Early Stages Of Activation Research Articles

Functional analysis of a tripartite stability element within the CD40 ligand 3′ untranslated region

We previously identified a cis-acting element within the 3' untranslated region of CD40 ligand messenger RNA (mRNA) that is composed of three complex binding sites and acts to increase mRNA stability in both in vitro and in vivo systems. We now demonstrate the functional consequences of the three binding sites with respect to increasing both luciferase activity and mRNA stability in a heterologous transcript expressed in a T-cell line. The internal region B was shown to be a bona fide stability element because its presence increased luciferase activity fourfold over the unmodified transcript and its removal from the XbaI-HaeIII region resulted in rapid degradation of the transcript. Region A contained both a binding site for a polypyrimidine-tract-binding protein (PTB)-mediated complex (Complex I) and an upstream, adjacent sequence that was a negative regulator of mRNA stability. Region C bound Complex II, which contained both PTB and heterogeneous nuclear ribonucleoproteinL (hnRNPL), and was less effective as a stability element on its own compared to region B. Our findings demonstrate differential levels of activity for the three binding sites relative to the turnover of CD40 ligand mRNA, suggesting that the lack of binding of Complex I/II during the early stages of T-cell activation contributes to the rapid degradation of the CD40 ligand mRNA transcript.

Depletion of LAG-3 Positive Cells in Cardiac Allograft Reveals Their Role in Rejection and Tolerance

Lymphocyte-activated gene-3 (LAG-3, CD223) is upregulated during the early stages of T-cell activation and could be the target of cytotoxic antibodies for induction therapy in transplantation. Fully vascularized heterotopic allogeneic heart transplantation was performed in rats across a full major histocompatibility complex-mismatch barrier (LEW.1W into LEW.1A). Recipients received two injections (day 0 and 3) of cytotoxic antibodies directed to the extra-loop of LAG-3 immunoglobulin (Ig)-like N-terminal domain or control antibodies. LAG-3 mRNA transcripts accumulated in cardiac allografts undergoing rejection, but not in peripheral lymphoid organs. Administration of anti-LAG-3 antibodies on the day of transplantation did not modify alloreactivity of T lymphocytes from the spleen and did not change the alloantibody response. However, it inhibited graft infiltration by effector mononuclear cells, reduced intragraft levels of interferon-gamma mRNA and prolonged allograft survival from 6 days in controls to a median of 27 days. Anti-LAG-3 antibodies were also active in prolonging survival when administered in a delayed manner, after rejection onset. LAG-3 being also expressed by activated regulatory T (Treg) cells, we tested the effect of anti-LAG-3 antibodies on graft acceptance after donor blood transfusions, a Treg-dependent tolerance induction model. We found that tolerance induction was prevented by anti-LAG-3 antibodies. Targeting LAG-3-positive cells with cytotoxic antibodies is immunosuppressive in transplantation by depleting effectors T cells and therefore may represent a treatment for rejection episodes focused only on pathogenic cells. However, it might not be compatible with tolerance-induction strategies.

Room Temperature Deformation Properties of High Purity AZ31 Magnesium Alloy

A high purity ternary alloy corresponding to the composition of AZ31 alloy was prepared using distilled magnesium (> 99.99%) and high purity aluminum and zinc. The tensile and cold rolling properties were then examined and compared with a commercial purity AZ31 alloy. The high purity alloy exhibited excellent tensile ductility and cold rolling workability. It was found that during tensile testing of the high purity alloy, the number of twinned grains increased linearly with strain, indicative of uniform deformation, while with the commercial alloy, active twinning occurred in the early stages of plastic deformation and twinning activity decreased in the latter half of the deformation regime. In association with the high degree of cold reduction and the uniform deformation characteristics of the high purity alloy, the material after annealing exhibited a recrystallized structure consisting of fine grains each about 2 μm in size.

