Epinephrine correction of impaired platelet thromboxane receptor signaling

This study evaluated the mechanism of epinephrinepotentiation of platelet secretion induced by thromboxaneA₂ (TXA₂). Dog platelets that do not secrete inresponse to TXA₂ alone (TXA₂) were comparedwith dog platelets that do secrete (TXA₂+) and with humanplatelets. TXA₂ platelets had impaired TXA₂receptor (TP receptor)-G protein coupling, indicated by 1)impaired stimulated GTPase activity, 2) elevated basalguanosine 5'-O-(3-thiotriphosphate) binding, and3) elevated G_q palmitate turnover that wascorrected by preexposure to epinephrine. Kinetic agonist bindingstudies revealed biphasic dog and human platelet TP receptorassociation and dissociation. TXA₂ and TPreceptor-desensitized TXA₂+ dog and human platelets hadaltered ligand binding parameters compared with untreatedTXA₂+ or human platelets. These parameters were reversed,along with impaired secretion, by epinephrine. Basal phosphorylation ofTXA₂ platelet TP receptors was elevated 60% and wasnormalized by epinephrine. Epinephrine potentiates platelet secretionstimulated by TXA₂ by reducing basal TP receptorphosphorylation and facilitating TP receptor-G protein coupling inTXA₂ platelets and, probably, in normal platelets as well.

     

Recent developments in the intracellular degradation of oxidized proteins

The accumulation of oxidized proteins in cells and tissues is a feature of a number of age-related diseases and may also occur as a result of the aging process itself. In this article we review recent advances in our understanding of the cellular degradation of oxidized proteins directing our attention primarily to information which directly bears on the behavior of intact eukaryotic cells. We summarize new work on the key intracellular degradative machineries, proteasomes and lysosomes and examine evidence implicating an increase in protein hydrophobicity as the primary signal to the proteasome to initiate degradation. The data identifying the proteasome as the main route of degradation of oxidized proteins is examined, as well as recent data investigating changes in proteasome function after exposure of cells to oxidants and the altered catabolism of oxidized proteins in aging cells. Evidence for the cooperation between the lysosomal and proteasomal systems in the degradation of oxidized proteins is discussed. We conclude that the cellular catabolism of oxidized proteins may be a more complex process than it first appeared and suggest key issues that need to be resolved to improve our understanding of this important process.     

Pax genes in development and maturation of the vertebrate visual system: implications for optic nerve regeneration

Pax genes play a pivotal role in development of the vertebrate visual system. Pax6 is the master control gene for eye development: ectopic expression of Pax6 in Xenopus laevis and Drosphila melanogaster leads to the formation of differentiated eyes on the legs or wings. Pax6 is involved in formation of ganglion cells of the retina, as well as cells of the lens, iris and cornea. In addition Pax6 may play a role in axon guidance in the visual system. Pax2 regulates differentiation of the optic disk through which retinal ganglion cell axons exit the eye. Furthermore, Pax2 plays a critical role in development of the optic chiasm and in the guidance of axons along the contralateral or ipsilateral tracts of the optic nerve to visual targets in the brain. During development Pax7 is expressed in neuronal cells of one of the major visual targets in the brain, the optic tectum/superior colliculus. Neurons expressing Pax7 migrate towards the pia and concentrate in the stratum griseum superficiale (SGFS), the target site for retinal axons. Together, expression of Pax2, 6 and 7 may guide axons during formation of functional retinotectal/collicular projections. Highly regulated Pax gene expression is also observed in mature animals. Moreover, evidence suggests that Pax genes are important for regeneration of the visual system. We are currently investigating Pax gene expression in species that display a range of outcomes of optic nerve regeneration. We predict that such information will provide valuable insights for the induction of successful regeneration of the optic nerve and of other regions of the central nervous system in mammals including man.     

Extracellular matrix components cooperate to activate phosphatidyl inositol-4-phosphate 5-kinase

Interaction of mesangial cells with extracellular matrix proteins can provide a means to modify cellular anchorage and traction through an interaction of integrins with activation of the actin cytoskeleton. We investigated intracellular signalling of matrix components fibronectin and laminin in mesangial cells in monolayer and 3-dimensional configurations to show a fibronectin-dependent activation of phosphatidylinositol-4-phosphate 5-kinase (up to threefold), which is augmented by a laminin-dependent increase in phospholipase D activity. Functional responsiveness to fibronectin and laminin addition was seen in the contraction of free-floating 3-dimensional mesangial cell-embedded collagen gels, a well-defined system reflecting coupling of extracellular matrix-cell events to activation of the actin cytoskeleton. Activation of phosphatidylinositol-4-phosphate 5-kinase and contraction of mesangial cell-embedded collagen gels in response to fibronectin and laminin were inhibited by pretreatment of mesangial cells with lovastatin and restored by isoprenoid augmentation with geranylgeraniol, supporting a role for the ras-related protein Rho in this process.     

Atomic emission and proton microprobe studies of the ion content of otoliths of chinook salmon aimed at recovering the temperature life history of individuals

Atomic emission experiments on whole otoliths of the chinook salmon (Oncorhynchus tshawytcha) show that a statistically significant relationship exists between otolith ion content (Fr, Zn, Mn, Na, Sr, P), ambient temperature, body length and otolith weight amongst individuals maintained under controlled diet and water conditions. Direct proton microprobe studies confirm these results and suggest that it may be possible to recover the temperature life history of individual fishes from the otolith.     

Effects of a Balanced Translocation between Chromosomes 1 and 11 Disrupting the DISC1 Locus on White Matter Integrity

Objective

Individuals carrying rare, but biologically informative genetic variants provide a unique opportunity to model major mental illness and inform understanding of disease mechanisms. The rarity of such variations means that their study involves small group numbers, however they are amongst the strongest known genetic risk factors for major mental illness and are likely to have large neural effects. DISC1 (Disrupted in Schizophrenia 1) is a gene containing one such risk variant, identified in a single Scottish family through its disruption by a balanced translocation of chromosomes 1 and 11; t(1;11) (q42.1;q14.3).

Method

Within the original pedigree, we examined the effects of the t(1;11) translocation on white matter integrity, measured by fractional anisotropy (FA). This included family members with (n = 7) and without (n = 13) the translocation, along with a clinical control sample of patients with psychosis (n = 34), and a group of healthy controls (n = 33).

Results

We report decreased white matter integrity in five clusters in the genu of the corpus callosum, the right inferior fronto-occipital fasciculus, acoustic radiation and fornix. Analysis of the mixed psychosis group also demonstrated decreased white matter integrity in the above regions. FA values within the corpus callosum correlated significantly with positive psychotic symptom severity.

Conclusions

We demonstrate that the t(1;11) translocation is associated with reduced white matter integrity in frontal commissural and association fibre tracts. These findings overlap with those shown in affected patients with psychosis and in DISC1 animal models and highlight the value of rare but biologically informative mutations in modeling psychosis.