Missense mutations in the perforin (PRF1) gene as a cause of hereditary cancer predisposition

Perforin, a pore-forming toxin released from secretory granules of NK cells and CTLs, is essential for their cytotoxic activity against infected or cancerous target cells. Bi-allelic loss-of-function mutations in the perforin gene are invariably associated with a fatal immunoregulatory disorder, familial haemophagocytic lymphohistiocytosis type 2 (FHL2), in infants. More recently, it has also been recognized that partial loss of perforin function can cause disease in later life, including delayed onset FHL2 and haematological malignancies. Herein we report a family in which a wide range of systemic inflammatory and neoplastic manifestations have occurred across three generations. We found that disease was linked to two missense perforin gene mutations (encoding A91V, R410W) that cause protein misfolding and partial loss of activity. These cases link the partial loss of perforin function with some solid tumours that are known to be controlled by the immune system, as well as haematological cancers. Our findings also demonstrate that perforin gene mutations can contribute to hereditary cancer predisposition

Characterisation of the effects of salicylidene acylhydrazide compounds on type three secretion in Escherichia coli O157:H7

Recent work has highlighted a number of compounds that target bacterial virulence by affecting gene regulation. In this work, we show that small-molecule inhibitors affect the expression of the type III secretion system (T3SS) of <i>Escherichia coli</i> O157:H7 in liquid culture and when the bacteria are attached to bovine epithelial cells. The inhibition of T3SS expression resulted in a reduction in the capacity of the bacteria to form attaching and effacing lesions. Our results show a marked variation in the ability of four structurally-related compounds to inhibit the T3SS of a panel of isolates. Using transcriptomics, we provide a comprehensive analysis of the conserved- and inhibitor-specific transcriptional responses to the four compounds. These analyses of gene expression show that numerous virulence genes, located on horizontally-acquired DNA elements, are affected by the compounds but the number of genes significantly affected varied markedly between the compounds. Overall, we highlight the importance of assessing the effect of such "anti-virulence" agents on a range of isolates and discuss the possible mechanisms which may lead to the co-ordinate down-regulation of horizontally acquired virulence genes

Analytical Study of Certain Magnetohydrodynamic-alpha Models

In this paper we present an analytical study of a subgrid scale turbulence model of the three-dimensional magnetohydrodynamic (MHD) equations, inspired by the Navier-Stokes-alpha (also known as the viscous Camassa-Holm equations or the Lagrangian-averaged Navier-Stokes-alpha model). Specifically, we show the global well-posedness and regularity of solutions of a certain MHD-alpha model (which is a particular case of the Lagrangian averaged magnetohydrodynamic-alpha model without enhancing the dissipation for the magnetic field). We also introduce other subgrid scale turbulence models, inspired by the Leray-alpha and the modified Leray-alpha models of turbulence. Finally, we discuss the relation of the MHD-alpha model to the MHD equations by proving a convergence theorem, that is, as the length scale alpha tends to zero, a subsequence of solutions of the MHD-alpha equations converges to a certain solution (a Leray-Hopf solution) of the three-dimensional MHD equations.Comment: 26 pages, no figures, will appear in Journal of Math Physics; corrected typos, updated reference

Is there a highly magnetized neutron star in GX 301-2?

We present the results of an in-depth study of the long-period X-ray pulsar GX 301-2. Using archival data of INTEGRAL, RXTE ASM, and CGRO BATSE, we study the spectral and timing properties of the source. Comparison of our timing results with previously published work reveals a secular decay of the orbital period at a rate of \simeq -3.25 \times 10^{-5} d yr^{-1}, which is an order of magnitude faster than for other known systems. We argue that this is probably result either of the apsidal motion or of gravitational coupling of the matter lost by the optical companion with the neutron star, although current observations do not allow us to distinguish between those possibilities. We also propose a model to explain the observed long pulse period. We find that a very strong magnetic field B \sim 10^{14} G can explain the observed pulse period in the framework of existing models for torques affecting the neutron star. We show that the apparent contradiction with the magnetic field strength B_{CRSF} \sim 4 \times 10^{12} G derived from the observed cyclotron line position may be resolved if the line formation region resides in a tall accretion column of height \sim 2.5 - 3 R_{NS}. The color temperature measured from the spectrum suggests that such a column may indeed be present, and our estimates show that its height is sufficient to explain the observed cyclotron line position.Comment: 10 pages, 7 figures, accepted for publication in Astronomy and Astrophysics. Referee comments are implemented

'It seemed churlish not to': How living non-directed kidney donors construct their altruism

Our objective was to explore how prospective altruistic kidney donors construct their decision to donate. Using a qualitative design and biographical-narrative semistructured interviews, we aimed to produce text for analysis on two levels: the social implications for subjectivity and practice and a tentative psychodynamic explanation of the participants’ psychological investment in the discourses they used. A total of six prospective altruistic kidney donors were interviewed. A psychosocial approach to the analysis was taken. In-depth discourse analysis integrated Foucauldian with psychodiscursive approaches and psychodynamic theory was applied to sections of text in which participants seemed to have particular emotional investment. Analysis generated three major discursive themes: other-oriented, rational and self-oriented discourses. The desire to donate was experienced as compelling by participants. Participants used discourses to position themselves as concerned with the needs of the recipient, to resist questioning and criticism, and to manage difficult feelings around mortality. Participants tended to reject personal motivations for altruistic donation, positioning relatives’ disapproval as selfish and illogical. These results suggest that the term ‘altruistic’ for living non-directed organ donation constrains available discourses, severely limiting what can be said, felt, thought and done by donors, clinicians and the public. A more useful approach would acknowledge potential psychological motives and gains for the donor

