GDF-15 is an inhibitor of leukocyte integrin activation required for survival after myocardial infarction in mice

Inflammatory cell recruitment after myocardial infarction needs to be tightly controlled to permit infarct healing while avoiding fatal complications such as cardiac rupture. Growth differentiation factor-15 (GDF-15), a transforming growth factor-β (TGF-β)-related cytokine, is induced in the infarcted heart of mice and humans. We show that coronary artery ligation in Gdf15-deficient mice led to enhanced recruitment of polymorphonuclear leukocytes (PMNs) into the infarcted myocardium and an increased incidence of cardiac rupture. Conversely, infusion of recombinant GDF-15 repressed PMN recruitment after myocardial infarction. In vitro, GDF-15 inhibited PMN adhesion, arrest under flow and transendothelial migration. Mechanistically, GDF-15 counteracted chemokine-triggered conformational activation and clustering of β(2) integrins on PMNs by activating the small GTPase Cdc42 and inhibiting activation of the small GTPase Rap1. Intravital microscopy in vivo in Gdf15-deficient mice showed that Gdf-15 is required to prevent excessive chemokine-activated leukocyte arrest on the endothelium. Genetic ablation of β(2) integrins in myeloid cells rescued the mortality of Gdf15-deficient mice after myocardial infarction. To our knowledge, GDF-15 is the first cytokine identified as an inhibitor of PMN recruitment by direct interference with chemokine signaling and integrin activation. Loss of this anti-inflammatory mechanism leads to fatal cardiac rupture after myocardial infarction.     

CD4+CD25+ regulatory cells contribute to the regulation of colonic Th2 granulomatous pathology caused by schistosome infection

Eggs of the helminth Schistosoma mansoni accumulate in the colon following infection and generate Th2-biassed inflammatory granulomas which become down- modulated in size as the infection proceeds to chronicity. However, although CD4+CD25+FoxP3+ regulatory T cells (T(regs)) are known to suppress Th1-mediated colitis, it is not clear whether they control Th2-associated pathologies of the large intestine which characterise several helminth infections. Here we used a novel 3D-multiphoton confocal microscopy approach to visualise and quantify changes in the size and composition of colonic granulomas at the acute and chronic phases of S. mansoni infection. We observed decreased granuloma size, as well as reductions in the abundance of DsRed+ T cells and collagen deposition at 14 weeks (chronic) compared to 8 weeks (acute) post-infection. Th2 cytokine production (i.e. IL-4, IL-5) in the colonic tissue and draining mesenteric lymph node (mLN) decreased during the chronic phase of infection, whilst levels of TGF-β1 increased, co-incident with reduced mLN proliferative responses, granuloma size and fibrosis. The proportion of CD4+CD25+FoxP3+T(regs): CD4+ cells in the mLN increased during chronic disease, while within colonic granulomas there was an approximate 4-fold increase. The proportion of CD4+CD25+FoxP3+T(regs) in the mLN that were CD103+ and CCR5+ also increased indicating an enhanced potential to home to intestinal sites. CD4+CD25+ cells suppressed antigen-specific Th2 mLN cell proliferation in vitro, while their removal during chronic disease resulted in significantly larger granulomas, partial reversal of Th2 hypo-responsiveness and an increase in the number of eosinophils in colonic granulomas. Finally, transfer of schistosome infection-expanded CD4+CD25+T(regs) down-modulated the development of colonic granulomas, including collagen deposition. Therefore, CD4+CD25+FoxP3+T(regs) appear to control Th2 colonic granulomas during chronic infection, and are likely to play a role in containing pathology during intestinal schistosomiasis.     

