P75 interacts with the Nogo receptor as a co-receptor for Nogo,MAG and OMgp

In inhibiting neurite outgrowth, several myelin components, including the extracellular domain of Nogo-A (Nogo-66), oligodendrocyte myelin glycoprotein (OMgp) and myelin-associated glycoprotein (MAG), exert their effects through the same Nogo receptor (NgR). The glycosyl phosphatidylinositol (GPI)-anchored nature of NgR indicates the requirement for additional transmembrane protein(s) to transduce the inhibitory signals into the interior of responding neurons. Here, we demonstrate that p75, a transmembrane protein known to be a receptor for the neurotrophin family of growth factors, specifically interacts with NgR. p75 is required for NgR-mediated signalling, as neurons from p75 knockout mice are no longer responsive to myelin and to each of the known NgR ligands. Blocking the p75-NgR interaction also reduces the activities of these inhibitors. Moreover, a truncated p75 protein lacking the intracellular domain, when overexpressed in primary neurons, attenuates the same set of inhibitory activities, suggesting that p75 is a signal transducer of the NgR-p75 receptor complex. Thus, interfering with p75 and its downstream signalling pathways may allow lesioned axons to overcome most of the inhibitory activities associated with central nervous system myelin.     

Effect of diazepam (Valium®) on chronic stress-induced hypertension in the rat

Summary Chronic treatment with diazepam was effective in preventing chronic stress-induced hypertension in rats. It also prevented the stressful stimuli from maintaining a hypertensive level in animals previously made hypertensive by chronic stress.     

Enantiomeric cannabinoids: stereospecificity of psychotropic activity

The 1,1-dimethylheptyl homolog of (-)-(3R,4R)-7-hydroxy-delta-6- tetrahydrocannabinol (compound II) is highly psychotropic in mice, rats and pigeons. The (+)-(3S,4S) enantiomer (III) was found to be psychotropically inactive at doses up to several thousand times those of the ED50 of (II).     

Expression of a transfected human c-myc oncogene inhibits differentiation of a mouse erythroleukaemia cell line

The Friend-virus-derived mouse erythroleukaemia (MEL) cell lines represent transformed early erythroid precursors that can be induced to differentiate into more mature erythroid cells by a variety of agents including dimethyl sulphoxide (DMSO). There is a latent period of 12 hours after inducer is added, when 80-90% of the cells become irreversibly committed to the differentiation programme, undergoing several rounds of cell division before permanently ceasing to replicate. After DMSO induction, a biphasic decline in steady-state levels of c-myc and c-myb messenger RNAs occurs. Following the initial decrease in c-myc mRNA expression, the subsequent increase occurs in, and is restricted to, the G1 phase of the cell cycle. We sought to determine whether the down-regulation is a necessary step in chemically induced differentiation. Experiments reported here indicate that expression in MEL cells of a transfected human c-myc gene inhibits the terminal differentiation process.     

Robustness-epistasis link shapes the fitness landscape of a randomly drifting protein

The distribution of fitness effects of protein mutations is still unknown. Of particular interest is whether accumulating deleterious mutations interact, and how the resulting epistatic effects shape the protein's fitness landscape. Here we apply a model system in which bacterial fitness correlates with the enzymatic activity of TEM-1 beta-lactamase (antibiotic degradation). Subjecting TEM-1 to random mutational drift and purifying selection (to purge deleterious mutations) produced changes in its fitness landscape indicative of negative epistasis; that is, the combined deleterious effects of mutations were, on average, larger than expected from the multiplication of their individual effects. As observed in computational systems, negative epistasis was tightly associated with higher tolerance to mutations (robustness). Thus, under a low selection pressure, a large fraction of mutations was initially tolerated (high robustness), but as mutations accumulated, their fitness toll increased, resulting in the observed negative epistasis. These findings, supported by FoldX stability computations of the mutational effects, prompt a new model in which the mutational robustness (or neutrality) observed in proteins, and other biological systems, is due primarily to a stability margin, or threshold, that buffers the deleterious physico-chemical effects of mutations on fitness. Threshold robustness is inherently epistatic-once the stability threshold is exhausted, the deleterious effects of mutations become fully pronounced, thereby making proteins far less robust than generally assumed.     

