Carcinogens and DNA damage

Humans are variously and continuously exposed to a wide range of different DNA-damaging agents, some of which are classed as carcinogens. DNA damage can arise from exposure to exogenous agents, but damage from endogenous processes is probably far more prevalent. That said, epidemiological studies of migrant populations from regions of low cancer risk to high cancer risk countries point to a role for environmental and/or lifestyle factors playing a pivotal part in cancer aetiology. One might reasonably surmise from this that carcinogens found in our environment or diet are culpable. Exposure to carcinogens is associated with various forms of DNA damage such as single-stand breaks, double-strand breaks, covalently bound chemical DNA adducts, oxidative-induced lesions and DNA-DNA or DNA-protein cross-links. This review predominantly concentrates on DNA damage induced by the following carcinogens: polycyclic aromatic hydrocarbons, heterocyclic aromatic amines, mycotoxins, ultraviolet light, ionising radiation, aristolochic acid, nitrosamines and particulate matter. Additionally, we allude to some of the cancer types where there is molecular epidemiological evidence that these agents are aetiological risk factors. The complex role that carcinogens play in the pathophysiology of cancer development remains obscure, but DNA damage remains pivotal to this process. [Abstract copyright: © 2018 The Author(s).

Accelerated functional brain aging in pre-clinical familial Alzheimer's disease

Alzheimer's disease has been associated with increased structural brain aging. Here the authors describe a model that predicts brain aging from resting state functional connectivity data, and demonstrate this is accelerated in individuals with pre-clinical familial Alzheimer's disease. Resting state functional connectivity (rs-fMRI) is impaired early in persons who subsequently develop Alzheimer's disease (AD) dementia. This impairment may be leveraged to aid investigation of the pre-clinical phase of AD. We developed a model that predicts brain age from resting state (rs)-fMRI data, and assessed whether genetic determinants of AD, as well as beta-amyloid (A beta) pathology, can accelerate brain aging. Using data from 1340 cognitively unimpaired participants between 18-94 years of age from multiple sites, we showed that topological properties of graphs constructed from rs-fMRI can predict chronological age across the lifespan. Application of our predictive model to the context of pre-clinical AD revealed that the pre-symptomatic phase of autosomal dominant AD includes acceleration of functional brain aging. This association was stronger in individuals having significant A beta pathology

Interference, reduced action, and trajectories

Instead of investigating the interference between two stationary, rectilinear wave functions in a trajectory representation by examining the two rectilinear wave functions individually, we examine a dichromatic wave function that is synthesized from the two interfering wave functions. The physics of interference is contained in the reduced action for the dichromatic wave function. As this reduced action is a generator of the motion for the dichromatic wave function, it determines the dichromatic wave function's trajectory. The quantum effective mass renders insight into the behavior of the trajectory. The trajectory in turn renders insight into quantum nonlocality.Comment: 12 pages text, 5 figures. Typos corrected. Author's final submission. A companion paper to "Welcher Weg? A trajectory representation of a quantum Young's diffraction experiment", quant-ph/0605121. Keywords: interference, nonlocality, trajectory representation, entanglement, dwell time, determinis

Probucol Suppresses Enterocytic Accumulation of Amyloid-β Induced by Saturated Fat and Cholesterol Feeding

Amyloid-β (Aβ) is secreted from lipogenic organs such as intestine and liver as an apolipoprotein of nascent triacylglycerol rich lipoproteins. Chronically elevated plasma Aβ may compromise cerebrovascular integrity and exacerbate amyloidosis—a hallmark feature of Alzheimer’s disease (AD). Probucol is a hypocholesterolemic agent that reduces amyloid burden in transgenic amyloid mice, but the mechanisms for this effect are presently unclear. In this study, the effect of Probucol on intestinal lipoprotein-Aβ homeostasis was explored. Wild-type mice were fed a control low-fat diet and enterocytic Aβ was stimulated by high-fat (HF) diet enriched in 10% (w/w) saturated fat and 1% (w/w) cholesterol for the duration of 1 month. Mice treated with Probucol had the drug incorporated into the chow at 1% (w/w). Quantitative immunofluorescence was utilised to determine intestinal apolipoprotein B (apo B) and Aβ abundance. We found apo B in both the perinuclear region of the enterocytes and the lacteals in all groups. However, HF feeding and Probucol treatment increased secretion of apo B into the lacteals without any change in net villi abundance. On the other hand, HF-induced enterocytic perinuclear Aβ was significantly attenuated by Probucol. No significant changes in Aβ were observed within the lacteals. The findings of this study support the notion that Probucol suppresses dietary fat induced stimulation of Aβ biosynthesis and attenuate availability of apo B lipoprotein-Aβ for secretion

