Paleotemperature and productivity reconstruction of sediment core D11957P on the Iberian Margin

Foraminifera counts and climatic assemblages from the Tore Seamount are used to approach the glacial and interglacial changes in temperature and productivity on the Iberian Margin over the last 225 kyr. Chronostratigraphy is based on Globigerinoides ruber and Globigerina bulloides oxygen isotopes and supported by foraminifera and carbonate stadial fluctuations. Foraminifera indicate cooling from late interglacial stage 5 to the beginning of Termination I (TI). Neogloboquadnna pachyderma-s reflects cold conditions during glacial stages 4-2. In contrast, glacial stage 6 is dominated by warmer N. pachyderma-d and dutertrei and a restricted arctic assemblage. Past sea surface temperatures confirm the general cooling, reaching 4.3°C (SIMMAX.28) during stage 2. Multiple productivity proxies such as organic carbon, productivity-related foraminifera, and delta13C constrain the changes observed. A productivity increase occurs after interglacial stage 5, enhanced from late glacial stage 3 to TI Present-day satellite-detected phytoplankton plumes off Portugal would have accounted in the past glacial stages for the general productivity increase over the Tore. On top of this, welldefined peaks of organic carbon and productivity-related foraminifera correspond with Heinrich events 1-4.

Living benthic foraminifers from the central Arctic Ocean

Fifty short sediment cores collected with a multiple corer and five box cores from the central Arctic Ocean were analysed to study the ecology and distribution of benthic foraminifers. To work out living faunal associations, standing stock and diversity, separate analyses of living (Rose Bengal stained) and dead foraminifers were carried out for the sediment surface. The size fractions between 63 and 125 µm and >125 µm were counted separately to allow comparison with former Arctic studies and with studies from the adjacent Norwegian-Greenland Sea, Barents Sea and the North Atlantic Ocean. Benthic foraminiferal associations are mainly controlled by the availability of food, and competition for food, while water mass characteristics, bottom current activity, substrate composition, and water depth are of minor importance. Off Spitsbergen in seasonally ice-free areas, high primary production rates are reflected by high standing stocks, high diversities, and foraminiferal associations (>125 µm) that are similar to those of the Norwegian-Greenland Sea. Generally, in seasonally ice-free areas standing stock and diversity increase with increasing food supply. In the central Arctic Ocean, the oligotrophic permanently ice-covered areas are dominated by epibenthic species. The limited food availability is reflected by very low standing stocks and low diversities. Most of these foraminiferal associations do not correspond to those of the Norwegian-Greenland Sea. The dominant associations include simple agglutinated species such as Sorosphaerae, Placopsilinellae, Komokiacea and Aschemonellae, as well as small calcareous species such as Stetsonia horvathi and Epistominella arctica. Those of the foraminiferal species that usually thrive under seasonally ice-free conditions in middle bathyal to lower bathyal water depth are found under permanently ice-covered conditions in water depths about 1000 m shallower, if present at all.

Planktonic foraminifera abundances and isotopes of Late Quaternary sediments off New Zealand

A series of cores from east of New Zealand have been examined to determine the paleoceanographic history of the late Quaternary in the SW Pacific using planktonic foraminiferal data. Distinct shifts of species can be seen between glacial and interglacial times especially south of Chatham Rise east of South Island. Foraminiferal fragmentation ratios and benthic/planktonic foraminiferal ratios both show increased dissolution during glacials, especially isotope stage 2 to the south of Chatham Rise. The present-day Subtropical Convergence appears to be tied to the Chatham Rise at 44°S, but during glacial times this rise separated cold water to the south from much warmer water to the north, with an associated strong thermal gradient across the rise. We estimate that this gradient could have presented as much as an 8°C temperature change across 4° of latitude during the maximum of the last ice age. There is only weak evidence of the Younger Dryas cool event, but there is a clear climatic optimum between 8 and 6.4 ka with temperatures 1°-2°C higher than the present day. The marine changes compare well with vegetational changes on both South and North Island.

