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Detailed organic geochemical and carbon isotopic (δ13C and Δ14C) analyses are performed on permafrost deposits affected by coastal erosion (Herschel Island, Canadian Beaufort Sea) and adjacent marine sediments (Herschel Basin) to understand the fate of organic carbon in Arctic nearshore environments. We use an end‐member model based on the carbon isotopic composition of bulk organic matter to identify sources of organic carbon. Monte Carlo simulations are applied to quantify the contribution of coastal permafrost erosion to the sedimentary carbon budget. The models suggest that ~40% of all carbon released by local coastal permafrost erosion is efficiently trapped and sequestered in the nearshore zone. This highlights the importance of sedimentary traps in environments such as basins, lagoons, troughs, and canyons for the carbon sequestration in previously poorly investigated, nearshore areas. Plain Language Summary: Increasing air and sea surface temperatures at high latitudes leads to accelerated thaw, destabilization, and erosion of perennially frozen soils (i.e., permafrost), which are often rich in organic carbon. Coastal erosion leads to an increased mobilization of organic carbon into the Arctic Ocean, which there can be converted into greenhouse gases and may therefore contribute to further warming. Carbon decomposition can be limited if organic matter is efficiently deposited on the seafloor, buried in marine sediments, and thus removed from the short‐term carbon cycle. Basins, canyons, and troughs near the coastline can serve as sediment traps and potentially accommodate large quantities of organic carbon along the Arctic coast. Here we use biomarkers (source‐specific molecules), stable carbon isotopes, and radiocarbon to identify the sources of organic carbon in the nearshore zone of the southern Canadian Beaufort Sea near Herschel Island. We quantify the contribution of coastal permafrost erosion to the sedimentary carbon budget of the area and estimate that more than a third of all carbon released by local permafrost erosion is efficiently trapped in marine sediments. This highlights the importance of regional sediment traps for carbon sequestration. Key Points: Permafrost organic matter derived from coastal erosion dominates nearshore marine sedimentsNearshore basins trapping sediments in the Arctic Ocean efficiently sequester permafrost organic carbon [ABSTRACT FROM AUTHOR]

Wintertime ammonium nitrate aerosol pollution is a severe air quality issue affecting both developed and rapidly urbanizing regions from Europe to East Asia. In the United States, it is acute in western basins subject to inversions that confine pollutants near the surface. Measurements and modeling of a wintertime pollution episode in Salt Lake Valley, Utah, demonstrate that ammonium nitrate is closely related to photochemical ozone through a common parameter, total odd oxygen, Ox,total. We show that the traditional nitrogen oxide and volatile organic compound (NOx‐VOC) framework for evaluating ozone mitigation strategies also applies to ammonium nitrate. Despite being nitrate‐limited, ammonium nitrate aerosol pollution in Salt Lake Valley is responsive to VOCs control and, counterintuitively, not initially responsive to NOx control. We demonstrate simultaneous nitrate limitation and NOx saturation and suggest this phenomenon may be general. This finding may identify an unrecognized control strategy to address a global public health issue in regions with severe winter aerosol pollution. Plain Language Summary: Particulate matter (PM) is dangerous to human health and impacts visibility and climate. In the United States, Europe, and Asia, PM is severe in urban areas in the winter when ammonium nitrate, NH4NO3, comprises an appreciable fraction of the total PM mass. A key control strategy is to reduce emissions of the limiting reagent. Using measurements from a recent field campaign in the Salt Lake Valley, Utah, which experiences high PM levels in winter, we demonstrate that emission control strategies can be evaluated using the same framework commonly used to control ozone, another common pollutant that occurs at high levels in urban areas in the summer. We show that initial control of the NOx precursor is ineffective at reducing NH4NO3 aerosol in the Salt Lake Valley, while initial control of volatile organic compounds, which are not a direct precursor for either nitrate or ammonium, is effective due to their influence on oxidation cycles. This finding differs from many mitigation strategies in the western United States and may also be relevant to other regions in Europe and Asia which experience high wintertime PM. Key Points: Wintertime ammonium nitrate aerosol pollution is closely tied to photochemical ozone production through a common parameter, Ox,totalBox modeling reveals ammonium nitrate formation in the Salt Lake Valley is nitrate‐limited but NOx‐saturatedMitigation strategies that focus on NOx control in some wintertime‐polluted layers may initially increase ammonium nitrate [ABSTRACT FROM AUTHOR]

