Introduction and overview

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/26262/1/0000343.pd

Introduction to geochemistry of metalliferous black shales

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/29848/1/0000195.pd

Pore dilation occurs in TRPA1 but not in TRPM8 channels

Abundantly expressed in pain-sensing neurons, TRPV1, TRPA1 and TRPM8 are major cellular sensors of thermal, chemical and mechanical stimuli. The function of these ion channels has been attributed to their selective permeation of small cations (e.g., Ca2+, Na+ and K+), and the ion selectivity has been assumed to be an invariant fingerprint to a given channel. However, for TRPV1, the notion of invariant ion selectivity has been revised recently. When activated, TRPV1 undergoes time and agonist-dependent pore dilation, allowing permeation of large organic cations such as Yo-Pro and NMDG+. The pore dilation is of physiological importance, and has been exploited to specifically silence TRPV1-positive sensory neurons. It is unknown whether TRPA1 and TRPM8 undergo pore dilation. Here we show that TRPA1 activation by reactive or non-reactive agonists induces Yo-Pro uptake, which can be blocked by TRPA1 antagonists. In outside-out patch recordings using NMDG+ as the sole external cation and Na+ as the internal cation, TRPA1 activation results in dynamic changes in permeability to NMDG+. In contrast, TRPM8 activation does not produce either Yo-Pro uptake or significant change in ion selectivity. Hence, pore dilation occurs in TRPA1, but not in TRPM8 channels

Extraordinary magnetic response of an anisotropic 2D antiferromagnet via site-dilution

A prominent character of two-dimensional magnetic systems is the enhanced spin fluctuations, which however reduce the ordering temperature. Here we report that a magnetic field of only one-thousandth of the Heisenberg superexchange interaction can induce a crossover, which for practical purposes is the effective ordering transition, at temperatures about 6 times of the Neel transition in a site-diluted two-dimensional anisotropic quantum antiferromagnet. Such a strong magnetic response is enabled because the system directly enters the antiferromagnetically ordered state from the isotropic disordered state skipping the intermediate anisotropic stage. The underlying mechanism is achieved on a pseudospin-half square lattice realized in the [(SrIrO3)1/(SrTiO3)2] superlattice thin film that is designed to linearly couple the staggered magnetization to external magnetic fields by virtue of the rotational symmetry-preserving Dzyaloshinskii Moriya interaction. Our model analysis shows that the skipping of the anisotropic regime despite the finite anisotropy is due to the enhanced isotropic fluctuations under moderate dilution

Selective Inhibition of p300 HAT Blocks Cell Cycle Progression, Induces Cellular Senescence, and Inhibits the DNA Damage Response in Melanoma Cells

Epigenetic events, including covalent post-translational modifications of histones, have been demonstrated to have critical roles in tumor development and progression. The transcriptional coactivator p300/CBP possesses both histone acetyltransferase (HAT) activity and scaffolding properties that directly influence the transcriptional activation of targeted genes. We have used a potent and specific inhibitor of p300/CBP HAT activity, C646, in order to evaluate the functional contributions of p300/CBP HAT to tumor development and progression. Here we report that C646 inhibits the growth of human melanoma and other tumor cells and promotes cellular senescence. Global assessment of the p300 HAT transcriptome in human melanoma identified functional roles in promoting cell cycle progression, chromatin assembly, and activation of DNA repair pathways through direct transcriptional regulatory mechanisms. In addition, C646 is shown to promote sensitivity to DNA damaging agents, leading to the enhanced apoptosis of melanoma cells after combination treatment with cisplatin. Together, our data suggest that p300 HAT activity mediates critical growth regulatory pathways in tumor cells and may serve as a potential therapeutic target for melanoma and other malignancies by promoting cellular responses to DNA damaging agents that are currently ineffective against specific cancers

Sulfidation of organic matter associated with gold mineralization, Pueblo viejo, Dominican republic

The Pueblo Viejo district is one of the largest producers of precious metals in the world, yielding more than 11,000 kg of Au annually. Gold mineralization at Pueblo Viejo is hosted in spilite, and coarse clastic and finely laminated, fine grained carbonaceous sedimentary rocks of the Lower Cretaceous Los Ranchos Formation. Mineralization was accompanied by sulfidation as evidenced by (1) the occurrence of siderite distal to mineralization and pyrite proximal to mineralization, (2) increased S/Fe ratios associated with Au mineralization, (3) the occurrence of native S in and adjacent to mineralization, and (4) the presence of sulfidized organic matter (organo-S compounds) in mineralized rocks. Organic matter in the carbonaceous sedimentary rocks comprises vitrinite and pyrobitumen. Rock-Eval pyrolysis data indicate that this organic matter is overmature (HI 2S in the mineralizing fluid would have destabilized Au bisulfide complexes and caused deposition of gold. The restriction of S-rich organic matter to rocks in which all Fe occurs as pyrite indicates that sulfidation of organic matter postdates sulfidation of ferrous Fe and therefore, deposition of much of the Au.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/28847/1/0000682.pd