Brief Report: The Role of Task Support in the Spatial and Temporal Source Memory of Adults with Autism Spectrum Disorder

Adults with autism spectrum disorder (ASD) show intact recognition (supported procedure) but impaired recall (unsupported procedure) of incidentally-encoded context. Because this has not been demonstrated for temporal source, we compared the temporal and spatial source memory of adults with ASD and verbally matched typical adults. Because of difficulties with temporal processing in ASD, we predicted ASD adults would benefit from test support for location but not temporal occurrence of studied words. We found similar levels of recognition and source memory for both groups but there was a greater effect of support on memory for location source in the ASD group. The lack of an effect of support for temporal source may simply reflect a difficulty in operationalising temporal cues

Derivation of High Purity Neuronal Progenitors from Human Embryonic Stem Cells

The availability of human neuronal progenitors (hNPs) in high purity would greatly facilitate neuronal drug discovery and developmental studies, as well as cell replacement strategies for neurodegenerative diseases and conditions, such as spinal cord injury, stroke, Parkinson's disease, Alzheimer's disease, and Huntington's disease. Here we describe for the first time a method for producing hNPs in large quantity and high purity from human embryonic stem cells (hESCs) in feeder-free conditions, without the use of exogenous noggin, sonic hedgehog or analogs, rendering the process clinically compliant. The resulting population displays characteristic neuronal-specific markers. When allowed to spontaneously differentiate into neuronal subtypes in vitro, cholinergic, serotonergic, dopaminergic and/or noradrenergic, and medium spiny striatal neurons were observed. When transplanted into the injured spinal cord the hNPs survived, integrated into host tissue, and matured into a variety of neuronal subtypes. Our method of deriving neuronal progenitors from hESCs renders the process amenable to therapeutic and commercial use

Genome wide analysis of gene dosage in 24,092 individuals estimates that 10,000 genes modulate cognitive ability

International audienceGenomic copy number variants (CNVs) are routinely identified and reported back to patients with neuropsychiatric disorders, but their quantitative effects on essential traits such as cognitive ability are poorly documented. We have recently shown that the effect size of deletions on cognitive ability can be statistically predicted using measures of intolerance to haploinsufficiency. However, the effect sizes of duplications remain unknown. It is also unknown if the effect of multigenic CNVs are driven by a few genes intolerant to haploinsufficiency or distributed across tolerant genes as well. Here, we identified all CNVs > 50 kilobases in 24,092 individuals from unselected and autism cohorts with assessments of general intelligence. Statistical models used measures of intolerance to haploinsufficiency of genes included in CNVs to predict their effect size on intelligence. Intolerant genes decrease general intelligence by 0.8 and 2.6 points of intelligence quotient when duplicated or deleted, respectively. Effect sizes showed no heterogeneity across cohorts. Validation analyses demonstrated that models could predict CNV effect sizes with 78% accuracy. Data on the inheritance of 27,766 CNVs showed that deletions and duplications with the same effect size on intelligence occur de novo at the same frequency. We estimated that around 10,000 intolerant and tolerant genes negatively affect intelligence when deleted, and less than 2% have large effect sizes. Genes encompassed in CNVs were not enriched in any GOterms but gene regulation and brain expression were GOterms overrepresented in the intolerant subgroup. Such pervasive effects on cognition may be related to emergent properties of the genome not restricted to a limited number of biological pathways

Exome-wide Rare Variant Analysis Identifies TUBA4A Mutations Associated with Familial ALS

Exome sequencing is an effective strategy for identifying human disease genes. However, this methodology is difficult in late-onset diseases where limited availability of DNA from informative family members prohibits comprehensive segregation analysis. To overcome this limitation, we performed an exome-wide rare variant burden analysis of 363 index cases with familial ALS (FALS). The results revealed an excess of patient variants within TUBA4A, the gene encoding the Tubulin, Alpha 4A protein. Analysis of a further 272 FALS cases and 5,510 internal controls confirmed the overrepresentation as statistically significant and replicable. Functional analyses revealed that TUBA4A mutants destabilize the microtubule network, diminishing its repolymerization capability. These results further emphasize the role of cytoskeletal defects in ALS and demonstrate the power of gene-based rare variant analyses in situations where causal genes cannot be identified through traditional segregation analysis