Insulin stimulates generation of intracellular mediators in rat heart

Insulin treatment of rats results in an increased amount or activity of insulin mediators in heart muscle. The mediators stimulated mitochondrial pyruvate dehydrogenase and inhibited glucagon-stimulated adenylate cyclase. The mediators were copurified by ultrafiltration, ethanol extraction, Dowex cation-exchange, and QAE-Sephadex anion-exchange chromatography. The activities of the two mediators were separated by Sephadex G-10 chromatography. Fasting rats for 72 h diminished the mediator response to insulin treatment. These results, taken together with previous reports, indicate that insulin generates a number of mediators which have a ubiquitous tissue distribution. The activity of these mediators, like insulin responsiveness, is altered by the metabolic state of the animal.     

Cancer therapy

In recent years a growing recognition that molecularly-targeted therapies face formidable obstacles has revived interest in more generic tumor cell phenotypes that could be exploited for therapy. Two recent reports demonstrate that cancer cell survival is critically dependent on the activity of MTH1, a nucleotide pyrophosphatase that converts the oxidized nucleotides 8-oxo-dGTP and 2-OH-dATP to the corresponding monophosphates, thus preventing their incorporation into genomic DNA. Tumor cells frequently overexpress MTH1, probably because malignant transformation creates oxidative stress that renders the nucleotide pool highly vulnerable to oxidation. As a result, MTH1 inhibition in cancer cells results in accumulation and incorporation of 8-oxo-dGTP and 2-OH-dATP into DNA, leading to DNA damage and cell death. This toxic effect is highly cancer cell-specific, as MTH1 is generally dispensable for the survival of normal, untransformed cells. Importantly, MTH1 proves to be a “druggable” enzyme that can be inhibited both by an existing protein kinase inhibitor drug, crizotinib, and by novel compounds identified through screening. Inhibition of MTH1 leading to toxic accumulation of oxidized nucleotides specifically in tumor cells therefore represents an example of a “non-personalised” approach to cancer therapy.     

The control and biological importance of intratumoural aromatase in breast cancer

The existence of aromatase activity in human breast carcinomas has been established for about 20 years but the clinical and biological importance of this remains unclear. A number of studies in clinical material suggest that aromatase activity may be a prerequisite of response to aromatase inhibitors and that aromatase activity may be enhanced in those tumours relapsing during treatment with one such inhibitor, aminoglutethimide. These results would carry more significance, however, if it was demonstrable that the growth of breast carcinomas is affected by the conversion of androgens to oestrogens by intratumoural aromatase. We have tried to address this by establishing model systems with aromatase-transfected MCF7 breast cancer cells. We have demonstrated that these cells can be stimulated mitogenically with androgen and that this proliferation is suppressible with aromatase inhibitors. Similarly the growth of aromatase transfected cells but not wild type cells as xenografts is supported by androstenedione and inhibitable by both the steroidal aromatase inhibitor, 4-hydroxyandrostenedione and the non-steroidal inhibitor, CGS 20267. Work with the former of these, which is a suicide inhibitor allowed us to demonstrate that growth can proceed with aromatase activity approximating to the highest level seen in breast carcinomas indicating that at least at this extreme level the intratumoural conversion of androgens to oestrogens may indeed be able to support tumour growth. Further work with this model system should allow us to define the minimal amount of intratumoural activity which can support tumour growth.     

Variability of Euphausia superba populations near Elephant Island and the South Shetlands: 1981 vs. 1984