Spatial movement of adult leopard seals (Hydrurga leptonyx) in Prydz Bay, Eastern Antarctica

This is the first study that has used satellite telemetry to assess the spatial behaviour of adult leopard seals. Satellite tags on 11 leopard seals transmitted between 29 days and 282 days. Swim speeds, distances swum per day and distances from tagging site were significantly different among individuals and seasons. Swim speeds ranged from 0.004 km/h to 10.86 km/h; distances swum per day from 0 km/day to 150 km/day; and the maximum distances from tagging site ranged from 33.30 km to 319.97 km. Rather than moving north-south with the ice most seals remained within a 50 km radius of their tagging site from 11 days to 97 days. The relatively sedentary movement of the leopard seals was unexpected, particularly the movement of animals over winter, which although slightly offshore did not reflect the usual northward winter migration described for the leopard seal. But traditionally, the leopard seals spatial habits have been described from sightings of animals at higher latitudes. These are generally younger animals and their behaviour may not be representative of the adults. This study has focused on adult females and animals at the extreme southerly range of the leopard seal. This highlights the importance of understanding and reporting age structure and distribution when discussing animal spatial behaviour.     

Expression of mRNA encoding insulin-like growth factor binding protein-2 (IGFBP-2) during induced and natural regression of equine corpora lutea

The insulin-like growth factors, IGF-I and -II, have been shown to play a key role in luteal function in some species. The IGF binding proteins, IGFBP-2 and -3, have been shown to inhibit binding of IGF-I and -II to bovine luteal cells and decrease progesterone production. We have recently shown that equine follicles have the genetic capacity to produce IGFBP-2, and that levels decrease in healthy preovulatory follicles. In the present study expression of mRNAs encoding IGFBP-2, as well as the rate-limiting steroidogenic enzyme, P450scc, were studied in equine corpora lutea to investigate whether IGFBP-2 might be involved in luteolysis. Corpora lutea were collected from mares in mid-luteal phase (day 10), at early regression (day 14), late regression (day 17), and 12 and 36 h after intramuscular administration of the PGF(2alpha) analogue, cloprostenol (0.5 microg/kg). During early natural regression, and 12 h after administration of cloprostenol on day 10, steady state levels of mRNAs encoding P450scc had decreased significantly compared with day 10 of dioestrus (P < 0.001). Levels of mRNA encoding IGFBP-2 increased significantly between mid-diestrus and early (P < 0.01) and late (P < 0.001) regression, and 36 h after cloprostenol administration (P < 0.001). We conclude that the genetic capacity for increased IGFBP-2 production in the early stages of natural luteolysis in the mare may act to sequester IGF-I in the CL, assisting in inhibition of progesterone production. However the delay in increase in mRNA encoding IGFBP-2 after cloprostenol administration, combined with the sharp fall in expression of P450scc mRNA, suggests that the luteolytic action of a pharmacological dose of cloprostenol may not be mediated via IGFBP-2 in the mare.     

Bumps in the road: how replicative DNA polymerases see DNA damage

Significant advances have been made recently in the study of polymerases. First came the realization that there are many more DNA polymerases than originally thought; indeed, no fewer than 14 template-dependent DNA polymerases are found in mammals. Concurrent structural studies of DNA polymerases bound to DNA and incoming nucleotide have revealed how these remarkable copying machines select the correct deoxynucleoside triphosphate among a sea of nucleotides. A whole new level of insight into DNA replication fidelity has been reached as a result of recently determined crystal structures of DNA lesions in the context of the active sites of repair, replicative and specialized DNA polymerases. These structures illustrate why some lesions can be bypassed readily, whereas others are strong blocks to DNA replication.     

Effect of soil potassium availability on soybean aphid (Hemiptera: Aphididae) population dynamics and soybean yield

Studies were conducted to examine the effect of potassium (K) on soybean aphid, Aphis glycines Matsumura, population growth. A laboratory feeding assay examined the effect of K-deficient foliage on life table parameters of soybean aphids, and field experiments were designed to determine the effect of three soil K treatment levels on aphid populations and their impact on soybean yields. The feeding assay found that life table parameters differed between aphids feeding on the K-deficient and nondeficient soybean leaves. Soybean aphids in the K-deficient treatment exhibited significantly greater intrinsic rate of increase (r(m)), finite rate of increase (lambda), and net reproductive rate (Ro) relative to aphids feeding on nondeficient leaves. No significant difference was observed in mean generation time (T) between the two treatments. However, the field experiment repeated over 2 yr showed no effect of K on soybean aphid populations. Soybean aphid populations were high in unsprayed plots and feeding resulted in significant yield losses in 2002 at all three K treatment levels: when averaged across 2001 and 2002, unsprayed treatments yielded 22, 18, and 19.5% less than the sprayed plots in the low, medium, and high K treatments, respectively. No significant interaction was observed between aphid abundance and K level on soybean yields in either year. This study therefore suggests that although aphids can perform better on K-deficient plants, aphid abundance in the field may be dependent on additional factors, such as dispersal, that may affect final densities within plots.     