Sea-surface temperature reconstruction and calibration-function of sediment cores from the Southern Ocean

We provide a new multivariate calibration-function based on South Atlantic modern assemblages of planktonic foraminifera and atlas water column parameters from the Antarctic Circumpolar Current to the Subtropical Gyre and tropical warm waters (i.e., 60°S to 0°S). Therefore, we used a dataset with the abundance pattern of 35 taxonomic groups of planktonic foraminifera in 141 surface sediment samples. Five factors were taken into consideration for the analysis, which account for 93% of the total variance of the original data representing the regional main oceanographic fronts. The new calibration-function F141-35-5 enables the reconstruction of Late Quaternary summer and winter sea-surface temperatures with a statistical error of ~0.5°C. Our function was verified by its application to a sediment core extracted from the western South Atlantic. The downcore reconstruction shows negative anomalies in sea-surface temperatures during the early-mid Holocene and temperatures within the range of modern values during the late Holocene. This pattern is consistent with available reconstructions.

Characterization of bone pathologies in the ins2+/akita mouse, a new model for diabetes insulindependent: contribution for a better understanding of the disease in humans

Tese de Doutoramento, Ciências Biomédicas, Departamento de Ciências Biomédicas e Medicina, Universidade do Algarve, 2016

Retinal pigment epithelium protein of 65 kDA gene-linked retinal degeneration is not modulated by chicken acidic leucine-rich epidermal growth factor-like domain containing brain protein/Neuroglycan C/ chondroitin sulfate proteoglycan 5.

PURPOSE: To analyze in vivo the function of chicken acidic leucine-rich epidermal growth factor-like domain containing brain protein/Neuroglycan C (gene symbol: Cspg5) during retinal degeneration in the Rpe65̿5;/̿5; mouse model of Leber congenital amaurosis. METHODS: We resorted to mice with targeted deletions in the Cspg5 and retinal pigment epithelium protein of 65 kDa (Rpe65) genes (Cspg5̿5;/̿5;/Rpe65̿5;/̿5;). Cone degeneration was assessed with cone-specific peanut agglutinin staining. Transcriptional expression of rhodopsin (Rho), S-opsin (Opn1sw), M-opsin (Opn1mw), rod transducin ^5; subunit (Gnat1), and cone transducin ^5; subunit (Gnat2) genes was assessed with quantitative PCR from 2 weeks to 12 months. The retinal pigment epithelium (RPE) was analyzed at P14 with immunodetection of the retinol-binding protein membrane receptor Stra6. RESULTS: No differences in the progression of retinal degeneration were observed between the Rpe65̿5;/̿5; and Cspg5̿5;/̿5;/Rpe65̿5;/̿5; mice. No retinal phenotype was detected in the late postnatal and adult Cspg5̿5;/̿5; mice, when compared to the wild-type mice. CONCLUSIONS: Despite the previously reported upregulation of Cspg5 during retinal degeneration in Rpe65̿5;/̿5; mice, no protective effect or any involvement of Cspg5 in disease progression was identified.

Binding of Insulin-like Growth Factor (IGF)–Binding Protein-5 to Smooth-Muscle Cell Extracellular Matrix Is a Major Determinant of the Cellular Response to IGF-I

Insulin-like growth factor–binding protein-5 (IGFBP-5) has been shown to bind to fibroblast extracellular matrix (ECM). Extracellular matrix binding of IGFBP-5 leads to a decrease in its affinity for insulin-like growth factor-I (IGF-I), which allows IGF-I to better equilibrate with IGF receptors. When the amount of IGFBP-5 that is bound to ECM is increased by exogenous addition, IGF-I’s effect on fibroblast growth is enhanced. In this study we identified the specific basic residues in IGFBP-5 that mediate its binding to porcine smooth-muscle cell (pSMC) ECM. An IGFBP-5 mutant containing alterations of basic residues at positions 211, 214, 217, and 218 had the greatest reduction in ECM binding, although three other mutants, R214A, R207A/K211N, and K202A/R206N/R207A, also had major decreases. In contrast, three other mutants, R201A/K202N/R206N/R208A, and K217N/R218A and K211N, had only minimal reductions in ECM binding. This suggested that residues R207 and R214 were the most important for binding, whereas alterations in K211 and R218, which align near them, had minimal effects. To determine the effect of a reduction in ECM binding on the cellular replication response to IGF-I, pSMCs were transfected with the mutant cDNAs that encoded the forms of IGFBPs with the greatest changes in ECM binding. The ECM content of IGFBP-5 from cultures expressing the K211N, R214A, R217A/R218A, and K202A/R206N/R207A mutants was reduced by 79.6 and 71.7%, respectively, compared with cells expressing the wild-type protein. In contrast, abundance of the R201A/K202N/R206N/R208A mutant was reduced by only 14%. Cells expressing the two mutants with reduced ECM binding had decreased DNA synthesis responses to IGF-I, but the cells expressing the R201A/K202N/R206N/R208A mutant responded well to IGF-I. The findings suggest that specific basic amino acids at positions 207 and 214 mediate the binding of IGFBP-5 to pSMC/ECM. Smooth-muscle cells that constitutively express the mutants that bind weakly to ECM are less responsive to IGF-I, suggesting that ECM binding of IGFBP-5 is an important variable that determines cellular responsiveness.

