Pre- and Perinatal Ischemia-Hypoxia, the Ischemia-Hypoxia Response Pathway, and ADHD Risk

This review focuses on how measured pre- and perinatal environmental and (epi)genetic risk factors are interrelated and potentially influence one, of many, common developmental pathway towards ADHD. Consistent with the Developmental Origins of Health and Disease hypothesis, lower birth weight is associated with increased ADHD risk. Prenatal ischemia-hypoxia (insufficient blood and oxygen supply in utero) is a primary pathway to lower birth weight and produces neurodevelopmental risk for ADHD. To promote tissue survival in the context of ischemia-hypoxia, ischemia-hypoxia response (IHR) pathway gene expression is altered in the developing brain and peripheral tissues. Although altered IHR gene expression is adaptive in the context of ischemia-hypoxia, lasting IHR epigenetic modifications may lead to increased ADHD risk. Taken together, IHR genetic vulnerability to ischemia-hypoxia and IHR epigenetic alterations following prenatal ischemia-hypoxia may result in neurodevelopmental vulnerability for ADHD. Limitations of the extant literature and future directions for genetically-informed research are discussed

Effect of sintering temperature on properties of transparent YSZ-ceramics prepared by spark plasma sintering

Transparent yttria-stabilized zirconia (YSZ) ceramics were sintered with the spark plasma sintering (SPS) method at different temperatures. The influence of sintering temperature (1200-1400°С) on the ceramics microstructure and mechanical properties was investigated and discussed

Genomic approach to selective vulnerability of the hippocampus in brain ischemia-hypoxia

Transient global ischemia selectively damages neurons in specific brain areas. A reproducible pattern of selective vulnerability is observed in the dorsal hippocampus of rodents where ischemic damage typically affects neurons in the CA1 area while sparing neurons in CA3 and granule cells. The "neuronal factors" underlying the differential vulnerability of CA1 versus CA3 have been of great interest. This review first provides on overview of the histological pattern of ischemic-hypoxic damage, the phenomenon of delayed neuronal death, the necrosis-apoptosis discussion, and multiple molecular mechanisms studied in the hippocampus. Subsequently, genomic studies of basal gene expression in CA1 and CA3 are summarized and changes in gene expression in response to global brain ischemia are surveyed. A formal analysis is presented for the overlap between genes expressed under basal conditions in the hippocampus and genes responding to ischemia-hypoxia in general. A possible role of the elusive vascular factors in selective vulnerability is reviewed, and a gene set for angiogenesis is then shown to be enriched in the CA3 gene set. A survey of selective vulnerability in the human hippocampus in relation to genomic studies in ischemia-hypoxia is presented, and neurodegeneration genes with high expression in CA1 are highlighted (e.g. WFS1). It is concluded that neuronal factors dominate the selective vulnerability of CA1 but that vascular factors also deserve more systematic studies

New aspects for the brain in Hartnup disease based on mining of high-resolution cellular mRNA expression data for SLC6A19

Hartnup disease is an autosomal recessive, metabolic disorder caused by mutations of the neutral amino acid transporter, SLC6A19/B0AT1. Reduced absorption in the intestine and kidney results in deficiencies in neutral amino acids and their down-stream metabolites, including niacin, associated with skin lesions and neurological symptoms. The effects on the nervous system such as ataxia have been related to systemic deficiencies of tryptophan (and other neutral amino acids) as no expression of the B0AT1 transporter was found in the brain. In the intestine, SLC6A19 cooperates with ACE2 which has received major attention as the cellular receptor for SARS-CoV-2. When transcriptomics data for ACE2 and its partner proteins were examined, a previously unrecognized expression of Slc6a19 mRNA in the ependymal cells of the mouse brain was encountered that is set into the context of neurological manifestations of Hartnup disease with this communication. A novel role for SLC6A19/B0AT1 in amino acid transport from CSF into ependymal cells is proposed and a role of niacin in ependymal cells highlighted