31 research outputs found
Qualitative extension of the EC′ Zone Diagram to a molecular catalyst for a multi-electron, multi-substrate electrochemical reaction
Traverse the EC′ Zone Diagram with a molecular H 2 -evolving electrocatalyst through systematic variation of the acid p K a , scan rate, acid concentration and catalyst concentration
DNA Methylation and Normal Chromosome Behavior in Neurospora Depend on Five Components of a Histone Methyltransferase Complex, DCDC
Methylation of DNA and of Lysine 9 on histone H3 (H3K9) is associated with gene silencing in many animals, plants, and fungi. In Neurospora crassa, methylation of H3K9 by DIM-5 directs cytosine methylation by recruiting a complex containing Heterochromatin Protein-1 (HP1) and the DIM-2 DNA methyltransferase. We report genetic, proteomic, and biochemical investigations into how DIM-5 is controlled. These studies revealed DCDC, a previously unknown protein complex including DIM-5, DIM-7, DIM-9, CUL4, and DDB1. Components of DCDC are required for H3K9me3, proper chromosome segregation, and DNA methylation. DCDC-defective strains, but not HP1-defective strains, are hypersensitive to MMS, revealing an HP1-independent function of H3K9 methylation. In addition to DDB1, DIM-7, and the WD40 domain protein DIM-9, other presumptive DCAFs (DDB1/CUL4 associated factors) co-purified with CUL4, suggesting that CUL4/DDB1 forms multiple complexes with distinct functions. This conclusion was supported by results of drug sensitivity tests. CUL4, DDB1, and DIM-9 are not required for localization of DIM-5 to incipient heterochromatin domains, indicating that recruitment of DIM-5 to chromatin is not sufficient to direct H3K9me3. DIM-7 is required for DIM-5 localization and mediates interaction of DIM-5 with DDB1/CUL4 through DIM-9. These data support a two-step mechanism for H3K9 methylation in Neurospora
The genetic architecture of the human cerebral cortex
The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder
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Early role of vascular dysregulation on late-onset Alzheimer's disease based on multifactorial data-driven analysis
Multifactorial mechanisms underlying late-onset Alzheimer's disease (LOAD) are poorly characterized from an integrative perspective. Here spatiotemporal alterations in brain amyloid-β deposition, metabolism, vascular, functional activity at rest, structural properties, cognitive integrity and peripheral proteins levels are characterized in relation to LOAD progression. We analyse over 7,700 brain images and tens of plasma and cerebrospinal fluid biomarkers from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Through a multifactorial data-driven analysis, we obtain dynamic LOAD–abnormality indices for all biomarkers, and a tentative temporal ordering of disease progression. Imaging results suggest that intra-brain vascular dysregulation is an early pathological event during disease development. Cognitive decline is noticeable from initial LOAD stages, suggesting early memory deficit associated with the primary disease factors. High abnormality levels are also observed for specific proteins associated with the vascular system's integrity. Although still subjected to the sensitivity of the algorithms and biomarkers employed, our results might contribute to the development of preventive therapeutic interventions
Conversion Discriminative Analysis on Mild Cognitive Impairment Using Multiple Cortical Features from MR Images
Neuroimaging measurements derived from magnetic resonance imaging provide important information required for detecting changes related to the progression of mild cognitive impairment (MCI). Cortical features and changes play a crucial role in revealing unique anatomical patterns of brain regions, and further differentiate MCI patients from normal states. Four cortical features, namely, gray matter volume, cortical thickness, surface area, and mean curvature, were explored for discriminative analysis among three groups including the stable MCI (sMCI), the converted MCI (cMCI), and the normal control (NC) groups. In this study, 158 subjects (72 NC, 46 sMCI, and 40 cMCI) were selected from the Alzheimer's Disease Neuroimaging Initiative. A sparse-constrained regression model based on the l2-1-norm was introduced to reduce the feature dimensionality and retrieve essential features for the discrimination of the three groups by using a support vector machine (SVM). An optimized strategy of feature addition based on the weight of each feature was adopted for the SVM classifier in order to achieve the best classification performance. The baseline cortical features combined with the longitudinal measurements for 2 years