Cysteine Dioxygenase Enzyme Activity and Gene Expression in the Dimorphic Pathogenic Fungus \u3ci\u3eHistoplasma capsulatum\u3c/i\u3e Is in both the Mold and Yeast Morphotypes and Exhibits Substantial Strain Variation

In the dimorphism (mold/yeast) Histoplasma capsulatum (Hc) literature are reports that yeast (the so-called pathogenic form) uniquely expresses a cysteine dioxygenase (CDO, approx. 10,500 dal) activity which the mold morphotype (the so-called saprophytic soil form) does not express (C.F., Kumar et al., Biochem 22, 762, 1983). This yeast-specific CDO activity is postulated to play a critical role in the mold-to-yeast shift. A number of years ago, our lab isolated the gene encoding the Hc cysteine dioxygenase (CDO1, Genbank accession AY804144) and noted significant expression in the mold morphotype of several Histoplasma strains and also determined that the predicted protein would be over double the 10,500 dal reported by Kumar et al. Our report demonstrates (in the class 1 Downs strain, the class 2 G271B strain and two Panamanian strains, 184AS and 186AS) that the CDO1 gene is expressed in both the mold and yeast morphotypes and both morphotypes show significant CDO activity. Furthermore, we show via a FLAG-tag analysis that the expressed protein is approximately 24.7 ± 2.4 kd, in agreement with the putative protein sequence (determined from cDNA sequence) which yields 23.8 kd and is consistent with most other eukaryotic CDO enzymes. Additionally, we demonstrate that intracellular cysteine levels are actually significantly higher in the mold form of the two Panamanian strains, 184AS and 186AS, equal in both mold and yeast in the class 1 Downs strain and significantly higher in yeast of the more pathogenic class 2 G217B strain

Use of historic metabolic biotransformation data as a means of anticipating metabolic sites using MetaPrint2D and Bioclipse.

BACKGROUND: Predicting metabolic sites is important in the drug discovery process to aid in rapid compound optimisation. No interactive tool exists and most of the useful tools are quite expensive. RESULTS: Here a fast and reliable method to analyse ligands and visualise potential metabolic sites is presented which is based on annotated metabolic data, described by circular fingerprints. The method is available via the graphical workbench Bioclipse, which is equipped with advanced features in cheminformatics. CONCLUSIONS: Due to the speed of predictions (less than 50 ms per molecule), scientists can get real time decision support when editing chemical structures. Bioclipse is a rich client, which means that all calculations are performed on the local computer and do not require network connection. Bioclipse and MetaPrint2D are free for all users, released under open source licenses, and available from http://www.bioclipse.net.RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are

Charger 1: A New Facility for Z-Pinch Research

Charger 1 is a multipurpose pulsed power laboratory located on Redstone Arsenal, with a focus on fusion propulsion relevant experiments involving testing z-pinch diodes, pulsed magnetic nozzle and other related physics experiments. UAH and its team of pulsed power researchers are investigating ways to increase and optimize fusion production from Charger 1. Currently the team has reached high-power testing. Due to the unique safety issues related to high power operations the UAH/MSFC team has slowed repair efforts to develop safety and operations protocols. The facility is expected to be operational by the time DZP 2017 convenes. Charger 1 began life as the Decade Module 2, an experimental prototype built to prove the Decade Quad pinch configuration. The system was donated to UAH by the Defense Threat Reduction Agency (DRTA) in 2012. For the past 5 years a UAH/MSFC/Boeing team has worked to refurbish, assemble and test the system. With completion of high power testing in summer 2017 Charger 1 will become operational for experimentation. Charger 1 utilizes a Marx Bank of 72 100-kV capacitors that are charged in parallel and discharged in series. The Marx output is compressed to a pulse width of approximately 200 ns via a pulse forming network of 32 coaxial stainless steel tubes using water as a dielectric. After pulse compression a set of SF6 switches are triggered, allowing the wave front to propagate through the output line to the load. Charger 1 is capable of storing 572-kJ of energy and time compressing discharge to less than 250 ns discharge time producing a discharge of about 1 TW of discharge with 1 MV and 1 MA peak voltage and current, respectively. This capability will be used to study energy yield scaling and physics from solid density target as applied to advanced propulsion research

