Susceptibility versus resistance in alveolar echinococcosis (larval infection with Echinococcus multilocularis).

Epidemiological studies have demonstrated that the majority of human individuals exposed to infection with Echinococcus spp. eggs exhibit resistance to disease as shown by either seroconversion to parasite--specific antigens, and/or the presence of 'dying out' or 'aborted' metacestodes, not including hereby those individuals who putatively got infected but did not seroconvert and who subsequently allowed no development of the pathogen. For those individuals where infection leads to disease, the developing parasite is partially controlled by host immunity. In infected humans, the type of immune response developed by the host accounts for the subsequent trichotomy concerning the parasite development: (i) seroconversion proving infection, but lack of any hepatic lesion indicating the failure of the parasite to establish and further develop within the liver; or resistance as shown by the presence of fully calcified lesions; (ii) controlled susceptibility as found in the "conventional" alveolar echinococcosis (AE) patients who experience clinical signs and symptoms approximately 5-15 years after infection, and (iii) uncontrolled hyperproliferation of the metacestode due to an impaired immune response (AIDS or other immunodeficiencies). Immunomodulation of host immunity toward anergy seems to be triggered by parasite metabolites. Beside immunomodulating IL-10, TGFβ-driven regulatory T cells have been shown to play a crucial role in the parasite-modulated progressive course of AE. A novel CD4+CD25+ Treg effector molecule FGL2 recently yielded new insight into the tolerance process in Echinococcus multilocularis infection.

AUGMENTATION OF RECONSTITUTION OF GUT ASSOCIATED LYMPHOID TISSUE IN THE SYNGENEIC MURINE BONE MARROW TRANSPLANTATION MODEL

Gut was studied as a prototypical mucosal membrane in the murine BDF-1 syngeneic bone marrow transplant model. Measures of jejunal intraepithelial lymphocytes (IELs) and crypt cells were obtained by standard techniques and a method of quantifying gut lamina propria plasma cells (PCs) was developed. The degree of ablation of gut PCs and IELs after 900 rads total body irradiation with ('60)Co, and their repopulation effected by transplantation with 2.0 x 10('5) or 1.0 x 10('6) bone marrow cells demonstrated a prolonged period of profound depression in population levels of these cells which was not reflected by the extent of damage sustained to the epithelium. Differences in the depopulation and recovery of gut PCs and IELs revealed a tendency towards initial differentiation of effector cells. A positive dose response to high bone marrow cell innocula was obtained. Subsequent studies determined that gut IEL and PC repopulation was potentiated by the addition of IELs or buffy coat cells (BCs) to the bone marrow transplant. A method of isolating 1.4 - 4.0 x 10('7) viable IELs per gram of murine small bowel was devised employing intralumenal hyaluronidase digestion of the epithelial layer and centrifugation of the resulting suspension through discontinuous Percoll gradients. Irradiated mice received 2.0 x 10('5) bone marrow cells along with an equal number of IELs or BCs. The extent and duration of depression of numbers of IELs and PCs was markedly reduced by the addition of the IEL isolate to the transplantation innocula, and to a lesser degree by the addition of BCs. The augmentation of repopuation far exceeded that expected by simple lodging of cells suggesting that the additionally transplanted cells contained a subpopulation of mucosal membrane lymphoid stem cells or helper cells. Correlation analysis of PC versus IEL levels suggests a possible feedback mechanism governing the relative size of their populations. Normal ratios of IgA, IgM, and IgG bearing PCs was maintained post transplantation with all of the regimens. ^

Effects of asbestos and silica on superoxide anion production in the guinea pig alveolar macrophage

