Marginally stable current sheets in collisionless magnetic reconnection.

Noncollisional current sheets that form during the nonlinear development of spontaneous magnetic reconnection are characterized by a small thickness, of the order of the electron skin depth. They can become unstable to the formation of plasmoids, which allows the magnetic reconnection process to reach high reconnection rates. In this work, we investigate the marginal stability conditions for the development of plasmoids when the forming current sheet is purely collisionless and in the presence of a strong guide field. We analyze the geometry that characterizes the reconnecting current sheet, and what promotes its elongation. Once the reconnecting current sheet is formed, we identify the regimes for which it is plasmoid unstable. Our study shows that plasmoids can be obtained, in this context, from current sheets with an aspect ratio much smaller than in the collisional regime, and that the plasma flow channel of the marginally stable current layers maintains an inverse aspect ratio of 0.1.

A novel spatiotemporal tool for the automatic classification of fMRI noise based on Independent Component Analysis.

In this study, a semi-automatic, easy-to-use classification method for the identification and removal of fMRI noise is proposed and tested. The method relies on subject-level spatial independent component analysis (ICA) of fMRI data. Starting from a reference set of labeled independent components (ICs), novel ICs are classified as physiological/artefactual by combining a spatial correlation (SC) analysis with the reference ICs and relative power spectral (PS) analysis. Here, ICs from a task-based fMRI dataset were used as reference. SC and SP thresholds were set using a test dataset (5 subjects, same fMRI protocol) based on Receiving Operating Characteristic curves. The tool performance and versatility were measured on a resting-state fMRI dataset (5 subjects). Our results show that the method can automatically identify noise-related ICs with accuracy, specificity and sensitivity higher than 80% across different fMRI protocols. These findings also suggest that the reference set provided in the present study might be used to mark ICs coming from independent taskrelated or resting-state fMRI datasets.Clinical relevance- The new method will be included in a userfriendly, open-source tool for removal of noisy contributions from fMRI datasets to be used in clinical and research practices.

Physiological and biochemical responses of sunflower (Helianthus annuus L.) exposed to nano-CeO2 and excess boron: Modulation of boron phytotoxicity.

Little is known about the interaction of nanoparticles (NPs) with soil constituents and their effects in plants. Boron (B), an essential micronutrient that reduces crop production at both deficiency and excess, has not been investigated with respect to its interaction with cerium oxide NPs (nano-CeO2). Considering conflicting results on the nano-CeO2 toxicity and protective role as antioxidant, their possible modulation on B toxicity in sunflower (Helianthus annuus L.) was investigated. Sunflower was cultivated for 30 days in garden pots containing original or B-spiked soil amended with nano-CeO2 at 0-800 mg kg-1. At harvest, Ce and B concentrations in tissues, biomass, and activities of stress enzymes in leaves were determined. Results showed that in the original soil, Ce accumulated mainly in roots, with little translocation to stems and leaves, while reduced root Ce was observed in plants from B-spiked soil. In the original soil, higher levels of nano-CeO2 reduced plant B concentration. Although morphological effects were not visible, changes in biomass and oxidative stress response were observed. Sunflower leaves from B-spiked soil showed visible symptoms of B toxicity, such as necrosis and chlorosis in old leaves, as well as an increase of superoxide dismutase (SOD) activity. However, at high nano-CeO2 level, SOD activity decreased reaching values similar to that of the control. This study has shown that nano-CeO2 reduced both the B nutritional status of sunflower in original soil and the B phytotoxicity in B-spiked soil.

Synergistic anti-tumor activity and inhibition of angiogenesis by cotargeting of oncogenic and death receptor pathways in human melanoma.

Improving treatment of advanced melanoma may require the development of effective strategies to overcome resistance to different anti-tumor agents and to counteract relevant pro-tumoral mechanisms in the microenvironment. Here we provide preclinical evidence that these goals can be achieved in most melanomas, by co-targeting of oncogenic and death receptor pathways, and independently of their BRAF, NRAS, p53 and PTEN status. In 49 melanoma cell lines, we found independent susceptibility profiles for response to the MEK1/2 inhibitor AZD6244, the PI3K/mTOR inhibitor BEZ235 and the death receptor ligand TRAIL, supporting the rationale for their association. Drug interaction analysis indicated that a strong synergistic anti-tumor activity could be achieved by the three agents and the AZD6244-TRAIL association on 20/21 melanomas, including cell lines resistant to the inhibitors or to TRAIL. Mechanistically, synergy was explained by enhanced induction of caspase-dependent apoptosis, mitochondrial depolarization and modulation of key regulators of extrinsic and intrinsic cell death pathways, including c-FLIP, BIM, BAX, clusterin, Mcl-1 and several IAP family members. Moreover, silencing experiments confirmed the central role of Apollon downmodulation in promoting the apoptotic response of melanoma cells to the combinatorial treatments. In SCID mice, the AZD6244-TRAIL association induced significant growth inhibition of a tumor resistant to TRAIL and poorly responsive to AZD6244, with no detectable adverse events on body weight and tissue histology. Reduction in tumor volume was associated not only with promotion of tumor apoptosis but also with suppression of the pro-angiogenic molecules HIF1α, VEGFα, IL-8 and TGFß1 and with inhibition of tumor angiogenesis. These results suggest that synergistic co-targeting of oncogenic and death receptor pathways can not only overcome melanoma resistance to different anti-tumor agents in vitro but can also promote pro-apoptotic effects and inhibition of tumor angiogenesis in vivo.

