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

Intense synchrotron radiation from a magnetically compressed relativistic electron layer

Using a simple model of a relativistic electron layer rotating in an axial magnetic field, energy gain by an increasing magnetic field and energy loss by synchrotron radiation were considered. For a typical example, initial conditions were approximately 8 MeV electron in approximately 14 kG magnetic field, at a layer radius of approximately 20 mm, and final conditions were approximately 4 MG magnetic field approximately 100 MeV electron layer energy at a layer radius of approximately 1.0 mm. In the final state, the intense 1-10 keV synchrotron radiation imposes an electron energy loss time constant of approximately 100 nanoseconds. In order to achieve these conditions in practice, the magnetic field must be compressed by an imploding conducting liner; preferably two flying rings in order to allow the synchrotron radiation to escape through the midplane. The synchrotron radiation loss rate imposes a lower limit to the liner implosion velocity required to achieve a given final electron energy (approximately 1 cm/$mu$sec in the above example). In addition, if the electron ring can be made sufficiently strong (field reversed), the synchrotron radiation would be a unique source of high intensity soft x-radiation. (auth

Concentrations of Homovanillic Acid and 5-Hydroxyindoleacetic Acid in Cerebrospinal Fluid from Human Infants in the Perinatal Period

To assess maturation of central serotonin and catecholamine pathways at birth, we measured lumbar CSF homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA), stable acid metabolites of dopamine and serotonin, using HPLC with electrochemical detection. CSFs from 57 neonates (38 premature and 19 at term) and 13 infants 1–6 months old were studied. HVA levels increased with maturity (p < 0.05; ANOVA), whereas, 5-HIAA levels were similar in all these subjects. HVA/5-HIAA ratios increased markedly from 1 ± 0.12 in the most premature neonates to 1.98 ± 0.17 in the older infants (p < 0.01; t test). There were no sex differences for these values.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/66233/1/j.1471-4159.1984.tb06109.x.pd

SODIUM-AIR ACCIDENT STUDY FOR A SODIUM COOLED REACTOR. Technical Memorandum No. 20

The design requirements of a containnment building for a sodium-cooled reactor have been investigated from the point of view of a hypothetical sodium - air reaction. In particular, this study was directed toward the containment building of the Enrico Fermi Atomic Power Plant. The hypothetical accident assumes a major leak in the sodium system with a concurrent or earlier failure of the ventilation and cooling systems which allows air to enter the areas around the sodium system which are normally maintained in an atmosphere inert insofar as sodium burning is concerned. The resulting sodium pool, equivalent in burning surface to the fraction of the cross sectional area of the containment buildings which is flooded, burns at a rate depending upon oxygen concentration and gas temperature in the containment building. A series of experiments were carried out to determine this burning rate and its mechanism. The resulting gas temperature and pressure due to the sodium-air incident were determined by solving a system of equations based on time dependent heat balances on the containment building and its contents. The assumed incident gives a maximum gas pressure of about 26 psig and a corresponding gas temperature of 1115 F. This pressure is well below the design pressure of 32 psig for the containment vessel. In addition to the study of the sodium-air reaction in the assumed incident, the theoretical maximum pressure and temperature for the constant volume adiabatic sodium-air reaction is also discussed. (auth

DEVELOPMENT OF PULSED NEUTRON APPLICATION TO POWER REACTOR START-UP PROCEDURES. First Quarterly Progress Report, April 1-June 30, 1962

Activities in a program to develop techniques in the use of pulsed neutron sources to measure shutdown parameters related to large thermal power reactors are reported. The experimental work centers around aspects of detecting neutrons in the presence of 10/sup 7/ r/hr gamma fields. The feasibility of U/ sup 235/ coated solid state detectors for use in these measurements is being studied. A theoretlcal investigation is also in progress on the effects of a multi-region assembly on the fundamental decay constant of injected bursts of neutrons. Other work is reported on the time-dependent neutron thermalization for bare multiplying media, particular attention is directed to the exponential time decay for pulsed bare multiplying homogeneous assemblies. Numerical expressions are given for the fundsmental eigenfunction and eigenvalue to the first and second order, respectively. An explicit analytical expression for the eigenfunction is included. (J.R.D.

Cyclic AMP in the plasma of chronic schizophrenics, before and after treatment

1. 1. Concentrations of cAMP in plasma were measured by a protein binding method in a selected group of 10 chronic schizophrenics before and after pimozide treatment. Subjects were hospitalized for a mean period of 23.7 years and had not received any physical treatment for 1-10 years. Ten age-matched volunteers from the hospital staff, served as controls. 2. 2. Before treatment, cAMP in the patient group was not significantly different from control values. After pimozide (8 mg/day for one month) there was a striking decrease of cAMP by far exceeding normal levels (p&lt;0.001). Clinical improvement was slight and extrapyramidal manifestions were moderate in most patients. 3. 3. The &quot;overshooting&quot; effect of pimozide on cAMP provides evidence of inadequate mechanisms of compensation in schizophrenia. © 1977

Analysis of the suspension system of the M47 tank by means of simulation techniques

http://deepblue.lib.umich.edu/bitstream/2027.42/7936/5/bad1843.0001.001.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/7936/4/bad1843.0001.001.tx