Amyloid Plaques Beyond Aβ: A Survey of the Diverse Modulators of Amyloid Aggregation

Aggregation of the amyloid-β (Aβ) peptide is strongly correlated with Alzheimer’s disease (AD). Recent research has improved our understanding of the kinetics of amyloid fibril assembly and revealed new details regarding different stages in plaque formation. Presently, interest is turning toward studying this process in a holistic context, focusing on cellular components which interact with the Aβ peptide at various junctures during aggregation, from monomer to cross-β amyloid fibrils. However, even in isolation, a multitude of factors including protein purity, pH, salt content, and agitation affect Aβ fibril formation and deposition, often producing complicated and conflicting results. The failure of numerous inhibitors in clinical trials for AD suggests that a detailed examination of the complex interactions that occur during plaque formation, including binding of carbohydrates, lipids, nucleic acids, and metal ions, is important for understanding the diversity of manifestations of the disease. Unraveling how a variety of key macromolecular modulators interact with the Aβ peptide and change its aggregation properties may provide opportunities for developing therapies. Since no protein acts in isolation, the interplay of these diverse molecules may differentiate disease onset, progression, and severity, and thus are worth careful consideration

Variability in Working Memory Performance Explained by Epistasis vs Polygenic Scores in the ZNF804A Pathway

Importance: We investigated the variation in neuropsychological function explained by risk alleles at the psychosis susceptibility gene ZNF804A and its interacting partners using single nucleotide polymorphisms (SNPs), polygenic scores, and epistatic analyses. Of particular importance was the relative contribution of the polygenic score vs epistasis in variation explained. Objectives To (1) assess the association between SNPs in ZNF804A and the ZNF804A polygenic score with measures of cognition in cases with psychosis and (2) assess whether epistasis within the ZNF804A pathway could explain additional variation above and beyond that explained by the polygenic score. Design, Setting, and Participants: Patients with psychosis (n = 424) were assessed in areas of cognitive ability impaired in schizophrenia including IQ, memory, attention, and social cognition. We used the Psychiatric GWAS Consortium 1 schizophrenia genome-wide association study to calculate a polygenic score based on identified risk variants within this genetic pathway. Cognitive measures significantly associated with the polygenic score were tested for an epistatic component using a training set (n = 170), which was used to develop linear regression models containing the polygenic score and 2-SNP interactions. The best-fitting models were tested for replication in 2 independent test sets of cases: (1) 170 individuals with schizophrenia or schizoaffective disorder and (2) 84 patients with broad psychosis (including bipolar disorder, major depressive disorder, and other psychosis). Main Outcomes and Measures: Participants completed a neuropsychological assessment battery designed to target the cognitive deficits of schizophrenia including general cognitive function, episodic memory, working memory, attentional control, and social cognition. Results: Higher polygenic scores were associated with poorer performance among patients on IQ, memory, and social cognition, explaining 1% to 3% of variation on these scores (range, P = .01 to .03). Using a narrow psychosis training set and independent test sets of narrow phenotype psychosis (schizophrenia and schizoaffective disorder), broad psychosis, and control participants (n = 89), the addition of 2 interaction terms containing 2 SNPs each increased the R2 for spatial working memory strategy in the independent psychosis test sets from 1.2% using the polygenic score only to 4.8% (P = .11 and .001, respectively) but did not explain additional variation in control participants. Conclusions and Relevance: These data support a role for the ZNF804A pathway in IQ, memory, and social cognition in cases. Furthermore, we showed that epistasis increases the variation explained above the contribution of the polygenic score

2017 HRS/EHRA/ECAS/APHRS/SOLAECE expert consensus statement on catheter and surgical ablation of atrial fibrillation: executive summary.

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2017 HRS/EHRA/ECAS/APHRS/SOLAECE expert consensus statement on catheter and surgical ablation of atrial fibrillation: executive summary.

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withdrawn 2017 hrs ehra ecas aphrs solaece expert consensus statement on catheter and surgical ablation of atrial fibrillation

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On the local structure of Ti during in situ desorption of Ti(OBu)(4) and TiCl3 doped NaAlH4

The local structures of Ti doped NaAlH4 were investigated with extended X-ray absorption fine structure (EXAFS) and X-ray absorption near edge structure (XANES) using Ti(OBU)(4) and TiCl3 precursors. The local structures were linked to literature data on hydrogen desorption and absorption kinetics. In the Ti(OBU)4 doped NaAlH4, butoxide or decomposition products thereof (C, 0 atoms) was bonded to Ti after ball-trulling, inhibiting the performance of the Ti catalyst. Upon heating, the C and 0 atoms were removed and Ti-Al species were formed. The thermodynamical most stable specie, TiAl3, was not formed at T<300 degrees C, contrarily to TiCl3 doped NaAlH4- Probably the initially present butoxide group gave rise to inhibition of its formation. Besides that, the butoxide or decompostion products thereof (C, 0 atoms) are also suspected to interfere with the hydrogen uptake of a desorbed NaAlH4. (C) 2006 Elsevier B.V. All rights reserved

On the local structure of Ti during in situ desorption of Ti(OBu)(4) and TiCl3 doped NaAlH4

The local structures of Ti doped NaAlH4 were investigated with extended X-ray absorption fine structure (EXAFS) and X-ray absorption near edge structure (XANES) using Ti(OBU)(4) and TiCl3 precursors. The local structures were linked to literature data on hydrogen desorption and absorption kinetics. In the Ti(OBU)4 doped NaAlH4, butoxide or decomposition products thereof (C, 0 atoms) was bonded to Ti after ball-trulling, inhibiting the performance of the Ti catalyst. Upon heating, the C and 0 atoms were removed and Ti-Al species were formed. The thermodynamical most stable specie, TiAl3, was not formed at T<300 degrees C, contrarily to TiCl3 doped NaAlH4- Probably the initially present butoxide group gave rise to inhibition of its formation. Besides that, the butoxide or decompostion products thereof (C, 0 atoms) are also suspected to interfere with the hydrogen uptake of a desorbed NaAlH4. (C) 2006 Elsevier B.V. All rights reserved