Observation of soft-x-ray spatial coherence from resonance transition radiation

We have observed the spatial distribution of coherent or resonant transition radiation (RTR) in the soft-x-ray region of the spectrum (1-2 keV). Resonance transition radiators were constructed and tested at two accelerators using electron-beam energies ranging from 50 to 228 MeV. These radiators emitted soft x-rays in a circularly symmetrical annulus with a half-angle divergence of 2.5-9.0 mrad. The angle of peak emission was found to increase with electron-beam energy, in contrast to the incoherent case, for which the angle of emission varied inversely with electron-beam energy. By careful selection of foil thickness and spacing, one may design radiators whose angle of emission varies over a range of charged-particle energies. A particular RTR mode (r=m=1) was found to give a sharp annular ring that becomes more accentuated as the number of foils is increased. The RTR effect has application in particle detection, beam diagnostics, x-ray source brightness enhancement, and x-ray free-electron-laser emission.This work was supported by the Department of Energy under the Small Business Innovative Research (SBIR) program, Grant Number DE-AC03-86ER80428, Canadian Natural Science and Engineering Research Council (NSERC), and the Naval Postgraduate SchoolApproved for public release; distribution is unlimited

Mitochondrial tRNA methylation in Alzheimer’s disease and progressive supranuclear palsy

Abstract Background Methylation of mitochondrial tRNAs (mt-tRNA) at the 9th position (“p9 site”) is known to impact translational efficiency and downstream mitochondrial function; however, direct assessment of mt-RNA methylation is challenging. Recent RNA sequence-based methods have been developed to reliably identify post-transcriptional methylation. Though p9 methylation has been studied in healthy human populations and in the context of cancer, it has not yet been analyzed in neurodegenerative disease, where mitochondrial dysfunction is a prominent and early hallmark of disease progression. Methods Mitochondrial p9 methylation was inferred from multi-allelic calls in RNA-seq data. Gene-based association studies were performed in FUMA. Correlations between nuclear gene expression and p9 methylation were tested using Spearman’s rho. Fisher’s Exact test was used in PANTHER and IPA to test for overrepresentation and enrichment of biological processes and pathways in the top nuclear genes correlated with p9 methylation. Results Variable methylation was observed at 11 p9 sites in post-mortem cerebellar tissue of elderly subjects who were either healthy or diagnosed with Alzheimer’s disease (AD), progressive supranuclear palsy (PSP) or pathological aging (PA). Similarities in degree of methylation were observed between AD and PSP. Certain nuclear encoded genes were identified as significantly associated with p9 methylation. Expression of 5300 nuclear encoded genes was significantly correlated with p9 methylation, with AD and PSP subjects exhibiting similar expression profiles. Overrepresentation and enrichment testing using the top transcripts revealed enrichment for a number of molecular processes, terms and pathways including many of which that were mitochondrial-related. Conclusion With mitochondrial dysfunction being an established hallmark of neurodegenerative disease pathophysiology, this work sheds light on the potential molecular underpinnings of this dysfunction. Here we show overlap in cerebellar pathophysiology between common tauopathies such as Alzheimer’s disease and progressive supranuclear palsy. Whether p9 hypermethylation is a cause or consequence of pathology remains an area of focus. </jats:sec

Mitochondrial tRNA methylation in Alzheimer's disease and progressive supranuclear palsy

