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

Attributing scientific and technical progress: the case of holography

Holography, the three-dimensional imaging technology, was portrayed widely as a paradigm of progress during its decade of explosive expansion 1964–73, and during its subsequent consolidation for commercial and artistic uses up to the mid 1980s. An unusually seductive and prolific subject, holography successively spawned scientific insights, putative applications and new constituencies of practitioners and consumers. Waves of forecasts, associated with different sponsors and user communities, cast holography as a field on the verge of success—but with the dimensions of success repeatedly refashioned. This retargeting of the subject represented a degree of cynical marketeering, but was underpinned by implicit confidence in philosophical positivism and faith in technological progressivism. Each of its communities defined success in terms of expansion, and anticipated continual progressive increase. This paper discusses the contrasting definitions of progress in holography, and how they were fashioned in changing contexts. Focusing equally on reputed ‘failures’ of some aspects of the subject, it explores the varied attributes by which success and failure were linked with progress by different technical communities. This important case illuminates the peculiar post-World War II environment that melded the military, commercial and popular engagement with scientific and technological subjects, and the competing criteria by which they assessed the products of science

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

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

Death ideation in cancer patients: contributing factors

Advances in cancer research and therapy have improved prognosis and the quality of life of many patients. However, previous epidemiological studies in oncologic patients have shown an increased risk of suicide. Suicidal thoughts, relatively well known in those terminally ill, may be just as important for cancer patients who are survivors or are living with the disease. Nonetheless, there is a relative paucity of data about suicidality in this setting. The authors conducted a prospective observational study to identify death thoughts and to explore the factors associated with suicidal ideation in cancer patients. A sample of 130 patients referred for psychiatric consultation was obtained following informed consent and authorization from the local ethics committee. A semistructured interview assessed sociodemographic data, psychosocial support, and information regarding the cancer process and its treatment. Psychometric instruments were used to evaluate psychopathology, namely the Hospital Anxiety and Depression Scale, the Beck Hopelessness Scale, and the Beck Scale for Suicide Ideation. Psychiatric diagnoses were obtained through the application of the Mini International Neuropsychiatric Interview. Death ideation was identified in 34.6% of patients, yet only 10% had active suicidal thoughts. Risk of suicide was associated with female gender, a psychiatric diagnosis (major depressive disorder, panic disorder, or dysthymia), difficult interpersonal relationships, associated pain, high hopelessness, and depressive and anxiety symptoms. Although suicidal thoughts are frequent in cancer patients at different stages of disease, most are transitory. Risk factors for suicidal ideation have been identified, such as depression, hopelessness, uncontrolled pain, and difficult interpersonal relationships. Further assessment is necessary to identify those at higher risk of attempting suicide, and underlying psychiatric disorders should be vigorously treated

Estimated Ultraviolet Radiation Doses in Wetlands in Six National Parks

Ultraviolet-B radiation (UV-B, 280–320-nm wavelengths) doses were estimated for 1024 wetlands in six national parks: Acadia (Acadia), Glacier (Glacier), Great Smoky Mountains (Smoky), Olympic (Olympic), Rocky Mountain (Rocky), and Sequoia/ Kings Canyon (Sequoia). Estimates were made using ground-based UV-B data (Brewer spectrophotometers), solar radiation models, GIS tools, field characterization of vegetative features, and quantification of DOC concentration and spectral absorbance. UV-B dose estimates were made for the summer solstice, at a depth of 1 cm in each wetland. The mean dose across all wetlands and parks was 19.3 W-h m-2 (range of 3.4–32.1 W-h m-2). The mean dose was lowest in Acadia (13.7 W-h m-2) and highest in Rocky (24.4 W-h m-2). Doses were significantly different among all parks. These wetland doses correspond to UV-B flux of 125.0 µW cm-2 (range 21.4–194.7 µW cm)2) based on a day length, averaged among all parks, of 15.5 h. Dissolved organic carbon (DOC), a key determinant of water-column UV-B flux, ranged from 0.6 (analytical detection limit) to 36.7 mg C L-1 over all wetlands and parks, and reduced potential maximal UV-B doses at 1-cm depth by 1%–87 %. DOC concentration, as well as its effect on dose, was lowest in Sequoia and highest in Acadia (DOC was equivalent in Acadia, Glacier, and Rocky). Landscape reduction of potential maximal UV-B doses ranged from zero to 77% and was lowest in Sequoia. These regional differences in UV-B wetland dose illustrate the importance of considering all aspects of exposure in evaluating the potential impact of UV-B on aquatic organisms

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