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Endogenously formed reactive oxygen species continuously damage cellular constituents including DNA. These challenges, coupled with exogenous exposure to agents that generate reactive oxygen species, are both associated with normal aging processes and linked to cardiovascular disease, cancer, cataract formation, and fatty liver disease. Although not all of these diseases have been definitively shown to originate from mutations in nuclear DNA or mitochondrial DNA, repair of oxidized, saturated, and ring-fragmented bases via the base excision repair pathway is known to be critical for maintaining genomic stability. One enzyme that initiates base excision repair of ring-fragmented purines and some saturated pyrimidines is NEIL1, a mammalian homolog to Escherichia coli endonuclease VIII. To investigate the organismal consequences of a deficiency in NEIL1, a knockout mouse model was created. In the absence of exogenous oxidative stress, neill knockout ($neil1^{-/-}$) and heterozygotic ($neil1^{-/-}$) mice develop severe obesity, dyslipidemia, and fatty liver disease and also have a tendency to develop hyperinsulinemia. In humans, this combination of clinical manifestations, including hypertension, is known as the metabolic syndrome and is estimated to affect >40 million people in the United States. Additionally, mitochondrial DNA from$neil1^{-/-}$mice show increased levels of steady-state DNA damage and deletions relative to wild-type controls. These data suggest an important role for NEIL1 in the prevention of the diseases associated with the metabolic syndrome.

Transgenic mice expressing MyrAkt from a proximal Lck promoter construct develop thymomas at an early age, whereas transgenic mice expressing constitutively active Lck-AktE40K develop primarily tumors of the peripheral lymphoid organs later in life. The thymus of 6- to 8-week-old MyrAkt transgenic mice is normal in size but contains fewer, larger cells than the thymus of nontransgenic control and AktE40K transgenic mice. Earlier studies had shown that cell size and cell cycle are coordinately regulated. On the basis of this finding, and our observations that the oncogenic potential of Akt correlates with its effect on cell size, we hypothesized that mechanisms aimed at maintaining the size of the thymus dissociate cell size and cell cycle regulation by blocking MyrAkt-promoted G1progression and that failure of these mechanisms may promote cell proliferation resulting in an enlarged neoplastic thymus. To address this hypothesis, we examined the cell cycle distribution of freshly isolated and cultured thymocytes from transgenic and nontransgenic control mice. The results showed that although neither transgene alters cell cycle distribution in situ, the MyrAkt transgene promotes G1progression in culture. Freshly isolated MyrAkt thymocytes express high levels of cyclins D2 and E and cdk4 but lower than normal levels of cyclin D3 and cdk2. Cultured thymocytes from MyrAkt transgenic mice, on the other hand, express high levels of cyclin D3, suggesting that the hypothesized organ size control mechanisms may down-regulate the expression of this molecule. Primary tumor cells, similar to MyrAkt thymocytes in culture, express high levels of cyclin D3. These findings support the hypothesis that tumor induction is caused by the failure of organ size control mechanisms to down-regulate cyclin D3 and to block MyrAkt-promoted G1progression.

Background Canavan disease (CD) is an autosomal recessive leukodystrophy characterized by deficiency of aspartoacylase (ASPA) and increased levels of N‐acetylaspartic acid (NAA) in brain and body fluids, severe mental retardation and early death. Gene therapy has been attempted in a number of children with CD. The lack of an animal model has been a limiting factor in developing vectors for the treatment of CD. This paper reports the successful creation of a knock‐out mouse for Canavan disease that can be used for gene transfer. Methods Genomic library λ knock‐out shuttle (λKOS) was screened and a specific pKOS/Aspa clone was isolated and used to create a plasmid with 10 base pair (bp) deletion of exon four of the murine aspa. Following linearization, the plasmid was electroporated to ES cells. Correctly targeted ES clones were identified following positive and negative selection and confirmed by Southern analysis. Chimeras were generated by injection of ES cells to blastocysts. Germ line transmission was achieved by the birth of heterozygous mice as confirmed by Southern analysis. Results Heterozygous mice born following these experiments have no overt phenotype. The homozygous mice display neurological impairment, macrocephaly, generalized white matter disease, deficient ASPA activity and high levels of NAA in urine. Magnetic resonance imaging (MRI) and spectroscopy (MRS) of the brain of the homozygous mice show white matter changes characteristic of Canavan disease and elevated NAA levels. Conclusion The newly created ASPA deficient mouse establishes an important animal model of Canavan disease. This model should be useful for developing gene transfer vectors to treat Canavan disease. Vectors for the central nervous system (CNS) and modulation of NAA levels in the brain should further add to the understanding of the pathophysiology of Canavan disease. Data generated from this animal model will be useful for developing strategies for gene therapy in other neurodegenerative diseases. Copyright © 2000 John Wiley & Sons, Ltd.

