Versatility and nuances of the architecture of haematopoiesis - Implications for the nature of leukaemia

For many years there was a widely accepted picture of how a haematopoietic stem cell (HSC) gives rise to the multiple types of blood and immune cells. This described the general nature of stem and progenitor cells and the pathways of cell development. Recent years have seen many attempts to re-draw the map of haematopoiesis. These have become increasingly complex, and they often envisage multiples routes to some cell types. The ‘established’ view that self-renewal in haematopoiesis only occurs in HSCs has been challenged by the recognition of self-renewing HSC-derived progenitor cells that display at least some fate restriction. This evolution of how normal haematopoiesis is viewed has inevitable implications for understanding the origins, disease progression and classification of the leukaemias. In essence, some progenitor cells are now seen as possessing a larger repertoire of routes to end-fates than was previously thought. This leads one to ask whether leukaemia stem cells are equally or less versatile than their normal counterparts?     

Groupwise surface correspondence by optimization: representation and regularization

Groupwise optimization of correspondence across a set of unlabelled examples of shapes or images is a well-established technique that has been shown to produce quantitatively better models than other approaches. However, the computational cost of the optimization is high, leading to long convergence times. In this paper, we show how topologically non-trivial shapes can be mapped to regular grids, hence represented in terms of vector-valued functions defined on these grids (the shape image representation). This leads to an initial reduction in computational complexity. We also consider the question of regularization, and show that by borrowing ideas from image registration, it is possible to build a non-parametric, fluid regularizer for shapes, without losing the computational gain made by the use of shape images. We show that this non-parametric regularization leads to a further considerable gain, when compared to parametric regularization methods. Quantitative evaluation is performed on biological datasets, and shown to yield a substantial decrease in convergence time, with no loss of model quality.     

A stromal cell free culture system generates mouse pro‐T cells that can reconstitute T‐cell compartments in vivo

T‐cell lymphopenia following BM transplantation or diseases such as AIDS result in immunodeficiency. Novel approaches to ameliorate this situation are urgently required. Herein, we describe a novel stromal cell free culture system in which Lineage^?Sca1⁺c‐kit⁺ BM hematopoietic progenitors very efficiently differentiate into pro‐T cells. This culture system consists of plate‐bound Delta‐like 4 Notch ligand and the cytokines SCF and IL‐7. The pro‐T cells developing in these cultures express CD25, CD117, and partially CD44; express cytoplasmic CD3ε; and have their TCRβ locus partially D–J rearranged. They could be expanded for over 3 months and used to reconstitute the T‐cell compartments of sublethally irradiated T‐cell‐deficient CD3ε^?/? mice or lethally irradiated WT mice. Pro‐T cells generated in this system could partially correct the T‐cell lymphopenia of pre‐Tα^?/? mice. However, reconstituted CD3ε^?/? mice suffered from a wasting disease that was prevented by co‐injection of purified CD4⁺ CD25^high WT Treg cells. In a T‐cell‐sufficient or T‐lymphopenic setting, the development of disease was not observed. Thus, this in vitro culture system represents a powerful tool to generate large numbers of pro‐T cells for transplantation and possibly with clinical applications.     

Multiple myeloma and monoclonal IgA with anti-actin reactivity.

Serum containing a monoclonal IgA protein from a patient with multiple myeloma gave intense immunofluorescent staining of smooth muscle fibres and the striations of skeletal muscle, cardiac muscle and thymic myoid cells. It also gave a weaker reaction with hepatocytes in a 'polygonal' pattern, and with renal glomeruli in a diffuse pattern. In culture fibroblasts, the serum stained long, parallel cytoplasmic filaments. Specificity of the staining reactions for actin was established by their prevention on serum absorption with skeletal muscle actin, but not by skeletal muscle myosin, tropomyosin or troponin, and by the demonstration that eluates obtained by acid dissociation of the serum-actin precipitates gave the same staining reactions as the original serum. Localization of the anti-actin reactivity to the monoclonal IgA protein was established by the observation that the same staining reactions were obtained with a monospecific IgA conjugate, with the eluate derived from the gamma globulin band of a serumel ectrophoretic strip, and with a purified euglobulin (IgA) fraction; also, the eluates obtained by acid dissociation of the serum actin precipitates contained monoclonal IgA.     

Fluid intelligence loss linked to restricted regions of damage within frontal and parietal cortex

Tests of fluid intelligence predict success in a wide range of cognitive activities. Much uncertainty has surrounded brain lesions producing deficits in these tests, with standard group comparisons delivering no clear result. Based on findings from functional imaging, we propose that the uncertainty of lesion data may arise from the specificity and complexity of the relevant neural circuit. Fluid intelligence tests give a characteristic pattern of activity in posterolateral frontal, dorsomedial frontal, and midparietal cortex. To test the causal role of these regions, we examined fluid intelligence in 80 patients with focal cortical lesions. Damage to each of the proposed regions predicted fluid intelligence loss, whereas damage outside these regions was not predictive. The results suggest that coarse group comparisons (e.g., frontal vs. posterior) cannot show the neural underpinnings of fluid intelligence tests. Instead, deficits reflect the extent of damage to a restricted but complex brain circuit comprising specific regions within both frontal and posterior cortex.     

