DNA damage occurs on exposure to genotoxic agents and during physiological DNA transactions. DNA double-strand breaks (DSBs) are particularly dangerous lesions that activate DNA damage response (DDR) ...kinases, leading to initiation of a canonical DDR (cDDR). This response includes activation of cell cycle checkpoints and engagement of pathways that repair the DNA DSBs to maintain genomic integrity. In adaptive immune cells, programmed DNA DSBs are generated at precise genomic locations during the assembly and diversification of lymphocyte antigen receptor genes. In innate immune cells, the production of genotoxic agents, such as reactive nitrogen molecules, in response to pathogens can also cause genomic DNA DSBs. These DSBs in adaptive and innate immune cells activate the cDDR. However, recent studies have demonstrated that they also activate non-canonical DDRs (ncDDRs) that regulate cell type-specific processes that are important for innate and adaptive immune responses. Here, we review these ncDDRs and discuss how they integrate with other signals during immune system development and function.
Mitochondrial membrane biogenesis and lipid metabolism require phospholipid transfer from the endoplasmic reticulum (ER) to mitochondria. Transfer is thought to occur at regions of close contact of ...these organelles and to be nonvesicular, but the mechanism is not known. Here we used a novel genetic screen in S. cerevisiae to identify mutants with defects in lipid exchange between the ER and mitochondria. We show that a strain missing multiple components of the conserved ER membrane protein complex (EMC) has decreased phosphatidylserine (PS) transfer from the ER to mitochondria. Mitochondria from this strain have significantly reduced levels of PS and its derivative phosphatidylethanolamine (PE). Cells lacking EMC proteins and the ER-mitochondria tethering complex called ERMES (the ER-mitochondria encounter structure) are inviable, suggesting that the EMC also functions as a tether. These defects are corrected by expression of an engineered ER-mitochondrial tethering protein that artificially tethers the ER to mitochondria. EMC mutants have a significant reduction in the amount of ER tethered to mitochondria even though ERMES remained intact in these mutants, suggesting that the EMC performs an additional tethering function to ERMES. We find that all Emc proteins interact with the mitochondrial translocase of the outer membrane (TOM) complex protein Tom5 and this interaction is important for PS transfer and cell growth, suggesting that the EMC forms a tether by associating with the TOM complex. Together, our findings support that the EMC tethers ER to mitochondria, which is required for phospholipid synthesis and cell growth.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Ocean acidification (OA), a consequence of anthropogenic carbon dioxide emissions, poses a serious threat to marine organisms in tropical, open-ocean, coastal, deep-sea, and high-latitude sea ...ecosystems. The diversity of taxonomic groups that precipitate calcium carbonate from seawater are at particularly high risk. Here we review the rapidly expanding literature concerning the biological and ecological impacts of OA on calcification, using a cross-scale, process-oriented approach. In comparison to calcification, we find that areas such as fertilization, early life-history stages, and interaction with synergistic stressors are understudied. Although understanding the long-term consequences of OA are critical, available studies are largely short-term experiments that do not allow for tests of long-term acclimatization or adaptation. Future research on the phenotypic plasticity of contemporary organisms and interpretations of performance in the context of current environmental heterogeneity of pCO
2
will greatly aid in our understanding of how organisms will respond to OA in the future.
•Evidence supports an association between PFOA and kidney and testicular cancer.•Consistent evidence for a link with cholesterol, but not with heart disease.•Suggestive evidence for a link between ...PFOA and ulcerative colitis.•A link with liver and immune function but little link for liver or infectious disease.•A possible link with low birthweight may be due to reverse causality or confounding.
The C8 Science Panel was composed of three epidemiologists charged with studying the possible health effects of PFOA in a highly exposed population in the mid-Ohio Valley. The Panel determined in 2012 there was a ‘probable link’ (i.e., more probable than not based on the weight of the available scientific evidence) between PFOA and high cholesterol, thyroid disease, kidney and testicular cancer, pregnancy-induced hypertension, and ulcerative colitis.
Here, former C8 Science Panel members and collaborators comment on the PFOA literature regarding thyroid disorders, cancer, immune and auto-immune disorders, liver disease, hypercholesterolemia, reproductive outcomes, neurotoxicity, and kidney disease. We also discuss developments regarding fate and transport, and pharmacokinetic models, and discuss causality assessment in cross-sectional associations among low-exposed populations.
For cancer, the epidemiologic evidence remains supportive but not definitive for kidney and testicular cancers. There is consistent evidence of a positive association between PFOA and cholesterol, but no evidence of an association with heart disease. There is evidence for an association with ulcerative colitis, but not for other auto-immune diseases. There is good evidence that PFOA is associated with immune response, but uneven evidence for an association with infectious disease. The evidence for an association between PFOA and thyroid and kidney disease is suggestive but uneven. There is evidence of an association with liver enzymes, but not with liver disease. There is little evidence of an association with neurotoxicity. Suggested reductions in birthweight may be due to reverse causality and/or confounding. Fate and transport models and pharmacokinetic models remain central to estimating past exposure for new cohorts, but are difficult to develop without good historical data on emissions of PFOA into the environment.
