Graphical Abstract Highlights d SIRT6 KO mice accumulate L1 cDNA, triggering interferon response via cGAS pathway d Wild-type aged mice accumulate L1 cDNA and display type I interferon response d Reverse-transcriptase inhibitors rescue type I interferon response and DNA damage d Reverse-transcriptase inhibitors extend lifespan and improve health of SIRT6 KO mice SUMMARYMice deficient for SIRT6 exhibit a severely shortened lifespan, growth retardation, and highly elevated LINE1 (L1) activity. Here we report that SIRT6-deficient cells and tissues accumulate abundant cytoplasmic L1 cDNA, which triggers strong type I interferon response via activation of cGAS.Remarkably, nucleoside reverse-transcriptase inhibitors (NRTIs), which inhibit L1 retrotransposition, significantly improved health and lifespan of SIRT6 knockout mice and completely rescued type I interferon response. In tissue culture, inhibition of L1 with siRNA or NRTIs abrogated type I interferon response, in addition to a significant reduction of DNA damage markers. These results indicate that L1 activation contributes to the pathologies of SIRT6 knockout mice. Similarly, L1 transcription, cytoplasmic cDNA copy number, and type I interferons were elevated in the wild-type aged mice. As sterile inflammation is a hallmark of aging, we propose that modulating L1 activity may be an important strategy for attenuating age-related pathologies. Context and SignificanceMammalian aging is complex and likely reflects accumulated damage to our genes/DNA. Retrotransposons are a special class of parasitic genetic elements that can replicate their DNA within our genes, at times amounting to up to 20% of human DNA. Retrotransposons, such as the commonly occurring L1, have been associated with aging, neurodegeneration, and cancer. University of Rochester scientists uncovered L1 retrotransposons as the culprit in many aspects of accelerated aging in mice, a model for human aging. They also linked these special gene elements to inflammation. Experimentally blocking retrotransposon amplification improved the health and lifespan of mice. Although there is a long road ahead, inhibiting retrotransposon activity, and the related inflammation, could eventually be a therapy for age-related diseases.

We suggest a new scheme of derivation of a non-linear ballistic σ-model for a long range disorder and quantum billiards. The derivation is based on writing equations for quasiclassical Green functions for a fixed long range potential and exact represention of their solutions in terms of functional integrals over supermatrices Q with the constraint Q 2 = 1. Averaging over the long range disorder or energy we are able to write a ballistic σ-model for all distances exceeding the electron wavelength (Eq. 3.13). Neither singling out slow modes nor a saddle-point approximation are used in the derivation. Carrying out a course graining procedure that allows us to get rid off scales in the Lapunov region we come to a reduced σ-model containing a conventional collision term. For quantum billiards, we demonstrate that, at not very low frequencies, one can reduce the σ-model to a one-dimensional σ-model on periodic orbits. Solving the latter model, first approximately and then exactly, we resolve the problem of repetitions.PACS: 05.45. Mt, 73.23.Ad

General and specific effects of molecular genetic responses to adverse environmental factors are not well understood. This study examines genome-wide gene expression profiles of Drosophila melanogaster in response to ionizing radiation, formaldehyde, toluene, and 2,3,7,8-tetrachlorodibenzo-p-dioxin. We performed RNA-seq analysis on 25,415 transcripts to measure the change in gene expression in males and females separately. An analysis of the genes unique to each treatment yielded a list of genes as a gene expression signature. In the case of radiation exposure, both sexes exhibited a reproducible increase in their expression of the transcription factors sugarbabe and tramtrack. The influence of dioxin up-regulated metabolic genes, such as anachronism, CG16727, and several genes with unknown function. Toluene activated a gene involved in the response to the toxins, Cyp12d1-p; the transcription factor Fer3’s gene; the metabolic genes CG2065, CG30427, and CG34447; and the genes Spn28Da and Spn3, which are responsible for reproduction and immunity. All significantly differentially expressed genes, including those shared among the stressors, can be divided into gene groups using Gene Ontology Biological Process identifiers. These gene groups are related to defense response, biological regulation, the cell cycle, metabolic process, and circadian rhythms. KEGG molecular pathway analysis revealed alteration of the Notch signaling pathway, TGF-beta signaling pathway, proteasome, basal transcription factors, nucleotide excision repair, Jak-STAT signaling pathway, circadian rhythm, Hippo signaling pathway, mTOR signaling pathway, ribosome, mismatch repair, RNA polymerase, mRNA surveillance pathway, Hedgehog signaling pathway, and DNA replication genes. Females and, to a lesser extent, males actively metabolize xenobiotics by the action of cytochrome P450 when under the influence of dioxin and toluene. Finally, in this work we obtained gene expression signatures pollutants (dioxin, toluene), low dose of gamma-irradiation and common molecular pathways for different kind of stressors.

We analysed the electron-hole or, in another words, branch imbalance (BI) and the related electric potential V imb which may arise in a mesoscopic superconductor/normal metal (S/N) structure under non-equilibrium conditions in the presence of a supercurrent. Non-equilibrium conditions can be created in different ways: a) a quasiparticle current flowing between the N reservoirs; b) a temperature gradient between the N reservoirs and no quasiparticle current. It is shown that the voltage V imb oscillates with the phase difference ϕ. In a cross-geometry structure the voltage V imb arises in the vertical branch and affects the conditions for a transition into the π−state.A few decades ago a great deal of interest was paid to the study of effects related to the so called branch imbalance (BI) (see Refs. [1,2] and for example the reviews [3,4]). The BI implies that populations of the electron-like and hole-like branches of the excitation spectrum in a superconductor or a normal metal are different. For example, the BI may arise in a superconductor near the S/N interface if a current flows through this interface and the temperature is close to T c . The conversion of the quasiparticle current j Q into the condensate current j S occurs over a rather long length λ Q called a BI relaxation length. Over this length populations of the electron-like and hole-like branches of the energy spectrum differ from each other. The difference between these populations is characterized by the distribution function f − = −(n ↑ − p ↓ ); the function n ↑ is the distribution function of the electron-like excitations and p ↓ (ǫ) = 1−n ↓ (−ǫ) is the distribution function of the hole-like excitations. In the considered case of a spin-independent interaction one has n ↑ = n ↓ and p ↑ = p ↓ . One can show that the function f − differs from zero if divj Q = 0. The non-zero distribution function f − leads to the appearance of an electric potential V imb in a superconductor (or in a normal metal) which can be expressed in terms of the function f − (see below). The BI may also arise in a bulk superconductor. For example, if longitudinal collective oscillations with a finite wave vector q are excited in the superconductor, the BI arises because in this case divj Q = iqj Q = 0 . When these modes are excited (they are weakly damped only near T c ), the quasiparticle current j Q oscillates in a counter phase with the condensate current j S , so that the total current remains equal to zero. These oscillations have been observed experimentally by Carlson and Goldman (Carlson-Goldman mode) [5] and have been explained theoretically in Refs. [6,7]. Another example of a system, in which the BI arises, is a uniform superconducting film in the presence of a temperature gradient ∇T and a condensate flow. It was established experimentally [8] and theoretically [9,10,11] that in this case the BI has a magnitude which is proportional to v s ∇T , where v s is the condensate velocity.Recently there has been growing interest in the study of transport properties of S/...