The Induction of APC with a Distinct Tolerogenic Phenotype via Contact-Dependent STAT3 Activation

BACKGROUND: Activation of the signal transducer and activator of transcription 3 (STAT3) within antigen presenting cells (APCs) is linked to abnormal APCs differentiation and function. We have previously shown that STAT3 is activated within APC by a novel contact-dependent mechanism, which plays a key role in mediating the immunomodulatory effects of hMSC. In order to better understand the underlying mechanisms that control APC maturation in a contact dependent manner, we extended our observation to tumor cells. Tumors were shown to secrete a variety of tumor-derived factors that activate STAT3 within infiltrating APCs. We now tested whether tumor cells can activate STAT3 within APC using the contact-dependent mechanism, in addition to soluble factors, and compared these two STAT3 activating pathways. PRINCIPAL FINDINGS: We demonstrate that in addition to tumor-derived secreted factors tumor cells activate STAT3 by a mechanism that is based on cell-cell interaction. We further demonstrate that these two STAT3 activating mechanisms differ in their JAK usage and their susceptibility to JSI-124 inhibition thereby representing two distinct pathways. Significantly, although both pathways activate STAT3, they modulate DCs maturation in a different manner that results in disparate phenotypic outcomes. Whereas the soluble-dependent pathway results in an immature phenotype, the contact-dependent pathway results in an apparently mature phenotype. Albeit their mature-like phenotype these latter cells express the tolerogenic markers ILT3 and ILT4 and possess T cell inhibitory activity. SIGNIFICANCE: This data suggests that, in at least certain cellular microenvironments, cell:cell interactions represent a novel way to activate STAT3 signaling, uncouple APC activation events and consequently regulate immunity and tolerance. Significantly, we have now demonstrated that this contact-dependent signaling pathway differs from that mediated by soluble factors and cytokines, inducing disparate phenotypic outcome, suggesting these two mechanisms have different and possibly complementary biological functions

Tumour macrophages as potential targets of bisphosphonates

Tumour cells communicate with the cells of their microenvironment via a series of molecular and cellular interactions to aid their progression to a malignant state and ultimately their metastatic spread. Of the cells in the microenvironment with a key role in cancer development, tumour associated macrophages (TAMs) are among the most notable. Tumour cells release a range of chemokines, cytokines and growth factors to attract macrophages, and these in turn release numerous factors (e.g. VEGF, MMP-9 and EGF) that are implicated in invasion-promoting processes such as tumour cell growth, flicking of the angiogenic switch and immunosuppression. TAM density has been shown to correlate with poor prognosis in breast cancer, suggesting that these cells may represent a potential therapeutic target. However, there are currently no agents that specifically target TAM's available for clinical use

Connectivity of Default-Mode Network Is Associated with Cerebral Edema in Hepatic Encephalopathy

Cerebral edema, a well-known feature of acute liver disease, can occur in cirrhotic patients regardless of hepatic encephalopathy (HE) and adversely affect prognosis. This study characterized and correlated functional HE abnormalities in the brain to cerebral edema using resting-state functional magnetic resonance imaging (rs-fMRI) and diffusion tensor imaging (DTI). Forty-one cirrhotic patients (16 without HE, 14 minimal HE, 11 overt HE) and 32 healthy controls were assessed. The HE grade in cirrhotic patients was evaluated by the West Haven criteria and neuro-psychological examinations. Functional connectivity correlation coefficient (fc-CC) of the default mode network (DMN) was determined by rs-fMRI, while the corresponding mean diffusivity (MD) was obtained from DTI. Correlations among inter-cortical fc-CC, DTI indices, Cognitive Ability Screening Instrument scores, and laboratory tests were also analyzed. Results showed that gradual reductions of HE-related consciousness levels, from “without HE” or “minimal HE” to “overt HE”, correlated with decreased anterior-posterior fc-CC in DMN [F(4.415), p = 0.000)]. The MD values from regions with anterior-posterior fc-CC differences in DMN revealed significant differences between the overt HE group and other groups. Increased MD in this network was inversely associated with decreased fc-CC in DMN and linearly correlated with poor cognitive performance. In conclusion, cerebral edema can be linked to altered cerebral temporal architecture that modifies both within- and between-network connectivity in HE. Reduced fc-CC in DMN is associated with behavior and consciousness deterioration. Through appropriate targets, rs-fMRI technology may provide relevant supplemental information for monitoring HE and serve as a new biomarker for clinical diagnosis

