p38 alpha MAP Kinase Controls IL-17 Synthesis in Vogt-Koyanagi-Harada Syndrome and Experimental Autoimmune Uveitis

PURPOSE. Interleukin (IL)-17, which is responsible for the initial influx of leukocytes into the target tissue, was recently described as the main cytokine involved in autoimmune diseases. Vogt-Koyanagi-Harada (VKH) syndrome is a significant cause of noninfectious blindness in the world. Herein the authors aimed at unraveling the involvement of IL-17 in VKH and in experimental autoimmune uveitis, focusing on the signaling pathways involved in IL-17 synthesis. METHODS. Mice were immunized with 161-180 peptide and pertussis toxin. Draining lymph node cells, harvested 21 days after immunization, were cultured in the presence or absence of p38 alpha mitogen-activated protein kinase (MAPK) inhibitor (SB203580) and assayed for cytokine production and quantification of CD4(+)IL-17(+) cells. Mice received intraocular injections of SB203580, and disease severity was evaluated by histologic examination of the enucleated eyes at day 21. CD4(+) lymphocytes from MSK-1/2-deficient mice, human CD4(+) cells silenced with MSK1 siRNA, or peripheral blood mononuclear cells (PBMCs) from VKH patients were cultured in the presence or absence of p38 alpha MAPK inhibitor and then assayed for IL-17, IFN-gamma, and IL-4 production. RESULTS. The inhibition of p38 alpha MAPK fully blocked the synthesis of IL-17 by PBMCs from VKH patients and lymphocytes from EAU mice. The absence of the msk1/2 gene resulted in failure to produce IL-17 by murine and human lymphocytes. Interestingly, intraocular injections of SB203580 in EAU mice did not suppress development of the disease. CONCLUSIONS. These data show that p38 alpha MAPK-MSK1/2 is involved in the control of IL-17 synthesis by CD4(+) T cells and that inhibition of p38 alpha MAPK in vitro suppresses IL-17 synthesis but that inhibition of this kinase in vivo did not protect from EAU. (Invest Ophthalmol Vis Sci. 2010;51:3567-3574) DOI: 10.1167/iovs.09-4393

Autoantibody response to chromatographic fractions from oxidized LDL in unstable angina patients and healthy controls

Levels of autoantibodies to oxidized low-density lipoprotein (oxLDL) have been correlated to atherosclerosis; however, contradictory results have been shown. To better understand the role of autoantibodies to oxLDL in atherogenesis, and their potential to predict risk of developing coronary artery disease we investigated the antibody response of unstable angina (UA) patients and healthy controls against chromatographic separated fractions of oxLDL. Five major peaks were detected after chromatographic separation of oxLDL and 10 fractions were collected. Surprisingly, when the response to high molecular weight fractions was analysed, we observed a significant increase in the levels of autoantibodies in controls compared to UA. In contrast, when the autoantibody response to intermediate and low molecular weight fractions was analysed, we observed that the UA group showed consistently higher levels compared with controls. Our data demonstrates that within oxLDL there are major fractions that can be recognized by autoantibodies from either UA patients or healthy individuals, and that the use of total oxLDL as an antigen pool may mask the presence of some antigenic molecules and their corresponding antibodies. Further studies are needed, but the analysis of antibody profiles may indeed open up a novel approach for evaluation and prevention against atherosclerosis.

Fur controls iron homeostasis and oxidative stress defense in the oligotrophic alpha-proteobacterium Caulobacter crescentus

In most bacteria, the ferric uptake regulator (Fur) is a global regulator that controls iron homeostasis and other cellular processes, such as oxidative stress defense. In this work, we apply a combination of bioinformatics, in vitro and in vivo assays to identify the Caulobacter crescentus Fur regulon. A C. crescentus fur deletion mutant showed a slow growth phenotype, and was hypersensitive to H(2)O(2) and organic peroxide. Using a position weight matrix approach, several predicted Fur-binding sites were detected in the genome of C. crescentus, located in regulatory regions of genes not only involved in iron uptake and usage but also in other functions. Selected Fur-binding sites were validated using electrophoretic mobility shift assay and DNAse I footprinting analysis. Gene expression assays revealed that genes involved in iron uptake were repressed by iron-Fur and induced under conditions of iron limitation, whereas genes encoding iron-using proteins were activated by Fur under conditions of iron sufficiency. Furthermore, several genes that are regulated via small RNAs in other bacteria were found to be directly regulated by Fur in C. crescentus. In conclusion, Fur functions as an activator and as a repressor, integrating iron metabolism and oxidative stress response in C. crescentus.