Gold deposition by sulfidation of ferrous Fe in the lacustrine sediments of the Pueblo Viejo district (Dominican Republic): The effect of Fe-C-S diagenesis on later hydrothermal mineralization in a Maar-Diatreme complex

The Pueblo Viejo district, located in the Cordillera Central of the Dominican Republic, contains large Au-Ag deposits associated with acid-sulfate alteration within spilites, conglomerates and carbonaceous sedimentary rocks that were deposited in a maar-diatreme complex. Much of the Au mineralization occurs in pyritic, carbonaceous siltstones of the Pueblo Viejo Maar-Diatreme Member of the Cretaceous Los Ranchos Formation. Pyrite is the only Fe-bearing phase in mineralized rock, whereas siderite is the dominant Fe-bearing phase in siltstones distal to mineralization. Disseminated pyrite occurs as framboids, cubes, pyritohedra, concretions and cement. Early framboids occur throughout the district. Au occurs as inclusions in later non-framboid disseminated pyrite (NFDP); an occurrence that is interpreted to be indicative of contemporaneous deposition. Pyrite framboids exhibit a wide range of [delta]34S-values (-17.5 to +4.8[per mille sign]) and are interpreted to have formed during biogenic reduction of pore-water sulfate. The NFDP yield restricted [delta]34S-values (, s = +/-2.4[per mille sign], n = 43) similar to those obtained from later vein pyrite (, s = +/-1.5[per mille sign], n = 12). Alunite and barite have [delta]34S-values ranging from +18.8 to +21.6[per mille sign]. The interpretation that the NFDP, vein pyrite, alunite and barite, and possibly even the framboidal pyrite share a common source of igneous sulfur is supported by the [delta]34S data. Siderite occurs as concretions and cement, contains abundant Mg (Fe0.75Mg0.19Mn0.03Ca0.02CO3) and has [delta]13C- and [delta]18O-values ranging from -2.5 to +1.1%. and +14.6 to +19.5[per mille sign], respectively. These data are consistent with the interpretation that the siderite formed in lacustrine sediments and that the carbonate in the siderite is probably methanogenic, although contributions from oxidation of organic matter during biogenic sulfate reduction, thermal decarboxylation of organic matter, or magmatic vapor cannot be ruled out.Disseminated Au mineralization in the sedimentary rocks formed when a hydrothermal fluid encountered reactive Fe2+ in diagenetic siderite. The ensuing pyrite deposition consumed H2S and destabilized the Au (HS)-2 complex, leading to precipitation of Au. The capacity of the sedimentary rocks to consume H2S and precipitate Au was controlled by the amount of non-pyrite Fe present as siderite. The abundance of siderite was controlled by the extent of pyrite formation during diagenesis.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/29846/1/0000193.pd

Paradoxical enhancement of fear extinction memory and synaptic plasticity by inhibition of the histone acetyltransferase p300

It is well established that the coordinated regulation of activity-dependent gene expression by the histone acetyltransferase (HAT) family of transcriptional coactivators is crucial for the formation of contextual fear and spatial memory, and for hippocampal synaptic plasticity. However, no studies have examined the role of this epigenetic mechanism within the infralimbic prefrontal cortex (ILPFC), an area of the brain that is essential for the formation and consolidation of fear extinction memory. Here we report that a postextinction training infusion of a combined p300/CBP inhibitor (Lys-CoA-Tat), directly into the ILPFC, enhances fear extinction memory in mice. Our results also demonstrate that the HAT p300 is highly expressed within pyramidal neurons of the ILPFC and that the small-molecule p300-specific inhibitor (C646) infused into the ILPFC immediately after weak extinction training enhances the consolidation of fear extinction memory. C646 infused 6 h after extinction had no effect on fear extinction memory, nor did an immediate postextinction training infusion into the prelimbic prefrontal cortex. Consistent with the behavioral findings, inhibition of p300 activity within the ILPFC facilitated long-term potentiation (LTP) under stimulation conditions that do not evoke long-lasting LTP. These data suggest that one function of p300 activity within the ILPFC is to constrain synaptic plasticity, and that a reduction in the function of this HAT is required for the formation of fear extinction memory