191.9 and 637.5 cm(-1)), and ClSC (1137.0 cm(-1)) were observed upon annealing. The assignments were based on comparison of observed vibrational wavenumbers and (13)C- and (34)S-isotopic ratios with those predicted with density-functional theories (B3LYP and BPW91/aug-cc-pVTZ). These results demonstrate that the cage effect of solid p-H(2) is diminished so that isolated Cl was produced via photodissociation of Cl(2) in situ and subsequently reacted with CS(2) to form ClSCS, but not ClC(=S)SCl, upon annealing; typically ClC(=S)SCl was produced as the major product on irradiation of noble-gas matrices containing Cl(2) and CS(2). Observation of ClSCS but not ClCS(2) is consistent with the theoretical prediction that only formation of the former proceeds via a barrierless path. Similarly, upon irradiation of ClSCS at 355 nm, Cl, CS, and CS(2) were produced; subsequent annealing of the irradiated matrix produced ClSC and ClCS via barrierless paths.

Quantitative Effects of Disorder on Chemically Modified Amorphous Carbon Electrodes.

Real materials are disordered. This disorder influences the properties of these materials and the chemical processes that occur at their interfaces. Gaining a molecular-level understanding of the underlying physical manifestations caused by disordered materials is crucial to unraveling and ultimately controlling the efficiency and performance of these materials in a range of energy-related devices. This understanding necessitates measurement techniques through which disorder can be detected, quantified, and monitored. However, such quantitative measurements are notoriously difficult, as effects often average out in ensemble measurements. In this work, we describe how a combination of electrochemical and spatially resolved surface spectroscopy measurements illuminate a molecular-level picture of disorder in materials. Using amorphous carbon as an intrinsically disordered material, we covalently attached a monolayer of ferrocene. Interfacial electron transfer across the amorphous carbon-ferrocene interface is highly sensitive to disruptions of order. By systematically varying linker properties and surface loadings, the influence of lateral interactions between nonuniformly distributed ferrocene headgroups on ensemble electrochemical measurements is demonstrated. Electrochemical and imaging data collectively indicate that conformational flexibility of the ferrocene moieties provides a mechanism to elude repulsive and unbalanced lateral interactions, while rigid linkages provide direct information about the underlying disorder of the material. This study is the first of its kind to quantify and visualize molecular disorder and heterogeneity with an experimental model accessed through ensemble measurements.

Association of hippocampal volume polygenic predictor score with baseline and change in brain volumes and cognition among cognitively healthy older adults.

A high hippocampal volume polygenic predictor score (HV-PPS), computed based on GWAS summary statistics (n = 33,536), could be protective against declines in brain volume and cognition in older adults. Linear mixed-effects models with random intercepts and slopes were used to estimate associations of HV-PPS with baseline and annual rate of change in both brain volumes (n = 508) and cognitive performance (n = 1041) in Caucasian Baltimore Longitudinal Study of Aging participants. Higher HV-PPS was associated with greater baseline volumes of the hippocampus and parahippocampal gyrus, and slower rates of ventricular enlargement and volume loss in frontal and parietal white matter, all adjusted for intracranial volume. In addition, higher HV-PPS was associated with better executive function performance and slower rates of decline in verbal fluency scores over time. Individuals with a genetic predisposition toward larger hippocampal volumes show better baseline executive function, slower decline in verbal fluency performance, and slower rates of longitudinal brain atrophy.