Asymmetric thymocyte death underlies the CD4:CD8 T-cell ratio in the adaptive immune system

It has long been recognized that the T-cell compartment has more CD4 helper than CD8 cytotoxic T cells, and this is most evident looking at T-cell development in the thymus. However, it remains unknown how thymocyte development so favors CD4 lineage development. To identify the basis of this asymmetry, we analyzed development of synchronized cohorts of thymocytes in vivo and estimated rates of thymocyte death and differentiation throughout development, inferring lineage-specific efficiencies of selection. Our analysis suggested that roughly equal numbers of cells of each lineage enter selection and found that, overall, a remarkable ∼75% of cells that start selection fail to complete the process. Importantly it revealed that class I-restricted thymocytes are specifically susceptible to apoptosis at the earliest stage of selection. The importance of differential apoptosis was confirmed by placing thymocytes under apoptotic stress, resulting in preferential death of class I-restricted thymocytes. Thus, asymmetric death during selection is the key determinant of the CD4:CD8 ratio in which T cells are generated by thymopoiesis

Drink wise, age well; reducing alcohol related harm among people over 50: a study protocol

Background: Evidence suggests that the use of alcohol among older adults (defined as those aged 50+) has increased in recent years, with people aged 55-64 now more likely to exceed the recommended weekly guidelines than any other age group. Methods/ design: This is a quasi-experimental study with a before-after design. A postal questionnaire will be sent to 76,000 people aged 50 and over registered with a general practice in five different 'demonstration' (intervention) and control areas in the UK. Multiple interventions will then be delivered in demonstration areas across the UK. At the end of the programme, a postal questionnaire will be sent to the same individuals who completed it pre-programme to establish if there has been a reduction in alcohol use, at-risk drinking and alcohol related problems. Qualitative interviews with clients and staff will explore how the interventions were experienced; how they may work to bring about change and to identify areas for practice improvements. Discussion: This study protocol describes a multi-level, multi-intervention prevention-to-treatment programme which aims to reduce alcohol-related harm in people aged 50 and over

Entropy-driven formation of the gyroid cubic phase

We show, by computer simulation, that tapered or pear-shaped particles, interacting through purely repulsive interactions, can freely self-assemble to form the three-dimensionally periodic, gyroid cubic phase. The Ia3d gyroid cubic phase is formed by these particles both on compression of an isotropic configuration and on expansion of a smectic A bilayer arrangement. For the latter case, it is possible identify the steps by which the topological transformation from non-intersecting planes to fully interpenetrating, periodic networks takes place</p

Evidence for polarised boron in Co-B and Fe-B alloys

By exploiting the tunability of synchrotron radiation in measurements of spin-resolved photoemission it has proved possible to obtain information on the polarisation of the valence electrons of Co-B and Fe-B amorphous magnetic alloys, Both the spin-integrated and spin-resolved energy distribution curves show a marked dependence on photon energy indicating that the p states of boron hybridise with the d states of the transition metals giving rise to mixed states in the binding energy range 1 to 5 eV, The observed polarisation and spin-resolved densities of states imply that in the above restricted energy range there is a net negative polarisation of the boron states

Kinetics and mechanism of the interconversion of inverse bicontinuous cubic mesophases

This paper describes time-resolved x-ray diffraction data monitoring the transformation of one inverse bicontinuous cubic mesophase into another, in a hydrated lipid system. The first section of the paper describes a mechanism for the transformation that conserves the topology of the bilayer, based on the work of Charvolin and Sadoc, Fogden and Hyde, and Benedicto and O'Brien in this area. We show a pictorial representation of this mechanism, in terms of both the water channels and the lipid bilayer. The second section describes the experimental results obtained. The system under investigation was 2:1 lauric acid: dilauroylphosphatidylcholine at a hydration of 50% water by weight. A pressure-jump was used to induce a phase transition from the gyroid (Q(II)(G)) to the diamond (Q(II)(D)) bicontinuous cubic mesophase, which was monitored by time-resolved x-ray diffraction. The lattice parameter of both mesophases was found to decrease slightly throughout the transformation, but at the stage where the Q(II)(D) phase first appeared, the ratio of lattice parameters of the two phases was found to be approximately constant for all pressure-jump experiments. The value is consistent with a topology-preserving mechanism. However, the polydomain nature of our sample prevents us from confirming that the specific pathway is that described in the first section of the paper. Our data also reveal signals from two different intermediate structures, one of which we have identified as the inverse hexagonal (H-II) mesophase. We suggest that it plays a role in the transfer of water during the transformation. The rate of the phase transition was found to increase with both temperature and pressure-jump amplitude, and its time scale varied from the order of seconds to minutes, depending on the conditions employed

Surface bubble nucleation phase space

Recent research has revealed several different techniques for nanoscopic gas nucleation on submerged surfaces, with findings seemingly in contradiction with each other. In response to this, we have systematically investigated the occurrence of surface nanobubbles on a hydrophobised silicon substrate for various different liquid temperatures and gas concentrations, which we controlled independently. We found that nanobubbles occupy a distinct region of this phase space, occurring for gas concentrations of approximately 100-110%. Below the nanobubble phase we did not detect any gaseous formations on the substrate, whereas micropancakes (micron wide, nanometer high gaseous domains) were found at higher temperatures and gas concentrations. We moreover find that supersaturation of dissolved gases is not a requirement for nucleation of bubbles.Comment: 4 pages, 4 figure

Models of self-peptide sampling by developing T cells identify candidate mechanisms of thymic selection

Conventional and regulatory T cells develop in the thymus where they are exposed to samples of self-peptide MHC (pMHC) ligands. This probabilistic process selects for cells within a range of responsiveness that allows the detection of foreign antigen without excessive responses to self. Regulatory T cells are thought to lie at the higher end of the spectrum of acceptable self-reactivity and play a crucial role in the control of autoimmunity and tolerance to innocuous antigens. While many studies have elucidated key elements influencing lineage commitment, we still lack a full understanding of how thymocytes integrate signals obtained by sampling self-peptides to make fate decisions. To address this problem, we apply stochastic models of signal integration by T cells to data from a study quantifying the development of the two lineages using controllable levels of agonist peptide in the thymus. We find two models are able to explain the observations; one in which T cells continually re-assess fate decisions on the basis of multiple summed proximal signals from TCR-pMHC interactions; and another in which TCR sensitivity is modulated over time, such that contact with the same pMHC ligand may lead to divergent outcomes at different stages of development. Neither model requires that T and T are differentially susceptible to deletion or that the two lineages need qualitatively different signals for development, as have been proposed. We find additional support for the variable-sensitivity model, which is able to explain apparently paradoxical observations regarding the effect of partial and strong agonists on T and T development

Knudsen gas provides nanobubble stability

We provide a model for the remarkable stability of surface nanobubbles to bulk dissolution. The key to the solution is that the gas in a nanobubble is of Knudsen type. This leads to the generation of a bulk liquid flow which effectively forces the diffusive gas to remain local. Our model predicts the presence of a vertical water jet immediately above a nanobubble, with an estimated speed of $\sim3.3\,\mathrm{m/s}$, in good agreement with our experimental atomic force microscopy measurement of $\sim2.7\,\mathrm{m/s}$. In addition, our model also predicts an upper bound for the size of nanobubbles, which is consistent with the available experimental data