The addition of biochar to soils appears to be attractive for sequestering carbon and improving soil fertility. Biochar has been shown to alter carbon, nutrient and element cycling, but there is little information on the cycling of trace elements, which will be introduced increasingly into soils because of their use in modern technologies (e.g. rare earth elements) and significant concentrations in phosphate fertilizers. This study investigated, using column experiments, the effect of biochar addition on the leaching of soil-derived trace metals from a soil contaminated with heavy metals. The biochar used in this study showed a clear potential to reduce soil-derived trace metals, including transition metals, rare earth elements and heavy metals such as cadmium (Cd) and lead (Pb), while increasing the amounts of essential nutrients such as potassium (K) and molybdenum (Mo). Uranium was mobilized in the presence of biochar, indicating a risk of increased leaching in biochar-amended soils. During elution under anoxic conditions manganese (Mn) and iron (Fe) oxides were reduced and a release of metals typically bound to these oxides such as Pb, cobalt (Co), zirconium (Zr) and niobium (Nb) was observed. The retention of dissolved organic matter (DOM) in the amended soil led to a retention of DOM-associated elements such as copper (Cu), zinc (Zn) and nickel (Ni). Analysis by liquid chromatography followed by ICP-MS indicated an association with UV-active DOM. In previous studies conducted with inorganic metal species added to soil, an increased retention of metals has often been interpreted as being caused by cation exchange with the biochar. Our results indicate that the decreased mobility of trace elements is at least partly caused by an enhanced retention of metal-binding DOM after biochar application. [ABSTRACT FROM AUTHOR]

Background and Purpose: It is assumed that ATP induces closure of the binding jaw of ligand-gated P2X receptors, which eventually results in the opening of the membrane channel and the flux of cations. Immobilization by cysteine mutagenesis of the binding jaw inhibited ATP-induced current responses, but did not allow discrimination between disturbances of binding, gating, subunit assembly or trafficking to the plasma membrane.Experimental Approach: A molecular model of the pain-relevant human (h)P2X3 receptor was used to identify amino acid pairs, which were located at the lips of the binding jaw and did not participate in agonist binding but strongly approached each other even in the absence of ATP.Key Results: A series of cysteine double mutant hP2X3 receptors, expressed in HEK293 cells or Xenopus laevis oocytes, exhibited depressed current responses to α,β-methylene ATP (α,β-meATP) due to the formation of spontaneous inter-subunit disulfide bonds. Reducing these bonds with dithiothreitol reversed the blockade of the α,β-meATP transmembrane current. Amino-reactive fluorescence labelling of the His-tagged hP2X3 receptor and its mutants expressed in HEK293 or X. laevis oocytes demonstrated the formation of inter-subunit cross links in cysteine double mutants and, in addition, confirmed their correct trimeric assembly and cell surface expression.Conclusions and Implications: In conclusion, spontaneous tightening of the binding jaw of the hP2X3 receptor by inter-subunit cross-linking of cysteine residues substituted at positions not directly involved in agonist binding inhibited agonist-evoked currents without interfering with binding, subunit assembly or trafficking. [ABSTRACT FROM AUTHOR]

Background and Purpose It is assumed that ATP induces closure of the binding jaw of ligand-gated P2 X receptors, which eventually results in the opening of the membrane channel and the flux of cations. Immobilization by cysteine mutagenesis of the binding jaw inhibited ATP-induced current responses, but did not allow discrimination between disturbances of binding, gating, subunit assembly or trafficking to the plasma membrane. Experimental Approach A molecular model of the pain-relevant human (h)P2 X3 receptor was used to identify amino acid pairs, which were located at the lips of the binding jaw and did not participate in agonist binding but strongly approached each other even in the absence of ATP. Key Results A series of cysteine double mutant hP2 X3 receptors, expressed in HEK293 cells or X enopus laevis oocytes, exhibited depressed current responses to α,β-methylene ATP (α,β- meATP) due to the formation of spontaneous inter-subunit disulfide bonds. Reducing these bonds with dithiothreitol reversed the blockade of the α,β- meATP transmembrane current. Amino-reactive fluorescence labelling of the His-tagged hP2 X3 receptor and its mutants expressed in HEK293 or X . laevis oocytes demonstrated the formation of inter-subunit cross links in cysteine double mutants and, in addition, confirmed their correct trimeric assembly and cell surface expression. Conclusions and Implications In conclusion, spontaneous tightening of the binding jaw of the hP2 X3 receptor by inter-subunit cross-linking of cysteine residues substituted at positions not directly involved in agonist binding inhibited agonist-evoked currents without interfering with binding, subunit assembly or trafficking. [ABSTRACT FROM AUTHOR]

Background and Purpose: P2X7 receptors are ATP-gated cation channels mediating important functions in microglial cells, such as the release of cytokines and phagocytosis. Electrophysiological evidence that these receptors also occur in CNS astroglia is rare and rather incomplete.Experimental Approach: We used whole-cell patch-clamp recordings to search for P2X7 receptors in astroglial-neuronal co-cultures prepared from the cerebral cortex of rats.Key Results: All the astroglial cells investigated responded to ATP with membrane currents, reversing around 0 mV. These currents could be also detected in isolated outside-out patch vesicles. The results of the experiments with the P2X [alpha,beta-methylene ATP and 2'-3'-O-(4-benzoyl) ATP] and P2Y receptor agonists [adenosine 5'-O-(2-thiodiphosphate), uridine 5'-diphosphate, uridine 5'-triphosphate (UTP) and UDP-glucose] suggested the involvement of P2X receptors in this response. The potentiation of ATP responses in a low divalent cation or alkaline bath, but not by ivermectin, made it likely that a P2X7 receptor is operational. Blockade of the ATP effect by the P2X7 antagonists Brilliant Blue G, calmidazolium and oxidized ATP corroborated this assumption.Conclusions and Implications: Rat cultured cortical astroglia possesses functional P2X7 receptors. It is suggested that astrocytic P2X7 receptors respond to high local ATP concentrations during neuronal injury. [ABSTRACT FROM AUTHOR]

Prediction of treatment response is clinically important in chronic hepatitis C virus (HCV) genotype 4 infection. Early viral kinetics is useful in this respect for genotype 1 but interpretation is dependent on assay linearity and reproducibility. The VERSANT HCV RNA 3.0 (bDNA-3.0) and the COBAS Amplicor HCV Monitor 2.0 (HCM-2.0) have been widely used quantitative assays. We wanted to comparatively evaluate the two tests in a large genotype 4 sample. Genotyping was performed by NS5b sequencing. Viral load was tested in parallel in 32 patients at least six times on antiviral therapy with interferon α (IFN α). Totally, 198 samples within a quantitative range from undetectable to about 7.... [ABSTRACT FROM AUTHOR]

summary. Even with pegylated (PEG) interferons (IFN), therapy of chronic hepatitis C (genotype 1) remains unsatisfactory. The initial viral response to IFN identifies patients infected with IFN resistant viruses not responding to standard IFN/ribavirin therapy. The impact of primary IFN unresponsiveness for PEG-IFN-α -2a/ribavirin therapy is unknown. Viral load was measured in 22 chronic hepatitis C (genotype 1) patients before and 24 h after 9 MU IFN-α -2a (days 0 and 1), and before and during weekly 180 μ g PEG-IFN-α -2a (days 7, 8, 11, 14 and 21) administration. Thereafter, ribavirin (800 mg/d) was added for 6 months. Virological responders continued treatment for a further 6 months. Twenty-eight patients treated with standard IFN/ribavirin therapy in a previous study using an analogous protocol served as historic controls. After 6 months 15 (68.2%) patients were (HCV-RNA) negative, eight of whom (36.4%) had a sustained response. The decrease in viral load 24 h after 9 MU IFN-α -2a was greater in virological responders (1.05 log [0.25–1.67]) than in nonresponders (NR) (0.34 [0.14–0.65]; P =0.003). In contrast, viral decline was not different between responders and NRs during the first 2 weeks on PEG-IFN-α -2a. All patients with an initial decline > 1.4 log became sustained responders. Five of 12 patients with a log change < 0.8 became end of treatment responders, two had a sustained response. Antiviral response to PEG-IFN-α -2a is different to that on standard IFN. In spite of a lower initial response PEG-IFN-α -2a/ribavirin combination therapy may overcome predicted IFN unresponsiveness. [ABSTRACT FROM AUTHOR]

This trial investigated the efficacy of a combination of high-dose interferon-α (IFN-α) with ribavirin in IFN nonresponders. Study protocol: 304 patients with chronic hepatitis C were treated with 5 MU IFN-α2b (IntronA®, Schering-Plough) per TIW for 3 months. Nonresponders (defined by HCV-RNA positivity in serum after the 3 months of therapy) were randomized either to continue with IFN (5 MU IFN per TIW followed by 10 MU per TIW for each 3 months) alone (group A) or in combination with ribavirin (1-1.2 g per day) (group B). ALT was measured in monthly intervals, HCV-RNA in 3 monthly intervals. Pretreatment characteristics of the randomized patients were as follows: group A, n = 76; m/f, 54/22; 16% cirrhosis, age, 45.7 ± 12 years; ALT (U per litre), 66 ± 35; group B, n = 81; m/f, 57/24; 17% cirrhosis, age, 48.2 ± 12; ALT, 71 ± 40. After 9 months of treatment, nine (11.6%) and 27 (32.5%, P = 0.0066) patients were HCV-RNA negative and 51 and 39 were HCV-RNA positive, in groups A and B, respectively. There were 17 drop-outs in group A and 15 in group B. Six months after treatment only two patients in group A (2.5%) and five (6%, P = 0.06) in group B had normal ALT and no detectable HCV-RNA in serum. In addition to the well-known side-effects of IFN the mean haemoglobin concentration dropped by 2 g per litre in group B. These data indicate that a combination of high-dose IFN with ribavirin is effective in inducing a short-lasting complete response in one-third of IFN nonresponders. Prolonged treatment with IFN/ribavirin may be necessary to obtain a sustained response. [ABSTRACT FROM AUTHOR]

Investigates the effectiveness of a combination of high-dose interferon alpha (IFN) with ribavrin in IFN nonresponders with chronic hepatitis C. Pretreatment characteristics of patients; Mean hemoglobin concentration; Short-lasting complete response in IFN nonresponders.

Purpose: The purpose of this study was to investigate the tolerability and intraocular pressure (IOP) reducing effect of the first preservative-free prostaglandin tafluprost (Taflotan) in patients exhibiting ocular surface side-effects during latanoprost (Xalatan) treatment., Methods: A total of 158 patients were enrolled in this open-label multicentre study. Eligible patients had to have at least two ocular symptoms, or one sign and one symptom, during treatment with latanoprost. At baseline, the patients were directly switched from latanoprost to preservative-free tafluprost for 12 weeks. The patients were queried for ocular symptoms, and ocular signs were assessed by using tear break-up time, Schirmer's test, fluorescein staining and evaluation of conjunctival hyperaemia and blepharitis. In addition, HLA-DR and MUC5AC in conjunctival impression cytology specimens were analyzed, and a drop discomfort/quality of life (QoL) questionnaire was employed. IOP was measured at all visits., Results: Preservative-free tafluprost maintained IOP at the same level after 12- weeks treatment (16.4 +/- 2.7 mmHg) as latanoprost at baseline (16.8 +/- 2.5 mmHg). During treatment with preservative-free tafluprost, the number of patients having irritation/burning/stinging (56.3%), itching (46.8%), foreign body sensation (49.4%), tearing (55.1%) and dry eye sensation (64.6%) decreased to 28.4%, 26.5%, 27.1%, 27.1% and 39.4% correspondingly. The number of the patients with abnormal fluorescein staining of cornea (81.6%) and conjunctiva (84.2%), blepharitis (60.1%), conjunctival hyperaemia (84.2%) and abnormal Schirmer's test (71.5%) was also reduced significantly to 40.6%, 43.2%, 40.6%, 60.0% and 59.4% correspondingly. The tear break-up time improved significantly from 4.5 +/- 2.5 seconds to 7.8 +/- 4.9 seconds. A reduction in the number of patients with abnormal conjunctival cells based on HLA-DR and MUC5AC was also detected., Conclusions: Preservative-free tafluprost maintained IOP at the same level as latanoprost, but was better tolerated in patients having signs or symptoms while on preserved latanoprost. Preservative-free tafluprost treatment resulted in improved QoL, increased patient satisfaction and drop comfort.