Asbestos and silica are important industrial hazards. Exposure to these dusts can result in pulmonary fibrosis and, in the case of asbestos, cancer. Although the hazards of asbestos and silica exposure have long been known, the pathogenesis of dust-related disease is not well understood. Both silica and asbestos are thought to alter the function of the alveolar macrophage, but the nature of the biochemical alteration is unknown. Therefore, this study examined the effect of asbestos and silica on the activation pathway of the guinea pig alveolar macrophage. Activation of macrophages by physiological agents results in stimulation of phospholipase C causing phosphatidyl inositol turnover and intracellular calcium mobilization. Phosphatidyl inositol turnover produces diacylglycerol which activates protein kinase C causing superoxide anion production.^ Chrysotile stimulated alveolar macrophages to produce superoxide anion. This stimulation proceeded via phospholipase C, since chrysotile stimulated phosphatidyl inositol turnover and intracellular calcium mobilization. The possible involvement of a coupling protein was evaluated by pretreating cells with pertussis toxin. Pertussis toxin pretreatment partially inhibited chrysotile stimulation, suggesting that chrysotile activates a coupling protein in an non-classical manner. Potential binding sites for chrysotile stimulation were examined using a series of nine lectins. Chrysotile-stimulated superoxide anion production was blocked by pretreatment with lectins which bound to N-acetylglucosamine, but not by lectins which bound to mannose, fucose, or N-acetylgalactosamine. In addition, incubation with the N-acetylglucosamine polymer, chitin, inhibited chrysotile-stimulated superoxide anion production, suggesting that chrysotile stimulated superoxide anion production by binding to N-acetylglucosamine residues.^ On the other hand, silica did not stimulate superoxide anion production. The effect of silica on agonist stimulation of this pathway was examined using two stimulants of superoxide anion production, N-formyl-nle-leu-phe (FNLP, which stimulates through phospholipase C) and phorbol-12,13-dibutyrate (which directly activates protein kinase C). Sublethal doses of silica inhibited FNLP-stimulated superoxide anion production, but did not affect phorbol-12,13-dibutyrate-stimulated superoxide anion production, suggesting that the site of inhibition precedes protein kinase C. This inhibition was not due to cell membrane damage, since cell permeability to calcium-45 and rubidium-86 was not increased. It is concluded that chrysotile binds to N-acetylglucosamine residues on macrophage surface glycoproteins to stimulate the physiological pathway resulting in superoxide anion production. In contrast, silica does not stimulate superoxide anion production, but it did inhibit FNLP-stimulated superoxide anion production. ^

Differential stress response and susceptibility to oxidative injury in alveolar macrophages from C57BL/6J and C3H/HeJ mice following oxidant exposure

Studies have demonstrated a variable response to ozone among individuals and animal species and strains. For instance, C57BL/6J mice have a greater inflammatory response to ozone exposure than C3H/HeJ mice. In these studies, I utilized these strain differences in an effort to derive a mechanistic explanation to the variable strain sensitivity to ozone exposure. Therefore, alveolar macrophages (AM) from C57BL/6J and C3H/HeJ mice were exposed in vitro to hydrogen peroxide ($\rm H\sb2O\sb2$), heat and acetyl ceramide or in vivo to ozone. Necrosis and DNA fragmentation in macrophages from the two murine strains were determined to assess cytotoxicity following these treatments. In addition, synthesis and expression of the stress proteins, stress protein 72 (SP72) and heme oxygenase (HO-1), were examined following treatments. The in vitro experiments were conducted to eliminate the possibility of in vivo confounders (i.e., differences in breathing rates in the two strains) and thus directly implicate some inherent difference between cells from the two murine strains. $\rm H\sb2O\sb2$ and heat caused greater cytotoxicity in AM from C57BL/6J than C3H/HeJ mice and DNA fragmentation was a particularly sensitive indicator of cell injury. Similarly, AM from C57BL/6J mice were more sensitive to ozone exposure than cells from C3H/HeJ mice. Exposure to either 1 or 0.4 ppm ozone caused greater cytotoxicity in macrophages from C57BL/6J mice compared to macrophages from C3H/HeJ mice. The increased sensitivity of AM to injury was associated with decreased synthesis and expression of stress proteins. AM from C57BL/6J mice synthesized and expressed significantly less stress proteins in response to heat and ozone than AM from C3H/HeJ mice. Heat treatment resulted in greater synthesis and expression of SP72. In addition, macrophages from C57BL/6J mice expressed lower amounts of HO-1 than macrophages from C3H/HeJ mice following 0.4 ppm ozone exposure. Therefore, AM from C57BL/6J mice are more susceptible to oxidative injury than AM from C3H/HeJ mice which might be due to differential expression of stress proteins in these cells. ^