The nuclear coactivator amplified in breast cancer 1 maintains tumor-initiating cells during development of ductal carcinoma in situ.

The key molecular events required for the formation of ductal carcinoma in situ (DCIS) and its progression to invasive breast carcinoma have not been defined. Here, we show that the nuclear receptor coactivator amplified in breast cancer 1 (AIB1) is expressed at low levels in normal breast but is highly expressed in DCIS lesions. This is of significance since reduction of AIB1 in human MCFDCIS cells restored a more normal three-dimensional mammary acinar structure. Reduction of AIB1 in MCFDCIS cells, both before DCIS development or in existing MCFDCIS lesions in vivo, inhibited tumor growth and led to smaller, necrotic lesions. AIB1 reduction in MCFDCIS cells was correlated with significant reduction in the CD24-/CD44+ breast cancer-initiating cell (BCIC) population, and a decrease in myoepithelial progenitor cells in the DCIS lesions in vitro and in vivo. The loss of AIB1 in MCFDCIS cells was also accompanied by a loss of expression of NOTCH 2, 3 and 4, JAG2, HES1, GATA3, human epidermal growth factor receptor 2 (HER2) and HER3 in vivo. These signaling molecules have been associated with differentiation of breast epithelial progenitor cells. These data indicate that AIB1 has a central role in the initiation and maintenance of DCIS and that reduction of AIB1 causes loss of BCIC, loss of components of the NOTCH, HER2 and HER3 signaling pathways and fewer DCIS myoepithelial progenitor cells in vivo. We propose that increased expression of AIB1, through the maintenance of BCIC, facilitates formation of DCIS, a necessary step before development of invasive disease.

Using a plant hormone and a thioligand to improve phytoremediation of Hg-contaminated soil from a petrochemical plant.

Mercury-contaminated soils from a petrochemical plant in southern Italy were investigated to assess the phytoextraction efficiency of crop plants treated with the phytohormone, cytokinine (CK foliar treatment), and with the thioligand, ammonium thiosulfate (TS, soil application). Plant biomass, evapotranspiration, Hg uptake and distribution in plant tissues following treatment were compared. Results indicate the effectiveness of CK in increasing plant biomass and the evapotranspiration rate while TS treatment promoted soil Hg solubility and availability. The simultaneous addition of CK and TS treatments increased Hg uptake and translocation in both tested plants with up to 248 and 232% in Brassica juncea (Indian mustard) and Helianthus annuus (sunflower) respectively. B. juncea was more effective in Hg uptake, whereas H. annuus gave better response regarding plant biomass production. The effectiveness of the treatments was confirmed by the calculation of Hg phytoextraction and evaluation of labile-Hg residue in the soil after plant growth. In one growing cycle the plants subject to simultaneous CK and TS treatment significantly reduced labile-Hg pools that were characterized by the soil sequential extraction, but did not significantly affect the pseudototal metal content in the soil. Results support the use of plant growth regulators in the assisted phytoextraction process for Hg-contaminated soils.

Uptake of heavy metals by native species growing in a mining area in Sardinia, Italy: discovering native flora for phytoremediation.

This study assessed the distribution and availability of plant uptake of Zn, Pb, and Cd present in an abandoned mine at Ingurtosu, Sardinia (Italy). Geological matrix samples (sediments, tailings, and soil from a nearby pasture site) and samples of the predominant plant species growing on sediments and tailings were collected. Mean values of total Zn, Pb and Cd were respectively (mg kg(-1)) 7400, 1800, and 56 in tailings, 31000, 2900, and 100 in sediments, and 400, 200, and 8 in the pasture soil. The metal concentration values were high even in the mobile fractions evaluated by simplified sequential extraction (Zn 7485-103, Pb 1015-101, Cd 47-4 mg kg(-1)). Predominant native species were identified and analyzed for heavy metal content in various tissues. Among the plant species investigated Inula viscosa, Euphorbia dendroides, and Poa annua showed the highest metal concentration in aboveground biomass (mean average of Zn: 1680, 1020, 1400; Pb: 420, 240, 80; Cd: 28, 7, 19 mg kg(-1), respectively). The above mentioned species and A. donax could be good candidates for a phytoextraction procedure. Cistus salvifolius and Helichrysum italicus generally showed behavior more suitable for a phytostabilizer.