of follow-up data yielded prominent classification results. In particular, the cortical thickness produced a classification with 98.84% accuracy, 97.5% sensitivity, and 100% specificity for the sMCI–cMCI comparison; 92.37% accuracy, 84.78% sensitivity, and 97.22% specificity for the cMCI–NC comparison; and 93.75% accuracy, 92.5% sensitivity, and 94.44% specificity for the sMCI–NC comparison. The best performances obtained by the SVM classifier using the essential features were 5–40% more than those using all of the retained features. The feasibility of the cortical features for the recognition of anatomical patterns was certified; thus, the proposed method has the potential to improve the clinical diagnosis of sub-types of MCI and predict the risk of its conversion to Alzheimer's disease
Quantitative 18F-AV1451 Brain Tau PET Imaging in Cognitively Normal Older Adults, Mild Cognitive Impairment, and Alzheimer's Disease Patients
Recent developments of tau Positron Emission Tomography (PET) allows assessment of regional neurofibrillary tangles (NFTs) deposition in human brain. Among the tau PET molecular probes, 18F-AV1451 is characterized by high selectivity for pathologic tau aggregates over amyloid plaques, limited non-specific binding in white and gray matter, and confined off-target binding. The objectives of the study are (1) to quantitatively characterize regional brain tau deposition measured by 18F-AV1451 PET in cognitively normal older adults (CN), mild cognitive impairment (MCI), and AD participants; (2) to evaluate the correlations between cerebrospinal fluid (CSF) biomarkers or Mini-Mental State Examination (MMSE) and 18F-AV1451 PET standardized uptake value ratio (SUVR); and (3) to evaluate the partial volume effects on 18F-AV1451 brain uptake.Methods: The study included total 115 participants (CN = 49, MCI = 58, and AD = 8) from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Preprocessed 18F-AV1451 PET images, structural MRIs, and demographic and clinical assessments were downloaded from the ADNI database. A reblurred Van Cittertiteration method was used for voxelwise partial volume correction (PVC) on PET images. Structural MRIs were used for PET spatial normalization and region of interest (ROI) definition in standard space. The parametric images of 18F-AV1451 SUVR relative to cerebellum were calculated. The ROI SUVR measurements from PVC and non-PVC SUVR images were compared. The correlation between ROI 18F-AV1451 SUVR and the measurements of MMSE, CSF total tau (t-tau), and phosphorylated tau (p-tau) were also assessed.Results:18F-AV1451 prominently specific binding was found in the amygdala, entorhinal cortex, parahippocampus, fusiform, posterior cingulate, temporal, parietal, and frontal brain regions. Most regional SUVRs showed significantly higher uptake of 18F-AV1451 in AD than MCI and CN participants. SUVRs of small regions like amygdala, entorhinal cortex and parahippocampus were statistically improved by PVC in all groups (p < 0.01). Although there was an increasing tendency of 18F-AV-1451 SUVRs in MCI group compared with CN group, no significant difference of 18F-AV1451 deposition was found between CN and MCI brains with or without PVC (p > 0.05). Declined MMSE score was observed with increasing 18F-AV1451 binding in amygdala, entorhinal cortex, parahippocampus, and fusiform. CSF p-tau was positively correlated with 18F-AV1451 deposition. PVC improved the results of 18F-AV-1451 tau deposition and correlation studies in small brain regions.Conclusion: The typical deposition of 18F-AV1451 tau PET imaging in AD brain was found in amygdala, entorhinal cortex, fusiform and parahippocampus, and these regions were strongly associated with cognitive impairment and CSF biomarkers. Although more deposition was observed in MCI group, the 18F-AV-1451 PET imaging could not differentiate the MCI patients from CN population. More tau deposition related to decreased MMSE score and increased level of CSF p-tau, especially in ROIs of amygdala, entorhinal cortex and parahippocampus. PVC did improve the results of tau deposition and correlation studies in small brain regions and suggest to be routinely used in 18F-AV1451 tau PET quantification
Potential-Dependent Electrocatalytic Pathways: Controlling Reactivity with p<i>K</i><sub>a</sub> for Mechanistic Investigation of a Nickel-Based Hydrogen Evolution Catalyst
A detailed mechanistic analysis is
presented for the hydrogen evolution
catalyst [NiÂ(P<sub>2</sub><sup>Ph</sup>N<sub>2</sub><sup>Ph</sup>)<sub>2</sub>(CH<sub>2</sub>CN)]Â[BF<sub>4</sub>]<sub>2</sub> in acetonitrile (P<sub>2</sub><sup>Ph</sup>N<sub>2</sub><sup>Ph</sup> = 1,3,5,7-tetraphenyl-1,5-diaza-3,7-diphosphacyclooctane).