DISTRIBUTION FUNCTIONS, MEAN SQUARED ERRORS, AND CONFIDENCE LIMITS FOR RIDGE REGRESSION ESTIMATORS

A large number of ridge regression estimators have been proposed and used with little knowledge of their true distributions. Because of this lack of knowledge, these estimators cannot be used to test hypotheses or to form confidence intervals.^ This paper presents a basic technique for deriving the exact distribution functions for a class of generalized ridge estimators. The technique is applied to five prominent generalized ridge estimators. Graphs of the resulting distribution functions are presented. The actual behavior of these estimators is found to be considerably different than the behavior which is generally assumed for ridge estimators.^ This paper also uses the derived distributions to examine the mean squared error properties of the estimators. A technique for developing confidence intervals based on the generalized ridge estimators is also presented. ^

THE IMPROVEMENT REGION IN RIDGE REGRESSION

One of the difficulties in the practical application of ridge regression is that, for a given data set, it is unknown whether a selected ridge estimator has smaller squared error than the least squares estimator. The concept of the improvement region is defined, and a technique is developed which obtains approximate confidence intervals for the value of ridge k which produces the maximum reduction in mean squared error. Two simulation experiments were conducted to investigate how accurate these approximate confidence intervals might be. ^

Mechanism of silica -induced apoptosis in human alveolar macrophages

The mechanisms involved in the development of pulmonary silicosis have not been well defined, however most current evidence implicates a central role for alveolar macrophages in this process. We propose that the fibrotic potential of a particulate depends upon its ability to cause apoptosis in alveolar macrophage (AM). The overall goal of this study was to determine the mechanism of silica-induced apoptosis of AM. Human AM were treated with fibrogenic, poorly fibrogenic and nonfibrogenic model particulates, such as, silica, amorphous silica and titanium dioxide, respectively (equal surface area). Treatment with silica resulted in apoptosis in human AM as observed by morphology, DNA fragmentation and Cell Death ELISA assays. In contrast, amorphous silica and titanium dioxide demonstrated no significant apoptotic potential. To elucidate the possible mechanism by which silica causes apoptosis, we investigated the role of the scavenger receptor (SR) in silica-induced apoptosis. Cells were pretreated with and without SR ligand binding inhibitors, polyinosinic acid (Poly I), fucoidan and high density lipoprotein (HDL), prior to silica treatment. Pretreatment with Poly I and fucoidan resulted in significant inhibition of silica-induced apoptosis suggesting that silica-induced AM apoptosis is mediated via the SR. Further, we examined the involvement of interleukin converting enzyme (ICE) family of proteases in silica-mediated apoptosis. Silica activated ICE, Ich-1L, cpp32 beta and cleavage of PARP. Taken together, these results suggested that (1) fibrogenic particulates, such as, silica caused apoptosis of alveolar macrophages, (2) this apoptotic potential of fibrogenic particulates may be a critical factor in initiating an inflammatory response resulting in fibrosis, (3) silica-induced apoptosis of alveolar macrophages may be due to the interaction of silica particulates with the SR, and (4) silica-induced apoptosis involves the activation of the ICE family of proteases. An understanding of the molecular events involved in fibrogenic particulate-induced apoptosis may provide a useful insight into the mechanism involved in particulate-induced fibrosis. ^

Geochemical and palynological results of IODP Hole 302-M0004A from Lomonosov Ridge, Arctic Ocean

Several episodes of abrupt and transient warming, each lasting between 50,000 and 200,000 years, punctuated the long-term warming during the Late Palaeocene and Early Eocene (58 to 51 Myr ago) epochs**1,2. These hyperthermal events, such as the Eocene Thermal Maximum 2 (ETM2) that took place about 53.5 Myr ago**2, are associated with rapid increases in atmospheric CO2 content. However, the impacts of most events are documented only locally**3,4. Here we show, on the basis of estimates from the TEX86' proxy, that sea surface temperatures rose by 3-5 °C in the Arctic Ocean during the ETM2. Dinoflagellate fossils demonstrate a concomitant freshening and eutrophication of surface waters, which resulted in euxinia in the photic zone. The presence of palm pollen implies**5 that coldest month mean temperatures over the Arctic land masses were no less than 8 °C, in contradiction of model simulations that suggest hyperthermal winter temperatures were below freezing**6. In light of our reconstructed temperature and hydrologic trends, we conclude that the temperature and hydrographic responses to abruptly increased atmospheric CO2 concentrations were similar for the ETM2 and the better-described Palaeocene-Eocene Thermal Maximum**7,8, 55.5 Myr ago.