Notch signaling controls the balance of ciliated and secretory cell fates in developing airways

Although there is accumulated evidence of a role for Notch in the developing lung, it is still unclear how disruption of Notch signaling affects lung progenitor cell fate and differentiation events in the airway epithelium. To address this issue, we inactivated Notch signaling conditionally in the endoderm using a Shh-Cre deleter mouse line and mice carrying floxed alleles of the Pofut1 gene, which encodes an O-fucosyltransferase essential for Notch-ligand binding. We also took the same conditional approach to inactivate expression of Rbpjk, which encodes the transcriptional effector of canonical Notch signaling. Strikingly, these mutants showed an almost identical lung phenotype characterized by an absence of secretory Clara cells without evidence of cell death, and showed airways populated essentially by ciliated cells, with an increase in neuroendocrine cells. This phenotype could be further replicated in cultured wild-type lungs by disrupting Notch signaling with a gamma-secretase inhibitor. Our data suggest that Notch acts when commitment to a ciliated or non-ciliated cell fate occurs in proximal progenitors, silencing the ciliated program in the cells that will continue to expand and differentiate into secretory cells. This mechanism may be crucial to define the balance of differentiated cell profiles in different generations of the developing airways. It might also be relevant to mediate the metaplastic changes in the respiratory epithelium that occur in pathological conditions, such as asthma and chronic obstructive pulmonary disease.

Global solutions for impulsive abstract partial differential equations

In this paper, we study the existence of global solutions for a class of impulsive abstract functional differential equation. An application involving a parabolic system With impulses is considered. (c) 2008 Elsevier Ltd. All rights reserved.

Poisson stability for impulsive semidynamical systems

In this paper, the concept of Poisson stability is investigated for impulsive semidynamical systems. Recursive properties are also investigated. (C) 2009 Elsevier Ltd. All rights reserved.

LaSalle`s theorems in impulsive semidynamical systems

We consider a semidynamical system subject to variable impulses and we obtain the LaSalle invariance principle and the asymptotic stability theorem for this semidynamical system. (C) 2009 Elsevier Ltd. All rights reserved.

Oscillation for a second-order neutral differential equation with impulses

We consider a certain type of second-order neutral delay differential systems and we establish two results concerning the oscillation of solutions after the system undergoes controlled abrupt perturbations (called impulses). As a matter of fact, some particular non-impulsive cases of the system are oscillatory already. Thus, we are interested in finding adequate impulse controls under which our system remains oscillatory. (C) 2009 Elsevier Inc. All rights reserved.

Limit sets and the Poincare-Bendixson Theorem in impulsive semidynamical systems

We consider semidynamical systems with impulse effects at variable times and we discuss some properties of the limit sets of orbits of these systems such as invariancy, compactness and connectedness. As a consequence we obtain a version of the Poincare-Bendixson Theorem for impulsive semidynamical systems. (C) 2008 Elsevier Inc. All rights reserved.

Atmosphere and hydrological controls of the evapotranspiration over a floodplain forest in the Bananal Island region, Amazonia

This article discusses seasonal and interannual variations of the evapotranspiration (ET) rates in Bananal Island floodplain, Brazil. Measurements included ET and sensible heat flux using the eddy covariance method, atmospheric forcings (net radiation, Rn, vapor pressure deficit, VPD, wind speed and air temperature), soil moisture profiles, groundwater level and flood height, taken from November 2003 to December 2006. For the hydrological years (October-September) of 2003/2004, 2004/2005 and 2005/2006, the accumulated precipitation was 1692, 1471, 1914 mm and the accumulated ET was 1361, 1318 and 1317 mm, respectively. Seasonal analyses indicated that ET decreased in the dry season (average 3.7 mm day(-1)), despite the simultaneous increase in Rn, air temperature and VPD. The increase of ET in the wet season and particularly in the flood period (average 4.1 mm day(-1)) showed that the free water surface evaporation strongly influenced the energy exchange. Soil moisture, which was substantially depleted during the dry season, and adaptative vegetation mechanisms such as leaf senescence contributed to limit the dry season ET. Strong drainage within permeable sandy soils helped to explain the soil moisture depletion. These results suggest that the Bananal flooding area shows a different pattern in relation to the upland Amazon forests, being more similar to the savanna strictu senso areas in central Brazil. For example, seasonal ET variation was not in phase with Rn; the wet season ET was higher than the dry season ET; and the system stored only a tiny memory of the flooding period, being sensitive to extended drought periods.