Overall, the epidemiologic evidence remains limited. For a few outcomes there has been some replication of our earlier findings. More longitudinal research is needed in large populations with large exposure contrasts. Additional cross-sectional studies of low exposed populations may be less informative.
This paper develops an approach for household appliance identification and classification of household activities of daily living (ADLs) using residential smart meter data. The process of household ...appliance identification, i.e., decomposing a mains electricity measurement into each of its constituent individual appliances, is a very challenging classification problem. Recent advances have made deep learning a dominant approach for classification in fields, such as image processing and speech recognition. This paper presents a deep learning approach based on multilayer, feedforward neural networks that can identify common household electrical appliances from a typical household smart meter measurement. The performance of this approach is tested and validated using publicly available smart meter data sets. The identified appliances are then mapped to household activities, or ADLs. The resulting ADL classifier can provide insights into the behavior of the household occupants, which has a number of applications in the energy domain and in other fields.
DNA double-strand breaks (DSBs) arise during physiological transcription, DNA replication, and antigen receptor diversification. Mistargeting or misprocessing of DSBs can result in pathological ...structural variation and mutation. Here we describe a sensitive method (END-seq) to monitor DNA end resection and DSBs genome-wide at base-pair resolution in vivo. We utilized END-seq to determine the frequency and spectrum of restriction-enzyme-, zinc-finger-nuclease-, and RAG-induced DSBs. Beyond sequence preference, chromatin features dictate the repertoire of these genome-modifying enzymes. END-seq can detect at least one DSB per cell among 10,000 cells not harboring DSBs, and we estimate that up to one out of 60 cells contains off-target RAG cleavage. In addition to site-specific cleavage, we detect DSBs distributed over extended regions during immunoglobulin class-switch recombination. Thus, END-seq provides a snapshot of DNA ends genome-wide, which can be utilized for understanding genome-editing specificities and the influence of chromatin on DSB pathway choice.
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•END-seq provides a high-resolution view of DNA breaks and end resection•END-seq detects at least one DSB among 10,000 cells not harboring DSBs•END-seq maps DSBs during antigen receptor rearrangements and genome editing•END-seq can be used to study DSB formation/repair in various tissues and organisms
Canela et al. develop a sensitive and quantitative method that provides a landscape of DNA double-strand breaks and end resection in vivo prior to DNA repair. This opens up the possibility for better understanding the causes and consequences of genome instability.
The performance of lead‐halide perovskite light‐emitting diodes (LEDs) has increased rapidly in recent years. However, most reports feature devices operated at relatively small current densities ...(<500 mA cm−2) with moderate radiance (<400 W sr−1 m−2). Here, Joule heating and inefficient thermal dissipation are shown to be major obstacles toward high radiance and long lifetime. Several thermal management strategies are proposed in this work, such as doping charge‐transport layers, optimizing device geometry, and attaching heat spreaders and sinks. Combining these strategies, high‐performance perovskite LEDs are demonstrated with maximum radiance of 2555 W sr−1 m−2, peak external quantum efficiency (EQE) of 17%, considerably reduced EQE roll‐off (EQE > 10% to current densities as high as 2000 mA cm−2), and tenfold increase in operational lifetime (when driven at 100 mA cm−2). Furthermore, with proper thermal management, a maximum current density of 2.5 kA cm−2 and an EQE of ≈1% at 1 kA cm−2 are shown using electrical pulses, which represents an important milestone toward electrically driven perovskite lasers.
Several thermal management strategies are proposed and applied to perovskite light‐emitting diodes (LEDs), resulting in greatly reduced efficiency roll‐off, record high radiance, and significantly improved operational lifetime. Furthermore, these thermal management strategies enable pulsed operation of perovskite LEDs in the kA cm‐2 range with much improved device performance, an important step toward electrically driven perovskite lasers.
In order to increase the power conversion efficiency of organic solar cells, their absorption spectrum should be broadened while maintaining efficient exciton harvesting. This requires the use of ...multiple complementary absorbers, usually incorporated in tandem cells or in cascaded exciton-dissociating heterojunctions. Here we present a simple three-layer architecture comprising two non-fullerene acceptors and a donor, in which an energy-relay cascade enables an efficient two-step exciton dissociation process. Excitons generated in the remote wide-bandgap acceptor are transferred by long-range Förster energy transfer to the smaller-bandgap acceptor, and subsequently dissociate at the donor interface. The photocurrent originates from all three complementary absorbing materials, resulting in a quantum efficiency above 75% between 400 and 720 nm. With an open-circuit voltage close to 1 V, this leads to a remarkable power conversion efficiency of 8.4%. These results confirm that multilayer cascade structures are a promising alternative to conventional donor-fullerene organic solar cells.
Next-generation displays and lighting technologies require efficient optical sources that combine brightness, color purity, stability, substrate flexibility. Metal halide perovskites have potential ...use in a wide range of applications, for they possess excellent charge transport, bandgap tunability and, in the most promising recent optical source materials, intense and efficient luminescence. This review links metal halide perovskites’ performance as efficient light emitters with their underlying materials electronic and photophysical attributes.
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