Augmentation of proliferation and in vitro production of cytotoxic cells by 2-ME in the rat.

Low concentrations (10(-5) to 10(-8) M) of 2-mercaptoethanol (2-ME) greatly enhance the proliferation of allogeneic cells in the rat mixed lymphocyte culture (MLC). Studies were undertaken to determine the mode of action of 2-ME. MLC proliferation can occur in the absence of serum proteins (fetal calf serum, FCS) only if 2-ME is present; however, a synergistic effect is present with FCS plus 2-ME, with a 3-fold increase in 3HTdR incorporation with FCS concentrations as low as 0.1%. Kinetic studies show no shift in the peak of proliferation (92 hr) when comparing cultures with and without 2-ME; however, 2-ME-supplemented cultures have significant 3HTdR uptake at 24 hr, and the peak amount of uptake at 92 hr is two to four times higher. Delayed addition of 2-ME until 92 and 166 hr produces a further increase in 3HTdR uptake, indicating that the entire effect is not expressed at the time of allogeneic recognition. L-ascorbic acid, another reducing agent which lacks sulfhydryl groups, elicits a much lower effect on DNA synthesis than does 2-ME. The cytotoxicity of cells harvested from MLC supplemented with 2-ME is increased without loss of target specificity, whereas the same concentration of 2-ME has no direct effect upon the cytotoxicity assay except at higher concentrations where 2-ME suppresses cytotoxicity.     

Reaching out: Cortical Mechanisms of Directed Action

Recordings from monkey cortex have demonstrated a sophisticated neural mechanism for the complex transformational mapping demanded by visually guided reaching.     

Pressure wave propagation in fluid-filled co-axial elastic tubes. Part 2: Mechanisms for the pathogenesis of syringomyelia

Our aim in this paper is to use a simple theoretical model of the intraspinal cerebrospinal-fluid system to investigate mechanisms proposed for the pathogenesis of syringomyelia. The model is based on an inviscid theory for the propagation of pressure waves in co-axial, fluid-filled, elastic tubes. According to this model, the leading edge of a pressure pulse tends to steepen and form an elastic jump, as it propagates up the intraspinal cerebrospinal-fluid system. We show that when an elastic jump is incident on a stenosis of the spinal subarachnoid space, it reflects to form a transient, localized region of high pressure within the spinal cord that for a cough-induced pulse is estimated to be 50 to 70 mm Hg or more above the normal level in the spinal subarachnoid space. We propose this as a new mechanism whereby pressure pulses created by coughing or sneezing can generate syrinxes. We also use the same analysis to investigate Williams' suck mechanism. Our results do not support his concept, nor, in cases where the stenosis is severe, the differential-pressure-propagation mechanism recently proposed by Greitz et al. Our analysis does provide some support for the piston mechanism recently proposed by Oldfield et al. and Heiss et al. For instance, it shows clearly how the spinal cord is compressed by the formation of elastic jumps over part of the cardiac cycle. What appears to be absent for this piston mechanism is any means whereby the elastic jumps can be focused (e.g., by reflecting from a stenosis) to form a transient, localized region of high pressure within the spinal cord. Thus it would seem to offer a mechanism for syrinx progression, but not for its formation.     

The EGF receptor: a nexus for trafficking and signaling

Ligand binding to the EGF receptor initiates both the activation of mitogenic signal transduction pathways plus trafficking events that relocalize the receptor on the cell surface and within intracellular compartments. The trafficking compartments include caveolae, clathrin-coated pits, and various endosome populations prior to receptor degradation in lysosomes. Evidence is presented that distinct signaling pathways are initiated from these different compartments. These include the Ras/MAP kinase cascade and the PLC-dependent hydrolysis of PI-4,5 P(2). Multiple tyrosine kinase substrates that facilitate EGF receptor trafficking between these various compartments, as well as the participation of phosphoinositides and Ras-like G proteins in the trafficking pathway are also described.     

Temporal Aspects of Foot-Pad Dermatitis in Swedish Broilers

This study aimed at analysing the temporal aspects of foot-pad dermatitis in Swedish broilers. The information on disease prevalence and severity was based on a 2-year foot-health surveillance programme where information on producer, breed, feed manufacturer, region, abattoir, date of slaughter and several other variables was recorded. The seasonal effects were evaluated using classical multiplicative decomposition time series analysis. This study shows that there has been a significantly consistent decrease in the prevalence of severe foot-pad lesions during the first 2 years of the programme. Looking at the development over time we found a trend-cycle component of 10.4% and a seasonal component of 48.7% resulting in a total adjusted R-square value of 58.5% for the total foot-pad score. This means that almost 60% of the variation in flock foot-pad score can be explained by the variable 'time', and that this variation was mainly related to seasonal effects but also to a general decreasing trend over the study period. However, substantial differences in temporal patterns among slaughterhouses, feed suppliers and regions were found. The time series analysis approach was found to be useful for this type of investigation when evaluating the effects of an intervention programme, and it can also be applied for projecting the future development of disease status in a stable population.     

Mistletoes as parasites: Host specificity and speciation

Recent research on parasite evolution has highlighted the importance of host specialization in speciation, either through host-switching or cospeciation. Many parasites show common patterns of host specificity, with higher host specificity where host abundance is high and reliable, phylogenetically conservative host specificity, and formation of races on or in different host species. Recent advances in our understanding of host specificity and speciation patterns in a variety of animal parasites provides valuable insights into the evolutionary biology of mistletoes.     

Methylcytosine and Normal Cytosine Deamination by the Foreign DNA Restriction Enzyme APOBEC3A

Multiple studies have indicated that the TET oxidases and, more controversially, the activation-induced cytidine deaminase/APOBEC deaminases have the capacity to convert genomic DNA 5-methylcytosine (MeC) into altered nucleobases that provoke excision repair and culminate in the replacement of the original MeC with a normal cytosine (C). We show that human APOBEC3A (A3A) efficiently deaminates both MeC to thymine (T) and normal C to uracil (U) in single-stranded DNA substrates. In comparison, the related enzyme APOBEC3G (A3G) has undetectable MeC to T activity and 10-fold less C to U activity. Upon 100-fold induction of endogenous A3A by interferon, the MeC status of bulk chromosomal DNA is unaltered, whereas both MeC and C nucleobases in transfected plasmid DNA substrates are highly susceptible to editing. Knockdown experiments show that endogenous A3A is the source of both of these cellular DNA deaminase activities. This is the first evidence for nonchromosomal DNA MeC to T editing in human cells. These biochemical and cellular data combine to suggest a model in which the expanded substrate versatility of A3A may be an evolutionary adaptation that occurred to fortify its innate immune function in foreign DNA clearance by myeloid lineage cell types.     

Advances in schizophrenia

Recent studies into the etiology of schizophrenia have yielded both promising leads and disappointing dead ends, indicating the multifactored and complex nature of the disorder. The focus has subsequently shifted back to refining the phenotype and identifying clinical and biological subtypes. Recent technological breakthroughs in genomics and proteomics hold promise for advancing our understanding of the molecular pathophysiology of schizophrenia.