Room Temperature Deformation Properties of High Purity AZ31 Magnesium Alloy

A high purity ternary alloy corresponding to the composition of AZ31 alloy was prepared using distilled magnesium (> 99.99%) and high purity aluminum and zinc. The tensile and cold rolling properties were then examined and compared with a commercial purity AZ31 alloy. The high purity alloy exhibited excellent tensile ductility and cold rolling workability. It was found that during tensile testing of the high purity alloy, the number of twinned grains increased linearly with strain, indicative of uniform deformation, while with the commercial alloy, active twinning occurred in the early stages of plastic deformation and twinning activity decreased in the latter half of the deformation regime. In association with the high degree of cold reduction and the uniform deformation characteristics of the high purity alloy, the material after annealing exhibited a recrystallized structure consisting of fine grains each about 2 μm in size.

Different Hemoglobin Switching Pattern of β-Thalassemia Mutations at the Proximal and Distal Human β-Globin CACCC Box.

The CACCC box is duplicated in the β globin gene promoter of humans and other mammals. While the function of the proximal element as a binding site for EKLF has already been well established, the role of the distal element remains unclear The distal CACCC box has been previously reported not to bind EKLF in vitro. A minor role of the distal CACCC element in β globin gene promoter function is suggested by the observation that naturally occurring β thalassemia mutations affecting the proximal CACCC box are far more severe than those affecting the distal element. Nevertheless recent evidences demonstrate:1.that EKLF does indeed bind to the distal CACCC motif, although with low affinity.2.that the CCTCACCC is required for maximal stimulation of the β-globin gene by EKLF3.and that silent β-thalassemia due to mutations of the distal CACCC box affects the binding and responsiveness to EKLF of the β-globin gene promoter.Our interest in the function of the distal CACCC element springs from the observation that β thalassemia mutation affecting the distal box show an age related pattern of expression being more severe in the childhood than in the adulthood. In order to get light inside the role of this element in the function of the β globin gene and in the γ to β hemoglobin switching we have analyzed the effect of mutations at the proximal and distal element “in vivo”. We have engineered, by site specific mutagenesis, the β-101 (distal CACCC element) and β-87 (proximal CACCC element) mutations inside the “minilocus “ γ-β construct. The minilocus construct has been widely used to study hemoglobin switching in vivo. This construct contains the full β-globin Locus Control Region (LCR), the Aγ globin gene, the β-globin gene and the 3′ hypersensitive site (HS) of the β-globin cluster. Three mice transgenic lines have been produced. The pattern of g versus β-globin switching has been analyzed during the development by S1 analysis and real time PCR. We have dissected the yolk sac at 10 days post conception (pc) to asses the embryonic stage of erythopoiesis; the fetal liver at 12, 14 and 16 days pc to asses the fetal stage or erythropoiesis when the g to b competitive switching take place; and the adult blood. Our results indicated that neither the β-101 nor the β-87 thalassemia mutations affect the competitive silencing of the b-globin gene in the yolk sac. During the fetal liver stage of erythropoiesis, were both human g and b human transgenes are expressed, the pattern of γ-β hemoglobin switching is striking different for the two different constructs. The b-87 minilocus γ-β construct shows a delayed switching patter mainly due to the low activation of the mutated β globin gene. The impairment of the expression of the β-87 globin gene became more severe during the fetal development compared to the control line. On the other hand the β-101 minilocus γ-β construct shows a γ-β hemoglobin switching pattern which is anticipated respect to the control line. In addition the effect of the β-101 mutation became less severe during the fetal development. These results highlight a possible role of the distal CACCC element in hemoglobin switching and in particular in the early stage of β-globin activation.

ITF1697, a Stable Lys-Pro-Containing Peptide, Inhibits Weibel-Palade Body Exocytosis Induced by Ischemia/Reperfusion and Pressure Elevation

