Impact of Oxidative DNA Damage and the Role of DNA Glycosylases in Neurological Dysfunction

The human brain requires a high rate of oxygen consumption to perform intense metabolic activities, accounting for 20% of total body oxygen consumption. This high oxygen uptake results in the generation of free radicals, including reactive oxygen species (ROS), which, at physiological levels, are beneficial to the proper functioning of fundamental cellular processes. At supraphysiological levels, however, ROS and associated lesions cause detrimental effects in brain cells, commonly observed in several neurodegenerative disorders. In this review, we focus on the impact of oxidative DNA base lesions and the role of DNA glycosylase enzymes repairing these lesions on brain function and disease. Furthermore, we discuss the role of DNA base oxidation as an epigenetic mechanism involved in brain diseases, as well as potential roles of DNA glycosylases in different epigenetic contexts. We provide a detailed overview of the impact of DNA glycosylases on brain metabolism, cognition, inflammation, tissue loss and regeneration, and age-related neurodegenerative diseases based on evidence collected from animal and human models lacking these enzymes, as well as post-mortem studies on patients with neurological disorders.

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The impact of Piscirickettsia Salmonis infection on genome-wide DNA methylation profile in Atlantic Salmon

10.1101/2021.12.20.473279 ◽

2021 ◽

Author(s):

Robert Mukiibi ◽

Carolina Peñaloza ◽

Alejandro Gutierrez ◽

José M. Yáñez ◽

Ross D. Houston ◽

...

Keyword(s):

Gene Expression ◽

Dna Methylation ◽

Atlantic Salmon ◽

Negative Correlation ◽

Regulation Of Gene Expression ◽

Head Kidney ◽

Epigenetic Mechanism ◽

Piscirickettsia Salmonis ◽

The Impact

Salmon rickettsial septicaemia (SRS), caused by the intracellular bacteria Piscirickettsia Salmonis, generates significant mortalities to farmed Atlantic salmon, particularly in Chile. Due to its economic importance, a wealth of research has focussed on the biological mechanisms underlying pathogenicity of P. salmonis, the host response, and genetic variation in host resistance. DNA methylation is a fundamental epigenetic mechanism that influences almost every biological process via the regulation of gene expression and plays a key role in the response of an organism to stimuli. In the current study, the role of head kidney and liver DNA methylation in the response to P. salmonis infection was investigated in a commercial Atlantic salmon population. A total of 66 salmon were profiled using reduced representation bisulphite sequencing (RRBS), with head kidney and liver methylomes compared between infected animals (3 and 9 days post infection) and uninfected controls. These included groups of salmon with divergent (high or low) breeding values for resistance to P. salmonis infection, to examine the influence of genetic resistance. Head kidney and liver showed organ-specific global methylation patterns, but with similar distribution of methylation across gene features. Integration of methylation with RNA-Seq data revealed that methylation levels predominantly showed a negative correlation with gene expression, although positive correlations were also observed. Methylation within the first exon showed the strongest negative correlation with gene expression. A total of 911 and 813 differentially methylated CpG sites were identified between infected and control samples in the head kidney at 3 and 9 days respectively, whereas only 30 and 44 sites were differentially methylated in the liver. Differential methylation in the head kidney was associated with immunological processes such as actin cytoskeleton regulation, phagocytosis, endocytosis and pathogen associated pattern receptor signaling. We also identified 113 and 48 differentially methylated sites between resistant and susceptible fish in the head kidney and liver respectively. Our results contribute to the growing understanding of the role of methylation in regulation of gene expression and response to infectious diseases, and in particular reveal key immunological functions regulated by methylation in Atlantic salmon in response to P. salmonis.

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Active DNA demethylation regulates tracheary element differentiation in Arabidopsis

Science Advances ◽

10.1126/sciadv.aaz2963 ◽

2020 ◽

Vol 6 (26) ◽

pp. eaaz2963

Author(s):

Wei Lin ◽

Linhua Sun ◽

Run-Zhou Huang ◽

Wenjie Liang ◽

Xinyu Liu ◽

...

