SLC19A1 transports immunoreactive cyclic dinucleotides.

The accumulation of DNA in the cytosol serves as a key immunostimulatory signal associated with infections, cancer and genomic damage1,2. Cytosolic DNA triggers immune responses by activating the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway3. The binding of DNA to cGAS activates its enzymatic activity, leading to the synthesis of a second messenger, cyclic guanosine monophosphate-adenosine monophosphate (2'3'-cGAMP)4-7. This cyclic dinucleotide (CDN) activates STING8, which in turn activates the transcription factors interferon regulatory factor 3 (IRF3) and nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB), promoting the transcription of genes encoding type I interferons and other cytokines and mediators that stimulate a broader immune response. Exogenous 2'3'-cGAMP produced by malignant cells9 and other CDNs, including those produced by bacteria10-12 and synthetic CDNs used in cancer immunotherapy13,14, must traverse the cell membrane to activate STING in target cells. How these charged CDNs pass through the lipid bilayer is unknown. Here we used a genome-wide CRISPR-interference screen to identify the reduced folate carrier SLC19A1, a folate-organic phosphate antiporter, as the major transporter of CDNs. Depleting SLC19A1 in human cells inhibits CDN uptake and functional responses, and overexpressing SLC19A1 increases both uptake and functional responses. In human cell lines and primary cells ex vivo, CDN uptake is inhibited by folates as well as two medications approved for treatment of inflammatory diseases, sulfasalazine and the antifolate methotrexate. The identification of SLC19A1 as the major transporter of CDNs into cells has implications for the immunotherapeutic treatment of cancer13, host responsiveness to CDN-producing pathogenic microorganisms11 and-potentially-for some inflammatory diseases

Synergistic effects of the invasive Chinese tallow (Triadica sebifera) and climate change on aquatic amphibian survival

Changes in climate and the introduction of invasive species are two major stressors to amphibians, although little is known about the interaction between these two factors with regard to impacts on amphibians. We focused our study on an invasive tree species, the Chinese tallow (Triadica sebifera), that annually sheds its leaves and produces leaf litter that is known to negatively impact aquatic amphibian survival. The purpose of our research was to determine whether the timing of leaf fall from Chinese tallow and the timing of amphibian breeding (determined by weather) influence survival of amphibian larvae. We simulated a range of winter weather scenarios, ranging from cold to warm, by altering the relative timing of when leaf litter and amphibian larvae were introduced into aquatic mesocosms. Our results indicate that amphibian larvae survival was greatly affected by the length of time Chinese tallow leaf litter decomposes in water prior to the introduction of the larvae. Larvae in treatments simulating warm winters (early amphibian breeding) were introduced to the mesocosms early in the aquatic decomposition process of the leaf litter and had significantly lower survival compared with cold winters (late amphibian breeding), likely due to significantly lower dissolved oxygen levels. Shifts to earlier breeding phenology, linked to warming climate, have already been observed in many amphibian taxa, and with most climate models predicting a significant warming trend over the next century, the trend toward earlier breeding should continue if not increase. Our results strongly suggest that a warming climate can interact with the effects of invasive plant species, in ways we have not previously considered, to reduce the survival of an already declining group of organisms

Molecular dissection of the domain architecture and catalytic activities of human PrimPol

PrimPol is a primase–polymerase involved in nuclear and mitochondrial DNA replication in eukaryotic cells. Although PrimPol is predicted to possess an archaeo-eukaryotic primase and a UL52-like zinc finger domain, the role of these domains has not been established. Here, we report that the proposed zinc finger domain of human PrimPol binds zinc ions and is essential for maintaining primase activity. Although apparently dispensable for its polymerase activity, the zinc finger also regulates the processivity and fidelity of PrimPol's extension activities. When the zinc finger is disrupted, PrimPol becomes more promutagenic, has an altered translesion synthesis spectrum and is capable of faithfully bypassing cyclobutane pyrimidine dimer photolesions. PrimPol's polymerase domain binds to both single- and double-stranded DNA, whilst the zinc finger domain binds only to single-stranded DNA. We additionally report that although PrimPol's primase activity is required to restore wild-type replication fork rates in irradiated PrimPol−/− cells, polymerase activity is sufficient to maintain regular replisome progression in unperturbed cells. Together, these findings provide the first analysis of the molecular architecture of PrimPol, describing the activities associated with, and interplay between, its functional domains and defining the requirement for its primase and polymerase activities during nuclear DNA replication

Hyperthermophilic Aquifex aeolicus initiates primer synthesis on a limited set of trinucleotides comprised of cytosines and guanines