Exogenous cytokinin treatments of an Ni hyper-accumulator, Alyssum murale, grown in a serpentine soil: implications for phytoextraction.

Application of exogenous plant growth regulators was examined as a viable technique to increase the efficiency of plant metal extraction from contaminated soils. The aim of this study was to investigate the alteration of Ni phytoextraction by Alyssum murale, a Ni hyperaccumulator, following the application of cytokinins. The following parameters were investigated: Ni accumulation, plant growth, gas exchange, stomata behavior and the concentration of nonprotein thiols (glutathione, y-Glu-Cys, and phytochelatins). In a pot experiment, A. murale plants grown in a serpentine soil were treated with a mix of naturally occurring cytokinins. Results showed that Ni accumulation in plants ranged from 4000 to 7000 mg kg(-1) confirming the hyper-accumulation ability from the soil used. Cytokinin treatments produced a significant increase in plant biomass and transpiration rate whereas no significant variation in Ni accumulation or the concentration of non-protein thiols was observed. The results suggest that A. murale is a plant species sensitive to cytokinin treatment and that cytokinin treatment is potentially useful in increasing the phytoextraction capability by increasing biomass. Moreover, for first time, evidence was obtained that the Ni hyperaccumulation mechanism is independent of water flux and transpiration rate.

Strategies to use phytoextraction in very acidic soil contaminated by heavy metals.

In microcosm experiments, the use of inorganic and organic amendments has been studied as potential agents to reduce heavy metal bioavailability in an acidic soil highly contaminated by Cu, Zn and Ni, that has to be remediated by phytoremediation. The concentrations of heavy metals in the original soil (O-Soil) produced phytotoxic effects with a strong reduction in biomass yield that hinder the utilization of this technology. To overcome phytotoxicity the use of three immobilizing agents was evaluated. The results obtained showed that all the strategies decreased the mobile fractions of heavy metals in soil and increased the metal removal efficiency. In the case of Brassica juncea the best results for Zn and Ni were obtained after zeolites addition (Z-Soil) with an increase of about 6 times with respect to the value found in the O-Soil. In the case of Cu, the more efficient treatment was Ca(OH)(2) addition (Ca-Soil). The B. juncea plants accumulated Cu amounts 8 times greater than in the O-Soil. For this metal, relevant results were obtained also with compost, that increased the amount of Cu in the plants of 7 times with respect to the O-Soil. Similar results were obtained with Helianthus annuus the highest Zn and Ni accumulation was detected in the Z-Soil and compost-treated soils (C-Soil), with an increase of nearly 11 times with respect to the accumulation in the O-Soil. In the case of Cu the highest increase of total uptake was found in the C-Soil: 28 times higher than in the O-Soil. Total accumulation in Poa annua plants showed the highest removal efficiency in the Z-Soil for all metals. The values obtained increased of 4, 11 and 12 times for Cu, Zn and Ni, respectively.

Inclusive K(S);(0)K(S);(0) resonance production in ep collisions at HERA.

Inclusive K_{S};{0}K_{S};{0} production in ep collisions at the DESY ep collider HERA was studied with the ZEUS detector using an integrated luminosity of 0.5 fb;{-1}. Enhancements in the mass spectrum were observed and are attributed to the production of f_{2}(1270)/a_{2};{0}(1320), f_{2};{'}(1525) and f_{0}(1710). Masses and widths were obtained using a fit which takes into account theoretical predictions based on SU(3) symmetry arguments, and are consistent with the Particle Data Group values. The f_{0}(1710) state, which has a mass consistent with a glueball candidate, was observed with a statistical significance of 5 standard deviations. However, if this state is the same as that seen in gammagamma-->K_{S};{0}K_{S};{0}, it is unlikely to be a pure glueball state.

Human JIK, a novel member of the STE20 kinase family that inhibits JNK and is negatively regulated by epidermal growth factor.