A number of Lys-Pro-containing short peptides have been described as possessing a variety of biological activities in vitro. Because of limited metabolic stability, however, their efficacy in vivo is uncertain. To exploit the pharmacological potential of Lys-Pro-containing short peptides, we synthesized a series of chemically modified forms of these peptides. One of them, ITF1697 (Gly-(Nalpha-Et)Lys-Pro-Arg) was stable in vivo and particularly efficacious in experimental models of disseminated endotoxemia and of cardiovascular disorders. Using intravital fluorescence microscopy, we studied the peptide cellular and molecular basis of protection in the Syrian hamster cheek pouch microcirculation subjected to ischemia/reperfusion (I/R) and in pressure elevation-induced proinflammatory responses in isolated Sprague-Dawley rat lungs. Continuous intravenous infusion of ITF1697 at 0.1 to 100 mug/kg/min nearly completely protected the cheek pouch microcirculation from I/R injury as measured by decreased vascular permeability and increased capillary perfusion. Adhesion of leukocytes and platelets to blood vessels was strongly inhibited by the peptide. ITF1697 exerted its activity at the early stages of endothelial activation and inhibited P-selectin and von Willebrand factor secretion. Further mechanistic studies in the rat lung preparation revealed that the peptide inhibited the intracellular Ca(2+)-dependent fusion of Weibel-Palade bodies with the plasma membrane. The ability of ITF1697 to inhibit the early functions of activated endothelial cells, such as the exocytosis of Weibel-Palade bodies, represents a novel and promising pharmacological tool in model of pathologies of a variety of microvascular disorders.

Entrepreneurship and Social Capital

Governments have invested heavily in building local and regional entrepreneurial networks in order improve economic performance and regeneration. However, there are many types of network, and different types of network are appropriate for different purposes. Some types of network are most useful in the early stages of entrepreneurial activity and others at later stages. Careful definitions are necessary in order to analyse the role of networks in generating interpersonal and inter-organizational trust, and hence in augmenting the stock of social capital. Effective networks are normally intermediated by reputable trust-brokers. The reputation of government gives it a significant role as a trust-broker, but there is a danger that its reputation may be undermined when it extends its activities into areas where it lacks the competence to intervene effectively.

Expression of EAAT1 reflects a possible neuroprotective function of reactive astrocytes and activated microglia following human traumatic brain injury.

Glutamate-mediated excitotoxicity is known to cause secondary brain damage following stroke and traumatic brain injury (TBI). However, clinical trials using NMDA antagonists failed. Thus, glial excitatory amino acid transporters (EAATs) might be a promising target for therapeutic intervention. We examined expression of EAAT1 (GLAST) and EAAT2 (Glt-1) in 36 TBI cases by immunohistochemistry. Cortical expression of both EAATs decreased rapidly and widespread throughout the brain (in lesional, adjacent and remote areas) following TBI. In the white matter numbers of EAAT1+ parenchymal cells increased 39-fold within 24h (p<0.001) and remained markedly elevated till later stages in the lesion (90-fold, p<0.01) and in peri-lesional regions (86-fold, p<0.01). In contrast, EAAT2+ parenchymal cells and EAAT1+ or EAAT2+ perivascular cells did not increase significantly. Within the first days following TBI mainly activated microglia and thereafter mainly reactive astrocytes expressed EAAT1. Perivascular monocytes and foamy macrophages lacked EAAT1 immunoreactivity. We conclude that following TBI i) loss of cortical EAATs contributes to secondary brain damage, ii) glial EAAT1 expression reflects a potential neuroprotective function of microglia and astrocytes, iii) microglial EAAT1 expression is restricted to an early stage of activation, iv) blood-derived monocytes do not express EAAT1 and v) pharmacological modification of glial EAAT expression might further limit neuronal damage.

Expression of MMPs and TIMPs in liver fibrosis – a systematic review with special emphasis on anti-fibrotic strategies

In liver tissue matrix metalloproteinases (MMPs) and their specific inhibitors (tissue inhibitors of metalloproteinases, TIMPs) play a pivotal role in both, fibrogenesis and fibrolysis. The current knowledge of the pathophysiology of liver fibrogenesis with special emphasis on MMPs and TIMPs is presented. A systematic literature search was conducted. All experimental models of liver fibrosis that evaluated a defined anti-fibrotic intervention in vivo or in vitro considering MMPs and TIMPs were selected. The methodological quality of all these publications has been critically appraised using an objective scoring system and the content has been summarized in a table.

