CTLA4 mediates antigen-specific apoptosis of human T cells

The regulation of T cell-mediated immune responses requires a balance between amplification and generation of effector function and subsequent selective termination by clonal deletion. Although apoptosis of previously activated T cells can be induced by signaling of the tumor necrosis factor receptor family, these molecules do not appear to regulate T-cell clonal deletion in an antigen-specific fashion. We demonstrate that cross-linking of the inducible T-cell surface molecule CTLA4 can mediate apoptosis of previously activated human T lymphocytes. This function appears to be antigen-restricted, since a concomitant signal T-cell receptor signal is required. Regulation of this pathway may provide a novel therapeutic strategy to delete antigen-specific activated T cells.     

Aggression and the psychic self

In this paper we explore the idea of aggression as a defence against threats to the psychological self. This aspect of the self allows reflection about people in psychological terms and develops, in the first three years of life, through appreciation of mental states in the other. When the object is unpredictable or hostile, recognition of this is painful to the child, and his reflective function will not be adequately established. The defences of aggression or avoidance will be invoked very frequently. In time, aggression may become an organising influence in the construction of the self; pathological destructiveness then takes the place of emotional relatedness and concern for the other. Psychoanalytic treatment no longer works primarily by addressing conflict. Instead, particularly through interpretations of transference and countertransference, the analyst recreates an intersubjective process which enhances the patient's reflective self, this time in the safety of a benign relationship.     

Investigation of the presynaptic effects of quinine and quinidine on the release and uptake of monoamines in rat brain tissue

Quinine and quinidine are reported to potentiate the behavioural effects of serotonergic agents and monoamine uptake inhibitors. We have therefore investigated the presynaptic actions of quinine and quinidine on monoamine uptake and release in rat brain tissue in vitro. Quinidine evoked the release of [3H]5-HT, [3H]noradrenaline and [3H]dopamine from pre-loaded rat brain slices in a concentration dependent manner with EC50 values of 175, 486 and 150 microM, respectively. Quinine induced [3H]monoamine release with similar potencies. Both quinine and quinidine also inhibited the active uptake of [3H]5-HT, [3H]noradrenaline and [3H]dopamine into rat brain synaptosomes with IC50 values in the range 0.13-12.4 microM. The potency of each drug to inhibit [3H]5-HT uptake was significantly higher than that for [3H]noradrenaline or [3H]dopamine. The relative potency of quinidine compared to quinine was more marked in the case of [3H]5-HT (58-fold) than for [3H]noradrenaline (3-fold) or [3H]dopamine (4-fold). The inhibition of [3H]5-HT uptake by quinine and quinidine was competitive in nature and corresponded with the potencies of these drugs to inhibit [3H]paroxetine binding. No correlation was observed between the potencies of quinine and quinidine to induce the release of [3H]monoamines and to inhibit their uptake, suggesting that these effects are mediated by two distinct mechanisms. We conclude that the presynaptic actions of quinine and quinidine on monoamine uptake and release may be implicated in their potentiation of the effects of serotonergic agents and uptake blockers.     

The safer choices project: methodological issues in school-based health promotion intervention research

Randomized trials of school-based health promotion programs present unique design and analytical issues not widely discussed in the research literature. This article describes the Safer Choices study--a school-based program for prevention of HIV, other sexually transmitted diseases, and pregnancy--to illustrate critical methodological issues involved in large-scale, school-based intervention trials, particularly those evaluating interventions with a school-wide focus. The issues presented are: 1) comparability of the intervention and control groups even when few units are randomized; 2) factors that affect the decision to use a cohort or cross-sectional design; and 3) appropriate analysis strategy when the unit of randomization and intervention is at the school level, but observations are at the student level.     

Feedback transformations on tori

Here we investigate the problem of transforming a nonlinear system on the torusT ⁿ by using global feedback and global changes of coordinates into an invariant system (i.e., a control system of whichf andg _i are (left and right) invariant vector fields whenT ² is considered as a Lie group). We provide a complete answer whenn=2 and give a sufficient condition and necessary conditions in the more general case.     