The B cell receptor, but not the pre-B cell receptor, mediates arrest of B cell differentiation

B cell development in organ cultures of fetal liver from mice at day 14 of gestation resembles in kinetics and cell numbers generated the one observed in vivo. This development in vitro can be blocked by an IL-7 receptor-specific monoclonal antibody. Monoclonal antibodies specific for the pre-B cell receptor, i. e. for VpreB, lambda5, or muH chains, do not perturb B cell development in these organ cultures up to and including the CD25+ small pre-BII cell stage. However, muH chain-specific antibodies inhibit the appearance of the subsequent surface IgM+ immature B cells. In organ cultures of muH chain allotype heterozygous (muHa x muHb)F1 fetal livers a dose-dependent inhibition by allotype-specific monoclonal antibodies of sIgM+ immature B cells expressing the corresponding, but not the other, allotype was observed. By combining cell sorting with limiting dilution analysis of lipopolysaccharide-reactive cells, the probable target cell of this muH chain-specific inhibition was identified as an IgM+, CD23-immature B cell. Hence, engagement of the pre-B cell receptor by specific antibodies does not influence B cell development, while engagement of the B cell receptor on immature B cells does.     

Contingency management voucher redemption as an indicator of delayed gratification

This prospective analysis tested whether frequency of voucher redemptions during a contingency management (CM) substance use intervention was significantly associated with participants' ongoing substance use. Homeless, substance-dependent men who have sex with men (N = 131) were randomized into either a “full” or “lite” voucher-based CM intervention. All participants earned vouchers for attendance and participation; participants in the CM-full condition also received vouchers for substance abstinence and enactment of prosocial and/or health-promoting behaviors. Multivariate longitudinal negative binomial regression analyses (n = 118) assessed the association between substance use during the intervention and frequency of voucher redemptions. Participants who used methamphetamine (IRR = 0.66; 95% CI = 0.44–0.99) and/or opiates (IRR = 0.60; 95% CI = 0.40–0.99) during the intervention exhibited less time between voucher redemptions than individuals who achieved abstinence from these substances. Voucher redemption logs can be cost-effective and unobtrusive tools for measuring study participants' tendency to delay gratification.     

An evaluation of the use of passive shimming to improve frontal sensitivity in fMRI

The presence of the head in an MRI scanner leads to inhomogeneities in the magnetic field. These cause the 'susceptibility artifacts' of image distortion and signal dropout. In this paper, we evaluate a technique called passive shimming, which has the potential to reduce field inhomogeneities and the resultant artifacts. A piece of a magnetically active material (pyrolytic graphite) is held on the roof of the participant's mouth by a plastic mouth mould. We evaluate the effects in several different ways. We show that the presence of a shim reduces field inhomogeneity across much of the brain. From field maps, we generate simulations of EPI image intensity and BOLD sensitivity. Both of these are mainly improved by the presence of shim, although there were small reductions in some regions. Measured EPI image intensity also mostly increased. Finally, we ran a reward-punishment task in our subjects, and found that the presence of a shim increased functional sensitivity in the orbitofrontal cortex. Using the BOLD sensitivity measure, we provide estimates of the improvement to be expected in functional studies for a range of neural structures. Passive shims are quick to make and reasonably comfortable to wear, and have substantial potential for researchers investigating inferior frontal brain regions using MRI.     

Intrathymic proliferation of perinatal mouse alpha beta and gamma delta T cell receptor-expressing mature T cells

Using three colour flow microfluorimetry to analyse simultaneously two cell surface molecules and DNA content, CD4 SP cells in the late foetal and early postnatal thymus were found to contain significant numbers of cells in the S and G2 + M phases of the cell cycle. In contrast to neonatal thymocytes, CD4 SP cells in the adult thymus were found to be non-cycling. Two other phenotypic properties, namely expression of J11d and larger cell size, also distinguish perinatal from adult CD4 SP cells. In the perinatal thymus of (B/6 x D2)F1 mice, CD4 SP thymocytes expressing either V beta 6 (Mls-reactive) or V beta 11 (I-E-reactive) TCR are deleted by negative selection yet cell cycle analysis showed that, coincident with deletion, they were cycling. Thus negative selection in the perinatal thymus was operating on a population of cycling cells. Finally, perinatal CD3+, gamma delta TCR-expressing DN thymocytes were also found to be cycling. Taken together, these results show that, prior to migration to peripheral lymphoid tissues, in the perinatal period there is intrathymic proliferation of developing gamma delta- and alpha beta-expressing T cells.