Functions of Phenylalanine Residues within the β-Barrel Stem of the Anthrax Toxin Pore

Background: A key step of anthrax toxin action involves the formation of a protein-translocating pore within the endosomal membrane by the Protective Antigen (PA) moiety. Formation of this transmembrane pore by PA involves interaction of the seven 2b2–2b3 loops of the heptameric precursor to generate a 14-strand transmembrane b barrel. Methodology/Principal Findings: We examined the effects on pore formation, protein translocation, and cytotoxicity, of mutating two phenylalanines, F313 and F314, that lie at the tip the b barrel, and a third one, F324, that lies part way up the barrel. Conclusions/Significance: Our results show that the function of these phenylalanine residues is to mediate membrane insertion and formation of stable transmembrane channels. Unlike F427, a key luminal residue in the cap of the pore, F313, F314, and F324 do not directly affect protein translocation through the pore. Our findings add to our knowledge of structure-function relationships of a key virulence factor of the anthrax bacillus

Coronal structure of the cTTS V2129 Oph

The nature of the magnetic coupling between T Tauri stars and their disks determines not only the mass accretion process but possibly the spin evolution of the central star. We have taken a recently-published surface magnetogram of one moderately-accreting T Tauri star (V2129 Oph) and used it to extrapolate the geometry of its large-scale field. We determine the structure of the open (wind-bearing) field lines, the closed (X-ray bright) field lines and those potentially accreting field lines that pass through the equatorial plane inside the Keplerian co-rotation radius. We consider a series of models in which the stellar magnetic field is opened up by the outward pressure of the hot coronal gas at a range of radii. As this radius is increased, accretion takes place along simpler field structures and impacts on fewer sites at the stellar surface. This is consistent with the observed variation in the Ca II IRT and HeI lines which suggests that accretion in the visible hemisphere is confined to a single high-latitude spot. By determining the density and velocity of the accretion flows, we find that in order to have most of the total mass accretion rate impacting on a single high-latitude region we need disk material to accrete from approximately 7R*, close to the Keplerian co-rotation radius at 6.8R*. We also calculate the coronal density and X-ray emission measure. We find that both the magnitude and rotational modulation of the emission measure increase as the source surface is increased. For the field structure of V2129 Oph which is dominantly octupolar, the emission forms a bright, high-latitude ring that is always in view as the star rotates. Since the accretion funnels are not dense enough to cause significant scattering of coronal X-ray photons, they provide only a low rotational modulation of around 10% at most.Comment: 10 pages, 9 figure

EVALUATING ARTIFICIAL INTELLIGENCE METHODS FOR USE IN KILL CHAIN FUNCTIONS

Current naval operations require sailors to make time-critical and high-stakes decisions based on uncertain situational knowledge in dynamic operational environments. Recent tragic events have resulted in unnecessary casualties, and they represent the decision complexity involved in naval operations and specifically highlight challenges within the OODA loop (Observe, Orient, Decide, and Assess). Kill chain decisions involving the use of weapon systems are a particularly stressing category within the OODA loop—with unexpected threats that are difficult to identify with certainty, shortened decision reaction times, and lethal consequences. An effective kill chain requires the proper setup and employment of shipboard sensors; the identification and classification of unknown contacts; the analysis of contact intentions based on kinematics and intelligence; an awareness of the environment; and decision analysis and resource selection. This project explored the use of automation and artificial intelligence (AI) to improve naval kill chain decisions. The team studied naval kill chain functions and developed specific evaluation criteria for each function for determining the efficacy of specific AI methods. The team identified and studied AI methods and applied the evaluation criteria to map specific AI methods to specific kill chain functions.Civilian, Department of the NavyCivilian, Department of the NavyCivilian, Department of the NavyCaptain, United States Marine CorpsCivilian, Department of the NavyCivilian, Department of the NavyApproved for public release. Distribution is unlimited

Elevated hypothalamic beacon gene expression in Psammomys obesus prone to develop obesity and type 2 diabetes

