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Genomic instability resulting from defective DNA damage responses or repair causes several abnormalities, including progressive cerebellar ataxia, for which the molecular mechanisms are not well understood. Here, we report a new murine model of cerebellar ataxia resulting from concomitant inactivation of POLB and ATM. POLB is one of key enzymes for the repair of damaged or chemically modified bases, including methylated cytosine, but selective inactivation of Polb during neurogenesis affects only a subpopulation of cortical interneurons despite the accumulation of DNA damage throughout the brain. However, dual inactivation of Polb and Atm resulted in ataxia without significant neuropathological defects in the cerebellum. ATM is a protein kinase that responds to DNA strand breaks, and mutations in ATM are responsible for Ataxia Telangiectasia, which is characterized by progressive cerebellar ataxia. In the cerebella of mice deficient for both Polb and Atm, the most downregulated gene was Itpr1, likely because of misregulated DNA methylation cycle. ITPR1 is known to mediate calcium homeostasis, and ITPR1 mutations result in genetic diseases with cerebellar ataxia. Our data suggest that dysregulation of ITPR1 in the cerebellum could be one of contributing factors to progressive ataxia observed in human genomic instability syndromes. © The Author(s) 2020. Published by Oxford University Press on behalf of Nucleic Acids Research.BACKGROUND Over the past several decades, treatment of cancer in adolescents and young adults (AYAs) has evolved substantially, leading to steady improvements in estimated five-year survival at diagnosis. However, the impact on late mortality in this population is largely unexamined. We investigated temporal trends in mortality among five-year AYA cancer survivors. METHODS The Surveillance, Epidemiology, and End Results database was used to identify AYAs (age 15-39) diagnosed with cancer during 1975-2011 who survived ≥5 years beyond diagnosis. Survival months were accrued from five years post-diagnosis until death or end of 2016. GLXC-25878 supplier Cumulative mortality from all causes, the primary cancer, other cancers, and noncancer/nonexternal causes (i.e. excluding accidents, suicide, homicide) were estimated according to diagnosis era. RESULTS Among 282,969 five-year AYA cancer survivors, five-year mortality (i.e. from 5 through 10 years post-diagnosis) from all causes decreased from 8.3% (95% CI 8.0%-8.6%) among those diagnosed in 1975-1984 to 5.4% (95% CI 5.3%-5.6%) among those diagnosed in 2005-2011. This was largely explained by decreases in mortality from the primary cancer (6.8% to 4.2%) between these periods. However, for specific cancer types, including colorectal, bone, sarcomas, cervical/uterine, and bladder, cumulative mortality curves demonstrated little improvement in primary cancer-mortality over time. Some reduction in late mortality from noncancer/nonexternal causes was apparent for Hodgkin lymphoma, leukemia, kidney cancer, head and neck cancers, and trachea, lung, and bronchus cancers. CONCLUSION Over the past four decades, all-cause and cancer-specific mortality have decreased among five-year AYA cancer survivors overall, but several cancer types have not shared in these improvements. © The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please email [email protected] time series transcriptome analysis is a powerful tool to study development, evolution, aging, disease progression and cancer prognosis. We develop TimeMeter, a statistical method and tool to assess temporal gene expression similarity, and identify differentially progressing genes where one pattern is more temporally advanced than the other. We apply TimeMeter to several datasets, and show that TimeMeter is capable of characterizing complicated temporal gene expression associations. Interestingly, we find (i) the measurement of differential progression provides a novel feature in addition to pattern similarity that can characterize early developmental divergence between two species; (ii) genes exhibiting similar temporal patterns between human and mouse during neural differentiation are under strong negative (purifying) selection during evolution; (iii) analysis of genes with similar temporal patterns in mouse digit regeneration and axolotl blastema differentiation reveals common gene groups for appendage regeneration with potential implications in regenerative medicine. © The Author(s) 2020. Published by Oxford University Press on behalf of Nucleic Acids Research.We conducted a molecular survey of Rickettsia in fleas collected from opossums, road-killed and live-trapped in peridomestic and rural settings, state parks, and from pet cats and dogs in Georgia, United States during 1992-2014. The cat flea, Ctenocephalides felis (Bouché) was the predominant species collected from cats and among the archival specimens from opossums found in peridomestic settings. Polygenis gwyni (Fox) was more prevalent on opossums and a single cotton rat trapped in sylvatic settings. Trapped animals were infested infrequently with the squirrel flea, Orchopeas howardi (Baker) and C. felis. TaqMan assays targeting the BioB gene of Rickettsia felis and the OmpB gene of Rickettsia typhi were used to test 291 flea DNAs for Rickettsia. A subset of 53 C. felis collected from a cat in 2011 was tested in 18 pools which were all bioB TaqMan positive (34% minimum infection prevalence). Of 238 fleas tested individually, 140 (58.8%, 95% confidence interval [CI] 52.5-64.9%) DNAs were bioB positive. Detection of bioB was more prevalent in individual C. felis (91%) compared to P. gwyni (13.4%). Twenty-one (7.2%) were ompB TaqMan positive, including 18 C. felis (9.5%) and 3 P. gwyni (3.2%). Most of these fleas were also positive with bioB TaqMan; however, sequencing of gltA amplicons detected only DNA of Rickettsia asembonensis. Furthermore, only the R. asembonensis genotype was identified based on NlaIV restriction analysis of a larger ompB fragment. These findings contribute to understanding the diversity of Rickettsia associated with fleas in Georgia and emphasize the need for development of more specific molecular tools for detection and field research on rickettsial pathogens. © The Author(s) 2020. Published by Oxford University Press on behalf of Entomological Society of America.All rights reserved. For permissions, please e-mail [email protected].
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