BACKGROUND: Methylation of mitochondrial tRNAs (mt-tRNA) at the 9th position ("p9 site") is known to impact translational efficiency and downstream mitochondrial function; however, direct assessment of mt-RNA methylation is challenging. Recent RNA sequence-based methods have been developed to reliably identify post-transcriptional methylation. Though p9 methylation has been studied in healthy human populations and in the context of cancer, it has not yet been analyzed in neurodegenerative disease, where mitochondrial dysfunction is a prominent and early hallmark of disease progression. METHODS: Mitochondrial p9 methylation was inferred from multi-allelic calls in RNA-seq data. Gene-based association studies were performed in FUMA. Correlations between nuclear gene expression and p9 methylation were tested using Spearman's rho. Fisher's Exact test was used in PANTHER and IPA to test for overrepresentation and enrichment of biological processes and pathways in the top nuclear genes correlated with p9 methylation. RESULTS: Variable methylation was observed at 11 p9 sites in post-mortem cerebellar tissue of elderly subjects who were either healthy or diagnosed with Alzheimer's disease (AD), progressive supranuclear palsy (PSP) or pathological aging (PA). Similarities in degree of methylation were observed between AD and PSP. Certain nuclear encoded genes were identified as significantly associated with p9 methylation. Expression of 5300 nuclear encoded genes was significantly correlated with p9 methylation, with AD and PSP subjects exhibiting similar expression profiles. Overrepresentation and enrichment testing using the top transcripts revealed enrichment for a number of molecular processes, terms and pathways including many of which that were mitochondrial-related. CONCLUSION: With mitochondrial dysfunction being an established hallmark of neurodegenerative disease pathophysiology, this work sheds light on the potential molecular underpinnings of this dysfunction. Here we show overlap in cerebellar pathophysiology between common tauopathies such as Alzheimer's disease and progressive supranuclear palsy. Whether p9 hypermethylation is a cause or consequence of pathology remains an area of focus

Mito-nuclear compatibility in risk for cognitive decline in admixed populations

Background. The issue of missing heritability has vexed the study of many complex diseases, Alzheimer’s disease (AD) not excluded. Only ~35% of the heritability of AD has been accounted for, the majority of which lies in APOE allele e4, which has a less-pronounced effect in certain admixed populations. There are few genetic and/or mitochondrial studies of admixed populations, and our understanding of mitochondrially-related cognitive decline has largely been based on studies of highly homogenous populations (by design). The concept of mito-nuclear compatibility states that optimization of mitochondrial DNA (mtDNA) with nuclear genetic background is a source of significant selective evolutionary pressure. Evidence for this phenomenon in human populations is emerging (Zaidi and Makova, 2019), and opens the door for studies in the context of human disease. Purpose. The purpose of this study is to determine whether divergent nuclear and mitochondrial genomes confer risk for cognitive impairment and decline in admixed populations. Methods. Participants in the Texas Alzheimer’s Research and Care Consortium (TARCC) were used for this study. DNA extracts from peripheral blood buffy coat were genotyped on the Multi-Ethnic Genotyping Array (Illumina) which types 1.7 million SNPs and includes ancestry specific genetic variation. The top 10 eigenvectors (smartpca via Eigensoft) were generated via principle component analysis of nuclear DNA (nDNA) and used to cluster subjects with the 1000 Genomes population data in order to ascertain global, ancestral nDNA background. Mitochondrial DNA variants from the array were analyzed using HaploGrep/MitoTool for mtDNA haplotype assignment. Non-concordance of mtDNA:nDNA ancestry will be identified and scored as in Zaidi and Makova, 2019 and tested for association with cognitive state (normal, mild cognitive impairment, or Alzheimer’s disease) as well as cognitive decline between time points. Results. Preliminary studies indicate that cognitive decline is associated with mitochondrial phenotypes in Caucasian subjects; these results were dependent on sex. Mitochondrial copy number was a main driver in the predictive model in both males and females, but to a differing degree. Conclusion. Discrepancy between mtDNA and nDNA genomic backgrounds has been previously correlated with mtDNA copy number (Zaidi and Makova, 2019); similar discrepancy may explain health disparities in complex diseases that are more prevalent in particular admixed populations

Cognitive Issues in Bible Translation: The Biblical Text in the Context of Human Experience

Cognitive studies affect all disciplines that reflect the connection between the mind–brain and human behavior. To state the obvious, Bible translation is a multidisciplinary task influenced by cognitive processes. What, then, do Bible translators need to know about the intended communication of a biblical text on one hand and a people’s context-based inferences on the other? Can these disparate, but necessarily interactive, environments blend to reflect a totality of knowledge from the content of the biblical text? Together, the coauthors explore a variety of cognitive processes that reflect on the relationship between translation and human behavior. Our objective is to show how translated biblical text interfaces with human cognition to affect behavior in specific contexts.</jats:p

Genetically-regulated transcriptomics &amp; copy number variation of proctitis points to altered mitochondrial and DNA repair mechanisms in individuals of European ancestry

