Genomic changes and HPV type in cervical carcinoma

To identify chromosomal regions that may include the loci of abnormally expressed cellular genes and may be specifically altered depending on the histological subtype of the tumor, we studied primary cervical carcinoma using CGH and HPV genotyping. Eighty-seven percent of the primary tumors were positive for DNA of a "high-risk" HPV type (e.g., 16 or 18). In the cervical carcinomas, without reference to histologic subtype, overrepresentation of chromosome 3q was the most consistent chromosomal aberration with underrepresentation of chromosome 3p also a frequent finding. Chromosome arms 1q, 5p, 20q, and Xq were overrepresented in many tumors and 3p loss and 5p, 8q, and 16q gain were only associated with squamous cell carcinoma in this series.     

Ca2+ oscillations and the cell cycle at fertilisation of mammalian and ascidian eggs

At fertilisation of mammalian and ascidian eggs the sperm induces a series of Ca2+ oscillations. These Ca2+ oscillations are triggered by a sperm-borne Ca2+-releasing factor whose identity is still unresolved. In both mammals and ascidians Ca2+ oscillations in eggs are associated with the period leading up to exit from meiosis and entry into the first embryonic cell cycle. Thus, in mammals Ca2+ oscillations continue for several hours but are complete by within 30 min in the ascidian. In mammals and ascidians Ca2+ oscillations stop at around the time when pronuclei form in the 1-cell embryo. There is evidence to show that cell cycle factors are important in regulating the fertilisation Ca2+ signal. If the formation of pronuclei is blocked either in mammals (by spindle disruption) or in ascidians (by clamping maturation promoting factor levels high) then Ca2+ oscillations continue indefinitely. Here, we explore the nature of the sperm Ca2+-releasing factor and examine the relationship between cell cycle resumption and the control of Ca2+ oscillations at fertilisation.     

The initiation and propagation of the fertilization wave in sea urchin eggs

Calcium waves sweep across most eggs of the deuterostome lineage at fertilization. The precise timing of the initiation and propagation of a fertilization calcium wave has been best studied in sea urchin embryos, since the rapid depolarization caused by sperm egg fusion can be detected as a calcium influx using confocal imaging of calcium indicator dyes. The time between sperm egg fusion and the first sign of the calcium increase that constitutes the calcium wave is comparable to the time it takes for the wave to sweep across the egg, once initiated. The latency and rise time of the calcium response is sensitive to inhibitors of the InsP3 signalling pathway, as reported previously. Using calcium green dextran and confocal microscopy, we confirm that the propagation time of the calcium wave is lengthened and that initiation of the calcium wave involves activation of calcium release at hot spots that may represent clusters of calcium release channels, as has been seen in other cell types.     

Radiographic joint damage in rheumatoid arthritis is associated with differences in cartilage turnover and can be predicted by serum biomarkers: an evaluation from 1 to 4 years after diagnosis

Introduction  

The objective of this study was to determine whether serum biomarkers for degradation and synthesis of the extracellular matrix of cartilage are associated with, and can predict, radiographic damage in patients with rheumatoid arthritis (RA).     

Local inhibition of nitric oxide temporarily stimulates aldosterone secretion in conscious sheep in vivo

The effect of localized blockage of endogenous nitric oxide (NO) on basal aldosterone secretion was studied in conscious sheep with autotransplanted adrenal glands. We have shown that infusion of the NO synthase (NOS) inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME; 130 microg/l blood flow) significantly stimulated basal aldosterone secretion rate (ASR). This stimulatory effect was seen up to 4 h of infusion. Beyond this time point, however, the elevated ASR level was not sustained, and it was seen to drop markedly to lower than control values at 5 h. L-NAME had no effect on cortisol secretion rate (FSR) during the first 4 h of infusion, but a significant reduction in FSR was seen by the 8-h time point. Adrenal blood flow was consistently decreased in association with long L-NAME infusion. Additionally, L-NAME was shown to have no effect on aldosterone secretion when infused systemically. We conclude that the relationship between NO and aldosterone secretion is an inhibitory one, in which NO seems to have a negative effect on basal aldosterone secretion.     

Novel function of vitamin E in regulation of zebrafish (Danio rerio) brain lysophospholipids discovered using lipidomics

We hypothesized that brains from vitamin E-deficient (E−) zebrafish (Danio rerio) would undergo increased lipid peroxidation because they contain highly polyunsaturated fatty acids, thus susceptible lipids could be identified. Brains from zebrafish fed for 9 months defined diets without (E−) or with (E+) added vitamin E (500 mg RRR-α-tocopheryl acetate per kilogram diet) were studied. Using an untargeted approach, 1-hexadecanoyl-2-docosahexaenoyl-sn-glycero-3-phosphocholine [DHA-PC 38:6, PC 16:0/22:6]was the lipid that showed the most significant and greatest fold-differences between groups. DHA-PC concentrations were approximately 1/3 lower in E− (4.3 ± 0.6 mg/g) compared with E+ brains (6.5 ± 0.9 mg/g, mean ± SEM, n = 10 per group, P = 0.04). Using lipidomics, 155 lipids in brain extracts were identified. Only four phospholipids (PLs) were different (P < 0.05) between groups; they were lower in E− brains and contained DHA with DHA-PC 38:6 at the highest abundances. Moreover, hydroxy-DHA-PC 38:6 was increased in E− brains (P = 0.0341) supporting the hypothesis of DHA peroxidation. More striking was the depletion in E− brains of nearly 60% of 19 different lysophospholipids (lysoPLs) (combined P = 0.0003), which are critical for membrane PL remodeling. Thus, E− brains contained fewer DHA-PLs, more hydroxy-DHA-PCs, and fewer lysoPLs, suggesting that lipid peroxidation depletes membrane DHA-PC and homeostatic mechanisms to repair the damage resulting in lysoPL depletion.     

Retinitis pigmentosa: rapid neurodegeneration is governed by slow cell death mechanisms

For most neurodegenerative diseases the precise duration of an individual cell''s death is unknown, which is an obstacle when counteractive measures are being considered. To address this, we used the rd1 mouse model for retinal neurodegeneration, characterized by phosphodiesterase-6 (PDE6) dysfunction and photoreceptor death triggered by high cyclic guanosine-mono-phosphate (cGMP) levels. Using cellular data on cGMP accumulation, cell death, and survival, we created mathematical models to simulate the temporal development of the degeneration. We validated model predictions using organotypic retinal explant cultures derived from wild-type animals and exposed to the selective PDE6 inhibitor zaprinast. Together, photoreceptor data and modeling for the first time delineated three major cell death phases in a complex neuronal tissue: (1) initiation, taking up to 36 h, (2) execution, lasting another 40 h, and finally (3) clearance, lasting about 7 h. Surprisingly, photoreceptor neurodegeneration was noticeably slower than necrosis or apoptosis, suggesting a different mechanism of death for these neurons.