Influence of Caloric Restriction on Constitutive Expression of NF-κB in an Experimental Mouse Astrocytoma

Many of the current standard therapies employed for the management of primary malignant brain cancers are largely viewed as palliative, ultimately because these conventional strategies have been shown, in many instances, to decrease patient quality of life while only offering a modest increase in the length of survival. We propose that caloric restriction (CR) is an alternative metabolic therapy for brain cancer management that will not only improve survival but also reduce the morbidity associated with disease. Although we have shown that CR manages tumor growth and improves survival through multiple molecular and biochemical mechanisms, little information is known about the role that CR plays in modulating inflammation in brain tumor tissue.Phosphorylation and activation of nuclear factor κB (NF-κB) results in the transactivation of many genes including those encoding cycloxygenase-2 (COX-2) and allograft inflammatory factor-1 (AIF-1), both of which are proteins that are primarily expressed by inflammatory and malignant cancer cells. COX-2 has been shown to enhance inflammation and promote tumor cell survival in both in vitro and in vivo studies. In the current report, we demonstrate that the p65 subunit of NF-κB was expressed constitutively in the CT-2A tumor compared with contra-lateral normal brain tissue, and we also show that CR reduces (i) the phosphorylation and degree of transcriptional activation of the NF-κB-dependent genes COX-2 and AIF-1 in tumor tissue, as well as (ii) the expression of proinflammatory markers lying downstream of NF-κB in the CT-2A malignant mouse astrocytoma, [e.g. macrophage inflammatory protein-2 (MIP-2)]. On the whole, our date indicate that the NF-κB inflammatory pathway is constitutively activated in the CT-2A astrocytoma and that CR targets this pathway and inflammation.CR could be effective in reducing malignant brain tumor growth in part by inhibiting inflammation in the primary brain tumor

Renewable energy from Cyanobacteria: energy production optimization by metabolic pathway engineering

The need to develop and improve sustainable energy resources is of eminent importance due to the finite nature of our fossil fuels. This review paper deals with a third generation renewable energy resource which does not compete with our food resources, cyanobacteria. We discuss the current state of the art in developing different types of bioenergy (ethanol, biodiesel, hydrogen, etc.) from cyanobacteria. The major important biochemical pathways in cyanobacteria are highlighted, and the possibility to influence these pathways to improve the production of specific types of energy forms the major part of this review

A synvolcanic origin for magnetite-rich orebodies hosted by BIF in the Weld Range District, Western Australia

