Spatial Performance Is More Sensitive to Ethanol Than Nonspatial Performance Regardless of Cue Proximity

In rodents, ethanol produces a greater impact on the ability to perform spatial reference memory tasks than nonspatial reference memory tasks. Such evidence may reflect a selective disruption in the use of previously acquired spatial information. However, a rtonmnemonic explanation has yet to be ruled out Tasks used to study ethanol's effects on spatial memory commonly require subjects to utilize distal, or ex-tramaze, cues to respond correctly. In contrast, many previously used nonspatial tasks could be solved using cues located on the maze itself. Because ethanol has been shown to disrupt sensory processing, it is possible that previously observed differences in the effects of ethanol on spatial and nonspatial performance were actually due to differences in the proximity of relevant cues in the spatial and nonspatial tasks and not to a selective disruption in spatial memory. The present study compares the effects of ethanol on the performance of spatial and nonspatial reference memory tasks that require subjects to discriminate among extramaze cues for correct responding. Subjects were trained while sober to navigate to a goal arm on a 12-arm maze. In the spatial task, the goal arm was defined by its location with respect to a number of extramaze cues. In the nonspatial task, the goal arm was defined by the presence of a single extramaze cue located directly beyond the end of the arm. Subjects were tested under 1 of 4 doses of ethanol (0.0, 0.7, 1.4, and 2.1 g/kg). Performance on the nonspatial task was more resistant to the effects of ethanol than performance on the spatial task. The results suggest that differences in the effects of ethanol on spatial and nonspatial performance are not due to differences in the proximity of relevant cues in previously used spatial and nonspatial tasks. Key Words: Ethanol, Spatial, Nonspatial, Memory, Maze.     

Transforming growth factor-beta trans-modulates the expression of colony stimulating factor receptors on murine hematopoietic progenitor cell lines

Transforming growth factor beta (TGF-beta) is a potent and selective growth inhibitor of early hematopoietic progenitors and leukemic cells. The cellular mechanism(s) underlying this antiproliferative effect is, however, currently unknown. In the present study, we demonstrate that TGF-beta inhibits the expression of granulocyte-macrophage colony stimulating factor (GM-CSF), interleukin 3 (IL-3), and granulocyte-CSF (G-CSF) receptors on murine factor-dependent and independent hematopoietic progenitor cell lines without a significant change in receptor affinity. A maximum reduction in GM-CSF receptor numbers of 65% to 77% was observed by 96-hour incubation with TGF-beta. The TGF- beta induced trans-down-modulation of GM-CSF receptors was prolonged, noncytotoxic but reversible, and not due to endogenous production of GM- CSF. The TGF-beta induced reduction in CSF receptor numbers preceded TGF-beta's growth inhibitory action. In addition, the ED50 (1 to 10 pmol/L) for TGF-beta's CSF receptor modulatory and antiproliferative effect was similar. The effect of TGF-beta on cell surface CSF receptor expression was specific, because the expression of other cell surface proteins (Ly 5 and Ly 17) was not affected by TGF-beta treatment, and because other growth inhibitors (tumor necrosis factor and interferon) did not affect CSF receptor expression. These data suggest that the downregulation of the growth of hematopoietic progenitor cells by TGF- beta involves reducing the cell surface expression on growth factor receptors.     

Distribution of immunoreactive alkaline phosphatase in the adult rat ileum by immunoperoxidase staining at the light microscopic level

Our prior immunocytochemical studies using monospecific antibody to alkaline phosphatase, Bouin's fixation, and paraffin sections demonstrated a decreasing gradient of villus brush border staining from the proximal to the distal rat small intestine. In addition, we noted an unusual pattern of staining in the terminal centimeter of the adult rat ileum: the villus brush border staining was less intense than crypt brush border staining. To determine whether this pattern of staining was present throughout the entire ileum, we examined alkaline phosphatase staining in two separate jejunal sites and the entire lowest third of the intestine of adult Wistar rats. With Bouin's fixation and paraffin embedding, both conventional and germ-free rats showed the same unusual staining pattern throughout the entire ileum. This pattern suggested that bacterial proteases were not responsible for the diminished ileal brush border alkaline phosphatase. However, when acetone fixation and cryostat sections were used with the avidin-biotin-peroxidase complex system, the previously noted reversed gradient of staining between the ileal villus and crypt areas was no longer present. Rather, ileal crypt brush border staining was less than ileal villus brush border staining. With either methodology, jejunal villus brush border staining was significantly more intense than ileal brush border staining, whereas the deep crypt brush border staining was not significantly different between the two regions. The present study reinforces the need for a combination of methodologies in order to best and most accurately localize certain antigens with immunocytochemistry. It also confirms a decreasing proximal to distal gradient for villus brush border alkaline phosphatase despite similar deep crypt brush border staining throughout the small intestine.     

