Effects of Cranial Irradiation on Adult Hippocampal Neuronal Development and the Role of p53

Cranial radiotherapy is a standard treatment for brain tumours, but is associated with late side effects including compromised cognitive functions that can significantly impair patients’ quality of life. Cognitive impairment is a major dose-limiting factor for cranial radiotherapy, and has therefore been an important subject of study. A large body of preclinical studies suggest that injury to the hippocampus, a key structure for learning and memory, contributes to radiation-induced cognitive impairment. Hippocampus houses the life-long generation of new neurons, a process termed neurogenesis. Neurogenesis inhibition is considered to be one of the most important mechanisms leading to post-irradiation cognitive impairment. Mechanistic insights into how radiation affects neurogenesis could therefore help to alleviate the undesirable effects from cranial radiotherapy. I postulate that p53, an extensively studied tumor suppressor known to play an important role in both radiation biology and stem cell biology, regulates post-irradiation neurogenesis. The role of p53 in post-irradiation hippocampal neurogenesis was examined using transgenic mice with different copy numbers of the p53 gene. We also examined the effects of aging on post-irradiation hippocampal neurogenesis because of the reported age-dependent increase of p53 in the hippocampus. The impact of cranial irradiation on hippocampus was further evaluated using a set of endpoints characterizing cellular senescence to complement limitations associated with neurogenesis endpoints. We showed for the first time that p53 deficiency exacerbated the disruption of hippocampal neuronal development after irradiation in adult mouse brain (Chapter 3). This profound post-irradiation neurogenesis inhibition was associated with increased neural stem cell activation and the depletion of neuronal stem cell pool. Although p53 has been shown to increase with aging in the hippocampus, cranial irradiation was found to further inhibit the age-dependent decrease in hippocampal neurogenesis (Chapter 4). Cranial irradiation resulted in increased expression of senescence markers in mouse dentate gyrus (Chapter 5). Ablation of p53 may alter radiation-induced cellular senescence in the hippocampus, although further investigations are needed to determine the functional significance of this finding. These investigations provide mechanistic insight into the effects of cranial irradiation on hippocampal neuronal development and the pathophysiology of cognitive impairment after cranial irradiation.Ph.D

Differential Apoptosis Radiosensitivity of Neural Progenitors in Adult Mouse Hippocampus

Mammalian tissue-specific stem cells and progenitors demonstrate differential DNA damage response. Neural progenitors in dentate gyrus of the hippocampus are known to undergo apoptosis after irradiation. Using a mouse model of hippocampal neuronal development, we characterized the apoptosis sensitivity of the different neural progenitor subpopulations in adult mouse dentate gyrus after irradiation. Two different bromodeoxyuridine incorporation paradigms were used for cell fate mapping. We identified two apoptosis sensitive neural progenitor subpopulations after irradiation. The first represented non-proliferative and non-newborn neuroblasts and immature neurons that expressed doublecortin, calretinin or both. The second consisted of proliferative intermediate neural progenitors. The putative radial glia-like neural stem cells or type-1 cells, regardless of proliferation status, were apoptosis resistant after irradiation. There was no evidence of radiation-induced apoptosis in the absence of the Trp53 (p53) gene but absence of Cdkn1a (p21) did not alter the apoptotic response. Upregulation of nuclear p53 was observed in neuroblasts after irradiation. We conclude that adult hippocampal neural progenitors may demonstrate differential p53-dependent apoptosis sensitivity after irradiation

Differential Apoptosis Radiosensitivity of Neural Progenitors in Adult Mouse Hippocampus

Mammalian tissue-specific stem cells and progenitors demonstrate differential DNA damage response. Neural progenitors in dentate gyrus of the hippocampus are known to undergo apoptosis after irradiation. Using a mouse model of hippocampal neuronal development, we characterized the apoptosis sensitivity of the different neural progenitor subpopulations in adult mouse dentate gyrus after irradiation. Two different bromodeoxyuridine incorporation paradigms were used for cell fate mapping. We identified two apoptosis sensitive neural progenitor subpopulations after irradiation. The first represented non-proliferative and non-newborn neuroblasts and immature neurons that expressed doublecortin, calretinin or both. The second consisted of proliferative intermediate neural progenitors. The putative radial glia-like neural stem cells or type-1 cells, regardless of proliferation status, were apoptosis resistant after irradiation. There was no evidence of radiation-induced apoptosis in the absence of the Trp53 (p53) gene but absence of Cdkn1a (p21) did not alter the apoptotic response. Upregulation of nuclear p53 was observed in neuroblasts after irradiation. We conclude that adult hippocampal neural progenitors may demonstrate differential p53-dependent apoptosis sensitivity after irradiation

Aggregatibacter actinomycetemcomitans as the Aetiological Cause of Rheumatoid Arthritis: What Are the Unsolved Puzzles?

Leukotoxin A (LtxA) is the major virulence factor of an oral bacterium known as Aggregatibacter actinomycetemcomitans (Aa). LtxA is associated with elevated levels of anti-citrullinated protein antibodies (ACPA) in rheumatoid arthritis (RA) patients. LtxA targets leukocytes and triggers an influx of extracellular calcium into cytosol. The current proposed model of LtxA-mediated hypercitrullination involves the dysregulated activation of peptidylarginine deiminase (PAD) enzymes to citrullinate proteins, the release of hypercitrullinated proteins through cell death, and the production of autoantigens recognized by ACPA. Although model-based evidence is yet to be established, its interaction with the host’s immune system sparked interest in the role of LtxA in RA. The first part of this review summarizes the current knowledge of Aa and LtxA. The next part highlights the findings of previous studies on the association of Aa or LtxA with RA aetiology. Finally, we discuss the unresolved aspects of the proposed link between LtxA of Aa and RA

Influence of Mask Wearing during COVID-19 Surge and Non-Surge Time Periods in Two K-12 Public School Districts in Georgia, USA

Background: Into the third year of the COVID-19 pandemic and the second year of in-person learning for many K-12 schools in the United States, the benefits of mitigation strategies in this setting are still unclear. We compare COVID-19 cases in school-aged children and adolescents between a school district with a mandatory mask-wearing policy to one with an optional mask-wearing policy, during and after the peak period of the Delta variant wave of infection. Methods: COVID-19 cases during the Delta variant wave (August 2021) and post the wave (October 2021) were obtained from public health records. Cases of K-12 students, stratified by grade level (elementary, middle, and high school) and school districts across two counties, were included in the statistical and spatial analyses. COVID-19 case rates were determined and spatially mapped. Regression was performed adjusting for specific covariates. Results: Mask-wearing was associated with lower COVID-19 cases during the peak Delta variant period; overall, regardless of the Delta variant period, higher COVID-19 rates were seen in older aged students. Conclusion: This study highlights the need for more layered prevention strategies and policies that take into consideration local community transmission levels, age of students, and vaccination coverage to ensure that students remain safe at school while optimizing their learning environment