Iron ore deposits hosted by Archean banded iron-formation (BIF) in the Weld Range greenstone belt are representative of most of the documented iron ore deposits in the Yilgarn Craton. They include near-surface, supergene goethitehematite orebodies that overlie and partly modify deeper occurrences of hypogene magnetite and specular hematite ores. The Cenozoic goethite-hematite-rich orebodies in these deposits are unequivocally the product of meteoric fluid alteration affecting BIF in the near-surface supergene environment; however, the deeper and likely older magnetite- and specular hematite-rich orebodies have a more contentious origin. This study is the first to present a fluid-alteration model for hypogene iron mineralization in the Yilgarn Craton that uses fluid inclusion and mineral chemistry data to constrain the physical-chemical characteristics and source of hypogene fluids responsible formineralization. High-grade (> 57 wt% Fe), magnetite-rich iron ore at the Beebyn deposit defines a discontinuous series of 440 °C) and CO2-rich. Paired O and C stable isotope data for Stage 1 ferroan dolomite suggest that these fluids had a magmatic source, while Stage 1 magnetite chemistry (e.g. enrichments in Mg, Mn, Ca, and Na) indicates chemical exchange took place between the fluids and mafic igneous rocks prior to crystallization of magnetite. The presence of monophase carbonic fluid inclusions in Stage 1 ferroan dolomite suggest that phase separation of a bicarbonate-rich aqueous fluid took place in deeper parts of the hydrothermal system, which led to the separation of the resultant volatile-rich and brine phases during transport of the Stage 1 fluid to shallower crustal levels. Cooling of the hydrothermal system during the Stage 2 fluid event involved (i) an early brine (>275–327 °C; 36–40 equiv. wt% NaCl) with Cl/Br and C and O isotopes values that overlap the ranges for magmatic fluids, with minor involvement of Archean seawater, and extensive chemical exchange with country rocks; followed by (ii) pulses of moderate- and lower-temperature Stage 2 brines (> 125–260 °C; 2–24 equiv. wt% CaCl2) with Cl/Br, O and C isotope, Na/Br, and Ca/Ca+Na signatures that suggest cooling of magmatic-derived fluids that mixed with Archean seawater and reacted with mafic igneous country rocks in areas more distal to fluid pathways. The last stage of formation of magnetite-rich ore at the Beebyn deposit involved the flow of Stage 3 fluids through the existing fault network that controlled earlier fluids. Stage 3 fluids are lower-temperature (>98–175 °C), low to high-salinity brines with Cl/Br values that overlap reported ranges for 3.2 Ga vent fluids and seawater. Thus, they are likely the product of heated Archean seawater that was chemically-modified through interaction with mafic country rocks. Magnetite-talc veins at the Madoonga deposit have fluid halogen ratios for fluid inclusions hosted by magnetite that are compatible with a range of possible sources, including low-grade metamorphic fluids, geothermal brines, or oil field formation waters. Although, their common spatial association with semi-massive sulfides suggests their likely precipitation from brines derived from heated Archean seawater. More locally developed specular hematite-quartz veins that cut folded magnetite-rich ores at the Beebyn and Madoonga deposits are the product of iron redistribution in BIF by heated meteoric fluids or seawater, with precipitation of specular hematite as a consequence of oxidation and cooling of the fluid

Iron deposits hosted by banded iron-formations in the Yilgarn Craton: Products of sequential iron enrichment by magmatic, marine and meteoric fluids

Mesoarchean Algoma-type BIF in the Yilgarn Craton are locally enriched by secondary processes to iron concentrations approaching 72 wt% Fe. While their near-surface goethite–hematite ores are unequivocally the product of supergene fluid alteration, their deeper magnetite and crystalline hematite–martite ores have a contentious origin. This study shows that magnetite ores formed after diagenesis and peak greenschist facies metamorphism of BIF, coinciding with regional deformation events. The ores formed by a multi-stage process involving initial replacement of primary quartz bands in BIF by hypogene carbonate minerals, followed by the dissolution of the carbonate and concentration of magnetite. At the Beebyn deposit, the earliest fluids were hot (~440 °C), CO2–vapor-rich, and were likely derived from felsic magmatic fluids. In contrast, the fluids responsible for carbonate alteration at the Matthew Ridge, Koolyanobbing, and Windarling deposits were cooler (366–125 °C) and aqueous-rich with salinities from 0.3 to 43.9 wt% NaCl equiv. Their Cl–Br and C–O isotopic ratios suggest they are the product of mixing between magmatic fluids and heated seawater. In all deposits, later cooling (~178–98 °C) of these fluids led to dissolution of carbonate minerals and concentration of magnetite. Dated monazite and xenotime from magnetite ores demonstrates that fluid alteration of BIF began in the Mesoarchean and continued episodically through to the Paleoproterozoic. Later specular hematite-rich veins that cut and modify magnetite ores crystallized from aqueous-rich fluids that are more oxidized, with salinities from 0 to 28.7 wt% NaCl equiv. and crystallization temperatures of 243–85 °C. Their Cl–Br and C–O isotopic fluid ratios indicate that they formed from mixing between heated seawater and meteoric waters. The BIF-hosted iron deposits in the Yilgarn Craton show remarkable similarities with the well-studied iron deposits in the Carajás Mineral Province and Hamersley Basin. They all show the same transition through time from magnetite- to hematite-rich ores. Subsequent episodic, tectonically-driven, fluid alteration events led to further iron enrichment in these deposits. The transition in ore types most likely corresponds to a common guiding process, namely the uplift of crustal rocks containing BIF – resulting in the progressive shallowing of fluid alteration pathways and the greater influence of cooler, more oxidized, hydrothermal fluids. Unlike iron deposits hosted by Algoma-type BIF in the Yilgarn and Carajás, iron deposits hosted by Superior-type BIF in the Hamersley Basin display a greater influence of oxidized marine and meteoric waters, without involvement of magmatic fluids

