Constitutive mutants of the GM-CSF receptor reveal multiple pathways leading to myeloid cell survival, proliferation, and granulocyte-macrophage differentiation

Activation of the granulocyte-macrophage colony-stimulating factor (GM-CSF) family of receptors promotes the survival, proliferation, and differentiation of cells of the myeloid compartment. Several signaling pathways are activated downstream of the receptor, however it is not clear how these induce specific biologic outcomes. We have previously identified 2 classes of constitutively active mutants of the shared signaling subunit, human (h) betac, of the human GM-CSF/interieukin-3 (IL-3)/IL-5 receptors that exhibit different modes of signaling. In a factor-dependent bipotential myeloid cell line, FDB1, an activated mutant containing a substitution in the transmembrane domain (V449E) induces factor-independent proliferation and survival, while mutants in the extracellular domain induce factor-independent granulocyte-macrophage differentiation. Here we have used further mutational analysis to demonstrate that there are nonredundant functions for several regions of the cytoplasmic domain with regard to mediating proliferation, viability, and differentiation, which have not been revealed by previous studies with the wild-type GM-CSF receptor. This unique lack of redundancy has revealed an association of a conserved membrane-proximal region with viability signaling and a critical but distinct role for tyrosine 577 in the activities of each class of mutant.

Emulsion strategies in the microencapsulation of cells: Pathways to thin coherent membranes

Microencapsulation of cell spheroids in an immunoselective, highly biocompatible, biomembrane offers a way to create viable implantation options in the treatment of insulin-dependent diabetes mellitus (IDDM). Traditionally the encapsulation process has been achieved through the injection/extrusion of alginate/cell mixtures into a calcium chloride solution to produce calcium alginate capsules around the cells. A novel alternative is explored here through a procedure using an emulsion process to produce thin adherent calcium alginate membranes around cell spheroids. In this study, a thorough investigation has been used to establish the emulsion process parameters that are critical to the formation of a coherent alginate coat both on a model spheroid system and subsequently on cell spheroids. Optical and fluorescence microscopy are used to assess the morphology and coherence of the calcium alginate/ poly-L-ornithine/alginate (APA) capsules produced. (c) 2005 Wiley Periodicals, Inc.

Genetics and genomics of osteoclast differentiation: Integrating cell signaling pathways and gene networks

The regulation of osteoclast differentiation in the bone microenvironment is critical for normal bone remodeling, as well as for various human bone diseases. Over the last decade, our knowledge of how osteoclast differentiation occurs has progressed rapidly. We highlight some of the major advances in understanding how cell signaling and transcription are integrated to direct the differentiation of this cell type. These studies used genetic, molecular, and biochemical approaches. Additionally, we summarize data obtained from studies of osteoclast differentiation that used the functional genomic approach of global gene profiling applied to osteoclast differentiation. This genomic data confirms results from studies using the classical experimental approaches and also may suggest new modes by which osteoclast differentiation and function can be modulated. Two conclusions that emerge are that osteoclast differentiation depends on a combination of fairly ubiquitously expressed transcription factors rather than unique osteoclast factors, and that the overlay of cell signaling pathways on this set of transcription factors provides a powerful mechanism to fine tune the differentiation program in response to the local bone microenvironment.

Excitability changes in human forearm corticospinal projections and spinal reflex pathways during rhythmic voluntary movement of the opposite limb

Rhythmic movements brought about by the contraction of muscles on one side of the body give rise to phase-locked changes in the excitability of the homologous motor pathways of the opposite limb. Such crossed facilitation should favour patterns of bimanual coordination in which homologous muscles are engaged simultaneously, and disrupt those in which the muscles are activated in an alternating fashion. In order to examine these issues, we obtained responses to transcranial magnetic stimulation (TMS), to stimulation of the cervicomedullary junction (cervicomedullary-evoked potentials, CMEPs), to peripheral nerve stimulation (H-reflexes and f-waves), and elicited stretch reflexes in the relaxed right flexor carpi radialis (FCR) muscle during rhythmic (2 Hz) flexion and extension movements of the opposite (left) wrist. The potentials evoked by TMS in right FCR were potentiated during the phases of movement in which the left FCR was most strongly engaged. In contrast, CMEPs were unaffected by the movements of the opposite limb. These results suggest that there was systematic variation of the excitability of the motor cortex ipsilateral to the moving limb. H-reflexes and stretch reflexes recorded in right FCR were modulated in phase with the activation of left FCR. As the f-waves did not vary in corresponding fashion, it appears that the phasic modulation of the H-reflex was mediated by presynaptic inhibition of Ia afferents. The observation that both H-reflexes and f-waves were depressed markedly during movements of the opposite indicates that there may also have been postsynaptic inhibition or disfacilitation of the largest motor units. Our findings indicate that the patterned modulation of excitability in motor pathways that occurs during rhythmic movements of the opposite limb is mediated primarily by interhemispheric interactions between cortical motor areas.

A Critical Appraisal of Narrative in Sport History: Reading the Surf Lifesaving Debate

All debates in history—who started the Cold War, how successful were the Chartists in achieving their aims, to what extent was the recession of the American frontier culturally significant in American history— are debates between competing narrative interpretations. Moreover, because the historical imagination itself exists intertextually within our own social and political environment, the past is never discovered set aside from everyday life. History is designed and composed in the here and now.