Independent regulation of calcium revealed by imaging dendritic spines

The dendritic spine is a basic structural unit of neuronal organization. It is assumed to be a primary locus of synaptic plasticity, and to undergo long-term morphological and functional changes, at least some of which are regulated by intracellular calcium concentrations. It is known that physiological stimuli can cause marked increases in intracellular calcium levels in hippocampal dendritic shafts, but it is completely unknown to what extent such changes in the dendrites would also be seen by calcium-sensing structures within spines. Will calcium levels in all spines change in parallel with the dendrite or will there be a heterogeneous response? This study, through direct visualization and measurement of intracellular calcium concentrations in individual living spines, demonstrates that experimentally evoked changes in calcium concentrations in the dendritic shaft ([Ca2+]d).     

低碳锰钢中周期性带状组织

用扫描电镜和电子探针研究了低碳锰钢中的周期性带状组织，结果表明，在全部研究用钢中，钢锭经热轧后均出现这种组织，其严重程度随钢的成分而异，并随坯带加工顺序而增加，带状组织与锰的显微偏析等因素有关，适当的调整碳锰以及形成模跨铁素体带的转变产物可降低带状组织的严重程度。     

Specific targeting of cytotoxic T cells by anti-T3 linked to anti-target cell antibody

The specificity of cytotoxic T lymphocytes (Tc) cells is conferred by an antigen-specific receptor, Ti, which in humans is physically associated with an invariant cell-surface glycoprotein, T3. Monoclonal antibodies specific for either T3 and Ti are able to elicit a variety of T-cell responses such as lymphokine production, mitogenesis and cytotoxicity. For example, human Tc cells lyse anti-T3-expressing hybridoma cells, but not cells of other specificity, presumably because anti-T3 on the hybridoma cells binds to T3 on the Tc cells and triggers lysis. Here, we have adapted approaches used in a different cytotoxic effector system, antibody-dependent cellular cytotoxicity (ADCC), to alter the specificity of Tc cell. Studies of ADCC showed that heteroaggregates containing anti-Fc receptor (Fc gamma R) antibody cross-linked to a second antibody bind to Fc gamma R on ADCC effectors and cause them to kill target cells bearing antigen recognized by the second antibody. The present studies use anti-T3-containing heteroaggregates to re-target human Tc cells to cells for which we have appropriate antibodies, including xenogeneic tumour cells and chicken erythrocytes. These results extend previous observations on the role of T3 in triggering cytotoxicity and suggest that effector cell re-targeting could be used for in vivo treatment of neoplasms and other pathogens that express distinctive surface antigens.     

Killing activity of neutrophils is mediated through activation of proteases by K+ flux

According to the hitherto accepted view, neutrophils kill ingested microorganisms by subjecting them to high concentrations of highly toxic reactive oxygen species (ROS) and bringing about myeloperoxidase-catalysed halogenation. We show here that this simple scheme, which for many years has served as a satisfactory working hypothesis, is inadequate. We find that mice made deficient in neutrophil-granule proteases but normal in respect of superoxide production and iodinating capacity, are unable to resist staphylococcal and candidal infections. We also show that activation provokes the influx of an enormous concentration of ROS into the endocytic vacuole. The resulting accumulation of anionic charge is compensated for by a surge of K+ ions that cross the membrane in a pH-dependent manner. The consequent rise in ionic strength engenders the release of cationic granule proteins, including elastase and cathepsin G, from the anionic sulphated proteoglycan matrix. We show that it is the proteases, thus activated, that are primarily responsible for the destruction of the bacteria.