Identification of regions within the third FnIII-like domain of the IL-5R alpha involved in IL-5 interaction

Previously, two binding sites for interleukin 5 (IL-5) were identified on the IL-5 receptor alpha chain (IL-5R alpha). They are located within the CD loop of the first fibronectin type III (FnIII)-like domain and the EF loop of the second FnIII-like domain. The first binding site was identified by exploiting the different abilities of human IL-5R alpha (hIL-5R alpha) and mouse IL-5R alpha (mIL-5R alpha) to bind hIL-5. Here we show that ovine IL-5 (oIL-5) has the ability to activate the hIL-5R alpha but not the mIL-5R alpha. By using chimeras of the mIL-5R alpha and hIL-5R alpha we demonstrate that residues within the first and third FnIII-like domains of mIL-5R alpha are responsible for this lack of activity. Furthermore, mutation of residues on hIL-5R alpha to mIL-5R alpha within the predicted DE and FG loop regions of the third FnIII domain reduces oIL-5 activity, These results show that regions of the third FnIII domain of IL-5R alpha are involved in binding, in addition to the regions in domains one and two of the IL-5R alpha that were identified in an earlier study. (C) 2000 Academic Press.

Placental growth hormone (GH), GH-binding protein, and insulin-like growth factor axis in normal, growth-retarded, and diabetic pregnancies: Correlations with fetal growth

We previously described significant changes in GH-binding protein (GHBP) in pathological human pregnancy. There was a substantial elevation of GHBP in cases of noninsulin-dependent diabetes mellitus and a reduction in insulin-dependent diabetes mellitus. GHBP has the potential to modulate the proportion of free placental GH (PGH) and hence the impact on the maternal GH/insulin-like growth factor I (IGF-I) axis, fetal growth, and maternal glycemic status. The present study was undertaken to investigate the relationship among glycemia, GHBP, and PGH during pregnancy and to assess the impact of GHBP on the concentration of free PGH. We have extended the analysis of specimens to include measurements of GHBP, PGH, IGF-I, IGF-II, IGF-binding protein-1 (IGFBP-1), IGFSP-2, and IGFBP-3 and have related these to maternal characteristics, fetal growth, and glycemia. The simultaneous measurement of GHBP and PGH has for the first time allowed calculation of the free component of PGH and correlation of the free component to indexes of fetal growth and other endocrine markers. PGH, free PGH, IGF-I, and IGF-II were substantially decreased in IUGR at 28-30 weeks gestation (K28) and 36-38 weeks gestation (K36). The mean concentration (+/-SEM) of total PGH increased significantly from K28 to K36 (30.0 +/- 2.2 to 50.7 +/- 6.2 ng/mL; n = 40), as did the concentration of free PGH (23.4 +/- 2.3 to 43.7 +/- 6.0 ng/mL; n = 38). The mean percentage of free PGH was significantly less in IUGR than in normal subjects (67% vs. 79%; P < 0.01). Macrosomia was associated with an increase in these parameters that did not reach statistical significance. Multiple regression analysis revealed that PGH/IGF-I and IGFBP-5 account for 40% of the variance in birth weight. IGFBP-3 showed a significant correlation with IGF-I, IGF-II, and free and total PGK at K28 and K36. Noninsulin-dependent diabetes mellitus patients had a lower mean percentage of free PGH (65%; P < 0.01), and insulin-dependent diabetics had a higher mean percentage of free PGH (87%; P < 0.01) than normal subjects. Mean postprandial glucose at K28 correlated positively with PGH and free PGH (consistent with the hyperglycemic action of GH). GHBP correlated negatively with both postprandial and fasting glucose. Although GHBP correlated negatively with PGH (r = -0.52; P