Objective: To investigate hypothalamic beacon gene expression at various developmental stages in genetically selected diabetes-resistant and diabetes-prone Psammomys obesus. In addition, effects of dietary energy composition on beacon gene expression were investigated in diabetes-prone P. obesus. Methods: Hypothalamic beacon gene expression was measured using Taqman&Ocirc; fluorogenic PCR in 4-, 8- and 16-week-old animals from each genetically selected line. Results: Expression of beacon was elevated in the diabetes-prone compared with diabetes-resistant P. obesus at 4 weeks of age despite no difference in body weight between the groups. At 8 weeks of age, hypothalamic beacon gene expression was elevated in diabetes-prone animals fed a high-energy diet, and was correlated with serum insulin concentration. Conclusion: P. obesus with a genetic predisposition for the development of obesity and type 2 diabetes have elevated hypothalamic beacon gene expression at an early age. Overexpression of beacon may contribute to the development of obesity and insulin resistance in these animals.<br /

Lunar Surface Electric Potential Changes Associated with Traversals through the Earth's Foreshock

We report an analysis of one year of Suprathermal Ion Detector Experiment (SIDE) Total Ion Detector (TID) resonance events observed between January 1972 and January 1973. The study includes only those events during which upstream solar wind conditions were readily available. The analysis shows that these events are associated with lunar traversals through the dawn flank of the terrestrial magnetospheric bow shock. We propose that the events result from an increase in lunar surface electric potential effected by secondary electron emission due to primary electrons in the Earth's foreshock region (although primary ions may play a role as well). This work establishes (1) the lunar surface potential changes as the Moon moves through the terrestrial bow shock, (2) the lunar surface achieves potentials in the upstream foreshock region that differ from those in the downstream magnetosheath region, (3) these differences can be explained by the presence of energetic electron beams in the upstream foreshock region and (4) if this explanation is correct, the location of the Moon with respect to the terrestrial bow shock influences lunar surface potential

Accounting students' IT applicaton skills over a 10-year period

This paper reports on the changing nature of a range of information technology (IT) application skills that students declare on entering an accounting degree over the period from 1996 to 2006. Accounting educators need to be aware of the IT skills students bring with them to university because of the implications this has for learning and teaching within the discipline and the importance of both general and specific IT skills within the practice and craft of accounting. Additionally, IT skills constitute a significant element within the portfolio of employability skills that are increasingly demanded by employers and emphasized within the overall Higher Education (HE) agenda. The analysis of students' reported IT application skills on entry to university, across a range of the most relevant areas of IT use in accounting, suggest that their skills have continued to improve over time. However, there are significant differential patterns of change through the years and within cohorts. The paper addresses the generalizability of these findings and discusses the implications of these factors for accounting educators, including the importance of recognising the differences that are potentially masked by the general increase in skills; the need for further research into the changing nature, and implications, of the gender gap in entrants' IT application skills; and the low levels of entrants' spreadsheet and database skills that are a cause for concern

Fathers Taking Leave Alone in the UK – A Gift Exchange Between Mother and Father?

Over the last decade there has been a gradual enhancement of British fathers’ rights in the workplace, even though the UK has one of the longest maternity leaves in OECD countries. From April 2003, for the first time, British fathers were given a legal right to take a 2 week paid paternity leave after the birth of a child, building on a 3 month unpaid parental leave entitlement available since 1999. In April 2011 a new right to allow fathers to take up to 6 months Additional Paternity Leave (APL) during the child’s first year, if the mother returns to work before the end of her maternity leave, was introduced. This chapter examines the experiences of six British fathers who were some of the first to take up this opportunity. The study as a whole explored couples’ negotiations and experiences of leave divisions, drawing on the proposition that intimacy is a mediating factor in gender and parenting roles. The accounts portray how, despite men’s lack of formal individual entitlement to leave, they tended to be positioned as the decision makers in taking leave. Women’s structural agency, as higher earners and as holders of the policy entitlement, was often underplayed. Drawing on Hochschild’s writings on the ‘gift economy’ of couples, we suggest that couple negotiations around APL can be conceptualised as a form of gift exchange

Diffusion of MMPs on the Surface of Collagen Fibrils: The Mobile Cell Surface – Collagen Substratum Interface