This latest chromosome (Chr) 8 report contains 995 entries, incorporating data available by 11/98. Of the mapped loci on this chromosome, 29% are genes/pseudogenes, 8% are expressed sequence tags (ESTs), and 63% are anonymous markers. There are 78 additions to this year's map, of which 42 are ESTs, 24 are genes, 3 are quantitative trait loci (QTLs), and 9 are anonymous markers. The chromosome length of 84 cM is unchanged from the previous Chr 8 report. The most distal 12 cM of the chromosome has almost no known loci, and none of the new entries fell into this region. The current consensus genetic map of Chr 8, a locus table (Table 1), and a cytogenetic map (Figure 1) can be accessed electronically at The Jackson Laboratory World Wide Web site (http://www.informatics.jax.org/bin/ccr/index).

The mouse has three genes encoding alcohol dehydrogenase (ADH) enzymes of different tissue specificity and catalytic properties. Expression of the Adh-1 gene product is developmentally regulated in liver tissue and androgen-inducible in kidney tissue. In this investigation, an Adh-1 cDNA clone was isolated from a mouse liver cDNA library using a cDNA clone for the$\\beta$ -chain of human alcohol dehydrogenase as the probe. This cDNA clone was used as a hybridization probe to study the mechanism of androgen induction of kidney ADH activity. Induction of A/J female mice by androgen resulted in a 12-15 fold increase in the steady-state level of Adh-1 within 3 days after androgen treatment. Removal of androgen resulted in a rapid decrease in the relative concentration of Adh-1 mRNA. There was a very good correlation between the relative Adh-1 mRNA levels and the relative rates of ADH synthesis during androgen induction and deinduction. The results indicate that androgen stimulation of kidney ADH occurs by increasing the abundance of Adh-1 mRNA. In closely related mouse species, the ability of the Adh-1 gene to respond to androgen differed significantly. The developmental regulation of ADH in liver tissue was investigated in three inbred mouse strains which show genetic variation in ADH expression. A substantial increase in the relative concentration of Adh-1 mRNA was observed between 15-25 days of age. After 25 days of age, C57BL/6J mice had a two fold greater Adh-1 mRNA level than A/J and C3HeB/FeJ mice. There was a good correlation between relative Adh-1 mRNA levels and relative rates of ADH protein synthesis over the time course of development. The increase in mRNA concentration quantitatively accounts for the majority of the increase in ADH expression during development. Several genomic clones of Adh-1 were obtained from a Balb/cJ DNA library. The structure of the Adh-1 gene was investigated by detailed restriction mapping and DNA sequence analysis. The start site of transcription of this gene was suggested from S1 nuclease mapping studies and presumptive regulatory sequences in the 5 $\\sp\\prime$ -flanking region were identified, including a TATA box and a glucocorticoid responsive element. A non Adh-1 sequence in the genome was mapped to chromosome 3 approximately 9 centiMorgans from Adh-1. An ADH null mutation was previously identified in a pure breeding stock of Peromyscus maniculatus which lacks ADH activity and immunocrossreacting protein. This study revealed that these mice have no detectable Adh mRNA. Southern blot analysis suggested that there is a major deletion in the Adh structural gene.

Pervasive SARS-CoV-2 infections in humans have led to multiple transmission events to animals. While SARS-CoV-2 has a potential broad wildlife host range, most documented infections have been in captive animals and a single wildlife species, the white-tailed deer. The full extent of SARS-CoV-2 exposure among wildlife communities and the factors that influence wildlife transmission risk remain unknown. We sampled 23 species of wildlife for SARS-CoV-2 and examined the effects of urbanization and human use on seropositivity. Here, we document positive detections of SARS-CoV-2 RNA in six species, including the deer mouse, Virginia opossum, raccoon, groundhog, Eastern cottontail, and Eastern red bat between May 2022–September 2023 across Virginia and Washington, D.C., USA. In addition, we found that sites with high human activity had three times higher seroprevalence than low human-use areas. We obtained SARS-CoV-2 genomic sequences from nine individuals of six species which were assigned to seven Pango lineages of the Omicron variant. The close match to variants circulating in humans at the time suggests at least seven recent human-to-animal transmission events. Our data support that exposure to SARS-CoV-2 has been widespread in wildlife communities and suggests that areas with high human activity may serve as points of contact for cross-species transmission. The wildlife host range of SARS-CoV-2 is currently unknown. Here, the authors report evidence of infection in six common wild animal species (deer mouse, Virginia opossum, raccoon, groundhog, Eastern cottontail, Eastern red bat) out of 23 species tested in Virginia and Washington DC, USA in 2022/2023.