On the relationship between the critical temperature and the London penetration depth in layered organic superconductors

We present an analysis of previously published measurements of the London penetration depth of layered organic superconductors. The predictions of the BCS theory of superconductivity are shown to disagree with the measured zero temperature, in plane, London penetration depth by up to two orders of magnitude. We find that fluctuations in the phase of the superconducting order parameter do not determine the superconducting critical temperature as the critical temperature predicted for a Kosterlitz–Thouless transition is more than an order of magnitude greater than is found experimentally for some materials. This places constraints on theories of superconductivity in these materials.

Least energy solutions of a critical Neumann problem with a weight

We investigate the effect of the coefficient of the critical nonlinearity for the Neumann problem on the existence of least energy solutions. As a by-product we establish a Sobolev inequality with interior norm.

On a semilinear Schrodinger equation with critical Sobolev exponent

We consider the semilinear Schrodinger equation -Deltau+V(x)u= K(x) \u \ (2*-2 u) + g(x; u), u is an element of W-1,W-2 (R-N), where N greater than or equal to4, V, K, g are periodic in x(j) for 1 less than or equal toj less than or equal toN, K>0, g is of subcritical growth and 0 is in a gap of the spectrum of -Delta +V. We show that under suitable hypotheses this equation has a solution u not equal 0. In particular, such a solution exists if K equivalent to 1 and g equivalent to 0.

On the nonlinear Neumann problem with critical and supercritical nonlinearities

We investigate the solvability of the Neumann problem (1.1) involving a critical Sobolev exponent. In the first part of this work it is assumed that the coeffcients Q and h are at least continuous. Moreover Q is positive on overline Omega and lambda > 0 is a parameter. We examine the common effect of the mean curvature and the shape of the graphs of the coeffcients Q and h on the existence of low energy solutions. In the second part of this work we consider the same problem with Q replaced by - Q. In this case the problem can be supercritical and the existence results depend on integrability conditions on Q and h.

Two-body and three-body abrasion: A critical discussion

It is argued that the common classification of abrasive wear into 'two-body abrasion' and 'three-body abrasion' is seriously flawed. No definitions have been agreed upon for these terms, and indeed there are two quite different interpretations, the implications of which are mutually inconsistent. In the dominant interpretation, the primary thrust of the two-body/three-body concept is to describe whether the abrasive particles are constrained (two-body) or free to roll (three-body). In this view, two-body abrasion is generally much more severe than three-body. The alternative interpretation emphasises the presence (three-body) or absence (two-body) of a rigid counterface backing the abrasive. In this view, three-body abrasion is equated to high-stress (or grinding) abrasion and is generally more severe than two-body (low-stress) abrasion. This paper recommends that the 'two-body/three-body' terminology be abandoned, to be replaced by an alternative classification scheme based directly upon the manifest severity of wear. (C) 1998 Elsevier Science S.A.

Neuroplasticity and psychiatry

Objective: There is increasing concern that the course of psychiatric disorders may be affected by parameters such as the duration and intensity of symptoms of initial episodes of illness. As this indicates that abnormal function produces long-term changes within the brain, a review of the neuroscience literature regarding neuroplasticity is warranted. Method: This article is a selective review, focusing in particular on results obtained from physiological experiments assessing plasticity within the mammalian neocortex. The possible relevance of results to psychiatry is discussed. Results: While the most dramatic examples of neuroplasticity occur during a critical period of neural development, neuroplasticity can also occur in adult neocortex. Neuroplasticity appears to be activity-dependent: synaptic pathways that are intensively used may become strengthened, and conversely, there may be depression of transmission in infrequently used pathways. Conclusions: Results from neurophysiological experiments fend support to the clinical observation that the intensity and duration of a psychiatric disorder may adversely alter its long-term course. Rapid aggressive treatment may prevent this from occurring. While pharmacotherapy may reduce the duration and severity of symptoms, it may also have an independent, as yet unknown, effect on neuroplasticity.

The critical power function is dependent on the duration of the predictive exercise tests chosen

The linear relationship between work accomplished (W-lim) and time to exhaustion (t(lim)) can be described by the equation: W-lim = a + CP.t(lim). Critical power (CP) is the slope of this line and is thought to represent a maximum rate of ATP synthesis without exhaustion, presumably an inherent characteristic of the aerobic energy system. The present investigation determined whether the choice of predictive tests would elicit significant differences in the estimated CP. Ten female physical education students completed, in random order and on consecutive days, five art-out predictive tests at preselected constant-power outputs. Predictive tests were performed on an electrically-braked cycle ergometer and power loadings were individually chosen so as to induce fatigue within approximately 1-10 mins. CP was derived by fitting the linear W-lim-t(lim) regression and calculated three ways: 1) using the first, third and fifth W-lim-t(lim) coordinates (I-135), 2) using coordinates from the three highest power outputs (I-123; mean t(lim) = 68-193 s) and 3) using coordinates from the lowest power outputs (I-345; mean t(lim) = 193-485 s). Repeated measures ANOVA revealed that CPI123 (201.0 +/- 37.9W) > CPI135 (176.1 +/- 27.6W) > CPI345 (164.0 +/- 22.8W) (P < 0.05). When the three sets of data were used to fit the hyperbolic Power-t(lim) regression, statistically significant differences between each CP were also found (P < 0.05). The shorter the predictive trials, the greater the slope of the W-lim-t(lim) regression; possibly because of the greater influence of 'aerobic inertia' on these trials. This may explain why CP has failed to represent a maximal, sustainable work rate. The present findings suggest that if CP is to represent the highest power output that an individual can maintain for a very long time without fatigue then CP should be calculated over a range of predictive tests in which the influence of aerobic inertia is minimised.