SIRT7 mediates L1 elements transcriptional repression and their association with the nuclear lamina

Long interspersed elements-1 (LINE-1, L1) are retrotransposons that hold the capacity of self-propagation in the genome with potential mutagenic outcomes. How somatic cells restrict L1 activity and how this process becomes dysfunctional during aging and in cancer cells is poorly understood. L1s are enriched at lamin-associated domains, heterochromatic regions of the nuclear periphery. Whether this association is necessary for their repression has been elusive. Here we show that the sirtuin family member SIRT7 participates in the epigenetic transcriptional repression of L1 genome-wide in both mouse and human cells. SIRT7 depletion leads to increased L1 expression and retrotransposition. Mechanistically, we identify a novel interplay between SIRT7 and Lamin A/C in L1 repression. Our results demonstrate that SIRT7-mediated H3K18 deacetylation regulates L1 expression and promotes L1 association with elements of the nuclear lamina. The failure of such activity might contribute to the observed genome instability and compromised viability in SIRT7 knockout mice. Overall, our results reveal a novel function of SIRT7 on chromatin organization by mediating the anchoring of L1 to the nuclear envelope, and a new functional link of the nuclear lamina with transcriptional repression

Tensile Creep and Creep-Recovery Behavior of a SiC-Fiber Si 3 N 4 -Matrix Composite

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/65802/1/j.1151-2916.1993.tb03753.x.pd

Cognitive ability across the life course and cortisol levels in older age

Elevated cortisol levels have been hypothesised to contribute to cognitive ageing, but study findings are inconsistent. In the present study, we examined the association between salivary cortisol in older age and cognitive ability across the life course. We used data from 370 members of the 36-Day Sample of the Scottish Mental Survey 1947, who underwent cognitive testing at age 11, and were then followed up at around age 78, completing further cognitive tests and providing diurnal salivary cortisol samples. We hypothesised that higher cortisol levels would be associated with lower cognitive ability in older age and greater cognitive decline from childhood to older age, but also lower childhood cognitive ability. Few of the tested associations were significant, and of those that were, most suggested a positive relationship between cortisol and cognitive ability. Only one cognitive measure showed any sign of cortisol-related impairment. However, after correcting for multiple comparisons, no results remained significant. These findings suggest that cortisol may not play an important role in cognitive ageing across the life course

The older people, omega-3, and cognitive health (EPOCH) trial design and methodology: A randomised, double-blind, controlled trial investigating the effect of long-chain omega-3 fatty acids on cognitive ageing and wellbeing in cognitively healthy older adults

Extent: 18p.Background: Some studies have suggested an association between omega-3 long-chain polyunsaturated fatty acids (n-3 LC PUFAs) and better cognitive outcomes in older adults. To date, only two randomised, controlled trials have assessed the effect of n-3 LC PUFA supplementation on cognitive function in older cognitively healthy populations. Of these trials only one found a benefit, in the subgroup carrying the ApoE-ε4 allele. The benefits of n-3 LC PUFA supplementation on cognitive function in older normal populations thus still remain unclear. The main objective of the current study was to provide a comprehensive assessment of the potential of n-3 LC PUFAs to slow cognitive decline in normal elderly people, and included ApoE-ε4 allele carriage as a potential moderating factor. The detailed methodology of the trial is reported herein. Methods: The study was a parallel, 18-month, randomised, double-blind, placebo-controlled intervention with assessment at baseline and repeated 6-monthly. Participants (N = 391, 53.7% female) aged 65-90 years, English-speaking and with normal cognitive function, were recruited from metropolitan Adelaide, South Australia. Participants in the intervention arm received capsules containing fish-oil at a daily dosage of 1720 mg of docosahexaenoic acid and 600 mg of eicosapentaenoic acid while the placebo arm received the equivalent amount of olive oil in their capsules. The primary outcome is rate of change in cognitive performance, as measured by latent variables for the cognitive constructs (encompassing Reasoning, Working Memory, Short-term Memory, Retrieval Fluency, Inhibition, Simple and Choice-Reaction Time, Perceptual Speed, Odd-man-out Reaction Time, Speed of Memory Scanning, and Psychomotor Speed) and assessed by latent growth curve modeling. Secondary outcomes are change in the Mini-mental State Examination, functional capacity and well-being (including health status, depression, mood, and self-report cognitive functioning), blood pressure, and biomarkers of n-3 LC PUFA status, glucose, lipid metabolism, inflammation, oxidative stress, and DNA damage.Vanessa Danthiir, Nicholas R Burns, Ted Nettelbeck, Carlene Wilson and Gary Witter

Implications of EMG channel count: enhancing pattern recognition online prosthetic testing