Magmatic Hydrothermal Fluids at the Sedimentary Rock-hosted, Intrusion-related Telfer Gold-Copper Deposit, Paterson Orogen, Western Australia: P-T-X Constraints on the Ore Forming Fluids

The Neoproterozoic Telfer deposit, one of Australia’s largest gold-copper deposits is located in the Paterson Orogen. Several highly differentiated calc-alkaline to alkali-calcic peraluminous granites intruded the metasedimentary rocks near (5-20 km) Telfer contemporaneous with structurally controlled gold-copper mineralization. Fluid inclusion assemblages with different fluid inclusion types were identified in samples from a range of different vein types. These inclusion types range from three phase aqueous Laq+Vaq+Shalite, high salinity (≤ 50 wt % NaCl equiv), high temperature (≤ 460°C) inclusions to two phase aqueous or two phase aqueous carbonic, low to moderate salinity (2 - 22 wt % NaCl equiv.), moderate to high temperature (≤ 480°C) fluid inclusions. Fluid inclusion trapping mechanisms, and interpreted precipitation mechanisms for gold and copper include: (1) adiabatic cooling between 450 and 200°C in all veins, and (2) locally, fluid phase separation at around 300°C. The trapping pressure of fluid inclusion assemblages trapped during phase immiscibility was calculated to be approximately 1.5 kbars. For fluid inclusion assemblages that lack evidence for phase immiscibility a pressure, at the temperature of final homogenization, of up to 3 kbars was calculated. This high pressure value is interpreted to be related to local fluid overpressure, as a consequence of fault zone movement, in faults and fractures that localized gold at Telfer. Phase immiscibility and gold precipitation was induced during sharp pressure decrease accompanying fault zone movement. In situ laser ICP-MS analyses of fluid inclusions revealed high trace element contents in all fluid inclusion assemblages. Manganese/Fe ratios of 0.24 is observed. Given the high temperatures and salinities of up to 480°C and 42 wt % NaCl equiv., Au and Cu were likely transported as chloride complexes. This interpretation is supported by the observation that the highest base metal contents occurs in the highest salinity fluid inclusion. Potassium/Ca ratios of >1 in most assemblages, the high homogenization temperatures (≤ 480°C) in many fluid inclusion assemblages, and the high trace element contents (e.g., Fe, Mg, K, Na) in most of the fluid inclusion assemblages is compatible with involvement of a magmatic hydrothermal fluid during gold-copper mineralization. This fluid was probably derived from the coeval granites in the Telfer area and, thus Telfer is interpreted to be a distal, intrusion-related, metasedimentary rock hosted, gold-copper deposit type. Because of all the arguments mentioned above, Telfer can best be described as an unique intrusion-related, structurally controlled, metasedimentary rock hosted, gold-copper deposit

Structural control, hydrothermal alteration zonation, and fluid chemistry of the concealed, high-grade 4EE iron orebody at the paraburdoo 4E deposit, Hamersley Province, Western Australia