Determination of controls on Holocene barrier progradation through application of OSL dating: The Ilha Comprida Barrier example, Southeastern Brazil

Barrier development during the Holocene is studied using the example of the Ilha Comprida, Southeastern Brazil. Aerial photos, facies analysis, and optically stimulated luminescence dating are used to define the barrier emergence and evolution. Optically stimulated luminescence ages and facies successions indicate that the Ilha Comprida probably began as a Holocene transgressive barrier island 6000 years ago, just before the last relative sea-level maximum. Since then the barrier has progradated through the addition of curved beach ridges. Based on beach ridge alignments, six units of growth are identified with two growth directions, transverse and longitudinal. Rates of progradation with transverse growth vary from 0.13 to 4.6 m/year. Rates of longitudinal growth to NE range from 5.2 to 30 m/year. Variation in coastal progradation rates and sediment retention during the last 6000 years is compared with climate, physiography and relative sea-level changes. The physiography, represented by pre-Cenozoic hills, is the major control on sediment retention and alternation between longitudinal and transverse growth. Climate variations, such as the Little Ice Age event, apparently control the formation of ridges types: beach ridges, foredunes, and blowouts. These results allow the use of the Ilha Comprida Barrier as an example to analyze the major controls on barriers progradation. (C) 2011 Elsevier B.V. All rights reserved.

Controls of heavy minerals and grain size in a holocene regressive barrier (Ilha Comprida, southeastern Brazil)

Ilha Comprida is a regressive barrier island located in southeastern Brazil that was formed essentially by Quaternary sandy sediments. Ilha Comprida sediments were analyzed to assess heavy mineral indices and grain size variables. The spatial variation of heavy minerals and grain size was interpreted in terms of the present barrier dynamics and the barrier`s evolution since the Middle Holocene. These analyses allowed for the identification of the main factors and processes that control the variation of heavy minerals and grain size on the barrier. Rutile and zircon (RZi) and tourmaline and hornblende (THi) are significantly sensitive to provenance and exhibit the contributions of the Ribeira de Iguape River sediments, which reach the coast next to the northeastern end of Ilha Comprida. In addition to the influence of provenance, TZi responds mainly to hydraulic sorting processes. This agrees with a sediment transport pattern characterized by a divergence of two resultant net alongshore drifts southwest of the barrier. The sediments from the Ribeira de Iguape River reach the barrier directly through the river mouth and indirectly after temporary storage in the inner shelf. The combination of grain size and heavy mineral analyses is a reliable method for determining sediment transport patterns and provenance. (C) 2010 Elsevier Ltd. All rights reserved.

Grain size and heavy minerals of the Late Quaternary eolian sediments from the Imbituba-Jaguaruna coast, Southern Brazil: Depositional controls linked to relative sea-level changes