Activated carbon from olive kernels in a two-stage process: Industrial improvement

Activated carbons have been prepared from olive kernels and their adsorptive characteristics were investigated. A two stage process of pyrolysis-activation has been tested in two scales: (a) laboratory scale pyrolysis and chemical activation with KOH and (b) pilot/bench scale pyrolysis and physical activation with H 2O–CO 2. In the second case, olive kernels were first pyrolysed at 800 °C, during 45 min under an inert atmosphere in an industrial pyrolyser with a throughput of 1 t/h (Compact Power Ltd., Bristol, UK). The resulting chars were subsequently activated with steam and carbon dioxide mixtures at 970 °C in a batch pilot monohearth reactor at NESA facility (Louvain-la Neuve, Belgium). The active carbons obtained from both scales were characterized by N 2 adsorption at 77 K, methyl-blue adsorption (MB adsorption) at room temperature and SEM analysis. Surface area and MB adsorption were found to increase with the degree of burn-off. The maximum BET surface area was found to be around 1000–1200 m 2/g for active carbons produced at industrial scale with physical activation, and 3049 m 2/g for active carbons produced at laboratory with KOH activation. The pores of the produced carbons were composed of micropores at the early stages of activation and both micropores and mesopores at the late stages. Methylene blue removal capacity appeared to be comparable to that of commercial carbons and even higher at high degrees of activation.

T‐cell activation in the intestinal mucosa

The vast majority of peripheral T cells exist as resting lymphocytes until a signal for activation has been received. In response to antigen, this activation involves ligation of the T-cell receptor (TCR) and signal transmission through the CD3 complex, which then initiates a cascade of intracellular events that lead to the expression of genes used in T-cell activation. T-cell activation also requires soluble mediators in the form of cytokines and chemokines that regulate the process in both positive and negative ways, and costimulatory signals received in conjunction with TCR/CD3 signaling are important in the activation of T cells. Unlike T cells in other peripheral immune compartments, small and large intestinal intraepithelial lymphocytes (IELs) bear some but not all properties of activated T cells, suggesting that they constitute a large population of 'partially activated' effector cells. Thus, regulation of the IEL activation process must be held in tight check, yet it must be ready to respond to foreign antigen rapidly and effectively. We discuss how costimulatory molecules may hold the key to controlling IEL activation through a multiphase process beginning with cells that have already entered into the early stage of activation.