Mammalian members related to Saccharomyces cerevisiae serine/threonine kinase STE20 can be divided into two subfamilies based on their structure and function. The PAK subfamily is characterized by an N-terminal p21-binding domain (also known as CRIB domain), a C-terminal kinase domain, and is regulated by the small GTP-binding proteins Rac1 and Cdc42Hs. The second group is represented by the GCK-like members, which contain an N-terminal catalytic domain and lack the p21-binding domain. Some of them have been demonstrated to induce c-Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK) cascade, while others have been shown to be activated by a subset of stress conditions or apoptotic agents, although little is known about their specific function. Here, we have identified a novel human STE20-related serine/threonine kinase, belonging to the GCK-like subfamily. This kinase does not induce the JNK/SAPK pathway, but, instead, inhibits the basal activity of JNK/SAPK, and diminishes its activation in response to human epidermal growth factor (EGF). Therefore, we designated this molecule JIK for JNK/SAPK-inhibitory kinase. The inhibition of JNK/SAPK signaling pathway by JIK was found to occur between the EGF receptor and the small GTP-binding proteins Rac1 and Cdc42Hs. In contrast, JIK does not activate nor does it inhibit ERK2, ERK6, p38, or ERK5. Furthermore, JIK kinase activity is not modulated by any exogenous stimuli, but, interestingly, it is dramatically decreased upon EGF receptor activation. Thus, JIK might represent the first member of the STE20 kinase family whose activity can be negatively regulated by tyrosine kinase receptors, and whose downstream targets inhibit, rather than enhance, JNK/SAPK activation.

Enhancement of fibroblast growth factor (FGF) activity by an FGF-binding protein.

Fibroblast growth factor-binding protein (FGF-BP) 1 is a secreted protein that can bind fibroblast growth factors (FGFs) 1 and 2. These FGFs are typically stored on heparan sulfate proteoglycans in the extracellular matrix in an inactive form, and it has been proposed that FGF-BP1 functions as a chaperone molecule that can mobilize locally stored FGF and present the growth factor to its tyrosine kinase receptor. FGF-BP1 is up-regulated in squamous cell, colon, and breast cancers and can act as an angiogenic switch during malignant progression of epithelial cells. For the present studies, we focused on FGF-1 and -2 and investigated interactions with recombinant human FGF-BP1 protein as well as effects on signal transduction, cell proliferation, and angiogenesis. We show that recombinant FGF-BP1 specifically binds FGF-2 and that this binding is inhibited by FGF-1, heparan sulfate, and heparinoids. Furthermore, FGF-BP1 enhances FGF-1- and FGF-2-dependent proliferation of NIH-3T3 fibroblasts and FGF-2-induced extracellular signal-regulated kinase 2 phosphorylation. Finally, in the chicken chorioallantoic membrane angiogenesis assay, FGF-BP1 synergizes with exogenously added FGF-2. We conclude that FGF-BP1 binds directly to FGF-1 and FGF-2 and positively modulates the biological activities of these growth factors.

Binding specificity and in vivo targets of the EH domain, a novel protein-protein interaction module.

EH is a recently identified protein-protein interaction domain found in the signal transducers Eps15 and Eps15R and several other proteins of yeast nematode. We show that EH domains from Eps15 and Eps15R bind in vitro to peptides containing an asparagine-proline-phenylalanine (NPF) motif. Direct screening of expression libraries with EH domains yielded a number of putative EH interactors, all of which possessed NPF motifs that were shown to be responsible for the interaction. Among these interactors were the human homolog of NUMB, a developmentally reguated gene of Drosophila, and RAB, the cellular cofactor of the HIV REV protein. We demonstrated coimmunoprecipitation of Eps15 with NUMB and RAB. Finally, in vitro binding of NPF-containing peptides to cellular proteins and EST database screening established the existence of a family of EH-containing proteins in mammals. Based on the characteristics of EH-containing and EH-binding proteins, we propose that EH domains are involved in processes connected with the transport and sorting of molecules within the cell.

Induction of resistance to the Abelson inhibitor STI571 in human leukemic cells through gene amplification.

The 2-phenylaminopyrimidine derivative STI571 has been shown to selectively inhibit the tyrosine kinase domain of the oncogenic bcr/abl fusion protein. The activity of this inhibitor has been demonstrated so far both in vitro with bcr/abl expressing cells derived from leukemic patients, and in vivo on nude mice inoculated with bcr/abl positive cells. Yet, no information is available on whether leukemic cells can develop resistance to bcr/abl inhibition. The human bcr/abl expressing cell line LAMA84 was cultured with increasing concentrations of STI571. After approximately 6 months of culture, a new cell line was obtained and named LAMA84R. This newly selected cell line showed an IC50 for the STI571 (1.0 microM) 10-fold higher than the IC50 (0.1 microM) of the parental sensitive cell line. Treatment with STI571 was shown to increase both the early and late apoptotic fraction in LAMA84 but not in LAMA84R. The induction of apoptosis in LAMA84 was associated with the activation of caspase 3-like activity, which did not develop in the resistant LAMA84R cell line. LAMA84R cells showed increased levels of bcr/abl protein and mRNA when compared to LAMA84 cells. FISH analysis with BCR- and ABL-specific probes in LAMA84R cells revealed the presence of a marker chromosome containing approximately 13 to 14 copies of the BCR/ABL gene. Thus, overexpression of the Bcr/Abl protein mediated through gene amplification is associated with and probably determines resistance of human leukemic cells to STI571 in vitro. (Blood. 2000;95:1758-1766)