Keyword(s):

Dna Methylation ◽

Tracheary Element ◽

Dna Demethylation ◽

Epigenetic Mechanism ◽

Dna Glycosylases ◽

Tracheary Element Differentiation ◽

Xylem Development ◽

Active Dna Demethylation ◽

Genomic Regions

DNA demethylation is important for the erasure of DNA methylation. The role of DNA demethylation in plant development remains poorly understood. Here, we found extensive DNA demethylation in the CHH context around pericentromeric regions and DNA demethylation in the CG, CHG, and CHH contexts at discrete genomic regions during ectopic xylem tracheary element (TE) differentiation. While loss of pericentromeric methylation occurs passively, DNA demethylation at a subset of regions relies on active DNA demethylation initiated by DNA glycosylases ROS1, DML2, and DML3. The ros1 and rdd mutations impair ectopic TE differentiation and xylem development in the young roots of Arabidopsis seedlings. Active DNA demethylation targets and regulates many genes for TE differentiation. The defect of xylem development in rdd is proposed to be caused by dysregulation of multiple genes. Our study identifies a role of active DNA demethylation in vascular development and reveals an epigenetic mechanism for TE differentiation.

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Angiosome Concept in the Endovascular Management of Chronic Atherosclerotic Ischaemia of Lower Extremities in Diabetics

Journal of Indonesian Society for Vascular and Endovascular Surgery ◽

10.36864/jinasvs.2020.2.009 ◽

2020 ◽

Vol 1 (2) ◽

pp. 36-40

Author(s):

Ahmed Sayed ◽

Hussein Elwan ◽

Mostafa Elshal ◽

Ahmed Taha

Keyword(s):

Wound Healing ◽

Limb Salvage ◽

Tissue Loss ◽

Chi Square ◽

Sex Risk ◽

Run Off ◽

Foot Arch ◽

Chi Square Test ◽

The Impact

Introduction: The role of the angiosome theory in infrapopliteal disease is controversial. We aimed to study the impact of direct angiosomal revascularization on the outcome in the presence and absence of a complete foot arch. Method: We studied consecutive patients presenting with infrapopliteal disease from February 2013 to January 2014, Rutherford categories 5&6, where only one infrapopliteal vessel was successfully revascularized. Patients were classified into the following groups: (i)DF: direct angiosome revascularization with patent foot arch, (ii)DN: direct angiosome revascularization with no foot arch, (iii)IF: indirect angiosome revascularization with patent foot arch, and (iv)IN: indirect angiosome revascularization with no foot arch. The outcome of the four groups was compared using Chi square test and ANOVA tests. Results: 75 patients presented during the study period; 20 DF, 22 DN, 17 IF, & 16 IN. There were no statistical differences in age, sex, risk factors, run off vessel, or site of tissue loss. Limb salvage rates after 12 months were 95% in DF, 91% in DN, 76.5% in IF, and 44% in IN (p=0.0046). Mean number of days till wound healing was 72.2±16.7 in DF, 122.9±20.6 in DN, 229.4±30.3 in IF, and 308.1±29.6 in IN (p<0.001). Conclusion: Group DF showed significantly better results in limb salvage and wound healing, followed by DN, IF, and lastly IN. A complete foot arch had a significant impact on clinical outcome, in addition to direct angiosomal revascularization. Future studies on the angiosome concept should include the completeness of foot arch as an important factor contributing to healing and limb salvage. Keywords: angiosome, infrapopliteal angioplasty, foot arch

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NEIL1 and NEIL2 DNA glycosylases regulate anxiety and learning in a cooperative manner

10.1101/2021.02.08.430208 ◽

2021 ◽

Author(s):

Gunn A. Hildrestrand ◽

Veslemøy Rolseth ◽

Nicolas Kunath ◽

Rajikala Suganthan ◽

Vidar Jensen ◽

...

