Retroviruses are the only group of viruses known to have left a fossil record, in the form of endogenous proviruses, and some of 8% of the human genome is made up of these elements 1,2 . Although many other viruses, including non-retroviral RNA viruses, are known to generate DNA forms of their own genomes during replication3 , 4, none has been found as DNA in the germline of animals. Bornaviruses, a nonsegmented, negative-sense RNA virus, are unique among RNA viruses in that they establish persistent infection in the cell nucleus5 -7 . Here we show that elements homologous to the nucleoprotein (N) gene of Bornavirus exist in the genomes of several mammalian species, including humans, non-human primates, rodents and elephants. These sequences have been designated endogenous Bornalike N (EBLN) elements. Some of the primate EBLNs contain an intact open reading frame (ORF) and are expressed as mRNA. Phylogenetic analyses revealed that EBLNs appear to have been generated by different insertional events in each specific animal family. Furthermore, the EBLN of a ground squirrel was formed by a recent integration event, while those in primates must have been formed more than 40 million years ago. We also show that the N mRNA of a current mammalian Bornavirus, Borna disease virus (BDV), can form EBLN-like elements in the genomes of persistently infected cultured cells. Our results provide the first evidence for endogenization of non-retroviral virus-derived elements in mammalian genomes and give †To whom correspondence should be addressed. Dr. Keizo Tomonaga:

Transgenic mouse models of Alzheimer's disease (AD) with nonphysiologic overexpression of amyloid precursor protein (APP) exhibit various unnatural symptoms/dysfunctions. To overcome this issue, mice with single humanized App knock-in (KI) carrying Swedish (NL), Beyreuther/Iberian (F), and Arctic (G) mutations in different combinations were recently developed. The validity of these mouse models of AD from a behavioral viewpoint, however, has not been extensively evaluated. Thus, using an automated behavior monitoring system, we analyzed various behavioral domains, including executive function, and learning and memory. The App-KI mice carrying NL-G-F mutations showed clear deficits in spatial memory and flexible learning, enhanced compulsive behavior, and reduced attention performance. Mice carrying NL-F mutations exhibited modest abnormalities. The NL-G-F mice had a greater and more rapid accumulation of Aβ deposits and glial responses. These findings reveal that single pathologic App-KI is sufficient to produce deficits in broad cognitive domains and that App-KI mouse lines with different levels of pathophysiology are useful models of AD.

Malate transporters play a critical role in aluminum (Al) tolerance responses for some plant species, such as Arabidopsis (Arabidopsis thaliana). Here, we further characterize AtALMT1, an Arabidopsis aluminum-activated malate transporter, to clarify its specific role in malate release and Al stress responses. Malate excretion from the roots of accession Columbia was sharply induced by Al, which is concomitant with the induction of AtALMT1 gene expression. The malate release was specific for Al among rhizotoxic stressors, namely cadmium, copper, erbium, lanthanum, sodium, and low pH, which accounts for the specific sensitivity of a null mutant to Al stress. Al-specific malate excretion can be explained by a combined regulation of AtALMT1 expression and activation of AtALMT1 protein, which is specific for Al. Although low pH treatment slightly induced gene expression, other treatments did not. In addition, malate excretion in Al-activated seedlings was rapidly stopped by removing Al from the solution. Other rhizotoxic stressors were not effective in maintaining malate release. Protein kinase and phosphatase inhibitor studies indicated that reversible phosphorylation was important for the transcriptional and posttranslational regulation of AtALMT1. AtALMT1 promoter-β-glucuronidase fusion lines revealed that AtALMT1 has restricted expression within the root, such that unnecessary carbon loss is likely minimized. Lastly, a natural nonsense mutation allele of AtALMT1 was identified from the Al-hypersensitive natural accession Warschau-1.