Planktonic foraminifera in the latest Maastrichtian of Walvis Ridge, South Atlantic

An abrupt global warming of 3-4°C occurred near the end of the Maastrichtian at 65.45-65.10 Ma. The environmental effects of this warm event are here documented based on stable isotopes and quantitative analysis of planktonic foraminifera at the South Atlantic DSDP Site 525A. Stable isotopes of individual species mark a rapid increase in temperature and a reduction in the vertical water mass stratification that is accompanied by a decrease in niche habitats, reduced species diversity and/or abundance, smaller species morphologies or dwarfing, and reduced photosymbiotic activity. During the warm event, the relative abundance of a large number of species decreased, including tropical-subtropical affiliated species, whereas typical mid-latitude species retained high abundances. This indicates that climate warming did not create favorable conditions for all tropical-subtropical species at mid-latitudes and did not cause a massive retreat in the local mid-latitude population. A noticeable exception is the ecological generalist Heterohelix dentata Stenestad that dominated during the cool intervals, but significantly decreased during the warm event. However, dwarfing is the most striking response to the abrupt warming and occurred in various species of different morphologies and lineages (e.g. biserial, trochospiral, keeled globotruncanids). Dwarfing is a typical reaction to environmental stress conditions and was likely the result of increased reproduction rates. Similarly, photosymbiotic activity appears to have been reduced significantly during the maximum warming, as indicated by decreased delta13C values. The foraminiferal response to climate change is thus multifaceted resulting in decreased species diversity, decreased species populations, increased competition due to reduced niche habitats, dwarfing and reduced photosymbiotic activity.

Zircons, isotope ratios and element analyses from tonalite and oxide gabbro of the mid-ocean ridge from ODP Hole 176-735B

A limiting factor in the accuracy and precision of U/Pb zircon dates is accurate correction for initial disequilibrium in the 238U and 235U decay chains. The longest-lived-and therefore most abundant-intermediate daughter product in the 235U isotopic decay chain is 231Pa (T1/2 = 32.71 ka), and the partitioning behavior of Pa in zircon is not well constrained. Here we report high-precision thermal ionization mass spectrometry (TIMS) U-Pb zircon data from two samples from Ocean Drilling Program (ODP) Hole 735B, which show evidence for incorporation of excess 231Pa during zircon crystallization. The most precise analyses from the two samples have consistent Th-corrected 206Pb/238U dates with weighted means of 11.9325 ± 0.0039 Ma (n = 9) and 11.920 ± 0.011 Ma (n = 4), but distinctly older 207Pb/235U dates that vary from 12.330 ± 0.048 Ma to 12.140 ± 0.044 Ma and 12.03 ± 0.24 to 12.40 ± 0.27 Ma, respectively. If the excess 207Pb is due to variable initial excess 231Pa, calculated initial (231Pa)/(235U) activity ratios for the two samples range from 5.6 ± 1.0 to 9.6 ± 1.1 and 3.5 ± 5.2 to 11.4 ± 5.8. The data from the more precisely dated sample yields estimated DPazircon/DUzircon from 2.2-3.8 and 5.6-9.6, assuming (231Pa)/(235U) of the melt equal to the global average of recently erupted mid-ocean ridge basaltic glasses or secular equilibrium, respectively. High precision ID-TIMS analyses from nine additional samples from Hole 735B and nearby Hole 1105A suggest similar partitioning. The lower range of DPazircon/DUzircon is consistent with ion microprobe measurements of 231Pa in zircons from Holocene and Pleistocene rhyolitic eruptions (Schmitt (2007; doi:10.2138/am.2007.2449) and Schmitt (2011; doi:10.1146/annurev-earth-040610-133330)). The data suggest that 231Pa is preferentially incorporated during zircon crystallization over a range of magmatic compositions, and excess initial 231Pa may be more common in zircons than acknowledged. The degree of initial disequilibrium in the 235U decay chain suggested by the data from this study, and other recent high precision datasets, leads to resolvable discordance in high precision dates of Cenozoic to Mesozoic zircons. Minor discordance in zircons of this age may therefore reflect initial excess 231Pa and does not require either inheritance or Pb loss.

(Table 1) Chemical and isotopic analyses of Rajmahal Traps and Ninetyeast Ridge volcanics

The hypothesis that hotspots are the sources of many continental flood basalts is evaluated geochemically for the proposed Rajmahal Traps-Ninetyeast Ridge-Kerguelen hotspot system. It appears that the Kerguelen hotspot did not directly feed Rajmahal magmas, although it may have provided a source of heat for Rajmahal activity.