Abstract Background Proctitis is an inflammation of the rectum and may be induced by radiation treatment for cancer. The genetic heritability of developing radiotoxicity and prior role of genetic variants as being associated with side-effects of radiotherapy necessitates further investigation for underlying molecular mechanisms. In this study, we investigated gene expression regulated by genetic variants, and copy number variation in prostate cancer survivors with radiotoxicity. Methods We investigated proctitis as a radiotoxic endpoint in prostate cancer patients who received radiotherapy (n = 222). We analyzed the copy number variation and genetically regulated gene expression profiles of whole-blood and prostate tissue associated with proctitis. The SNP and copy number data were genotyped on Affymetrix® Genome-wide Human SNP Array 6.0. Following QC measures, the genotypes were used to obtain gene expression by leveraging GTEx, a reference dataset for gene expression association based on genotype and RNA-seq information for prostate (n = 132) and whole-blood tissue (n = 369). Results In prostate tissue, 62 genes were significantly associated with proctitis, and 98 genes in whole-blood tissue. Six genes - CABLES2, ATP6AP1L, IFIT5, ATRIP, TELO2, and PARD6G were common to both tissues. The copy number analysis identified seven regions associated with proctitis, one of which (ALG1L2) was also associated with proctitis based on transcriptomic profiles in the whole-blood tissue. The genes identified via transcriptomics and copy number variation association were further investigated for enriched pathways and gene ontology. Some of the enriched processes were DNA repair, mitochondrial apoptosis regulation, cell-to-cell signaling interaction processes for renal and urological system, and organismal injury. Conclusions We report gene expression changes based on genetic polymorphisms. Integrating gene-network information identified these genes to relate to canonical DNA repair genes and processes. This investigation highlights genes involved in DNA repair processes and mitochondrial malfunction possibly via inflammation. Therefore, it is suggested that larger studies will provide more power to infer the extent of underlying genetic contribution for an individual’s susceptibility to developing radiotoxicity. </jats:sec

Genetically-regulated transcriptomics & copy number variation of proctitis points to altered mitochondrial and DNA repair mechanisms in individuals of European ancestry

BACKGROUND: Proctitis is an inflammation of the rectum and may be induced by radiation treatment for cancer. The genetic heritability of developing radiotoxicity and prior role of genetic variants as being associated with side-effects of radiotherapy necessitates further investigation for underlying molecular mechanisms. In this study, we investigated gene expression regulated by genetic variants, and copy number variation in prostate cancer survivors with radiotoxicity. METHODS: We investigated proctitis as a radiotoxic endpoint in prostate cancer patients who received radiotherapy (n = 222). We analyzed the copy number variation and genetically regulated gene expression profiles of whole-blood and prostate tissue associated with proctitis. The SNP and copy number data were genotyped on Affymetrix(R) Genome-wide Human SNP Array 6.0. Following QC measures, the genotypes were used to obtain gene expression by leveraging GTEx, a reference dataset for gene expression association based on genotype and RNA-seq information for prostate (n = 132) and whole-blood tissue (n = 369). RESULTS: In prostate tissue, 62 genes were significantly associated with proctitis, and 98 genes in whole-blood tissue. Six genes - CABLES2, ATP6AP1L, IFIT5, ATRIP, TELO2, and PARD6G were common to both tissues. The copy number analysis identified seven regions associated with proctitis, one of which (ALG1L2) was also associated with proctitis based on transcriptomic profiles in the whole-blood tissue. The genes identified via transcriptomics and copy number variation association were further investigated for enriched pathways and gene ontology. Some of the enriched processes were DNA repair, mitochondrial apoptosis regulation, cell-to-cell signaling interaction processes for renal and urological system, and organismal injury. CONCLUSIONS: We report gene expression changes based on genetic polymorphisms. Integrating gene-network information identified these genes to relate to canonical DNA repair genes and processes. This investigation highlights genes involved in DNA repair processes and mitochondrial malfunction possibly via inflammation. Therefore, it is suggested that larger studies will provide more power to infer the extent of underlying genetic contribution for an individual's susceptibility to developing radiotoxicity.We would like to acknowledge the NIH ‒ Neurobiology of Aging T32 grant AG020494 for supporting this research. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health