Pre-B acute lymphoblastic leukemia cells may induce T-cell anergy to alloantigen

Even if neoplastic cells express tumor associated antigens they still may fail to function as antigen presenting cells (APC) if they lack expression of one or more molecules critical for the induction of productive immunity. These cellular defects can be repaired by physiologic activation, transfection, or fusion of tumor cells with professional APC. Although such defects can be repaired, antitumor specific T cells may still fail to respond in vivo if they may have been tolerized. Here, human pre-B cell acute lymphoblastic leukemia (pre-B ALL) was used as a model to determine if primary human tumor cells can function as alloantigen presenting cells (alloAPC) or alternatively whether they induce anergy. In the present report, we show that pre-B cell ALL express alloantigen and adhesion molecules but uniformly lack B7-1 (CD80) and only a subset express B7-2 (CD86). Pre-B ALL cells are inefficient or ineffective alloAPC and those cases that lack expression of B7-1 and B7-2 also induce alloantigen specific T- cell unresponsiveness. Under these circumstances, T-cell unresponsiveness could be prevented by physiologic activation of tumor cells via CD40, cross-linking CD28, or signaling through the common gamma chain of the interleukin-2 receptor on T cells. Taken together, these results suggest that pre-B ALL may be incapable of inducing clinically significant T-cell-mediated antileukemia responses. This defect may be not only due to their inability to function as APC, but also due to their potential to induce tolerance. Attempts to induce clinically significant antitumor immune responses may then require not only mechanisms to repair the antigen presenting capacity of the tumor cells, but also reversal of tolerance.     

Identification of small-molecule antagonists that inhibit an activator: coactivator interaction

Phosphorylation of the cAMP response element binding protein (CREB) at Ser-133 in response to hormonal stimuli triggers cellular gene expression via the recruitment of the histone acetylase coactivator paralogs CREB binding protein (CBP) and p300 to the promoter. The NMR structure of the CREB:CBP complex, using relevant interaction domains called KID and KIX, respectively, reveals a shallow hydrophobic groove on the surface of KIX that accommodates an amphipathic helix in phospho (Ser-133) KID. Using an NMR-based screening approach on a preselected small-molecule library, we identified several compounds that bind to different surfaces on KIX. One of these, KG-501 (2-naphthol-AS-E-phosphate), targeted a surface distal to the CREB binding groove that includes Arg-600, a residue that is required for the CREB:CBP interaction. When added to live cells, KG-501 disrupted the CREB: CBP complex and attenuated target gene induction in response to cAMP agonist. These results demonstrate the ability of small molecules to interfere with second-messenger signaling cascades by inhibiting specific protein-protein interactions in the nucleus.     

Reaction coordinates and rates from transition paths

The molecular mechanism of a reaction in solution is reflected in its transition-state ensemble and transition paths. We use a Bayesian formula relating the equilibrium and transition-path ensembles to identify transition states, rank reaction coordinates, and estimate rate coefficients. We also introduce a variational procedure to optimize reaction coordinates. The theory is illustrated with applications to protein folding and the dipole reorientation of an ordered water chain inside a carbon nanotube. To describe the folding of a simple model of a three-helix bundle protein, we variationally optimize the weights of a projection onto the matrix of native and nonnative amino acid contacts. The resulting one-dimensional reaction coordinate captures the folding transition state, with formation and packing of helix 2 and 3 constituting the bottleneck for folding.     

Nuclear magnetic resonance in hypertrophic cardiomyopathy.

The large differences in the spin lattice relaxation times (T1) of blood and myocardium (measured by nuclear magnetic resonance) allow the heart to be visualised without the use of contrast media. The findings using nuclear magnetic resonance in 11 unselected patients with hypertrophic cardiomyopathy were compared with those in equal numbers of normal subjects and patients with electrocardiographic features of left ventricular hypertrophy. In patients with hypertrophic cardiomyopathy characteristic septal hypertrophy was noted together with variable and sometimes pronounced hypertrophy of the left ventricular free wall, which is consistent with the heterogeneous nature of this disease. The mean (SD) ratio of septal to free wall thickness was 1.5(0.8) for patients with hypertrophic cardiomyopathy, 0.8(0.2) for those with left ventricular hypertrophy, and 0.9(0.2) for normal subjects. Although septal measurements by nuclear magnetic resonance were greater than those obtained by echocardiography there was a significant correlation between the two. Septal and free wall area were significantly smaller in normal subjects. There were no differences in septal or free wall T1 values between the three groups. Non-gated nuclear magnetic resonance can detect septal and free wall hypertrophy. With the addition of multiple slice acquisition, rapid estimation of myocardial mass will be possible allowing the potentially important assessment of progression or regression of myocardial hypertrophy.     

Let’s celebrate recovery. Inclusive Cities working together to support social cohesion

Abstract

Recovery from illicit drug and alcohol use takes place over time and is characterised by a dynamic interaction between internal and external components. An integral part of all recovery journeys is effective community reintegration. After all, recovery is not mainly an issue of personal motivation rather it is about acceptance by family, by friends and by a range of organisations and professionals across the community. Therefore to support pathways to recovery, structural and contextual endeavours are needed to supplement individually-oriented interventions and programmes. One way to do this, is by introducing Inclusive Cities. An Inclusive City promotes participation, inclusion, full and equal citizenship to all her citizens, including those in recovery, based on the idea of community capital. The aim of building recovery capital at a community level through connections and 'linking social capital' to challenge stigmatisation and exclusion, is seen as central to this idea. Inclusive Cities is an initiative to support the creation of Recovery-Oriented Systems of Care at a city level, that starts with but extends beyond substance using populations. This paper describes (and gives examples of) how it is possible to use recovery as a starting point for generating social inclusion, challenging the marginalisation of other excluded populations as well by building community connections.