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

Effect of the time to intervention on the outcome of thrombosed dialysis access grafts managed percutaneously

PURPOSEWe aimed to investigate the effect of the time interval from the clinical presentation of a thrombosed dialysis access graft to intervention on procedure success. MATERIALS AND METHODSRecords from two academic institutions for patients who underwent percutaneous thrombectomy of occluded surgical hemodialysis graft access sites in interventional radiology from 2006 to 2011 were reviewed retrospectively. The following data were recorded: gender, age, time and date of the initial request for a thrombectomy and the procedure, age of the surgical access, angiographic outcome, and clinical outcome (successful or unsuccessful postinterventional dialysis). Univariate and multivariate logistic regression were used to evaluate whether the time to intervention significantly affected the study endpoint. RESULTSIn total, 268 percutaneous thrombectomies were performed in 139 patients. Of these 224 (83.5%) were categorized as successful and 44 (16.4%) as unsuccessful. The time to intervention was 19.9±30.1 vs. 22±35 hours for successful and unsuccessful procedures, respectively. The difference between the two was not significant, and there were also no significant differences in covariate distributions between successful and unsuccessful outcomes. CONCLUSIONDuring the first 72 hours following clinical presentation of a thrombosed dialysis access graft, time to intervention may be considered independent of procedure outcome

Aerosol delivery of trail pheromone disrupts the foraging of the red imported fire ant, \u3ci\u3eSolenopsis invicta\u3c/i\u3e

BACKGROUND: The fire ant, Solenopsis invicta, is one of the most aggressive and invasive species in the world. The trail pheromone Z,E-α-farnesene (91% purity)was prepared, and disruption of worker trail orientation was tested using an ethanol based aerosol formulation presenting a single puff of this compound by airbrush and compressed air. Trail-following behavior was recorded by overhead webcam and ants digitized before and after presentation of the aerosol treatment at four rates (1.6, 16, 160 and 1600 ng cm−2). RESULTS: Ants preferred 110 ng cm−1 over 11, 1.1 and 0.11 ng cm−1 for trail following. Within seconds of presentation of 1600 ng cm−2, the highest dose tested, trail disruption was observed. Disruption was evident as reduced arrival success and reduction in the trail integrity statistic (r2), as well as increased deviation from the trail (deg). The distribution of walking track angles was also flattened. CONCLUSIONS: The feasibility of using aerosol for delivery of trail pheromone was demonstrated, but the need for high purity combined with the difficulty of commercial supply makes this technique impractical. However, the commercial production of Z,E-α-farnesene of high purity by industrial biotechnology or from (E)-nerolidol may be possible in future, which would facilitate further development of trail pheromone disruption of S. invicta

Non-Native Salmonids Affect Amphibian Occupancy at Multiple Spatial Scales

Aim The introduction of non-native species into aquatic environments has been linked with local extinctions and altered distributions of native species. We investigated the effect of non-native salmonids on the occupancy of two native amphibians, the long-toed salamander (Ambystoma macrodactylum) and Columbia spotted frog (Rana luteiventris), across three spatial scales: water bodies, small catchments and large catchments. Location Mountain lakes at ≥ 1500 m elevation were surveyed across the northern Rocky Mountains, USA. Methods We surveyed 2267 water bodies for amphibian occupancy (based on evidence of reproduction) and fish presence between 1986 and 2002 and modelled the probability of amphibian occupancy at each spatial scale in relation to habitat availability and quality and fish presence. Results After accounting for habitat features, we estimated that A. macrodactylum was 2.3 times more likely to breed in fishless water bodies than in water bodies with fish. Ambystoma macrodactylum also was more likely to occupy small catchments where none of the water bodies contained fish than in catchments where at least one water body contained fish. However, the probability of salamander occupancy in small catchments was also influenced by habitat availability (i.e. the number of water bodies within a catchment) and suitability of remaining fishless water bodies. We found no relationship between fish presence and salamander occupancy at the large-catchment scale, probably because of increased habitat availability. In contrast to A. macrodactylum, we found no relationship between fish presence and R. luteiventris occupancy at any scale. Main conclusions Our results suggest that the negative effects of non-native salmonids can extend beyond the boundaries of individual water bodies and increase A. macrodactylum extinction risk at landscape scales. We suspect that niche overlap between non-native fish and A. macrodactylum at higher elevations in the northern Rocky Mountains may lead to extinction in catchments with limited suitable habitat

New records of biting midges of the genus \u3ci\u3eCulicoides\u3c/i\u3e Latreille from the southeastern United States (Diptera: Ceratopogonidae)

We provide new state and county records of biting midges in the genus Culicoides Latreille (Diptera: Ceratopogonidae) from the southeastern United States collected with CDC miniature light traps during 2007–2012 in Florida, Georgia, Alabama, Mississippi, Louisiana, Arkansas, and Texas. The primary goals of the surveys were to identify the presence of exotic Culicoides, and determine the ranges of known and possible vectors of bluetongue virus (BTV) and epizootic hemorrhagic disease virus (EHDV). Included are the first records of: Culicoides (Amossovia) beckae Wirth and Blanton from Louisiana and Mississippi, C. (A.) oklahomensis Khalaf from Alabama and Arkansas, C. (Avaritia) alachua Jamnback and Wirth from Alabama, C. (Culicoides) neopulicaris Wirth from Alabama, C. (Drymodesmyia) butleri Wirth and Hubert from Texas, C. (Hoffmania) insignis Lutz from Mississippi, C. (Oecacta) barbosai Wirth and Blanton from Georgia, C. (Silvaticulicoides) loisae Jamnback from Alabama, and C. kirbyi Glick and Mullen from Mississippi. We also provide new Florida county records for C. alachua, C. barbosai, C. (Beltranmyia) hollensis (Melander and Brues), C. insignis, and C. (Monoculicoides) sonorensis Wirth and Jones; a new Georgia county record for C. alachua; and new Alabama county records for C. insignis, and C. sonorensis

Light-driven cycling of dimethylsulfide (DMS) in the Sargasso Sea : closing the loop

Author Posting. © American Geophysical Union, 2004. This article is posted here by permission of American Geophysical Union for personal use, not for redistribution. The definitive version was published in Geophysical Research Letters 31 (2004): L09308, doi:10.1029/2004GL019581.The factors driving dimethylsulfide (DMS) cycling in oligotrophic environments are isolated using a time-series of DMS sampled in the Sargasso Sea. The observed distribution of DMS is inconsistent with bottom-up processes related to phytoplankton production, biomass, or community structure changes. DMS concentrations and estimates of net biological community production are most highly correlated with physical and optical properties, with the dose of ultraviolet radiation (UVR) accounting for 77% of the variability in mixed layer DMS concentrations. Physiological stresses associated with shallow mixed layers and high UVR are the first order determinant of biological production of DMS, indicating that DMS cycling in open-ocean regions is fundamentally different than in eutrophic regions where phytoplankton blooms provide the conditions for elevated DMS concentrations. The stress regime presented here effectively closes the DMS-climate feedback loop for open-ocean environments. This response may also provide a climatic role for phytoplanktonic processes in response to anthropogenic forcing.This work was supported by a NASA Earth System Science Fellowship