The Y deletion gr/gr and susceptibility to testicular germ cell tumor

Testicular germ cell tumor (TGCT) is the most common cancer in young men. Despite a considerable familial component to TGCT risk, no genetic change that confers increased risk has been substantiated to date. The human Y chromosome carries a number of genes specifically involved in male germ cell development, and deletion of the AZFc region at Yq11 is the most common known genetic cause of infertility. Recently, a 1.6-Mb deletion of the Y chromosome that removes part of the AZFc region—known as the “gr/gr” deletion—has been associated with infertility. In epidemiological studies, male infertility has shown an association with TGCT that is out of proportion with what can be explained by tumor effects. Thus, we hypothesized that the gr/gr deletion may be associated with TGCT. Using logistic modeling, we analyzed this deletion in a large series of TGCT cases with and without a family history of TGCT. The gr/gr deletion was present in 3.0% (13/431) of TGCT cases with a family history, 2% (28/1,376) of TGCT cases without a family history, and 1.3% (33/2,599) of unaffected males. Presence of the gr/gr deletion was associated with a twofold increased risk of TGCT (adjusted odds ratio [aOR] 2.1; 95% confidence interval [CI] 1.3–3.6; P = .005) and a threefold increased risk of TGCT among patients with a positive family history (aOR 3.2; 95% CI 1.5–6.7; P = .0027). The gr/gr deletion was more strongly associated with seminoma (aOR 3.0; 95% CI 1.6–5.4; P = .0004) than with nonseminoma TGCT (aOR 1.5; 95% CI 0.72–3.0; P = .29). These data indicate that the Y microdeletion gr/gr is a rare, low-penetrance allele that confers susceptibility to TGCT.     

Nitrite as a vascular endocrine nitric oxide reservoir that contributes to hypoxic signaling, cytoprotection, and vasodilation

Accumulating evidence suggests that the simple and ubiquitous anion salt, nitrite (NO(2)(-)), is a physiological signaling molecule with potential roles in intravascular endocrine nitric oxide (NO) transport, hypoxic vasodilation, signaling, and cytoprotection after ischemia-reperfusion. Human and animal studies of nitrite treatment and NO gas inhalation provide evidence that nitrite mediates many of the systemic therapeutic effects of NO gas inhalation, including peripheral vasodilation and prevention of ischemia-reperfusion-mediated tissue infarction. With regard to nitrite-dependent hypoxic signaling, biochemical and physiological studies suggest that hemoglobin possesses an allosterically regulated nitrite reductase activity that reduces nitrite to NO along the physiological oxygen gradient, potentially contributing to hypoxic vasodilation. An expanded consideration of nitrite as a hypoxia-dependent intrinsic signaling molecule has opened up a new field of research and therapeutic opportunities for diseases associated with regional hypoxia and vasoconstriction.     

Urinary cortisol sampling: a non‐invasive technique for examining cortisol concentrations in the Weddell seal,Leptonychotes weddellii

This study investigated the feasibility and validity of using non‐invasively collected ice urine samples to measure cortisol concentrations in Weddell seals. Radio‐immunoassays were used to determine urinary cortisol, and spectrophotometric assay was used to determine creatinine concentrations. This allowed for urinary cortisol/creatinine ratios (UCCR) to be compared between pure urine and urine collected from the ice. Urinary cortisol/creatinine ratios values of ice urine proved an effective method of studying cortisol concentrations in Weddell seals as there was no difference between pure urine and ice urine UCCR values. There were no inter‐sexual or age‐related differences in UCCR values in either pure or ice urine. Zoo Biol 0:1–8, 2006. © 2006 Wiley‐Liss, Inc.