Compartmentation of glutamate metabolism in brain. Evidence for the existence of two different tricarboxylic acid cycles in brain

1. (14)C from [1-(14)C]glucose injected intraperitoneally into mice is incorporated into glutamate, aspartate and glutamine in the brain to a much greater extent than (14)C from [2-(14)C]glucose. This difference for [1-(14)C]glucose and [2-(14)C]glucose increases with time. The amount of (14)C in C-1 of glutamate increases steadily with time with both precursors. It is suggested that a large part of the glutamate and aspartate pools in brain are in close contact with intermediates of a fast-turning tricarboxylic acid cycle. 2. (14)C from [1-(14)C]acetate and [2-(14)C]acetate is incorporated to a much larger extent into glutamine than into glutamate. An examination of the time-course of (14)C incorporated into glutamine and glutamate reveals that glutamine is not formed from the glutamate pool, labelled extensively by glucose, but from a small glutamate pool. This small glutamate pool is not derived from an intermediate of a fast-turning tricarboxylic acid cycle. 3. It is proposed that two different tricarboxylic acid cycles exist in brain.     

HPAC,a new human glucocorticoid-sensitive pancreatic ductal adenocarcinoma cell line

Summary A new human pancreatic cancer (HPAC) cell line was established from a nude mouse xenograft (CAP) of a primary human pancreatic ductal adenocarcinoma. In culture, HPAC cells form monolayers of morphologically heterogenous, polar epithelial cells, which synthesize carcinoembryonic antigen, CA 19-9, CA-125, cytokeratins, antigens for DU-PAN-2, HMFG1, and AUA1, but do not express chromogranin A or vimentin indicative of their pancreatic ductal epithelial cell character. In the presence of serum, HPAC cell DNA synthesis was stimulated by insulin, insulin growth factor-I, epidermal growth factor, and TGF-α but inhibited by physiologic concentrations of hydrocortisone and dexamethasone. Dose-dependent inhibition of DNA synthesis was limited to steroids with glucocorticoid activity. The inhibitory effect of dexamethasone was abolished by the glucocorticoid antagonist RU 38486. Binding of [³H]dexamethasone to cytosolic proteins was specific and saturable at 4° C. Scatchard analysis of binding data demonstrated a single class of high-affinity binding sites (K_d=3.8±0.9 nM; B_max=523±128 fmol/mg protein). Western blot analysis revealed a major protein band that migrated at a M_r of 96 kDa. Northern blot analysis identified an mRNA of approximately 7 kilobases which hybridized with a specific glucocorticoid receptor complementary DNA probe (OB7). These findings support a role for glucocorticoids in the regulation of human malignant pancreatic cell function.     

Age-related changes in the tissue content of total iodine, its hormonal and nonhormonal compounds and their metabolic course

By the spectrophotometric method the age changes of total iodine content, its hormonal and non-hormonal compounds in rats and men tissues (muscles, liver, kidney, heart, lungs, brain, spleen and blood) have been studied. It was established that the total iodine content decreased at the expense of the protein-bound iodine concentration and also of the butyl-alcohol extractable iodine. The exchange of thyroid hormones intensity lowered.     

Resistance to receptor-mediated degradation of a murine epidermal growth factor analogue (EGF-Val-47) potentiates its mitogenic activity

In most cell types two classes of epidermal growth factor (EGF) receptors can be found: a major class that binds EGF with relatively low affinity and a minor class that binds with very high affinity. Structure-function studies have shown that mutations at amino acid 47 in the EGF molecule severely reduce its affinity for the EGF receptor but do not cause preferential binding to one or the other subclass of receptors. Using three EGF derivatives with a mutation at amino acid 47 (Ser-47, Leu-37-Tyr-47, and Val-47), we have investigated the relative contribution of the two receptor subclasses to the EGF-dependent mitogenic response. We show that mitogenicity correlates exclusively with occupancy of the high-affinity receptor and that full occupancy of this subclass is required for maximal stimulation. In addition we demonstrate that for the EGF-Val-47 analogue this requirement can be abrogated and half-maximal biological activity reached with a high-affinity receptor occupancy of only 8%. While the rate of internalization did not significantly differ between EGF-Val-47 and native mEGF, the analogue was much more resistant to degradation by cellular proteases and, after binding and receptor-mediated internalization, was released into the medium predominantly in an intact form. We propose that the increased mitogenicity of EGF-Val-47 is due to its prolonged half-life, resulting in continued occupancy of the high-affinity EGF receptor.     

Benthic ecoregionalization based on echinoid fauna of the Southern Ocean supports current proposals of Antarctic Marine Protected Areas under IPCC scenarios of climate change

The Southern Ocean (SO) is among the regions on Earth that are undergoing regionally the fastest environmental changes. The unique ecological features of its marine life make it particularly vulnerable to the multiple effects of climate change. A network of Marine Protected Areas (MPAs) has started to be implemented in the SO to protect marine ecosystems. However, considering future predictions of the Intergovernmental Panel on Climate Change (IPCC), the relevance of current, static, MPAs may be questioned under future scenarios. In this context, the ecoregionalization approach can prove promising in identifying well‐delimited regions of common species composition and environmental settings. These so‐called ecoregions are expected to show similar biotic responses to environmental changes and can be used to define priority areas for the designation of new MPAs and the update of their current delimitation. In the present work, a benthic ecoregionalization of the entire SO is proposed for the first time based on abiotic environmental parameters and the distribution of echinoid fauna, a diversified and common member of Antarctic benthic ecosystems. A novel two‐step approach was developed combining species distribution modeling with Random Forest and Gaussian Mixture modeling from species probabilities to define current ecoregions and predict future ecoregions under IPCC scenarios RCP 4.5 and 8.5. The ecological representativity of current and proposed MPAs of the SO is discussed with regard to the modeled benthic ecoregions. In all, 12 benthic ecoregions were determined under present conditions, they are representative of major biogeographic patterns already described. Our results show that the most dramatic changes can be expected along the Antarctic Peninsula, in East Antarctica and the sub‐Antarctic islands under both IPCC scenarios. Our results advocate for a dynamic definition of MPAs, they also argue for improving the representativity of Antarctic ecoregions in proposed MPAs and support current proposals of Conservation of Antarctic Marine Living Resources for the creation of Antarctic MPAs.