Geology of the Sari Gunay Epithermal Gold Deposit, Northwest Iran

The Sari Gunay epithermal gold deposit is located within a mildly alkaline latitic to trachytic volcanic complex in central-northwest Iran. Intrusive and volcanic rocks that host the deposit have been dated at between 11.7 and 11.0 Ma (with one younger sample at 8.0 Ma; 40Ar/39Ar dating of igneous biotite and hornblende), whereas sericitic alteration associated with an early stage of hydrothermal activity occurred between ~10.8 and ~10.3 Ma (the best age estimate is 10.7 Ma obtained by 40Ar/39Ar dating of sericite). The main hydrothermal system was structurally localized by a diatreme breccia complex centered on the Sari Gunay hill. Earliest hydrothermal activity, only encountered at depth (>300 m below surface), produced weak potassic alteration and quartz-sulfide-magnetite veining with low grades of Cu and Au mineralization, reminiscent of shallow-level (≤ 1.5-km depth) porphyry gold systems. Paragenetically later quartz-tourmaline breccias and veins followed the south-southwest–north-northeast trend of the diatreme breccias and produced strong sericitic alteration and silicification in igneous clasts and wall rocks. Fluid inclusions indicate temperatures of 246° to 360°C and salinities of 34.4 to 46.1 wt percent NaCl equiv in hypersaline inclusions coexisting with low-density, CO2-bearing vapor-phase inclusions. These fluids do not appear to have deposited gold, but the breccias provided further structural permeability for flow of later mineralizing epithermal fluids. Invisible gold occurs in solid solution in fine-grained arsenical pyrite and minor arsenopyrite, deposited in the early stages of quartz-adularia-pyrite-stibnite veins. Late-stage minerals in these veins include realgar, orpiment, cinnabar, and extremely rare wire gold. Liquid-rich fluid inclusions in these veins have an average homogenization temperature (≈ trapping temperature) of 199° ± 24°C, salinities of 3.6 ± 1.1 wt percent NaCl equiv, and coexist with low-density CO2-bearing vapor-phase inclusions, suggesting low-pressure conditions. Phase separation may have been a contributory cause of gold deposition, but precipitation of sulfides in response to rapid cooling of the system may have been the main control on deposition of pyrite-hosted gold. The Sari Gunay gold deposit and its host volcanic system form part of the Takab belt of structurally controlled, middle Miocene, mildly alkaline volcano-plutonic complexes. The sediment-hosted Zarshuran gold deposit, located ~190 km to the north-northwest along the belt, is also related to middle Miocene magmatism. The Takab belt is marginally younger than, and displaced to the southwest of, the extensive Eocene-Miocene Urumieh-Dokhtar calk-alkaline volcanic arc, which hosts several large porphyry Cu deposits (e.g., Sar Cheshmeh, Meiduk). Rocks of the Takab belt are also distinctly more alkaline than the Urumieh-Dokhtar rocks. Viewed in the context of plate tectonic models for Neogene closure of a Neo-Tethys ocean between the Afro-Arabian and Eurasian plates, these differences may reflect a normal subduction zone origin for the Urumieh-Dokhtar arc and contained porphyry Cu deposits but a collisional origin for the slightly younger Takab belt volcanic rocks and epithermal gold deposits. The Sari Gunay deposit may thus be classified as a collision-related alkalic-type epithermal system, although it is less alkaline than classic deposits of this group such as Porgera, Emperor, or Cripple Creek (the latter apparently being related to postcollisional or back-arc extensional rather than syncollisional processes).

Inhibitory and enhancing effects of piroxicam on whole blood chemiluminescence

The effects of piroxicam on the production of reactive oxygen species by stimulated phagocytes was studied in whole blood by a chemiluminescence (CL) technique in relation to maximum activity, localization and kinetics of radical generation. We found that piroxicam dose-dependently inhibited total (intra- and extracellular) zymosan-stimulated luminol CL (LCL) at a high stimulant concentration (p = 0.0001). Piroxicam additionally decreased cytochalasin B-reduced LCL, which shows that the effect of the drug should be sought in the extracellular component of the response. Piroxicam inhibited the first phase of extracellular LCL in a dose-dependent manner (p = 0.0001) and revealed itself as an enhancing agent of CL in later time intervals after the start of respiratory burst, in a model system containing horseradish peroxidase (HRP) and sodium azide. It enhanced LCL of a cell-free system, i.e. influenced the CL due to HRP-catalysed decomposition of hydrogen peroxide. It also dose-dependently inhibited the early extracellular superoxide production, evaluated by lucigenin CL (p = 0.022). Piroxicam inhibited the total fMLP-stimulated LCL by 70% approximately and, only by about 30%, the first phase of fMLP-stimulated extracellular LCL, which presupposes an effect on myeloperoxidase-catalysed formation of hypochloric acid. Piroxicam slightly increased the intracellular LCL by phagocytes (p = 0.02), an effect that is probably connected with its ability to induce the release of secondary messengers in signal transduction. In conclusion, the anti-inflammatory effect of piroxicam is probably related to the inhibition of the extracellular generation of superoxide and hypochloric acid in the early stages of phagocyte activation.

High extracellular K+ evokes changes in voltage-dependent K+ and Na+ currents and volume regulation in astrocytes