The placement of the extreme thermophile Aquifex aeolicus in the bacterial phylogenetic tree has evoked much controversy. We investigated whether adaptations for growth at high temperatures would alter a key functional component of the replication machinery, specifically DnaG primase. Although the structure of bacterial primases is conserved, the trinucleotide initiation specificity for A. aeolicus was hypothesized to differ from other microbes as an adaptation to a geothermal milieu. To determine the full range of A. aeolicus primase activity, two oligonucleotides were designed that comprised all potential trinucleotide initiation sequences. One of the screening templates supported primer synthesis and the lengths of the resulting primers were used to predict possible initiation trinucleotides. Use of trinucleotide-specific templates demonstrated that the preferred initiation trinucleotide sequence for A. aeolicus primase was 5′-d(CCC)-3′. Two other sequences, 5′-d(GCC)-3′ and d(CGC)-3′, were also capable of supporting initiation, but to a much lesser degree. None of these trinucleotides were known to be recognition sequences used by other microbial primases. These results suggest that the initiation specificity of A. aeolicus primase may represent an adaptation to a thermophilic environment

Using the internet in middle schools: A model for success

Los Alamos National Laboratory (LANL) developed a model for school networking using Los Alamos Middle School as a testbed. The project was a collaborative effort between the school and the Laboratory. The school secured administrative funding for hardware and software; and LANL provided the network architecture, installation, consulting, and training. The model is characterized by a computer classroom linked with two GatorBoxes and a UNIX-based workstation server. Six additional computers have also been networked from a teacher learning center and the library. The model support infrastructure includes: local school system administrators/lead teachers, introductory and intermediate hands-on teacher learning, teacher incentives for involvement and use, opportunities for student training and use, and ongoing LANL consulting. Formative evaluation data reveals that students and teachers alike are finding the Internet to be a tool that crosses disciplines, allowing them to obtain more, timely information and to communicate with others more effectively and efficiently. A lead teacher`s enthusiastic comments indicate some of the value gained: ``We have just scratched the surface. Each day someone seems to find something new and interesting on the Internet. The possibilities seem endless.`

DC-electric-field-induced and low-frequency electromodulation second-harmonic generation spectroscopy of Si(001)-SiO2_2 interfaces

The mechanism of DC-Electric-Field-Induced Second-Harmonic (EFISH) generation at weakly nonlinear buried Si(001)-SiO$_2$ interfaces is studied experimentally in planar Si(001)-SiO$_2$-Cr MOS structures by optical second-harmonic generation (SHG) spectroscopy with a tunable Ti:sapphire femtosecond laser. The spectral dependence of the EFISH contribution near the direct two-photon $E_1$ transition of silicon is extracted. A systematic phenomenological model of the EFISH phenomenon, including a detailed description of the space charge region (SCR) at the semiconductor-dielectric interface in accumulation, depletion, and inversion regimes, has been developed. The influence of surface quantization effects, interface states, charge traps in the oxide layer, doping concentration and oxide thickness on nonlocal screening of the DC-electric field and on breaking of inversion symmetry in the SCR is considered. The model describes EFISH generation in the SCR using a Green function formalism which takes into account all retardation and absorption effects of the fundamental and second harmonic (SH) waves, optical interference between field-dependent and field-independent contributions to the SH field and multiple reflection interference in the SiO$_2$ layer. Good agreement between the phenomenological model and our recent and new EFISH spectroscopic results is demonstrated. Finally, low-frequency electromodulated EFISH is demonstrated as a useful differential spectroscopic technique for studies of the Si-SiO$_2$ interface in silicon-based MOS structures.Comment: 31 pages, 14 figures, 1 table, figures are also available at http://kali.ilc.msu.su/articles/50/efish.ht

Modulated Entanglement Evolution Via Correlated Noises

We study entanglement dynamics in the presence of correlated environmental noises. Specifically, we investigate the quantum entanglement dynamics of two spins in the presence of correlated classical white noises, deriving Markov master equation and obtaining explicit solutions for several interesting classes of initial states including Bell states and X form density matrices. We show how entanglement can be enhanced or reduced by the correlation between the two participating noises.Comment: 9 pages, 4 figures. To be published in Quantum Information Processing, special issue on Quantum Decoherence and Entanglemen

User-made immobilities: a transitions perspective

In this paper we aim to conceptualize the role of users in creating, expanding and stabilizing the automobility system. Drawing on transition studies we offer a typology of user roles including user-producers, user-legitimators, user-intermediaries, user-citizens and user-consumers, and explore it on the historical transition to the automobile regime in the USA. We find that users play an important role during the entire transition process, but some roles are more salient than others in particular phases. Another finding is that the success of the transition depends on the stabilization of the emerging regime that will trigger upscaling in terms of the numbers of adopters. The findings are used to reflect on potential crossovers between transitions and mobilities research