This complex has a Ni<sup>II/I</sup> redox couple at −0.83
V and a Ni<sup>I/0</sup> redox couple at −1.03 V versus Fc<sup>+/0</sup>. These two closely spaced redox events both promote proton
reduction catalysis, each via a distinct mechanism: an electrochemical
ECEC pathway and an EECC route. The EECC mechanism, operative at more
negative potentials, was isolated through use of a weak acid (anilinium,
p<i>K</i><sub>a</sub> = 10.6 in CH<sub>3</sub>CN) to avert
protonation of the singly reduced species. Electroanalytical methods
and time-resolved spectroscopy were used to analyze the kinetics of
the elementary steps of hydrogen evolution catalysis. The rate constant
for the formation of a nickelÂ(II)–hydride intermediate was
determined via measurements of peak shift (<i>k</i><sub>1</sub> = 1.2 × 10<sup>6</sup> M<sup>–1</sup> s<sup>–1</sup>) and through foot-of-the-wave analysis (<i>k</i><sub>1</sub> = 6.5 × 10<sup>6</sup> M<sup>–1</sup> s<sup>–1</sup>). Reactivity of the isolated hydride with acid to release hydrogen
and regenerate the nickelÂ(II) complex was monitored by stopped-flow
spectroscopy. Kinetics obtained from stopped-flow measurements are
corroborated by current plateau analysis of the catalytic cyclic voltammograms.
These kinetic data suggest the presence of an off-cycle intermediate
in the reaction
Reactivity of Proton Sources with a Nickel Hydride Complex in Acetonitrile: Implications for the Study of Fuel-Forming Catalysts
The reactivity of
the nickel hydride complex [HNiÂ(P<sub>2</sub><sup>Ph</sup>N<sub>2</sub><sup>Ph</sup>)<sub>2</sub>]<sup>+</sup> (P<sub>2</sub><sup>Ph</sup>N<sub>2</sub><sup>Ph</sup> = 1,3,5,7-tetraphenyl-1,5-diaza-3,7-diphosphacyclooctane)
with a variety of acids to form hydrogen in acetonitrile was evaluated
using stopped-flow spectroscopy in order to gain a better understanding
of how the proton source influences the reaction kinetics when evaluating
fuel-forming catalysts in acetonitrile. This reaction is initiated
by the rate-determining step in the catalytic cycle for the hydrogen-evolving
catalyst [NiÂ(P<sub>2</sub><sup>Ph</sup>N<sub>2</sub><sup>Ph</sup>)<sub>2</sub>]<sup>2+</sup>. Proton sources were evaluated with respect to p<i>K</i><sub>a</sub>, homoconjugation, dimerization, heteroconjugation,
and aggregation (for water). The effects of water and conjugate base
were also studied. A linear free energy relationship between rate
constant and p<i>K</i><sub>a</sub> was revealed; rate constants
increased with the magnitude of the homoconjugation constant for acids
prone to homoconjugation, and second-order reactivity was observed
for trifluoroacetic and trichloroacetic acid, suggesting dimerization.
Upon the addition of water, an increase in the observed rate constant
was seen, in line with the formation of hydronium. When added to trifluoroacetic
acid, water was shown to cause a decrease in the observed rate constant,
suggesting that water inhibits acid dimerization. Collectively, these
findings highlight that the selection of proton sources for the study
of molecular electrocatalysts in acetonitrile must account for more
than acid p<i>K</i><sub>a</sub>