[K(+)](e) increase accompanies many pathological states in the CNS and evokes changes in astrocyte morphology and glial fibrillary acidic protein expression, leading to astrogliosis. Changes in the electrophysiological properties and volume regulation of astrocytes during the early stages of astrocytic activation were studied using the patch-clamp technique in spinal cords from 10-day-old rats after incubation in 50 mM K(+). In complex astrocytes, incubation in high K(+) caused depolarization, an input resistance increase, a decrease in membrane capacitance, and an increase in the current densities (CDs) of voltage-dependent K(+) and Na(+) currents. In passive astrocytes, the reversal potential shifted to more positive values and CDs decreased. No changes were observed in astrocyte precursors. Under hypotonic stress, astrocytes in spinal cords pre-exposed to high K(+) revealed a decreased K(+) accumulation around the cell membrane after a depolarizing prepulse, suggesting altered volume regulation. 3D confocal morphometry and the direct visualization of astrocytes in enhanced green fluorescent protein/glial fibrillary acidic protein mice showed a smaller degree of cell swelling in spinal cords pre-exposed to high K(+) compared to controls. We conclude that exposure to high K(+), an early event leading to astrogliosis, caused not only morphological changes in astrocytes but also changes in their membrane properties and cell volume regulation.

Anomalous early aftershock decay rate of the 2004 Mw6.0 Parkfield, California, earthquake

We analyze the seismicity rate immediately after the 2004 Mw6.0 Parkfield, California, earthquake from near‐source seismograms. By scrutinizing high‐frequency signals, we can distinguish mainshock coda from early aftershocks occurring as soon as 30 s after the mainshock. We find, as expected, that a significant fraction of aftershocks in the first few hours after the main shock are missing in the Northern California Seismic Network catalog. We observe a steady rate of aftershocks in the first 130 s, followed by a power‐law decay of aftershock activity. Thus, there appears to be a distinct early stage of aftershock activity that does not fit the Omori's law with a constant p value, a phenomenon that we refer to as Early Aftershock Deficiency (EAD). Our observation suggests that mainshock rupture and aftershocks are distinct processes, not described by a single Omori's law. Several physical models of aftershocks can explain the EAD.

Heat stress-induced H2O2 is required for effective expression of heat shock genes in Arabidopsis

The mechanisms of sensing and signalling of heat and oxidative stresses are not well understood. The central question of this paper is whether in plant cells oxidative stress, in particular H(2)O(2), is required for heat stress- and heat shock factor (HSF)-dependent expression of genes. Heat stress increases intracellular accumulation of H(2)O(2) in Arabidopsis cell culture. The accumulation was greatly diminished using ascorbate as a scavenger or respectively diphenyleneiodonium chloride (DPI) as an inhibitor of reactive oxygen species production. The mRNA of heat shock protein (HSP) genes, exemplified by Hsp17.6, Hsp18.2, and the two cytosolic ascorbate peroxidase genes Apx1, Apx2, reached similar levels by moderate heat stress (37 degrees C) or by treatment with H(2)O(2), butylperoxide and diamide at room temperature. The heat-induced expression levels were significantly reduced in the presence of ascorbate or DPI indicating that H(2)O(2) is an essential component in the heat stress signalling pathway. Rapid (15 min) formation of heat shock promoter element (HSE) protein-binding complex of high molecular weight in extracts of heat-stressed or H(2)O(2)-treated cells and the inability to form this complex after ascorbate treatment suggests that oxidative stress affects gene expression via HSF activation and conversely, that H(2)O(2) is involved in HSF activation during the early phase of heat stress. The heat stress induction of a high mobility HSE-binding complex, characteristic for later phase of heat shock response, was blocked by ascorbate and DPI. H(2)O(2 )was unable to induce this complex suggesting that H(2)O(2) is involved only in the early stages of HSF activation. Significant induction of the genes tested after diamid treatment and moderate expression of the sHSP genes in the presence of 50 mM ascorbate at 37 degrees C occurred without activation of HSF, indicating that other mechanisms may be involved in stress signalling.

Comparison of incipient plasticity in bcc and fcc metals studied using nanoindentation

Using nanoindentation, the incipient plasticity or early stages of dislocation activity has been studied for two bcc metals of different hardness, tungsten and iron, as well as fcc nickel. The deformation behavior of these metals has been probed using indenters of two different geometries, a Berkovich and a cube corner. From a critical analysis of the load–displacement curves, the initial displacement burst, often associated with the initiation of dislocation activity, was found to occur at values close to the theoretical shear stress of the material. Furthermore, the nature of these displacement bursts appears to vary both as a function of strain rate as well as the geometry of the indenter used during the nanoindentation experiments.