The stratigraphic subdivision and correlation of dune deposits is difficult, especially when age datings are not available. A better understanding of the controls on texture and composition of eolian sands is necessary to interpret ancient eolian sediments. The Imbituba-Jaguaruna coastal zone (Southern Brazil, 28 degrees-29 degrees S) stands out due to its four well-preserved Late Pleistocene (eolian generation 1) to Holocene eolian units (eolian generations 2, 3, and 4). In this study, we evaluate the grain-size and heavy-mineral characteristics of the Imbituba-Jaguartma eolian units through statistical analysis of hundreds of sediment samples. Grain-size parameters and heavy-mineral content allow us to distinguish the Pleistocene from the Holocene units. The grain size displays a pattern of fining and better sorting from generation 1 (older) to 4 (younger), whereas the content of mechanically stable (dense and hard) heavy minerals decreases from eolian generation 1 to 4. The variation in grain size and heavy-mineral content records shifts in the origin and balance (input versus output) of eolian sediment supply attributable mainly to relative sea-level changes. Dunefields submitted to relative sea-level lowstand conditions (eolian generation 1) are characterized by lower accumulation rates and intense post-depositional dissection by fluvial incision. Low accumulation rates favor deflation in the eolian system, which promotes concentration of denser and stable heavy minerals (increase of ZTR index) as well as coarsening of eolian sands. Dissection involves the selective removal of finer sediments and less dense heavy minerals to the coastal source area. Under a high rate of relative sea-level rise and transgression (eolian generation 2), coastal erosion prevents deflation through high input of sediments to the coastal eolian source. This condition favors dunefield growth. Coastal erosion feeds sand from local sources to the eolian system. including sands from previous dunefields (eolian generation 1) and from drowned incised valleys. Therefore, dunefields corresponding to transgressive phases inherit the grain-size and heavy-mineral characteristics of previous dunefields, leading to selective enrichment of finer sands and lighter minerals. Eolian generations 3 and 4 developed during a regressive-progradational phase (Holocene relative sea level highstand). The high rate of sediment supply during the highstand phase prevents deflation. The lack of coastal erosion favors sediment supply from distal sources (fluvial sediments rich in unstable heavy minerals). Thus, dunefields of transgressive and highstand systems tracts may be distinguished from dunefields of the lowstand systems tract through high rates of accumulation (low deflation) in the former. The sediment source of the transgressive dunefields (high input of previously deposited coastal sands) differs from that of the highstand dunefields (high input of fluvial distal sands). Based on this case study, we propose a general framework for the relation between relative sea level, sediment supply and the texture and mineralogy of eolian sediments deposited in siliciclastic wet coastal zones similar to the Imbituba-Jaguaruna coast (C) 2009 Elsevier B.V. All rights reserved.

A short proregion of trialysin, a pore-forming protein of Triatoma infestans salivary glands, controls activity by folding the N-terminal lytic motif

Triatoma infestans (Hemiptera: Reduviidae) is a hematophagous insect that transmits the protozoan parasite Trypanosoma cruzi, the etiological agent of Chagas` disease. Its saliva contains trialysin, a protein that forms pores in membranes. Peptides based on the N-terminus of trialysin lyse cells and fold into alpha-helical amphipathic segments resembling antimicrobial peptides. Using a specific antiserum against trialysin, we show here that trialysin is synthesized as a precursor that is less active than the protein released after saliva secretion. A synthetic peptide flanked by a fluorophore and a quencher including the acidic proregion and the lytic N-terminus of the protein is also less active against cells and liposomes, increasing activity upon proteolysis. Activation changes the peptide conformation as observed by fluorescence increase and CD spectroscopy. This mechanism of activation could provide a way to impair the toxic effects of trialysin inside the salivary glands, thus restricting damaging lytic activity to the bite site.

Base Excision Repair Activities Differ in Human Lung Cancer Cells and Corresponding Normal Controls

Oxidative damage to DNA is thought to play a role in carcinogenesis by causing Mutations, and indeed accumulation of oxidized DNA bases has been observed in samples obtained from tumors but not from surrounding tissue within the same patient. Base excision repair (BER) is the main pathway for the repair of oxidized modifications both in nuclear and mitochondrial, DNA. In order to ascertain whether diminished BER capacity might account for increased levels of oxidative DNA damage in cancer cells, the activities of BER enzymes in three different lung cancer cell lines and their non-cancerous counterparts were measured using oligonucleotide substrates with single DNA lesions to assess specific BER enzymes. The activities of four BER enzymes, OGG1, NTH1, UDG and APE1, were compared in mitochondrial and nuclear extracts. For each specific lesion, the repair activities were similar among the three cell lines used. However, the specific activities and cancer versus control comparison differed significantly between the nuclear and mitochondrial compartments. OGG1 activity, as measured by 8-oxodA incision, was upregulated in cancer cell mitochondria but down-regulated in the nucleus when compared to control cells. Similarly, NTH1 activity was also up-regulated in mitochondrial extracts from cancer cells but did not change significantly in the nucleus. Together, these results support the idea that alterations in BER capacity are associated with carcinogenesis.