Discrete-Time Expectation Maximization Algorithms for Markov-Modulated Poisson Processes

In this paper, we consider parameter estimation Markov-modulated Poisson processes via robust filtering and smoothing techniques. Using the expectation maximization algorithm framework, our filters and smoothers can be applied to estimate the parameters of our model in either an online configuration or an offline configuration. Further, our estimator dynamics do not involve stochastic integrals and our new formulas, in terms of time integrals, are easily discretized, and are written in numerically stable forms in W. P. Malcolm, R. J. Elliott, and J. van der Hoek, “On the numerical stability of time-discretized state estimation via clark transformations,” presented at the IEEE Conf. Decision Control, Mauii, HI, Dec. 2003.      

Inventive Tool Use to Comprehend Big Code

Software developers often need to understand a large body of unfamiliar code with little or no documentation, no experts to consult, and little time to do it. A post appeared in January 2008 on Slashdot, a technology news Web site, asking for tools and techniques that could help. This article analyzes 301 often passionate and sometimes articulate responses to this query, including the themes and the associated tool recommendations. The most common suggestions were to use a code navigation tool, use a design recovery tool, use a debugger to step through the code, create a runtime trace, use problem-based learning, ask people for help, study the code from top down, and print out all the code. This analysis presents an intriguing snapshot of how software developers in industry go about comprehending big code.     

Using electric actuation and detection of oscillations in microcantilevers for pressure measurements

Response characteristics of a microcantilever, such as resonant frequency, amplitude, phase and quality factor, can be used for absolute pressure measurements in the range of 10⁻⁴ to 10³ Torr. To this end, it would be very convenient to have the resonance of the microcantilever actuated and detected electrostatically. Herein, we report the nonlinear dynamics of microcantilevers under varying pressure and different gases using the harmonic detection of resonance (HDR) technique [J. Gaillard, M.J. Skove, R. Ciocan, A.M. Rao, Electrical detection of oscillations in 340 microcantilevers and nanocantilevers, Rev. Sci. Instrum. 77 (2006) 073907]. The HDR technique exploits nonlinearities in the cantilever-counter electrode system to allow electrostatic actuation and detection of the responses of the microcantilever to the pressure and gas composition. In particular, the 2nd and 3rd harmonics of the measured charge on the cantilever are investigated. The microcantilever demonstrates a quality factor of 10,000 at 10⁻³ Torr, and a usable response in the range from 10⁻³ to 10³ Torr. The use of different harmonics can enable us to adjust the range of pressures over which the sensor has an efficacious response, enhancing its sensitivity to a particular environment. The experimental results are in reasonable agreement with theoretical calculations, despite the nonlinearities involved.     

Characterisation of flucloxacillin and 5-hydroxymethyl flucloxacillin haptenated HSA in vitro and in vivo

Flucloxacillin is a synthetic penicillin used in the treatment of Staphylococcal infections. Adverse reactions to the drug are believed to arise through covalent modification of proteins, with tissue damage occurring secondary to an immune reaction. Serum proteins have been shown by adduct-specific antibodies to be modified by flucloxacillin, but the nature and sites of modification have not been characterised. Here, in vitro studies on HSA have shown by MS that the modification of protein lysine residues occurs in a dose-, time- and site-dependent manner. Affinity, cation exchange and reversed phase chromatography prior to MS revealed in vivo modification of HSA with flucloxacillin in tolerant patients, with up to nine modified lysine residues being detected in each patient, and with modification of Lys190 and Lys212 being detected in 8/8 patients. It was also revealed for the first time that plasma proteins could be modified with the 5-hydroxymethyl metabolite of flucloxacillin, and that essentially the same Lys residues were targeted by both the parent drug and its metabolite. This study provides a detailed characterisation of sites of chemical modification of an endogenous target and reveals candidate peptides for T-cell and antibody assays of flucloxacillin hypersensitivity.