MRI features of pediatric cerebral paragonimiasis in the active stage

We retrospectively reviewed the MR images of the brains of six children (age = 5-13 years) who had cerebral paragonimiasis in the early active stage. Diagnosis was based on a positive antibody test enzyme-linked immunosorbent assay (ELISA) for paragonimiasis in serum. The most common finding (in five patients) was irregular hemorrhage of various degrees. Moreover, in three cases some multiple irregular lesions with surrounding edema appeared to be conglomerated and aggregated. The rare appearance (in one patient) was a "tunnel sign," which showed the migrating track of the adult worm. In one patient with abscess and minimal hemorrhage, diffusion-weighted imaging (DWI) showed a heterogeneous high signal of lesions. Other findings included slight (one patient) or marked (one patient) irregular contrast enhancement, and large edematous areas surrounding small centers of hemorrhage (two patients). MR findings of conglomerated lesions with hemorrhage or tunnel sign may help to establish the diagnosis of active-stage cerebral paragonimiasis.

Induction of Enhanced Immunity to Intestinal Nematodes Using IL-9-Producing Dendritic Cells

Dendritic cells can be considered natural adjuvants and are able to act as cellular vaccines to protect against disease. Adoptive transfer of Ag-pulsed bone marrow-derived dendritic cells (BMDCs) enhanced expulsion of the intestinal nematode, Trichinella spiralis, from the small intestine. IL 9 is a critical cytokine in protective immunity to intestinal nematode infection and is believed to enhance Th2 immune responses. Deriving dendritic cells from an IL-9 transgenic (IL-9t) mouse has enabled a detailed investigation of the importance of IL-9 during Ag presentation. Indeed, IL-9t dendritic cells significantly enhanced T cell proliferation and Th2 responses and, after adoptive transfer, enhanced parasite-specific IgG1 and intestinal mastocytosis in vivo, leading to accelerated expulsion of adult worms from the intestine. Overall, this paper demonstrates that dendritic cell vaccination can be used to successfully protect the host against intestinal nematode infection and suggests that IL-9 can act as a potent type 2 adjuvant during Ag presentation and the early stages of Th2 activation.

Accelerated Ovarian Failure Induced by 4-Vinyl Cyclohexene Diepoxide in Nrf2 Null Mice

Genetic and biochemical analyses have uncovered an essential role for nuclear factor erythroid 2-related factor 2 (Nrf2) in regulating phase II xenobiotic metabolism and antioxidant response. Here we show that Nrf2 protects against the ovarian toxicity of 4-vinylcyclohexene diepoxide (VCD) in mice. Nrf2-/- female mice exposed to VCD exhibit an age-dependent decline in reproduction leading to secondary infertility accompanied by hypergonadotropic hypogonadism after 30 weeks of age. VCD is shown to selectively destroy small ovarian follicles, resulting in early depletion of functional follicles. Treatment with VCD induces apoptotic death in cultured cells and in ovarian follicles, suggesting apoptosis as a mechanism of follicle loss. Loss of Nrf2 function blocks the basal and inducible expression of microsomal epoxide hydrolase, a key enzyme in the detoxification of VCD, and increases the oxidative stress in cells that is further exacerbated by VCD. Foxo3a, a repressor in the early stages of follicle activation, displays reduced expression in Nrf2-/- ovaries, causing accelerated growth of follicles in the absence of exposure to exogenous chemicals. Furthermore, Foxo3a is degraded through the 26S proteasome pathway in untreated cells and is induced by VCD via both Nrf2-dependent transcription and protein stabilization. This study demonstrates that Nrf2 serves as an essential sensor and regulator of chemical homeostasis in ovarian cells, protecting the cells from toxic chemicals by controlling metabolic detoxification, reactive oxygen species defense, and Foxo3a expression. In addition, these findings raise the possibility that exposure to environmental or occupational ovotoxicants plays a role in the premature ovarian failure commonly associated with infertility and premature aging in women.