Expression of insulin-like growth factor-II and its receptor in pediatric and adult adrenocortical tumors

Background: Adrenocortical tumors are heterogeneous neoplasms with incompletely understood pathogenesis. IGF-II overexpression has been consistently demonstrated in adult adrenocortical carcinomas. Objectives: The objective of the study was to analyze expression of IGF-II and its receptor (IGF-IR) in pediatric and adult adrenocortical tumors and the effects of a selective IGF-IR kinase inhibitor (NVP-AEW541) on adrenocortical tumor cells. Patients: Fifty-seven adrenocortical tumors (37 adenomas and 20 carcinomas) from 23 children and 34 adults were studied. Methods: Gene expression was determined by quantitative real-time PCR. Cell proliferation and apoptosis were analyzed in NCI H295 cells and a new cell line established from a pediatric adrenocortical adenoma. Results: IGF-II transcripts were overexpressed in both pediatric adrenocortical carcinomas and adenomas. Otherwise, IGF-II was mainly overexpressed in adult adrenocortical carcinomas (270.5 +/- 130.2 vs. 16.1 +/- 13.3; P = 0.0001). IGF-IR expression was significantly higher in pediatric adrenocortical carcinomas than adenomas (9.1 +/- 3.1 vs. 2.6 +/- 0.3; P = 0.0001), whereas its expression was similar in adult adrenocortical carcinomas and adenomas. IGF-IR expression was a predictor of metastases in pediatric adrenocortical tumors in univariate analysis (hazard ratio 1.84; 95% confidence interval 1.28 -2.66; P = 0.01). Furthermore, NVP-AEW541 blocked cell proliferation in a dose-and time-dependent manner in both cell lines through a significant increase of apoptosis. Conclusion: IGF-IR overexpression was a biomarker of pediatric adrenocortical carcinomas. Additionally, a selective IGF-IR kinase inhibitor had antitumor effects in adult and pediatric adrenocortical tumor cell lines, suggesting that IGF-IR inhibitors represent a promising therapy for human adrenocortical carcinoma.

Insulin-like growth factor-1 and 17 beta-estradiol down-regulate prostate apoptosis response-4 expression in MCF-7 breast cancer cells

The PKC apoptosis WTI regulator gene, also named prostate apoptosis response-4 (PAR-4), encodes a pro-apoptotic protein that sensitizes cells to numerous apoptotic stimuli. Insulin-like growth factor-1 (IGF-1) and 17 beta-estradiol (E2), two important factors for breast cancer development and progression, have been shown to down-regulate PAR-4 expression and inhibit apoptosis induced by PAR-4 in neuronal cells. In this study, we sought to investigate the mechanisms of regulation of PAR-4 gene expression in MCF-7 cells treated with E2 or IGF-1. E2 (10 nM) and IGF-1 (12.5 nM) each down-regulated PAR-4 expression in MCF-7 cells after 24 h of treatment. The effect of E2 was dependent on ER activation, as demonstrated by an increase in PAR-4 expression when cells were pretreated for 1 h with 1 mu M ICI-182,780 (ICI) before receiving E2 plus ICI. The effect of IGF-1 was abolished by pre-treatment for 1 h with 30 mu M LY294002 (a specific PI3-K inhibitor), and significantly inhibited by 30 mu M SB202190 (a specific p38MAPK inhibitor). We also demonstrated that E2 acts synergistically with IGF-1, resulting in greater down-regulation of PAR-4 mRNA expression compared with E2 or IGF-1 alone. Our results show for the first time that E2 and IGF-1 inhibit PAR-4 gene expression in MCF-7 cells, suggesting that this down-regulation may provide a selective advantage for breast cancer cell survival.