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

Science Librarian Internship as a Way to Get Started in EScience

The Science Bibliographers’ Group of Boston College first proposed the creation of a paid science librarian internship position in Summer 2008. Since then, the three interns hired over time have gained exposure to a wide variety of activities undertaken by science librarians, and, at the same time, have significantly furthered the Library’s understanding of, and participation in, eScience. In addition to important contributions in reference and collection development activities, intern contributions have included an environmental scan/best practices review of relevant eScience initiatives, design of an eScience brochure, development of a faculty survey to gauge interest in library data management, and a capstone presentation on eScience for all library staff. Building upon that work, the Science Bibliographers’ Group developed a Vision Statement and Action Plans for eScience. Our current intern is working closely with members of the group on the creation of a LibGuide focused on data management and, concurrently, develop-ment of curricular materials for data management workshops to be implemented during the 2011/12 academic year. Ideally, these increased efforts in eScience-related work will result in an enhanced profile for eScience on the Boston College campus, and, ultimately, creation of a new, eScience-focused position in the Boston College Libraries. An internship program can provide current knowledge and skills to educate and support a university research library through the early learning stage of developing an eSciences program, while simultaneously providing a valuable hands-on learning experience for a potential science librarian

Identification of furfural resistant strains of Saccharomyces cerevisiae and Saccharomyces paradoxus from a collection of environmental and industrial isolates

Background Fermentation of bioethanol using lignocellulosic biomass as a raw material provides a sustainable alternative to current biofuel production methods by utilising waste food streams as raw material. Before lignocellulose can be fermented it requires physical, chemical and enzymatic treatment in order to release monosaccharides, a process that causes the chemical transformation of glucose and xylose into the cyclic aldehydes furfural and hydroxyfurfural. These furan compounds are potent inhibitors of Saccharomyces fermentation, and consequently furfural tolerant strains of Saccharomyces are required for lignocellulosic fermentation. Results This study investigated yeast tolerance to furfural and hydroxyfurfural using a collection of 71 environmental and industrial isolates of the baker’s yeast Saccharomyces cerevisiae and its closest relative Saccharomyces paradoxus. The Saccharomyces strains were initially screened for growth on media containing 100 mM glucose and 1.5 mg ml-1 furfural. Five strains were identified that showed a significant tolerance to growth in the presence of furfural and these were then screened for growth and ethanol production in the presence of increasing amounts (0.1-4 mg ml-1) of furfural. Conclusions Of the five furfural tolerant strains S. cerevisiae NCYC 3451 displayed the greatest furfural resistance, and was able to grow in the presence of up to 3.0 mg ml-1 furfural. Furthermore, ethanol production in this strain did not appear to be inhibited by furfural, with the highest ethanol yield observed at 3.0 mg ml-1 furfural. Although furfural resistance was not found to be a trait specific to any one particular lineage or population, three of the strains were isolated from environments where they might be continually exposed to low levels of furfural through the on-going natural degradation of lignocelluloses, and would therefore develop elevated levels of resistance to these furan compounds. Thus these strains represent good candidates for future studies of genetic variation relevant to understanding and manipulating furfural resistance and in the development of tolerant ethanologenic yeast strains for use in bioethanol production from lignocellulose processing

A systematic review of process evaluations for psychosocial interventions designed to improve the wellbeing and quality of life of community-dwelling people with dementia and their carers

Background: Psychosocial interventions improve the wellbeing and quality of life of People Living with Dementia (PLWD) and their family carers; but due to their complexity it can be challenging to identify mechanisms of action. We reviewed process evaluations that have sought to elucidate how these interventions work, to inform their implementation. Method: We systematically reviewed process evaluations of studies evaluating psychosocial interventions for PLWD in their own home and/or their family carers. We rated study quality using the Mixed Methods Appraisal Tool (MMAT). We described, with reference to Medical Research Council (2015) process evaluation guidance, how implementation, mechanisms of impact and contextual factors were investigated; and describe commonalities in the mechanisms of action identified across studies. Results: 24 included studies evaluated the processes of 22 interventions. These studies collectively applied five frameworks; almost all frameworks’ advised evaluations were theory-based and used mixed-methods analyses, but only 5/24 evaluation designs were informed by the intervention theory and 8/24 used mixed methods. 8/24 evaluations considered contextual factors in their design, though 20/24 cited contextual factors in findings. Interventions were more successful where PLWD were motivated and aware of potential benefits, and when carers could support engagement and were themselves supported by the intervention. How the intervention aligned with participants’ current needs and stage of dementia were key influencing factors. Conclusion: Knowing how interventions can influence change for community-dwelling people with dementia and their family carers will improve translation of trial findings into practice. Robust, theory-driven process evaluations can enable this

Bombus impatiens, Including observations on its egg eclosion.