Summary March 1981 and 1984 Euphausia superba populations were compared using acoustics and net catches near Elephant Island, the South Shetlands, and in the Bransfield Strait. In 1981, krill tended to form large, thick swarms and in 1984, smaller, more dispersed, shallower patches. March body lengths of juvenile-adult krill were 22–59 mm in 1981 and 13–59 mm in 1984. Near Elephant I. in 1981, krill >45 mm were most numerous; in 1984 sizes <45 mm were dominant. In March 1984, the larger (>45 mm) body-size group was prereproductive and occurred from just west of Elephant I. westward into waters north of the South Shetlands; in 1981 the larger krill were postreproductive and more widely distributed in the Elephant I. area. Overall, netted postlarval krill, 1981 vs. 1984, averaged 73 vs. 48 individuals/m², or 54 vs. 16 g/m²; acoustic biomass estimates were 229 vs. 134–201 g/m². Larvae near Elephant I. averaged >2000/m² in 1981 vs. <1/m² in 1984—compatible with respective March reproductive states. Net-type comparisons revealed short-term (15 min to 6h) variability of a similar scale in both MOCNESS and bongo net catches, but bongo abundances averaged greater. Variation in maturity composition across 1981 swarms, patches, and random transects was like variation among the random 1984 tows; spatial distributions were more heterogeneous in 1984. The March 1984 krill of 20–44 mm (Year-2, mode 34 mm) relate to November 1983 krill of 9–30 mm (mode 21 mm), indicating growth averaging 12 mm during the season. Body-lengths and size-frequency modes of Year-2 and combined Years-3,3+ krill from comparable Feb-Mar data collected since 1968 suggest trends between times when (1) Year-2 krill average small and peak reproduction seems to be late in the season and/or weak (1979, 1982–1984), and (2) Year-2 krill are larger, and reproduction is possibly earlier and more successful (1976, 1980, 1981).     

Comparison of phospholipid effects on insulin-sensitive low Km cyclic AMP phosphodiesterase in adipocyte plasma membranes and microsomes

Both adipocyte plasma membranes and microsomes possess insulin-sensitive low K_m cyclic AMP phosphodiesterase activity. The activity of the enzyme from both sources was susceptible to activation by several anionic phospholipids. Activators of the plasma membrane enzyme were lysophosphatidylglycerol > lysophosphatidylcholine > lysophosphatidylserine > phosphatidylserine > phosphatidylglycerol. These same phospholipids activated the microsomal enzyme but the extent of activation by each phospholipid was reversed. Neutral phospholipids and other anionic phospholipids were without effect. The phospholipids had no effect on high K_m cAMP phosphodiesterase in either membrane. The results suggest that the phospholipid headgroup was an important determinant for enzyme activation by phospholipid. The increased susceptibility of the plasma membrane enzyme to lysophospholipid may be attributed to a difference in the plasma membrane enzyme compared to the microsomal membrane enzyme or to differences in plasma membrane and microsomal membrane phospholipid composition and their ability to regulate low K_m cAMP phosphodiesterase activity.     

Meiosis and beyond – understanding the mechanistic and evolutionary processes shaping the germline genome

The separation of germ cell populations from the soma is part of the evolutionary transition to multicellularity. Only genetic information present in the germ cells will be inherited by future generations, and any molecular processes affecting the germline genome are therefore likely to be passed on. Despite its prevalence across taxonomic kingdoms, we are only starting to understand details of the underlying micro-evolutionary processes occurring at the germline genome level. These include segregation, recombination, mutation and selection and can occur at any stage during germline differentiation and mitotic germline proliferation to meiosis and post-meiotic gamete maturation. Selection acting on germ cells at any stage from the diploid germ cell to the haploid gametes may cause significant deviations from Mendelian inheritance and may be more widespread than previously assumed. The mechanisms that affect and potentially alter the genomic sequence and allele frequencies in the germline are pivotal to our understanding of heritability. With the rise of new sequencing technologies, we are now able to address some of these unanswered questions. In this review, we comment on the most recent developments in this field and identify current gaps in our knowledge.     

A collapsible opening-closing net for zooplankton sampling through ice

The English umbrella net is a new-design vertical closing netdeveloped to sample zooplankton populations in under-ice environments.Operating on the principle of an umbrella, this wide-mouth netfits through a hole drilled in sea ice and expands below theice to sample the water column. A messenger-activated releasecloses the net for a discrete sample and collapses the frameso that it can be retrieved back through the hole in the ice.Nets of this design were used for extensive sampling on Fletcher'sIce Island (T-3) in the Arctic Ocean.