Synthesis and Catalytic Activity of (3,4-Diphenylcyclopentadienone)Iron Tricarbonyl Compounds in Transfer Hydrogenations and Dehydrogenations

Four (3,4-diphenylcyclopentadienone)iron tricarbonyl compounds were synthesized, and their activities in transfer hydrogenations of carbonyl compounds and transfer dehydrogenations of alcohols were explored and compared to those of the well-established [2,5-(SiMe3)2-3,4-(CH2)4(η4-C4C═O)]Fe(CO)3 (3). A new compound, [2,5-bis(3,5-dimethylphenyl)-3,4-diphenylcyclopentadienone]iron tricarbonyl (7), was the most active catalyst in both transfer hydrogenations and dehydrogenations, and compound 3 was the least active catalyst in transfer hydrogenations. Evidence was found for product inhibition of both 3 and 7 in a transfer dehydrogenation reaction, with the activity of 3 being more heavily affected. A monomeric iron hydride derived from 7 was spectroscopically observed during a transfer hydrogenation, and no diiron bridging hydrides were found under reductive or oxidative conditions. Initial results in the transfer hydrogenation of N-benzylideneaniline showed that 3 was a significantly less active catalyst in comparison to the (3,4-diphenylcyclopentadienone)iron tricarbonyl compounds

on Performance

Abstract Ultra-marathons (footraces greater than 42.2 km) are increasing in popularity, however little is known about the habitual dietary intake of these runners. The aim of this investigation was to empirically describe the habitual training diet of ultra-marathon runners and determine if macronutrient intake was associated with 161-km race performance. To assess habitual diet, runners recruited from five 161-km ultra-marathons across the U.S. (N = 47) completed a diet and training questionnaire, and a web-based 24-hour dietary recall on three separate days within 1-4 weeks prior to a 161-km race. Multiple linear regression was used to predict finish time with covariates carbohydrate, fat and protein, expressed relative to body weight (g·kg -1 ) and total intake (% of diet). To determine differences in macronutrient intake between finishers and non-finishers, two-sample t-tests were used. Dietary intake was varied among participants; mean carbohydrate intake (5.19±2.62 g·kg ) predicted finish time (R 2 = 0.232, P =0.036), however fat was the only significant covariate (t = -2.90, P =0.007). Relative macronutrient intake (% of diet) did not predict finish time (R 2 =0.145, P =0.155). No significant differences were found in macronutrient intake between finishers (n=36) and non-finishers (n=11). Habitual dietary fat intake in ultra-marathon runners was a significant predictor of 161-km finish time, regardless of carbohydrate or protein intake. Further investigation is warranted to determine the optimal nutrient intake in ultra-marathon runners to maximize performance

Exploring common genetic contributors to neuroprotection from amyloid pathology

Preclinical Alzheimer’s disease describes some individuals who harbor Alzheimer’s pathologies but are asymptomatic. For this study, we hypothesized that genetic variation may help protect some individuals from Alzheimer’s-related neurodegeneration. We therefore conducted a genome-wide association study using 5,891,064 common variants to assess whether genetic variation modifies the association between baseline beta-amyloid, as measured by both cerebrospinal fluid and positron emission tomography, and neurodegeneration defined using MRI measures of hippocampal volume. We combined and jointly analyzed genotype, biomarker, and neuroimaging data from non-Hispanic white individuals who were enrolled in four longitudinal aging studies (n=1065). Using regression models, we examined the interaction between common genetic variants (Minor Allele Frequency > 0.01), including APOE-ε4 and APOE-ε2, and baseline cerebrospinal levels of amyloid (CSF Aβ42) on baseline hippocampal volume and the longitudinal rate of hippocampal atrophy. For targeted replication of top findings, we analyzed an independent dataset (n=808) where amyloid burden was assessed by Pittsburgh Compound B ([{11}^C]-PiB) PET. In this study, we found that APOE-ε4 modified the association between baseline CSF Aβ42 and hippocampal volume such that APOE-ε4 carriers showed more rapid atrophy, particularly in the presence of enhanced amyloidosis. We also identified a novel locus on chromosome 3 that interacted with baseline CSF Aβ42. Minor allele carriers of rs62263260, an expression quantitative trait locus for the SEMA5B gene, (p=1.46x10^{-8}; 3:122675327) had more rapid neurodegeneration when amyloid burden was high and slower neurodegeneration when amyloid was low. The rs62263260 x amyloid interaction on longitudinal change in hippocampal volume was replicated in an independent dataset (p=0.0112) where amyloid burden was assessed by PET. In addition to supporting the established interaction between APOE and amyloid on neurodegeneration, our study identifies a novel locus that modifies the association between beta-amyloid and hippocampal atrophy. Annotation results may implicate SEMA5B, a gene involved in synaptic pruning and axonal guidance, as a high-quality candidate for functional confirmation and future mechanistic analysis

Cross-Species Analyses Identify Dlgap2 as a Regulator of Age-Related Cognitive Decline and Alzheimer\u27s Dementia.