25 pages : illustrations (some color) ; 26 cm.This contribution results from an investigation of four commercially obtained colonies of Bombus (Pyrobombus) impatiens Cresson in an attempt to understand the functional anatomy and behavior of its immature stages. Eggs are described in detail, and their chorionic microstructure is contrasted with that of Bombus (Cullumanobombus) griseocollis (De Geer). They are deposited in groups consisting of a few to more than nine eggs into a single chamber. The study confirms that larvae pass through four instars. Although increasing in size dramatically from one instar to the next, larval anatomy and behavior change little during the first three instars. The last instar is the one that commences defecation and production of silk resulting in cocoon construction. In contrast to most bees, its larval activities result in substantial changes in size and shape of its brood chamber, whereas brood chambers of most bees are constructed by the female and modified little by the offspring. This study is a part of a series of investigations into the similarities and differences in the developmental biologies among corbiculate bees

CMBPol Mission Concept Study: Probing Inflation with CMB Polarization

We summarize the utility of precise cosmic microwave background (CMB) polarization measurements as probes of the physics of inflation. We focus on the prospects for using CMB measurements to differentiate various inflationary mechanisms. In particular, a detection of primordial B-mode polarization would demonstrate that inflation occurred at a very high energy scale, and that the inflaton traversed a super-Planckian distance in field space. We explain how such a detection or constraint would illuminate aspects of physics at the Planck scale. Moreover, CMB measurements can constrain the scale-dependence and non-Gaussianity of the primordial fluctuations and limit the possibility of a significant isocurvature contribution. Each such limit provides crucial information on the underlying inflationary dynamics. Finally, we quantify these considerations by presenting forecasts for the sensitivities of a future satellite experiment to the inflationary parameters.Comment: 107 pages, 14 figures, 17 tables; Inflation Working Group contribution to the CMBPol Mission Concept Study; v2: typos fixed and references adde

Risk factors for hospital morbidity and mortality after the Norwood procedure: A report from the Pediatric Heart Network Single Ventricle Reconstruction trial

ObjectivesWe sought to identify risk factors for mortality and morbidity during the Norwood hospitalization in newborn infants with hypoplastic left heart syndrome and other single right ventricle anomalies enrolled in the Single Ventricle Reconstruction trial.MethodsPotential predictors for outcome included patient- and procedure-related variables and center volume and surgeon volume. Outcome variables occurring during the Norwood procedure and before hospital discharge or stage II procedure included mortality, end-organ complications, length of ventilation, and hospital length of stay. Univariate and multivariable Cox regression analyses were performed with bootstrapping to estimate reliability for mortality.ResultsAnalysis included 549 subjects prospectively enrolled from 15 centers; 30-day and hospital mortality were 11.5% (63/549) and 16.0% (88/549), respectively. Independent risk factors for both 30-day and hospital mortality included lower birth weight, genetic abnormality, extracorporeal membrane oxygenation (ECMO) and open sternum on the day of the Norwood procedure. In addition, longer duration of deep hypothermic circulatory arrest was a risk factor for 30-day mortality. Shunt type at the end of the Norwood procedure was not a significant risk factor for 30-day or hospital mortality. Independent risk factors for postoperative renal failure (n = 46), sepsis (n = 93), increased length of ventilation, and hospital length of stay among survivors included genetic abnormality, lower center/surgeon volume, open sternum, and post-Norwood operations.ConclusionsInnate patient factors, ECMO, open sternum, and lower center/surgeon volume are important risk factors for postoperative mortality and/or morbidity during the Norwood hospitalization

Observing the Evolution of the Universe

How did the universe evolve? The fine angular scale (l>1000) temperature and polarization anisotropies in the CMB are a Rosetta stone for understanding the evolution of the universe. Through detailed measurements one may address everything from the physics of the birth of the universe to the history of star formation and the process by which galaxies formed. One may in addition track the evolution of the dark energy and discover the net neutrino mass. We are at the dawn of a new era in which hundreds of square degrees of sky can be mapped with arcminute resolution and sensitivities measured in microKelvin. Acquiring these data requires the use of special purpose telescopes such as the Atacama Cosmology Telescope (ACT), located in Chile, and the South Pole Telescope (SPT). These new telescopes are outfitted with a new generation of custom mm-wave kilo-pixel arrays. Additional instruments are in the planning stages.Comment: Science White Paper submitted to the US Astro2010 Decadal Survey. Full list of 177 author available at http://cmbpol.uchicago.ed

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead