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Widespread Lower Triassic microbial carbonates occur after the end-Permian mass extinction (EPME) and are commonly attributed to reduced metazoan competition after the EPME, or to paleoceanographic conditions that suppressed metazoan abundance and increased ocean carbonate saturation. Testing these hypotheses requires direct spatial (versus temporal) linkages between Lower Triassic microbial deposits and lithologic or geochemical proxy evidence for environmental perturbations. This study uses facies within and associated with an extensive Lower Triassic (Smithian) microbial carbonate mound complex, which developed across a > 400-km-wide middle-to-inner shelf in southern Utah, U.S.A., to assess potential controls on microbial carbonate development. Middle-shelf microbial mounds (1–2 m tall) are composed of stromatactis-rich peloidal boundstones that are laterally linked by microbial intermound beds. Inner-shelf microbial mounds ( Sparse, but persistent benthic fauna and bioturbation in all microbial facies and the lack of lithologic indicators of bottom-water anoxia indicate sufficient O2 levels to support animal life. The broad Utah shelf study area implies that shelf-edge, upwelling-derived, carbonate-saturated waters did not control microbial carbonate precipitation. Regional controls on microbial mound complex development include deposition during sea-level rise along a wide shallow shelf that maximized the areal extent of clear-water, low-energy subtidal environments and promoted growth of prolific photosynthesizing microbial communities. Probable global controls include the post-EPME reduction in skeletal metazoan competition, which permitted microbial mats to flourish, and elevated global-ocean carbonate saturation states and promoted extensive carbonate precipitation.

Widespread deposition of organic-rich shales during the Late Cretaceous Oceanic Anoxic Event 2 (OAE 2, ca. 94 Ma) occurred during a period of significant global paleo-environmental and geochemical change. It has been proposed that an increase in nutrient input to the ocean during OAE 2 was the key mechanism that generated and sustained high rates of organic-matter burial over time scales of 103–105 yr. Zinc is a bio-essential micronutrient and the proportion of Zn burial in oxic sediments relative to burial in organic-rich continental margin sediments is reflected in its seawater isotope composition. The first Zn-isotope records dating from the Cretaceous are presented here from three coeval carbonate successions: two from Europe (southern England and southern Italy) and one from southern Mexico. The new data show reproducible stratigraphic Zn-isotope patterns in spatially and lithologically diverse carbonate successions. Excursions to lower Zn-isotope values may be linked to the input of magmatic Zn, changes in the proportion of Zn burial into organic-rich sediments, and the liberation of previously buried Zn during an episode of widespread seafloor re-oxygenation during OAE 2 (the Plenus Cold Event).

Prostacyclin (PGI2) and phosphodiesterase 5 (PDE5) inhibitors are potent vasodilators that are used alone and in combination for the treatment of pulmonary arterial hypertension (PAH). Although these vasodilators are known to stimulate relaxation of vascular smooth muscle directly, other cells in circulation, including erythrocytes, express prostacyclin receptor (IPR) and contain PDE5. The binding of PGI2 analogs to the erythrocyte IPR results in activation of a signaling pathway that increases cyclic adenosine 3′,5′ monophosphate (cAMP), a requirement for adenosine 3′5′ triphosphate (ATP) release. Within this pathway, cAMP levels are regulated by phosphodiesterase 3 (PDE3), a PDE that is inhibited by cGMP, a cyclic nucleotide regulated by the activity of PDE5. Since inhibition of PDE3 enhances ATP release in response to PGI2 analogs, we investigated if the selective PDE5 inhibitors, zaprinast (ZAP) and tadalafil (TAD), would similarly increase cAMP and ATP release from human erythrocytes in response to the same stimulus. We determined that pretreatment of erythrocytes with one of two chemically dissimilar PDE5 inhibitors (ZAP or TAD, 10 µM) potentiated increases in cAMP and ATP release in response to incubation of human erythrocytes with the PGI2 analog, UT-15C (100 nM). These results suggest that a heretofore unrecognized synergism exists between IPR agonists and PDE5 inhibitors that could provide a new rationale for the co-administration of these agents as vasodilators in humans with PAH.

Distinct lateral and stratigraphic trends in paleosol morphology and clay mineralogy, in conjunction with the stable-isotope composition of sub-millimeter-scale spherulitic siderite (sphaerosiderite) and flint-clay kaolinite in middle–upper Pennsylvanian cyclic coal-bearing strata of the Illinois basin (IB) presented herein provide proxy records of middle–late Pennsylvanian equatorial terrestrial environments. Collectively, these data provide a better understanding of the polygenetic history of ancient soils preserved in cyclic strata and indicate that low-latitude Pennsylvanian IB soil profiles were influenced by a combination of autogenic and allogenic controls. Lateral variations in paleosol morphology from the interior of the basin to the northern margin indicate that soil development was dominantly influenced by autogenic controls, such as differences in local paleohydrology (i.e., groundwater fluctuations) and subsidence rates across the basin. Conversely, allogenic controls (i.e., glacioeustasy and climate) are interpreted to be principally responsible for the preservation of features in gleyed Protosols, gleyed Vertisols, and gleyed calcic Vertisols that occur in the interior of the IB. These paleosols are characterized by a polygenetic development history that includes (1) an initial period of soil formation in well-drained environments with seasonal wetting and drying of the profile, followed by (2) a subsequent period of waterlogging and development of reducing conditions. Paleosols that lack evidence for extensive periods of waterlogging are restricted, with the exception of two examples, to the northern margin of the basin, and they become abundant in the stratigraphic record near the middle–upper Pennsylvanian boundary (uppermost Desmoinesian). The stratigraphic distribution of these paleosols, in conjunction with a decrease in the relative abundance of kaolinite in the < 2 µm size fraction of IB paleosols near the Desmoinesian–Missourian (D-M) boundary, is interpreted to reflect a shift in the overall low-latitude regional climate to drier conditions. The stable-isotope compositions of sphaerosiderite and flint-clay kaolinite in middle–upper Pennsylvanian strata of the IB provide an additional proxy record of past equatorial terrestrial environments and are used to constrain the magnitude of paleoclimate change across the D-M (∼ Moscovian–Kasimovian) boundary. Sphaerosiderite δ18OV-PDB and δ13CV-PDB values range from −3.6‰ to −0.5‰ and −12.8‰ to −3.2‰, respectively. In particular, sphaerosiderite δ18O values from the B horizons of paleosols display an approximate −1.5‰ shift across the D-M boundary. This stratigraphically short isotopic shift occurs across the D-M boundary, on the order of one cyclothem (∼ 400 kyr), and is followed by a subsequent shift on the order of one cyclothem, back to more positive siderite δ18O values. The average δ18OV-SMOW and δDV-SMOW values of kaolinite isolated from the < 0.2 µm size fraction of a latest Desmoinesian flint-clay breccia are +21.0‰ and −46.5‰. These values correspond to a latest Desmoinesian crystallization temperature of 27 ± 2°C and a meteoric-water δ18OV-SMOW value of −3.1‰. Combination of sphaerosiderite δ18O values and co-occurring flint-clay kaolinite δD and δ18O values suggest a possible warming of up to 6°C across the D-M boundary, corresponding to an approximate temperature change of siderite crystallization from 27 to 33°C. This temperature increase, in conjunction with distinct stratigraphic trends in the clay mineralogy and morphology of IB paleosols, is consistent with previous paleoclimate interpretations, and it suggests that low-latitude Pennsylvanian paleoclimate became drier and warmer across the D-M boundary.

The morphology, mineralogy, and stratigraphic and lateral distribution of paleosols in Pennsylvanian (Moscovian–Gzhelian; Atokan–Virgilian) mixed marine and terrestrial coal-bearing strata (i.e., cyclothems) in the Illinois basin (IB) are presented in order to determine the dominant pedogenic processes within a cyclic sedimentary depositional framework. Paleosol morphologies range from weakly developed horizons with evidence of rooting and little to no pedogenic structure, to horizons with well-developed pedogenic slickensides, angular blocky structure, and carbonate nodules and tubules. The majority of paleosols in strata from the basin interior preserve (1) low chroma (gley) colors, (2) identifiable fossil plant organic matter that increases in abundance upward in the profiles toward the interpreted paleo-surface, and (3) calcite, sphaerosiderite, and pyrite cements and nodules. In contrast, paleosols in strata from the northern margin of the basin display high chroma colors and calcite cements and less fossil organic matter, sphaerosiderite, and pyrite cements. These observations indicate that paleosols from the basin interior underwent a multi-phase pedogenic and shallow burial history characterized by an initial better-drained, oxygenated stage under seasonal precipitation, followed by a poorly drained, reducing stage, while paleosols from the northern margin of the basin experienced overall more oxygenated conditions throughout their pedogenic development. X-ray diffraction analysis of the < 2 µm size fraction of paleosol matrix in IB paleosols indicates a mineralogical composition dominated by kaolinite, randomly interstratified (R0) and ordered (R1) illite–smectite (I/S), and subordinate amounts of chlorite. These combined observational and mineralogical datasets indicate that significant changes in paleohydrology were largely responsible for the development of Pennsylvanian soil profiles in the IB.

In 1,1′-bis[1,7-dicarba-closo-dodeca­borane(11)], the two {1,7-closo-C2B10H11} cages are linked across a centre of inversion. The position of the second non-linking cage C atom was established unambiguously by geometric and crystallographic methods and there is no evidence of C/B disorder., In the title compound, C4H22B20, the two {1,7-closo-C2B10H11} cages are linked across a centre of inversion, with C—C = 1.5401 (16) Å. The position of the second non-linking cage C atom was established unambiguously by geometric and crystallographic methods and there is no evidence of C/B disorder.

New legislation to reduce the amount of fertilizer leached into the environment by horticultural growers and the need to implement water-saving irrigation systems require an understanding of salt build-up and of nutrient cycles in order to develop efficient water-use strategies for growers. Solute transport in growing media is central to this process, but has received little attention thus far. The objectives of this study were to determine how solutes behave in sub-irrigated growing media and to assess a solute transport model for these media. A steady state evaporation (upward water flow) experiment was carried out with three different growing media in packed columns in the laboratory. Bromide, potassium and copper concentrations were determined using in-column pore water solution samplers and by sectioning the columns at the end of the experiment to obtain concentration profiles. The Hydrus-1D model was fitted to the solution sampler data assuming non-linear Freundlich adsorption, and then used to obtain favorable predictions of the measured concentration profiles. Independent adsorption isotherm results from batch experiments were found to be inadequate when used to predict solute movement and the results indicate that the preferred approach is an in-column evaluation of the transport parameters.Key words: Solute transport, sub-irrigation, peat, growing media

The stratigraphic and geochemical record of the mid-Cretaceous (Cenomanian–Turonian) Oceanic Anoxic Event 2 (OAE2) has been studied in numerous Tethyan and proto-Atlantic hemi-pelagic/pelagic successions, but little data comes from nearshore carbonate successions from the proto-Pacific region. Here we present the results of a combined stratigraphic and δ13C study of C–T platform carbonates from southern Mexico, which were deposited within the proto-Pacific. Two scales of sedimentary cyclicity are recognized. High-frequency peritidal and subtidal cycles (0.4–8 m) display little evidence of cycle-capping subaerial exposure and are not correlative between sections; these relationships suggest that the amplitudes of high-frequency sea-level changes were minimal during the peak mid-Cretaceous greenhouse. Longer-term transgressive-regressive sequences (18–40+ m) are correlated between sections, and using δ13C trends, can be correlated with sequences developed in northern Europe and India. The Mexican successions were sampled at a high resolution (~ 10 ky) for stable isotopes (inorganic, organic carbon and oxygen), total organic carbon, insoluble residues, and trace metals. The δ13Ccarb curve matches global trends (including 6 distinct isotopic stages) permitting identification of OAE2 despite the lack of characteristic anoxic facies. Using the δ13Ccarb trends, we tie the previously identified ammonite, planktonic foram, and nannofossil biostratigraphy from England and the Western Interior seaway of Colorado into the Mexican sections. The initiation of OAE2, defined by an abrupt positive 3–4‰ δ13C shift, coincides with a long-term sea-level rise, though the sedimentary expression of the deepening is no greater than that observed for any of the other sea-level events across the studied interval. OAE2 termination (transition from gradually decreasing to background δ13C values) is not associated with a particular sea-level trend. Stratigraphic changes in insoluble residues (proxy for continental sediment discharge) across OAE2 are not correlative between sections and do not show consistent systematic relationships with δ13C or sea-level variations, therefore do not support the hypothesis that OAE2 was associated with increased continental-derived nutrient influx. Two peaks in trace metal concentrations coincide with the abrupt increase in δ13C ratios (onset of OAE2) and during the transition from elevated-to-decreasing δ13C values (near the C–T stage boundary). These trends are similar to those recorded in coeval deposits of the Western Interior seaway, and are consistent with the hypothesis that OAE2 development was related to the release of reduced metals during the short-lived (

We describe a novel peptide-based in vitro method for the detection of reactive metabolites that is amenable for use with microsomal or purified enzyme systems. Covalently bound adducts are detected by mass spectrometry using a surface-enhanced laser desorption ionizationtime of flight detector. The trapping molecule is an 11 amino acid peptide (ECGHDRKAHYK) that contains cysteine and other nucleophilic amino acid residues, as well as charged residues to enhance binding to a weak cation exchange chip surface used with the detection system. The assay concept was initially tested using rat or human liver microsomes with a series of benzodioxolanes. The assay was refined using human recombinant cytochrome P450 3A4 as the bioactivation system and validated with a series of positive and negative reference compounds. Alternative individual human recombinant P450 enzymes (e.g., 1A1, 2C9, or 2D6) may be used in place of 3A4 as the bioactivation system, or several P450 enzymes can be combined together into a single bioactivation system. We found that a mixture of P450s 3A4, 2C9, and 2D6 was suitable as a rapid general screen for the detection of reactive metabolites that covalently bind to proteins. Combining results from assays of individual P450 enzymes with microsomal systems allows the rapid profiling of metabolic pathways involved in reactive metabolite generation and provides valuable information that can be used to guide structural modifications to minimize the potential for metabolic bioactivation. In addition, non-P450 enzymes may be used as activation systems, such as peroxidases or alcohol dehydrogenase. In summary, this peptide-based assay system is able to detect reactive metabolites generated from a structurally diverse set of drugs and xenobiotics using a variety of microsomal or purified enzyme activation systems.

The effects of Hurricanes Katrina and Rita and the subsequent unwatering of New Orleans, Louisiana, on the sediment chemistry of Lake Pontchartrain were evaluated by chemical analysis of samples of street mud and suspended and bottom sediments. The highest concentrations of urban-related elements and compounds (e.g., Pb, Zn, polycyclic aromatic hydrocarbons, and chlordane) in bottom sediments exceeded median concentrations in U.S. urban lakes and sediment-quality guidelines. The extent of the elevated concentrations was limited, however, to within a few hundred meters of the mouth of the 17th Street Canal, similar to results of historical assessments. Chemical and radionuclide analysis of pre- and post-Hurricane Rita samples indicates that remobilization of near-shore sediment by lake currents and storms is an ongoing process. The effects of Hurricanes Katrina and Rita on the sediment chemistry of Lake Pontchartrain are limited spatially and are most likely transitory.

The Human Genome Project provided the opportunity to use bioinformatic approaches to discover novel, endogenous hormones. Using this approach we have identified two novel peptide hormones and review here our strategy for the identification and characterization of the hormone, neuronostatin. We describe in this mini-review our strategy for determining neuronostatin's actions in brain, heart and pancreas. More importantly, we detail our deductive reasoning strategy for the identification of a neuronostatin receptor and our progress in establishing the physiological relevance of the peptide.

Hepatic enzyme inducers such as phenobarbital are often nongenotoxic rodent hepatocarcinogens. Currently, nongenotoxic hepatocarcinogens can only be definitively identified through costly and extensive long-term, repeat-dose studies (e.g., 2-year rodent carcinogenicity assays). Although liver tumors caused by these compounds are often not found to be relevant to human health, the mechanism(s) by which they cause carcinogenesis are not well understood. Toxicogenomic technologies represent a new approach to understanding the molecular bases of toxicological liabilities such as nongenotoxic carcinogenicity early in the drug discovery/development process. Microarrays have been used to identify mechanistic molecular markers of nongenotoxic rodent hepatocarcinogenesis in short-term, repeat-dose preclinical safety studies. However, the initial “noise” of early adaptive changes may confound mechanistic interpretation of transcription profiling data from short-term studies, and the molecular processes triggered by treatment with a xenobiotic agent are likely to change over the course of long-term treatment. Here, we describe the use of a differential display technology to understand the molecular mechanisms related to 13 weeks of dosing with the prototype rodent nongenotoxic hepatocarcinogen, phenobarbital. These findings implicate a continuing role for oxidative stress in nongenotoxic carcinogenicity. An Excel data file containing raw data is available in full at http://taylorandfrancis.metapress.com/openurl.asp?genre=journal&issn=0192-6233 . Click on the issue link for 33(1), then select this article. A download option appears at the bottom of this abstract. The file contains raw data for all gene changes detected by AFLP, including novel genes and genes of unknown function; sequences of detected genes; and animal body and liver weight ratios. In order to access the full article online, you must either have an individual subscription or a member subscription accessed through www.toxpath.org .

Peptide channel blockers found in venoms of many predators are useful pharmacological tools and potential therapeutic agents. The venom of the Brazilian spider Phoneutria nigriventer contains a fraction, ω-phonetoxin-IIA (ω-Ptx-IIA, 8360 MW), which blocks Ca2+channels. At frog neuromuscular junctions (NMJ) bathed in normal Ca2+(1.8 mM) saline, ω-Ptx IIA did not affect spontaneous transmitter release but reversibly reduced evoked transmitter release by 75 and 95% at 12 and 24 nM, respectively. In contrast, toxin effects were irreversible in low-Ca2+(0.5 mM) saline. Ca2+imaging in normal-Ca2+saline showed that ω-Ptx-IIA partially blocked stimulus-dependent presynaptic Ca2+signals, and the blockade was almost completely reversible. Increases in spontaneous release frequency induced by high extracellular K+were blocked by ω-Ptx-IIA. Therefore ω-Ptx-IIA blocks N-type Ca2+channels, which admit Ca2+that triggers transmitter release at the frog NMJ. Additional evidence predicts that ω-Ptx-IIA binds to N-type Ca2+channels at a different site from that of ω-Conotoxin-GVIA. ω-Ptx-IIA also gave a low-affinity partial blockade of transmitter release and presynaptic Ca2+signals at crayfish NMJs where P-type channels are blocked by ω-agatoxin-IVA. The Ca2+-dependent reversibility and promiscuity of this toxin may make it highly useful experimentally and therapeutically.

In mid-Middle Cambrian time, shallow-water sedimentation along the Cordilleran passive margin was abruptly interrupted by the development of the deep-water House Range embayment across Nevada and Utah. The Marjum Formation (330 m) in the central House Range represents deposition in the deepest part of the embayment and is composed of five deep-water facies: limestone–argillaceous limestone rhythmites; shale; thin carbonate mud mounds; bioturbated limestone; and cross-bedded limestone. These facies are cyclically arranged into 1·5 to 30 m thick parasequences that include rhythmite–mound, rhythmite–shale, rhythmite–bioturbated limestone and rhythmite–cross-bedded limestone parasequences. Using biostratigraphically constrained sediment accumulation rates, the parasequences range in duration from ≈14 to 270 kyr. The mud mounds are thin (

Neuronostatin (NST) is produced in pancreatic delta cells from the somatostatin preprohormone, and has been shown to inhibit glucose-stimulated insulin secretion from beta cells of primary islets, but not from isolated beta cell cultures. We have demonstrated that NST stimulates glucagon release and have hypothesized that this is necessary for the peptide’s in vivo effect to impair glucose tolerance. Here we demonstrate the action of NST to increase proglucagon message in alpha cells and identify a potential mechanism to be via phosphorylation of protein kinase A. The NST receptor, GPR107, is abundantly expressed in the pancreas, in particular in the alpha cell population and both the effect on proglucagon mRNA levels and PKA phosphrylation are absent in alpha cells in which the expression of the NST receptor has been compromised using siRNA. Taken together with our observation that NST infusion in conscious rats impairs glucose tolerance and that plasma levels of the peptide are elevated in the fasted co...

Pancreatic duodenal homeobox-1 (PDX-1) is a homeodomain protein that plays an important role in the development of the pancreas and in maintaining the identity and function of the islets of Langerhans. It also regulates the expression of the insulin gene in response to changes in glucose and insulin concentrations. Glucose and insulin regulate PDX-1 by way of a signaling pathway involving phosphatidylinositol 3-kinase (PI 3-kinase) and SAPK2/p38. Activation of this pathway leads to phosphorylation of PDX-1 and its movement into the nucleus. To investigate the intracellular trafficking of PDX-1, immunocytochemistry was used to localize PDX-1 in the human β-cell line NesPDX-1, in which PDX-1 is overexpressed, and in MIN6 β-cells. In low-glucose conditions, PDX-1 localized predominantly to the nuclear periphery, with some staining in the cytoplasm. After stimulation with glucose, PDX-1 was present in the nucleoplasm. The translocation of PDX-1 to the nucleoplasm was complete within 15 min and occurred in 5−10 mmol/l glucose. Insulin and sodium arsenite, an activator of the stress-activated pathway, also stimulated PDX-1 movement from the nuclear periphery to the nucleoplasm. When cells were transferred between high glucose− and low glucose−containing medium, PDX-1 rapidly shuttled between the nuclear periphery and the nucleoplasm. Glucose- and insulin-stimulated translocation of PDX-1 to the nucleoplasm was inhibited by wortmannin and SB 203580, indicating that a pathway involving PI 3-kinase and SAPK2/p38 was involved; translocation was unaffected by PD 098959 and rapamycin, suggesting that neither mitogen-activated protein kinase nor p70s6k were involved. Arsenite-stimulated import of PDX-1 into the nucleus was inhibited by SB 203580 but not by wortmannin. Export from the nucleoplasm to the nuclear periphery was inhibited by calyculin A and okadaic acid, suggesting that dephosphorylation of PDX-1 was involved. These results demonstrated that PDX-1 shuttles between the nuclear periphery and nucleoplasm in response to changes in glucose and insulin concentrations and that these events are dependent on PI 3-kinase, SAPK2/p38, and a nuclear phosphatase(s).

Previous studies in Silurian carbonates from Gotland (Sweden) have led to a model for the development of limestone-marl alternations. This model postulates that early diagenesis of precursor sediments without strong primary differences can result in a differentiation by selective dissolution of aragonite in marl beds and reprecipitation of calcite cement in limestone beds. This model is described as a set of mathematical equations that quantify the diagenetic processes (aragonite dissolution and calcite reprecipitation) that occur during the formation of limestone-marl interbeds from a hypothetical homogeneous precursor sediment. The calculations demonstrate that resulting hypothetical limestone-marl alternations show characteristic mathematical relationships between the ratios of the bed thicknesses of limestones and marls on one side, and the carbonate contents, on the other. By reversing this model, the original mineralogical composition of the precursor sediment of real-world rhythmic successions can be determined. In this study, alternations from the Silurian of Gotland, the Cambrian, Devonian, and Mississippian of North America, the Jurassic of France and Germany, and the Cretaceous of France are shown to exhibit mathematical relationships similar to those calculated for hypothetical precursor sediments without primary differences. Therefore, the mineralogical composition of their precursor sediments can be estimated. In contrast, the clear mismatch shown by the Lower Jurassic Belemnite Marls from Dorset indicates that these rhythms did not suffer an early diagenetic overprint. Our model helps to differentiate between rhythmites with strong depositional variations and those without; however, it cannot indicate whether a given alternation is the product of rhythmic diagenesis of a homogeneous precursor sediment or the result of diagenetic enhancement of subtle underlying sedimentary rhythms. For horizontally correlated patterns, such as laterally extensive beds and layers of nodules, an a priori unknown external signal has to be assumed.

Islet amyloid polypeptide (IAPP) and insulin are expressed in the beta-cells of the islets of Langerhans. They are co-secreted in response to changes in glucose concentration, and their mRNA levels are also regulated by glucose. The promoters of both genes share similar cis-acting sequence elements, and both bind the homeodomain transcription factor PDX1, which plays an important role in the regulation of the insulin promoter and insulin mRNA levels by glucose. Here we examine the role of PDX1 in the regulation of the human IAPP promoter by glucose. The experiments were facilitated by the availability of a human beta-cell line (NES2Y) that lacks PDX1. NES2Y cells also lack operational K(ATP) channels, resulting in a loss of control of calcium signaling. We have previously used these cells to show that glucose regulation of the insulin gene is dependent on PDX1, but not calcium. In the mouse beta-cell line Min6, glucose (16 mm) stimulated a 3.5-4-fold increase in the activity of a -222 to +450 IAPP promoter construct compared with values observed in 0.5 mm glucose. In NES2Y cells, glucose failed to stimulate transcriptional activation of the IAPP promoter. Overexpression of PDX1 in NES2Y cells failed to reinstate glucose-responsive control of the IAPP promoter. Glucose effects on the IAPP promoter were observed only in the presence of PDX1 when normal calcium signaling was restored by overexpression of the two K(ATP) channel subunits SUR1 and Kir6.2. The importance of calcium was further emphasized by an experiment in which glucose-stimulated IAPP promoter activity was inhibited by the calcium channel blocker verapamil (50 microm). Verapamil was further shown to inhibit the stimulatory effect of glucose on IAPP mRNA levels. These results demonstrate that like the insulin promoter, glucose regulation of the IAPP promoter is dependent on the activity of PDX1, but unlike the insulin promoter, it additionally requires the activity of another, as yet uncharacterized factor(s), the activity of which is calcium-dependent.

Pax4 is a paired-box transcription factor that plays an important role in the development of pancreatic β-cells. Two Pax4 cDNAs were isolated from a rat insulinoma library. One contained the full-length sequence of Pax4. The other, termed Pax4c, was identical to Pax4 but lacked the sequences encoding 117 amino acids at the COOH-terminus. Pax4 was found to inhibit the human insulin promoter through a sequence element, the C2 box, located at −253 to −244, and the islet amyloid polypeptide promoter through a sequence element located downstream of −138. The inhibitory activity of Pax4 was mapped to separate regions of the protein between amino acids 2–230 and 231–349.

Keywords: Physique du sol Reference HYDRAM-ARTICLE-1997-013View record in Web of Science Record created on 2005-10-11, modified on 2016-08-08

Basinal facies of the Middle Cambrian Marjum Formation (western Utah) and Middle Devonian Denay Limestone (central Nevada) are characterized by thin, rhythmically interbedded limestone and marl layers (deep-water rhythmites). Limestone layers (average thickness range of 4.3–5.5 cm) are composed of laminated to massive pelleted lime mudstone; marl layers (average thickness range of 0.7–1.7 cm) are characterized by laminated, argillaceous, dolomitic mudstone. The absence of current- or wave-reworked features, paucity of bioturbation and skeletal fossils, stratigraphic relationships with adjacent facies, and the dark color indicate that limestone and marl layers in both rhythmite successions were deposited in quiet, dysaerobic waters below storm-wave base. Both limestone and marl layers are composed of submillimeter-thick graded laminae which represent discrete depositional events from dilute density currents generated by high-frequency storms or distal turbidity currents. Fluctuations in primary pelagic productivity cannot account for variations in carbonate influx because calcareous microfossils did not evolve until the Mesozoic. Instead, the rhythmic interbedding is interpreted to reflect climatically controlled variations in fluvial and/or eolian influx, or changes in marine currents (storm or distal turbidity currents) which transported shallow platform-derived carbonate material into the deep-water region. Spectral analysis of carbonate time series were compared to lithologic rank series and, particularly for the Middle Cambrian rhythmites, were found to be statistically indistinguishable. The durations of significant spectral peaks were estimated from calculating the average sedimentation rates from the two biostratigraphically controlled stratigraphic sections; these rates range between 4.3 ± 4.1 cm/k.y. and 21.2 ± 29.2 cm/k.y. for the Cambrian, and 3.6 ± 1.8 cm/k.y. to 5.1 ± 7.4 cm/k.y. for the Middle Devonian. Application of these sedimentation rates to the Marjum couplets suggests that individual couplets represent between ∼190–2100 years of time. The Denay couplets represent ∼800–1900 years. The good agreement between empirical Holocene hemipelagic sedimentation rates and the sedimentologic evidence of relatively high depositional rates for the Paleozoic rhythmites supports this millennial-scale interpretation. These results, combined with that from previous work in Paleozoic evaporite and carbonate successions, suggest that millennial-scale paleoclimatic variations affected marine and marginal-marine sedimentation as far back in time as the Cambrian. Millennial-scale climatic change appears to be a permanent feature affecting the oceans and atmosphere, and is apparently largely unaffected by major changes in Phanerozoic paleogeography, tectonics and atmospheric composition.

Alterations in macroautophagy (hereafter referred to as “autophagy”) are a common feature of lysosomal storage disorders, and have been hypothesized to play a major role in the pathogenesis of these diseases. We have recently reported multiple defects in autophagy contributing to the lysosomal storage disorder Niemann-Pick type C (NPC). These include increased formation of autophagosomes, slowed turnover of autophagosomes secondary to impaired lysosomal proteolysis, and delivery of stored lipids to the lysosome via autophagy. The study summarized here describes novel methods for the interrogation of individual stages of the autophagic pathway, and suggests mechanisms by which lipid storage may result in broader lysosomal dysfunction.

Replacing a boron vertex in a [B(n)H(n)](2-) cluster with a smaller atom, e.g. carbon, results in the distance from that atom to the polyhedral centroid being shorter. This forms the basis of a simple but very effective method of distinguishing between B and C atoms in (hetero)carboranes that have been studied crystallographically, the Vertex-to-Centroid Distance (VCD) method. Examples of well-characterised icosahedral and sub-icosahedral closo carboranes, nido carboranes, icosahedral metallacarboranes and supraicosahedral metallacarboranes are used to illustrate the generality of the VCD method. In this process a number of structures are identified in which the method suggests B/C disorder not previously recognised and some structures in which it appears that a cage C atom has been wrongly assigned. The largest sub-group of heterocarboranes is the family of 3,1,2-MC(2)B(9) compounds, and for these species consideration of Exopolyhedral Ligand Orientation (ELO) can sometimes be used to quickly suggest when a literature structure is suspect in terms of cage C atom positioning. The crystal structure of one such compound, 3,3-NO(3)-3-PPh(3)-3,1,2-closo-RhC(2)B(9)H(11), has been redetermined and the correct location of the cage C atoms established.

The purinergic response of the guinea-pig vas deferens to long trains of pulses at high frequency consists of an initial twitch followed by a much lower plateau. Mechanical, neurochemical and electrophysiological techniques were used to examine the reason for the fade. Mechanical measurements. In tissues stimulated by trains of 180 pulses/10 Hz and treated with prazosin to suppress the noradrenergic contraction component, the response to alpha, beta-methylene ATP and to exogenous ATP was as high during the secondary plateau of the purinergic neurogenic contraction as it was outside electrical stimulation periods; the response to 50 pulses/100 Hz was also unchanged during the low plateau. The plateau was not increased by reactive blue 2,8-(p-sulphophenyl)theophylline, propranolol or capsaicin. Neurochemical measurements. In tissues preincubated with [3H]-noradrenaline, electrical stimulation elicited an overflow of tritium and of ATP. In the absence of drugs as well as in the presence of prazosin and suramin to suppress contractions, the overflow of tritium per pulse decreased slightly in the course of trains of 90 pulses/10 Hz; the overflow of ATP per pulse decreased to a greater extent on average, but the decrease was not statistically significant. In the presence of prazosin and nifedipine, also to suppress contractions, the overflow of tritium per pulse again decreased slightly in the course of trains of 105 pulses/10 Hz, but the overflow of ATP per pulse if anything tended to increase. Electrophysiological measurements.(ABSTRACT TRUNCATED AT 250 WORDS)

During the summer of 1990, 12 gravity cores were collected in Lake Coeur d'Alene, Idaho at various depths and in a variety of depositional environments. All core subsamples were analysed to determine the bulk sediment chemistry; selected subsamples were analysed for trace element partitioning and 137Cs activity. The purpose of these analyses was to determine the trace element concentrations and distributions in the sediment column and to try to establish a trace element geochemical history of the lake in relation to mining and mining-related discharge operations in the area. Substantial portions of the near-surface sediments in Lake Coeur d'Alene are markedly enriched in Ag, As, Cd, Hg, Pb, Sb and Zn, and slightly enriched in Cu, Fe and Mn. Variations in the thickness of the trace element-rich sediments, which range from more than 119 cm to as little as 17 cm, indicate that the source of much of this material is the Coeur d'Alene River. An estimated 75 million tonnes of trace element-rich sediments have been deposited on or in the lake bed. Estimated trace element masses in excess of those considered representative of background conditions range from a high of 468 000 tonnes of Pb to a low of 260 tonnes of Hg. The similarity between the trace element-rich surface and subsurface sediments with respect to their location, their bulk chemistry, their interelement relations and their trace element partitioning indicate that the sources and/or concentrating mechanisms causing the trace element enrichment in the lake sediments have probably been the same through-out their depositional history. Based on a Mt St Helens'ash layer from the 1980 eruption, ages estimated from 137Cs activity and the presence of 80 discernible and presumably annual layers in a core collected near the Coeur d'Alene River delta indicate that deposition rates for the trace element-rich sediments have ranges from 2.1 to 1.3 cm/year. These data also indicate that the deposition of trace element-rich sediments began, at least in the Coeur d'Alene River delta, some time between 1895 and 1910, dates consistent with the onset of mining and ore processing activities that began in the area in the 1880s.

Among environment scientists, the current and almost universally accepted definition of dissolved constituents is an operational one-only those materials which pass through a 0.45-μm membrane filter are considered to be dissolved. Detailed laboratory and field studies on Fe and Al indicate that a number of factors associated with filtration, other than just pore size, can substantially alter “dissolved” trace element concentrations; these include: filter type, filter diameter, filtration method, volume of sample processed, suspended sediment concentration, suspended sediment grain-size distribution, concentration of colloids and colloidally-associated trace elements and concentration of organic matter. As such, reported filtered-water concentrations employing the same pore size filter may not be equal. Filtration artifacts may lead to the production of chemical data that indicate seasonal or annual “dissolved” chemical trends which do not reflect actual environmental conditions. Further, the development of worldwide averages for various dissolved chemical constituents, the quantification of geochemical cycles, and the determination of short- or long-term environmental chemical trends may be subject to substantial errors, due to filtration artifacts, when data from the same or multiple sources are combined. Finally, filtration effects could have a substantial impact on various regulatory requirements.

Mining, milling, and processing wastes containing quantities of arsenopyrite were produced around Lead, South Dakota, from 1875 to 1977. Much of this material was discharged into Whitewood Creek, and from there portions of the waste were transported to the Belle Fourche River, thence to the Cheyenne River, and finally to the Missouri River. In 1958, the Missouri River was dammed at Pierre, forming Lake Oahe. Analyses of cores collected from the lake bottom showed the presence of arsenic-rich layers in the bed sediments; substantial portions of the arsenic are due to arsenopyrite in the 8–16 and 16–32 μm size fractions of the sediments. In addition, suspended-sediment samples collected from the Cheyenne River above Lake Oahe contain detectable quantities of arsenopyrite in the 8–16 and 16–32 μm fractions. Solid material collected from the banks and floodplains of the Belle Fourche River and Whitewood Creek contains reduced and oxidized phases. The reduced phases have arsenic maxima in the 16–32 and 32–63 μm size ranges. These fractions also contribute the most arsenic to the samples; the major source being arsenopyrite. The oxidized segments have arsenic maxima in the 63 μm size ranges. The 63 μm fractions contribute the most arsenic to the oxidized samples. This arsenic, despite the oxidized nature of the samples, is associated with arsenopyrite coated with thin iron oxide rinds. It has been calculated that 80% of the arsenic in these deposits is associated with sulfides (in the form of arsenopyrite), while 20% is associated with iron oxides. The arsenopyrite found in the banks and floodplains of Whitewood Creek and the Belle Fourche River are the likely source of the arsenopyrite found in the suspended sediments of the Cheyenne River and in the bed sediment of Lake Oahe.

The effects of Hurricanes Katrina and Rita and the subsequent unwatering of New Orleans, Louisiana, on the sediment chemistry of Lake Pontchartrain were evaluated by chemical analysis of samples of street mud and suspended and bottom sediments. The highest concentrations of urban-related elements and compounds (e.g., Pb, Zn, polycyclic aromatic hydrocarbons, and chlordane) in bottom sediments exceeded median concentrations in U.S. urban lakes and sediment-quality guidelines. The extent of the elevated concentrations was limited, however, to within a few hundred meters of the mouth of the 17th Street Canal, similar to results of historical assessments. Chemical and radionuclide analysis of pre- and post-Hurricane Rita samples indicates that remobilization of near-shore sediment by lake currents and storms is an ongoing process. The effects of Hurricanes Katrina and Rita on the sediment chemistry of Lake Pontchartrain are limited spatially and are most likely transitory.

The effect of liver growth stimulation [using the rodent PXR (pregnane X receptor) activator PCN (pregnenolone-16α-carbonitrile)] in rats chronically treated with carbon tetrachloride to cause repeated hepatocyte necrosis and liver fibrogenesis was examined. PCN did not inhibit the hepatotoxicity of carbon tetrachloride. However, transdifferentiation of hepatic stellate cells and the extent of fibrosis caused by carbon tetrachloride treatment was significantly inhibited by PCN in vivo. In vitro, PCN directly inhibited hepatic stellate cell transdifferentiation to a profibrogenic phenotype, although the cells did not express the PXR (in contrast with hepatocytes), suggesting that PCN acts independently of the PXR. Mice with a functionally disrupted PXR gene (PXR−/−) did not respond to the antifibrogenic effects of PCN, in contrast with wild-type (PXR+/+) mice, demonstrating an antifibrogenic role for the PXR in vivo. However, PCN inhibited the transdifferentiation of PXR−/−-derived mouse hepatic stellate cells in vitro, confirming that there is also a PXR-independent antifibrogenic effect of PCN through a direct interaction with hepatic stellate cells. These data suggest that the PXR is antifibrogenic in rodents in vivo and that a PXR-independent target for PXR activators exists in hepatic stellate cells that also functions to inhibit fibrosis.

Gliotoxin has been shown to promote a reversal of liver fibrosis in an animal model of the disease although its mechanism of action in the liver is poorly defined. The effects of gliotoxin on activated hepatic stellate cells (HSCs) and hepatocytes have therefore been examined. Addition of gliotoxin (1.5 μM) to culture-activated HSCs resulted in its rapid accumulation, resulting in increased levels of glutathione and apoptosis without any evidence of oxidative stress. In contrast, although hepatocytes also rapidly sequestered gliotoxin, cell death only occurred at high (50-μM) concentrations of gliotoxin and by necrosis. At high concentrations, gliotoxin was metabolized by hepatocytes to a reduced (dithiol) metabolite and glutathione was rapidly oxidized. Fluorescent dye loading experiments showed that gliotoxin caused oxidative stress in hepatocytes. Antioxidants—but not thiol redox active compounds—inhibited both oxidative stress and necrosis in hepatocytes. In contrast, HSC apoptosis was not affected by antioxidants but was potently abrogated by thiol redox active compounds. The adenine nucleotide transporter (ANT) is implicated in mitochondrial-dependent apoptosis. HSCs expressed predominantly nonliver ANT isoform 1, and gliotoxin treatment resulted in a thiol redox-dependent alteration in ANT mobility in HSC extracts, but not hepatocyte extracts. In conclusion, these data suggest that gliotoxin stimulates the apoptosis of HSCs through a specific thiol redox-dependent interaction with the ANT. Further understanding of this mechanism of cell death will aid in finding therapeutics that specifically stimulate HSC apoptosis in the liver, a promising approach to antifibrotic therapy. Supplementary material for this article can be found on the HEPATOLOGY website (http://interscience.wiley.com/jpages/0270-9139/suppmat/index.html). (HEPATOLOGY 2004;40:232–242.)

An RT-PCR based strategy to clone the membrane-associated steroid binding protein ratp28 additionally amplified a novel sequence-related PCR product termed HC5. The HC5 PCR product was cloned and sequenced and showed 94% nucleotide sequence similarity to ratp28. The HC5 cDNA sequence open reading frame encodes a predicted 75 amino acid (8.0 kDa) protein, and is therefore truncated compared to ratp28 (195 amino acids, 21.6 kDa). In vitro transcription and translation of the HC5 cDNA resulted in the production of 2 proteins of approximately 8 and 6 kDa. Restriction digests from various tissues demonstrated that liver and heart expressed primarily ratp28 mRNA whereas kidney and blood contained both ratp28 and HC5 transcripts. Phage display was employed to generate an antibody fragment to a peptide sequence conserved in ratp28 and HC5. Western blotting identified a 10 kDa protein in cytosolic fractions of rat kidney. The function of HC5 remains to be determined.

α-Latrotoxin (α-LTX) is a neurotoxin that accelerates spontaneous exocytosis independently of extracellular Ca2+. Although α-LTX increases spontaneous transmitter release at synapses, the mechanism is unknown. We tested the hypothesis that α-LTX causes transmitter release by mobilizing intracellular Ca2+in frog motor nerve terminals. Transmitter release was measured electrophysiologically and with the vesicle marker FM1-43; presynaptic ion concentration dynamics were measured with fluorescent ion-imaging techniques. We report that α-LTX increases transmitter release after release of a physiologically relevant concentration of intracellular Ca2+. Neither the blockade of Ca2+release nor the depletion of Ca2+from endoplasmic reticulum affected Ca2+signals produced by α-LTX. The Ca2+source is likely to be mitochondria, because the effects on Ca2+mobilization of CCCP (which depletes mitochondrial Ca2+) and of α-LTX are mutually occlusive. The release of mitochondrial Ca2+is partially attributable to an increase in intracellular Na+, suggesting that the mitochondrial Na+/Ca2+exchanger is activated. Effects of α-LTX were not blocked when Ca2+increases were reduced greatly in saline lacking both Na+and Ca2+and by application of intracellular Ca2+chelators. Therefore, although increases in intracellular Ca2+may facilitate the effects of α-LTX on transmitter release, these increases do not appear to be necessary. The results show that investigations of Ca2+-independent α-LTX mechanisms or uses of α-LTX to probe exocytosis mechanisms would be complicated by the release of intracellular Ca2+, which itself can trigger exocytosis.

α-latrocrustatoxin (α-LCTX), a component of black widow spider venom (BWSV), produced a 50-fold increase in the frequency of spontaneously occurring miniature excitatory postsynaptic potentials (mEPSPs) at crayfish neuromuscular junctions but did not alter their amplitude distribution. During toxin action, periods of high-frequency mEPSP discharge were punctuated by periods in which mEPSP frequency returned toward control levels. EPSPs were increased in amplitude during periods of enhanced mEPSP discharge. α-LCTX had no effect when applied in Ca2+-free saline, but subsequent addition of Ca2+ caused an immediate enhancement of mEPSP frequency even when α-LCTX was previously washed out of the bath with Ca2+-free saline. Furthermore removal of Ca2+from the saline after α-LCTX had elicited an effect immediately blocked the action on mEPSP frequency. Thus α-LCTX binding is insensitive to Ca2+, but toxin action requires extracellular Ca2+ ions. Preincubation with wheat germ agglutinin prevented the effect of α-LCTX but not its binding. These binding characteristics suggest that the toxin may bind to a crustacean homologue of latrophilin/calcium-independent receptor for latrotoxin, a G-protein-coupled receptor for α-latrotoxin (α-LTX) found in vertebrates. α-LCTX caused “prefacilitation” of EPSP amplitudes, i.e., the first EPSP in a train was enhanced in amplitude to a greater degree than subsequent EPSPs. A similar alteration in the pattern of facilitation was observed after application of the Ca2+ionophore, A23187, indicating that influx of Ca2+ may mediate the action of α-LCTX. In nerve terminals filled with the Ca2+ indicator, calcium green 1, α-LCTX caused increases in the fluorescence of the indicator that lasted for several minutes before returning to rest. Neither fluorescence changes nor toxin action on mEPSP frequency were affected by the Ca2+ channel blockers ω-agatoxin IVA or Cd2+, demonstrating that Ca2+ influx does not occur via Ca2+ channels normally coupled to transmitter release in this preparation. The actions of α-LCTX could be reduced dramatically by intracellular application of the Ca2+ chelator, bis-( o-aminophenoxy)- N,N,N′,N′-tetraacetic acid. We conclude that induction of extracellular Ca2+influx into nerve terminals is sufficient to explain the action of α-LCTX on both spontaneous and evoked transmitter release at crayfish neuromuscular junctions.

Imatinib mesylate (IM, Gleevec, Novartis), a specific inhibitor of the tyrosine kinase BCR-ABL, promotes an impressive complete cytogenetic remission rate in patients with chronic phase Chronic Myeloid Leukaemia (CML). In most cases however, molecular disease persists and may lead to eventual relapse. IM selectively interacts with BCR-ABL thereby inhibiting activation of downstream targets, in particular phosphorylation of CrkL. We have previously demonstrated the sensitivity of rare Ph+ CD34+ CML stem cells (

Air elutriation can be used for the separation of sediments into particle size classes for subsequent chemical analysis . Size distributions obtained by elutriation compare with those determined by non‐chetnically dispersed pipet analysis . Contaminant‐free fractions can be obtained for the analysis of Cu, Zn, Pb, Co, Cr, Fe, Mn, Al, Ti, and probably Cd.

Multiple linear regression models calculated from readily obtainable chemical and physical parameters can explain a high percentage (70 per cent or greater) of observed sediment-trace element variance for Cu, Zn, Pb, Cr, Ni, Co, As, Sb, Se, and Hg in a widely divergent suite of 61 sediment samples. The independent variables used in the models may be single parameters, principal component scores, or principal component scores combined with their cross-products. The most useful type of variable must be determined on a case-by-case basis. The independent variables (geochemical parameters) incorporated in the models calculated during this study probably are applicable to many aquatic sediments; albeit, use of a larger data set (>61) could alter the magnitude of the calculated coefficients. The geochemical parameters included in the models were of a physical (e.g. grain size, surface area) and a chemical (e.g. organic matter, amorphous iron oxides) nature. Comparison between actual and predicted trace element concentrations obtained from the models may provide a means of defining ‘average’ sediment-trace element concentrations. In this context, the models may also help identify either naturally or anthropogenically impacted sites for additional study.

The Guelph permeameter method is used in 0.02-m- and 0.03-m-radius wells to measure in situ the field-saturated hydraulic conductivity (K10) and matric flux potential (φm) of a heterogeneous, anisotropic, structured loam soil. The K10, estimates, obtained using both Richards (GP-R) and Laplace (GP-L

In brief: Distance runners are suggested as a new model for optimal health standards because normal values are now derived from the American public, which is notorious for its obesity, low level of physical fitness, bad eating habits, use of cigarettes and drugs, and high incidence of cardiovascular and other degenerative diseases. As a group, the 50 distance runners studied showed lower than normal body weight, body fat, resting heart rate, serum cholesterol and triglycerides; higher HDL cholesterol; and lower cholesterol/HDL cholesterol ratios. However, the runners who ate the average American diet sometimes had normal values.

The paper presents a chemical composition diagram which indicates the molar proportions of the oxides without the necessity for re-calculation.