Geometric Phases and Mielnik's Evolution Loops

The cyclic evolutions and associated geometric phases induced by time-independent Hamiltonians are studied for the case when the evolution operator becomes the identity (those processes are called {\it evolution loops}). We make a detailed treatment of systems having equally-spaced energy levels. Special emphasis is made on the potentials which have the same spectrum as the harmonic oscillator potential (the generalized oscillator potentials) and on their recently found coherent states.Comment: 11 pages, harvmac, 2 figures available upon request; CINVESTAV-FIS GFMR 11/9

Inclusive cross section and double helicity asymmetry for pi^0 production in p+p collisions at sqrt(s) = 62.4 GeV

The PHENIX experiment presents results from the RHIC 2006 run with polarized proton collisions at sqrt(s) = 62.4 GeV for inclusive pi^0 production at mid-rapidity. Unpolarized cross section results are measured for transverse momenta p_T = 0.5 to 7 GeV/c. Next-to-leading order perturbative quantum chromodynamics calculations are compared with the data, and while the calculations are consistent with the measurements, next-to-leading logarithmic corrections improve the agreement. Double helicity asymmetries A_LL are presented for p_T = 1 to 4 GeV/c and probe the higher range of Bjorken_x of the gluon (x_g) with better statistical precision than our previous measurements at sqrt(s)=200 GeV. These measurements are sensitive to the gluon polarization in the proton for 0.06 < x_g < 0.4.Comment: 387 authors from 63 institutions, 10 pages, 6 figures, 1 table. Submitted to Physical Review D. Plain text data tables for the points plotted in figures for this and previous PHENIX publications are (or will be) publicly available at http://www.phenix.bnl.gov/papers.htm

Upsilon (1S+2S+3S) production in d+Au and p+p collisions at sqrt(s_NN)=200 GeV and cold-nuclear matter effects

The three Upsilon states, Upsilon(1S+2S+3S), are measured in d+Au and p+p collisions at sqrt(s_NN)=200 GeV and rapidities 1.2<|y|<2.2 by the PHENIX experiment at the Relativistic Heavy-Ion Collider. Cross sections for the inclusive Upsilon(1S+2S+3S) production are obtained. The inclusive yields per binary collision for d+Au collisions relative to those in p+p collisions (R_dAu) are found to be 0.62 +/- 0.26 (stat) +/- 0.13 (syst) in the gold-going direction and 0.91 +/- 0.33 (stat) +/- 0.16 (syst) in the deuteron-going direction. The measured results are compared to a nuclear-shadowing model, EPS09 [JHEP 04, 065 (2009)], combined with a final-state breakup cross section, sigma_br, and compared to lower energy p+A results. We also compare the results to the PHENIX J/psi results [Phys. Rev. Lett. 107, 142301 (2011)]. The rapidity dependence of the observed Upsilon suppression is consistent with lower energy p+A measurements.Comment: 495 authors, 11 pages, 9 figures, 5 tables. Submitted to Phys. Rev. C. Plain text data tables for the points plotted in figures for this and previous PHENIX publications are (or will be) publicly available at http://www.phenix.bnl.gov/papers.htm

Fluorescence characterization of clinically-important bacteria

Healthcare-associated infections (HCAI/HAI) represent a substantial threat to patient health during hospitalization and incur billions of dollars additional cost for subsequent treatment. One promising method for the detection of bacterial contamination in a clinical setting before an HAI outbreak occurs is to exploit native fluorescence of cellular molecules for a hand-held, rapid-sweep surveillance instrument. Previous studies have shown fluorescence-based detection to be sensitive and effective for food-borne and environmental microorganisms, and even to be able to distinguish between cell types, but this powerful technique has not yet been deployed on the macroscale for the primary surveillance of contamination in healthcare facilities to prevent HAI. Here we report experimental data for the specification and design of such a fluorescence-based detection instrument. We have characterized the complete fluorescence response of eleven clinically-relevant bacteria by generating excitation-emission matrices (EEMs) over broad wavelength ranges. Furthermore, a number of surfaces and items of equipment commonly present on a ward, and potentially responsible for pathogen transfer, have been analyzed for potential issues of background fluorescence masking the signal from contaminant bacteria. These include bedside handrails, nurse call button, blood pressure cuff and ward computer keyboard, as well as disinfectant cleaning products and microfiber cloth. All examined bacterial strains exhibited a distinctive double-peak fluorescence feature associated with tryptophan with no other cellular fluorophore detected. Thus, this fluorescence survey found that an emission peak of 340nm, from an excitation source at 280nm, was the cellular fluorescence signal to target for detection of bacterial contamination. The majority of materials analysed offer a spectral window through which bacterial contamination could indeed be detected. A few instances were found of potential problems of background fluorescence masking that of bacteria, but in the case of the microfiber cleaning cloth, imaging techniques could morphologically distinguish between stray strands and bacterial contamination

Nonperturbative treatments of level shifts of excited states and high-order harmonic generation in strong fields

This is the published version, also available here: http://dx.doi.org/10.1364/JOSAB.7.000425.In this paper we accomplish three goals. First, we present new nonperturbative results of complex quasi-energies (shifts and widths) for several low-lying excited states of atomic H in strong fields, using the L2 non-Hermitian Floquet matrix technique. Second, we present a new nonperturbative L2 technique for the treatment of ac Stark shifts of arbitrary excited states. We found that all the Rydberg states in weak fields are upshifted and closely follow the quadratic field dependence described by the ponderomotive potential e2F2/4mω2. Large deviation from the ponderomotive shift and intricate level-shift behaviors, however, occur in strong fields. Finally, we present a classical nonperturbative treatment of the electronic motion in intense laser fields. We show that the spectral analysis of classical trajectories can provide detailed insights regarding the mechanisms responsible for the multiple-harmonic generation recently observed in high-intensity experiments