Genetic mechanisms underlying age-related cognitive decline and dementia remain poorly understood. Here, we take advantage of the Diversity Outbred mouse population to utilize quantitative trait loci mapping and identify Dlgap2 as a positional candidate responsible for modifying working memory decline. To evaluate the translational relevance of this finding, we utilize longitudinal cognitive measures from human patients, RNA expression from post-mortem brain tissue, data from a genome-wide association study (GWAS) of Alzheimer\u27s dementia (AD), and GWAS results in African Americans. We find an association between Dlgap2 and AD phenotypes at the variant, gene and protein expression, and methylation levels. Lower cortical DLGAP2 expression is observed in AD and is associated with more plaques and tangles at autopsy and faster cognitive decline. Results will inform future studies aimed at investigating the cross-species role of Dlgap2 in regulating cognitive decline and highlight the benefit of using genetically diverse mice to prioritize novel candidates

Sex differences in the genetic architecture of cognitive resilience to Alzheimer\u27s disease.

Approximately 30% of elderly adults are cognitively unimpaired at time of death despite the presence of Alzheimer\u27s disease neuropathology at autopsy. Studying individuals who are resilient to the cognitive consequences of Alzheimer\u27s disease neuropathology may uncover novel therapeutic targets to treat Alzheimer\u27s disease. It is well established that there are sex differences in response to Alzheimer\u27s disease pathology, and growing evidence suggests that genetic factors may contribute to these differences. Taken together, we sought to elucidate sex-specific genetic drivers of resilience. We extended our recent large scale genomic analysis of resilience in which we harmonized cognitive data across four cohorts of cognitive ageing, in vivo amyloid PET across two cohorts, and autopsy measures of amyloid neuritic plaque burden across two cohorts. These data were leveraged to build robust, continuous resilience phenotypes. With these phenotypes, we performed sex-stratified [n (males) = 2093, n (females) = 2931] and sex-interaction [n (both sexes) = 5024] genome-wide association studies (GWAS), gene and pathway-based tests, and genetic correlation analyses to clarify the variants, genes and molecular pathways that relate to resilience in a sex-specific manner. Estimated among cognitively normal individuals of both sexes, resilience was 20-25% heritable, and when estimated in either sex among cognitively normal individuals, resilience was 15-44% heritable. In our GWAS, we identified a female-specific locus on chromosome 10 [rs827389, β (females) = 0.08, P (females) = 5.76 × 10-09, β (males) = -0.01, P(males) = 0.70, β (interaction) = 0.09, P (interaction) = 1.01 × 10-04] in which the minor allele was associated with higher resilience scores among females. This locus is located within chromatin loops that interact with promoters of genes involved in RNA processing, including GATA3. Finally, our genetic correlation analyses revealed shared genetic architecture between resilience phenotypes and other complex traits, including a female-specific association with frontotemporal dementia and male-specific associations with heart rate variability traits. We also observed opposing associations between sexes for multiple sclerosis, such that more resilient females had a lower genetic susceptibility to multiple sclerosis, and more resilient males had a higher genetic susceptibility to multiple sclerosis. Overall, we identified sex differences in the genetic architecture of resilience, identified a female-specific resilience locus and highlighted numerous sex-specific molecular pathways that may underly resilience to Alzheimer\u27s disease pathology. This study illustrates the need to conduct sex-aware genomic analyses to identify novel targets that are unidentified in sex-agnostic models. Our findings support the theory that the most successful treatment for an individual with Alzheimer\u27s disease may be personalized based on their biological sex and genetic context

Genetic modifiers ameliorate endocytic and neuromuscular defects in a model of spinal muscular atrophy

© 2020 The Author(s). This article is licensed under a Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/), which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made.Background: Understanding the genetic modifiers of neurodegenerative diseases can provide insight into the mechanisms underlying these disorders. Here, we examine the relationship between the motor neuron disease spinal muscular atrophy (SMA), which is caused by reduced levels of the survival of motor neuron (SMN) protein, and the actin-bundling protein Plastin 3 (PLS3). Increased PLS3 levels suppress symptoms in a subset of SMA patients and ameliorate defects in SMA disease models, but the functional connection between PLS3 and SMN is poorly understood.Results: We provide immunohistochemical and biochemical evidence for large protein complexes localized in vertebrate motor neuron processes that contain PLS3, SMN and members of the hnRNP F/H family of proteins. Using a Caenorhabditis elegans (C. elegans) SMA model, we determine that overexpression of PLS3 or loss of the C. elegans hnRNP F/H ortholog SYM-2 enhances endocytic function and ameliorates neuromuscular defects caused by decreased SMN-1 levels. Furthermore, either increasing PLS3 or decreasing SYM-2 levels suppresses defects in a C. elegans ALS model.Conclusions: We propose that hnRNP F/H act in the same protein complex as PLS3 and SMN and that the function of this complex is critical for endocytic pathways, suggesting that hnRNP F/H proteins could be potential targets for therapy development.Peer reviewe

CpG-creating mutations are costly in many human viruses.

Mutations can occur throughout the virus genome and may be beneficial, neutral or deleterious. We are interested in mutations that yield a C next to a G, producing CpG sites. CpG sites are rare in eukaryotic and viral genomes. For the eukaryotes, it is thought that CpG sites are rare because they are prone to mutation when methylated. In viruses, we know less about why CpG sites are rare. A previous study in HIV suggested that CpG-creating transition mutations are more costly than similar non-CpG-creating mutations. To determine if this is the case in other viruses, we analyzed the allele frequencies of CpG-creating and non-CpG-creating mutations across various strains, subtypes, and genes of viruses using existing data obtained from Genbank, HIV Databases, and Virus Pathogen Resource. Our results suggest that CpG sites are indeed costly for most viruses. By understanding the cost of CpG sites, we can obtain further insights into the evolution and adaptation of viruses