Keyword(s):

Oxidative Dna Damage ◽

Excision Repair ◽

Synaptic Function ◽

Dna Glycosylases ◽

Knock Out ◽

Ca1 Region ◽

Hippocampal Ca1 Region ◽

Dna Base ◽

Base Lesion ◽

The Impact

AbstractOxidative DNA damage in the brain has been implicated in neurodegeneration and cognitive decline. DNA glycosylases initiate base excision repair (BER), the main pathway for oxidative DNA base lesion repair. NEIL1 and NEIL3 DNA glycosylases alter cognition in mice, the role of NEIL2 remains unclear. Here, we investigate the impact of NEIL2 and its potential overlap with NEIL1 on behavior in single and double knock-out mouse models. Neil1-/-Neil2-/- mice displayed hyperactivity, reduced anxiety and improved learning. Hippocampal oxidative DNA base lesion levels were comparable between genotypes, no mutator phenotype was found. Impaired canonical repair was thus not the cause of altered behavior. Electrophysiology indicated reduced stratum oriens afferents in the hippocampal CA1 region in Neil1-/-Neil2-/-. Within CA1, NEIL1 and NEIL2 jointly regulated transcription in genes relevant for synaptic function. Thus, we postulate a cooperative function of NEIL1 and NEIL2 in genome regulation beyond canonical BER modulating memory formation and anxiety.

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NEIL1 and NEIL2 DNA glycosylases modulate anxiety and learning in a cooperative manner in mice

Communications Biology ◽

10.1038/s42003-021-02864-x ◽

2021 ◽

Vol 4 (1) ◽

Author(s):

Gunn A. Hildrestrand ◽

Veslemøy Rolseth ◽

Nicolas Kunath ◽

Rajikala Suganthan ◽

Vidar Jensen ◽

...

Keyword(s):

Oxidative Dna Damage ◽

Excision Repair ◽

Synaptic Function ◽

Dna Glycosylases ◽

Ca1 Region ◽

Hippocampal Ca1 Region ◽

Dna Base ◽

Base Excision ◽

Base Lesion ◽

The Impact

AbstractOxidative DNA damage in the brain has been implicated in neurodegeneration and cognitive decline. DNA glycosylases initiate base excision repair (BER), the main pathway for oxidative DNA base lesion repair. NEIL1 and NEIL3 DNA glycosylases affect cognition in mice, while the role of NEIL2 remains unclear. Here, we investigate the impact of NEIL2 and its potential overlap with NEIL1 on behavior in knockout mouse models. Neil1−/−Neil2−/− mice display hyperactivity, reduced anxiety and improved learning. Hippocampal oxidative DNA base lesion levels are comparable between genotypes and no mutator phenotype is found. Thus, impaired canonical repair is not likely to explain the altered behavior. Electrophysiology suggests reduced axonal activation in the hippocampal CA1 region in Neil1−/−Neil2−/− mice and lack of NEIL1 and NEIL2 causes dysregulation of genes in CA1 relevant for synaptic function. We postulate a cooperative function of NEIL1 and NEIL2 in genome regulation, beyond canonical BER, modulating behavior in mice.

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Intergroup Threat and Outgroup Attitudes

Social Psychology ◽

10.1027/1864-9335/a000127 ◽

2013 ◽

Vol 44 (5) ◽

pp. 311-319 ◽

Cited By ~ 12

Author(s):

Marco Brambilla ◽

David A. Butz

Keyword(s):

Gay Men ◽

Social Group ◽

Welfare Recipients ◽

Intergroup Attitudes ◽

Social Policies ◽

Intergroup Threat ◽

Economic Threat ◽

The Impact ◽

General Climate

Two studies examined the impact of macrolevel symbolic threat on intergroup attitudes. In Study 1 (N = 71), participants exposed to a macrosymbolic threat (vs. nonsymbolic threat and neutral topic) reported less support toward social policies concerning gay men, an outgroup whose stereotypes implies a threat to values, but not toward welfare recipients, a social group whose stereotypes do not imply a threat to values. Study 2 (N = 78) showed that, whereas macrolevel symbolic threat led to less favorable attitudes toward gay men, macroeconomic threat led to less favorable attitudes toward Asians, an outgroup whose stereotypes imply an economic threat. These findings are discussed in terms of their implications for understanding the role of a general climate of threat in shaping intergroup attitudes.

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