Cytoplasmic chromatin triggers inflammation in senescence and cancer

Chromatin is traditionally viewed as a nuclear entity that regulates gene expression and silencing. However, we recently discovered the presence of cytoplasmic chromatin fragments that pinch off from intact nuclei of primary cells during senescence, a form of terminal cell-cycle arrest associated with pro-inflammatory responses. The functional significance of chromatin in the cytoplasm is unclear. Here we show that cytoplasmic chromatin activates the innate immunity cytosolic DNA-sensing cGAS-STING (cyclic GMP-AMP synthase linked to stimulator of interferon genes) pathway, leading both to short-term inflammation to restrain activated oncogenes and to chronic inflammation that associates with tissue destruction and cancer. The cytoplasmic chromatin-cGAS-STING pathway promotes the senescence-associated secretory phenotype in primary human cells and in mice. Mice deficient in STING show impaired immuno-surveillance of oncogenic RAS and reduced tissue inflammation upon ionizing radiation. Furthermore, this pathway is activated in cancer cells, and correlates with pro-inflammatory gene expression in human cancers. Overall, our findings indicate that genomic DNA serves as a reservoir to initiate a pro-inflammatory pathway in the cytoplasm in senescence and cancer. Targeting the cytoplasmic chromatin-mediated pathway may hold promise in treating inflammation-related disorders

Photoevaporation as a Truncation Mechanism for Circumplanetary Disks

We investigate the conditions under which the regular satellites of Jupiter and Saturn formed. The final stage of giant planet accretion is thought to occur slowly over a relatively long, 10 Myr, timescale. Gas accretion during this stage, through a completely or partially opened gap in the solar nebula, occurs slowly allowing for the condensation of ices, and incomplete differentiation, seen in the regular satellites of the giant planets. Furthermore, the dichotomy seen in the Jovian and Saturnian systems may be explained as this infall wanes or is completely shutoff as a result of gap opening or global depletion of gas in the solar nebula. We present one-dimensional simulations of circumplanetary disks that couple the viscous transport of material with the loss of mass at the disk outer edge by ultraviolet photoevaporation as well as the infall of material from the solar nebula. We find that the circumplanetary disks of these protoplanets are truncated, as a result of photoevaporation, at a range of values with the mean corresponding to $\approx$ 0.16 Hill radii. These truncation radii are broadly consistent with the current locations of the regular satellite systems of Jupiter and Saturn. We also find that photoevaporation can successfully act as a clearing mechanism for circumplanetary nebulae on the potentially short timescales, 100-10,000 yr, over which mass accretion from the solar nebula wanes as a result of gap opening. Such a rapid clearing of the circum-Jovian disk may be required to explain the survival of the Galilean satellites.Comment: 6 pages, 6 figures, accepted for publication in the Astronomical Journa

Cheminformatics Research at the Unilever Centre for Molecular Science Informatics Cambridge.

The Centre for Molecular Informatics, formerly Unilever Centre for Molecular Science Informatics (UCMSI), at the University of Cambridge is a world-leading driving force in the field of cheminformatics. Since its opening in 2000 more than 300 scientific articles have fundamentally changed the field of molecular informatics. The Centre has been a key player in promoting open chemical data and semantic access. Though mainly focussing on basic research, close collaborations with industrial partners ensured real world feedback and access to high quality molecular data. A variety of tools and standard protocols have been developed and are ubiquitous in the daily practice of cheminformatics. Here, we present a retrospective of cheminformatics research performed at the UCMSI, thereby highlighting historical and recent trends in the field as well as indicating future directions.J. E. F thanks the Medical Research Council for funding (Grant Number MR/K020919/1). Furthermore, the UCMSI acknowledges all funding sources for continuous support over the past 15 years.This is the final published version. It first appeared at http://onlinelibrary.wiley.com/doi/10.1002/minf.201400166/abstract