High-grade iron ore of the 4EE orebody of the 4E deposit (>200 Mt at 63.5 wt % Fe) occurs as a southerly dipping sheet within banded iron formation (BIF) of the Paleoproterozoic Dales Gorge and Joffre members of the Brockman Iron Formation. Structural reconstruction of the 4E deposit shows that reactivation of the 18E fault and development of the NW-striking, steeply SW dipping 4E and 4EE normal faults resulted in preservation of the 4EE orebody below the 4E deposit, and 400 m below the modern topographic surface. Three hypogene alteration zones between low-grade BIF and high-grade iron ore are observed: (1) distal magnetite-quartz-dolomite-stilpnomelane-hematite ± pyrite, (2) intermediate magnetite-dolomite-hematitechlorite-quartz- stilpnomelane, and (3) proximal hematite-dolomite-chlorite ± pyrite ± magnetite. Hydrothermal alteration is temporally and spatially constrained by NW-trending dolerite dikes that intruded the 4E and 4EE faults prior to hypogene alteration. Six vein types (V1-V6) are recognized at the 4E deposit. The veins both cut and parallel the primary BIF layers and were emplaced contemporaneously with the hydrothermal alteration zones that record the transformation of low-grade BIF to high-grade iron ore. Our integrated structural-hydrothermal alteration and fluid flow model proposes that during early stage 1a, hypogene fluid flow in the 4E orebody occurred during a period of continental extension and enhanced heat flow within sedimentary basins to the south of the Paraburdoo Range. Heated basinal brines were focused by the NW-striking, steeply SW dipping 4E and 4EE normal faults and reacted with BIF of the Dales Gorge and Joffre members. The warm to hot (160° -255°C), Ca-rich (26.6-31.9 equiv wt % CaCl2) basinal brine interacted with magnetite-chert layers, transforming them into magnetite-quartz-dolomite- stilpnomelane-hematite-pyrite BIF. The iron-rich brine (up to 2.8 wt % Fe) likely originated from evaporated seawater that had lost Mg and Na and gained Li and Ca through fluid-rock reactions with volcaniclastic rocks and carbonate successions within the Wittenoom Formation. The first incursion of deeply circulating, low-salinity (5.8-9.5 wt % NaCl equiv), heated (106°-201°C) modified meteoric water is recorded in late stage 1a minerals. This modified meteoric water had lost some of its Na through wall rock interaction with plagioclase, possibly by interaction with dolerite of the Weeli Wooli Formation that directly overlies the Joffre and Dales Gorge members. Stage 1b involved continuing reactions between the hydrothermal fluids and the magnetite-quartz-dolomite-stilpnomelane-hematite-pyrite BIF, and produced both the intermediate magnetite-dolomite-hematite-chlorite-pyrite and the proximal hematite-dolomite-magnetite-stilpnomelane alteration assemblages. Microplaty (10-80 μm), platy (100-250 μm), and anhedral hematite increasingly replace magnetite in the intermediate alteration zone, forming the proximal alteration zones that consist of microplaty, platy, anhedral hematite and magnetite. The intermediate and proximal alteration zones represent the mixing of a hot (250°-400°C), high-salinity, Ca-rich (30-40 wt % CaCl2 equiv), Sr-rich basinal brine with low-temperature and low-salinity (~5 wt % NaCl equiv) modified meteoric water that was heated (~100°-200°C) during its descent into the upper crust. Heterogeneous mixing of the two end-member fluids resulted in the trapping of primary fluid inclusion assemblages containing a wide range of trapping temperatures (up to 200°C) and salinities (up to 25 wt % NaCl equiv). Stage 1c of the hypogene hydrothermal fluid is characterized by low-temperature (<110°C), low-salinity (~5 wt % NaCl) meteoric water that interacted with the proximal hematite-dolomite-magnetite-stilpnomelane- altered BIF, leaving a porous, hematite-apatite high-grade ore. Supergene alteration affected the orebody since the Cretaceous and produced a hematite-goethite alteration assemblage, resulting in destruction of the hypogene alteration zones that are only preserved below the depth of modern weathering. Discovery of the concealed 4EE orebody of the 4E deposit demonstrates that structural geology plays a critical role in the exploration for high-grade iron orebodies. Structural reconstruction should be considered a critical exploration activity in structurally complex terranes where concealed orebodies may exist