Remodeling of the extracellular matrix catalyzed by MMPs is central to morphogenetic phenomena during development and wound healing as well as in numerous pathologic conditions such as fibrosis and cancer. We have previously demonstrated that secreted MMP-2 is tethered to the cell surface and activated by MT1-MMP/TIMP-2-dependent mechanism. The resulting cell-surface collagenolytic complex (MT1-MMP)2/TIMP-2/MMP-2 can initiate (MT1-MMP) and complete (MMP-2) degradation of an underlying collagen fibril. The following question remained: What is the mechanism of substrate recognition involving the two structures of relatively restricted mobility, the cell surface enzymatic complex and a collagen fibril embedded in the ECM? Here we demonstrate that all the components of the complex are capable of processive movement on a surface of the collagen fibril. The mechanism of MT1-MMP movement is a biased diffusion with the bias component dependent on the proteolysis of its substrate, not adenosine triphosphate (ATP) hydrolysis. It is similar to that of the MMP-1 Brownian ratchet we described earlier. In addition, both MMP-2 and MMP-9 as well as their respective complexes with TIMP-1 and -2 are capable of Brownian diffusion on the surface of native collagen fibrils without noticeable dissociation while the dimerization of MMP-9 renders the enzyme immobile. Most instructive is the finding that the inactivation of the enzymatic activity of MT1-MMP has a detectable negative effect on the cell force developed in miniaturized 3D tissue constructs. We propose that the collagenolytic complex (MT1-MMP)2/TIMP-2/MMP-2 represents a Mobile Cell Surface – Collagen Substratum Interface. The biological implications of MT1-MMP acting as a molecular ratchet tethered to the cell surface in complex with MMP-2 suggest a new mechanism for the role of spatially regulated peri-cellular proteolysis in cell-matrix interactions

CD4 count at presentation for HIV care in the United States and Canada: Are those over 50 years more likely to have a delayed presentation?

We assessed CD4 count at initial presentation for HIV care among ≥50-year-olds from 1997-2007 in 13 US and Canadian clinical cohorts and compared to <50-year-olds. 44,491 HIV-infected individuals in the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD) were included in our study. Trends in mean CD4 count (measured as cells/mm3) and 95% confidence intervals ([,]) were determined using linear regression stratified by age category and adjusted for gender, race/ethnicity, HIV transmission risk and cohort. From 1997-2007, the proportion of individuals presenting for HIV care who were ≥50-years-old increased from 17% to 27% (p-value < 0.01). The median CD4 count among ≥50 year-olds was consistently lower than younger adults. The interaction of age group and calendar year was significant (p-value <0.01) with both age groups experiencing modest annual improvements over time (< 50-year-olds: 5 [4 , 6] cells/mm3; ≥50-year-olds: 7 [5 , 9] cells/mm3), after adjusting for sex, race/ethnicity, HIV transmission risk group and cohort; however, increases in the two groups were similar after 2000. A greater proportion of older individuals had an AIDS-defining diagnosis at, or within three months prior to, first presentation for HIV care compared to younger individuals (13% vs. 10%, respectively). Due to the increasing proportion, consistently lower CD4 counts, and more advanced HIV disease in adults ≥50-year-old at first presentation for HIV care, renewed HIV testing efforts are needed

Propagation of the Madden–Julian Oscillation and scale interaction with the diurnal cycle in a high-resolution GCM

The Madden–Julian Oscillation (MJO) is the chief source of tropical intra-seasonal variability, but is simulated poorly by most state-of-the-art GCMs. Common errors include a lack of eastward propagation at the correct frequency and zonal extent, and too small a ratio of eastward- to westward-propagating variability. Here it is shown that HiGEM, a high-resolution GCM, simulates a very realistic MJO with approximately the correct spatial and temporal scale. Many MJO studies in GCMs are limited to diagnostics which average over a latitude band around the equator, allowing an analysis of the MJO’s structure in time and longitude only. In this study a wider range of diagnostics is applied. It is argued that such an approach is necessary for a comprehensive analysis of a model’s MJO. The standard analysis of Wheeler and Hendon (Mon Wea Rev 132(8):1917–1932, 2004; WH04) is applied to produce composites, which show a realistic spatial structure in the MJO envelopes but for the timing of the peak precipitation in the inter-tropical convergence zone, which bifurcates the MJO signal. Further diagnostics are developed to analyse the MJO’s episodic nature and the “MJO inertia” (the tendency to remain in the same WH04 phase from one day to the next). HiGEM favours phases 2, 3, 6 and 7; has too much MJO inertia; and dies out too frequently in phase 3. Recent research has shown that a key feature of the MJO is its interaction with the diurnal cycle over the Maritime Continent. This interaction is present in HiGEM but is unrealistically weak