IntroductionMyoelectric pattern recognition systems have shown promising control of upper limb powered prostheses and are now commercially available. These pattern recognition systems typically record from up to 8 muscle sites, whereas other control systems use two-site control. While previous offline studies have shown 8 or fewer sites to be optimal, real-time control was not evaluated.MethodsSix individuals with no limb absence and four individuals with a transradial amputation controlled a virtual upper limb prosthesis using pattern recognition control with 8 and 16 channels of EMG. Additionally, two of the individuals with a transradial amputation performed the Assessment for Capacity of Myoelectric Control (ACMC) with a multi-articulating hand and wrist prosthesis with the same channel count conditions.ResultsUsers had significant improvements in control when using 16 compared to 8 EMG channels including decreased classification error (p = 0.006), decreased completion time (p = 0.019), and increased path efficiency (p = 0.013) when controlling a virtual prosthesis. ACMC scores increased by more than three times the minimal detectable change from the 8 to the 16-channel condition.DiscussionThe results of this study indicate that increasing EMG channel count beyond the clinical standard of 8 channels can benefit myoelectric pattern recognition users

Influenza D virus diverges from its related influenza C virus in the recognition of 9-O-acetylated N-acetyl- or N-glycolyl-neuraminic acid-containing glycan receptors.

Influenza D virus (IDV) utilizes bovines as a primary reservoir with periodical spillover to other mammalian hosts. By using traditional hemagglutination assay coupled with sialoglycan microarray (SGM) platform and functional assays, we demonstrated that IDV is more efficient in recognizing both 9-O-acetylated N-acetylneuraminic acid (Neu5,9Ac2) and 9-O-acetylated N-glycolylneuraminic acid (Neu5Gc9Ac) than influenza C virus (ICV), a ubiquitous human pathogen. ICV seems to strongly prefer Neu5,9Ac2 over Neu5Gc9Ac. Since Neu5Gc9Ac is different from Neu5,9Ac2 only by an additional oxygen in the group at the C5 position, our results reveal that the hydroxyl group in Neu5Gc9Ac plays a critical role in determining receptor binding specificity, which as a result may discriminate IDV from ICV in communicating with 9-O-acetylated SAs. These findings shall provide a framework for further investigation towards better understanding of how newly discovered multiple-species-infecting IDV exploits natural 9-O-acetylated SA variations to expand its host range

Insertion of a chimeric retrotransposon sequence in mouse Axin1 locus causes metastable kinky tail phenotype

Transposable elements (TEs) make up >50% of the human genome, and the majority of retrotransposon insertions are truncated and many are located in introns. However, the effects of retrotransposition on the host genes remain incompletely known.ResultsWe report here that insertion of a chimeric L1 (cL1), but not IAP solo LTR, into intron 6 of Axin1 using CRIPSR/Cas9 induced the kinky tail phenotype with similar to 80% penetrance in heterozygous Axin(cL1) mice. Both penetrant (with kinky tails) and silent (without kinky tails) Axin(cL1) mice, regardless of sex, could transmit the phenotype to subsequent generations with similar penetrance (similar to 80%). Further analyses revealed that a longer Axin1 transcript isoform containing partial cL1-targeted intron was present in penetrant, but absent in silent and wild type mice, and the production of this unique Axin1 transcript appeared to correlate with altered levels of an activating histone modification, H3K9ac.ConclusionsThe mechanism for Axin(cL1) mice is different from those previously identified in mice with spontaneous retrotransposition of IAP, e.g., Axin(Fu) and A(vy), both of which have been associated with DNA methylation changes. Our data suggest that Axin1 locus is sensitive to genetic and epigenetic alteration by retrotransposons and thus, ideally suited for studying the effects of new retrotransposition events on target gene function in mice

Intact piRNA pathway prevents L1 mobilization in male meiosis

The PIWI-interacting RNA (piRNA) pathway is essential for retrotransposon silencing. In piRNA-deficient mice, L1-overexpressing male germ cells exhibit excessive DNA damage and meiotic defects. It remains unknown whether L1 expression simply highlights piRNA deficiency or actually drives the germ-cell demise. Specifically, the sheer abundance of genomic L1 copies prevents reliable quantification of new insertions. Here, we developed a codon-optimized L1 transgene that is controlled by an endogenous mouse L1 promoter. Importantly, DNA methylation dynamics of a single-copy transgene were indistinguishable from those of endogenous L1s. Analysis of Mov10l1-/- testes established that de novo methylation of the L1 transgene required the intact piRNA pathway. Consistent with loss of DNA methylation and programmed reduction of H3K9me2 at meiotic onset, the transgene showed 1,400-fold increase in RNA expression and consequently 70-fold increase in retrotransposition in postnatal day 14 Mov10l1-/- germ cells compared with the wild-type. Analysis of adult Mov10l1-/- germ-cell fractions indicated a stage-specific increase of retrotransposition in the early meiotic prophase. However, extrapolation of the transgene data to endogenous L1s suggests that it is unlikely insertional mutagenesis alone accounts for the Mov10l1-/- phenotype. Indeed, pharmacological inhibition of reverse transcription did not rescue the meiotic defect. Cumulatively, these results establish the occurrence of productive L1 mobilization in the absence of an intact piRNA pathway but leave open the possibility of processes preceding L1 integration in triggering meiotic checkpoints and germ-cell death. Additionally, our data suggest that many heritable L1 insertions originate from individuals with partially compromised piRNA defense