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Under increasing anthropogenic impacts, the hydrology, weathering, turbidity, and biogeochemistry of the Amazon and Pará river catchments are changing, potentially affecting the concentration and speciation of nitrogen (N) entering the estuary, as well as the subsequent primary productivity. Primary production and several N‐cycling rates have been studied in the northern river plume, and new studies focusing on specific processes in the river mouth emerged. Yet, a general overview is still lacking. For the first time, we provide an overview of primary production along with nitrification, ammonium (NH4+), nitrate (NO3−), and amino acid uptake rates in the Amazon and Pará river mouths which exhibit different degrees of catchment land use. Our results indicate that the Amazon supplies tenfold more NH4+and NO3−, and its nitrification rates are four times higher than in the Pará River. The stable isotope composition of ambient water and NO3−confirmed that nitrification is a dominant pathway, with fluxes reaching 8.5 × 108mol N d−1in the Amazon. Nutrients are transported to regions with reduced turbidity and little nitrification, facilitating NH4+(0.2–2.4 × 108mol N d−1) and carbon uptake (4.6 and 14.0 × 108mol C d−1in the Pará and the Amazon, respectively) by phytoplankton. The lower N‐cycling rates measured in the Pará relative to the Amazon River mouth likely originate from differences in river discharge and watershed characteristics. Riverine nitrogen can support intense production at the base of the food web in coastal oceans. Such productive ecosystems often show flourishing life and act as a strong atmospheric carbon sink. Since the extent of this nitrogen source is greatly influenced by the status of the river catchment area, it is crucial to have a good understanding of the amount and reactivity of riverine nitrogen at a given study site. Here, we used nitrogen isotope tracers to measure nitrogen assimilation and nitrification rates in the Amazon and Pará river mouths. We found that nitrification was happening at high rates in the Amazon River Mouth. In both estuaries, nitrate production is greater than consumption, allowing nitrate export beyond the turbid waters of the river mouths. Because the Amazon and Pará drainage basins are facing drastic changes, this nitrogen budget gives a baseline for nitrogen cycle pathways and export that will help to monitor the effect of these changes on estuarine nitrogen processes. Nitrogen uptake and nitrification measurements reveal intense nitrification of autochthonous ammonium in the Amazon and Pará estuariesIn the turbid parts, nitrate produced via nitrification is not entirely consumed by primary production, leading to its exportRates of nitrogen cycle processes are 10 times higher in the Amazon River mouth, likely due to higher riverine nitrogen discharged Nitrogen uptake and nitrification measurements reveal intense nitrification of autochthonous ammonium in the Amazon and Pará estuaries In the turbid parts, nitrate produced via nitrification is not entirely consumed by primary production, leading to its export Rates of nitrogen cycle processes are 10 times higher in the Amazon River mouth, likely due to higher riverine nitrogen discharged

DDX3 is a DEAD box RNA helicase with oncogenic properties. RK-33 is developed as a small-molecule inhibitor of DDX3 and showed potent radiosensitizing activity in preclinical tumor models. This study aimed to assess DDX3 as a target in breast cancer and to elucidate how RK-33 exerts its anti-neoplastic effects. High DDX3 expression was present in 35% of breast cancer patient samples and correlated with markers of aggressiveness and shorter survival. With a quantitative proteomics approach, we identified proteins involved in the mitochondrial translation and respiratory electron transport pathways to be significantly downregulated after RK-33 or DDX3 knockdown. DDX3 localized to the mitochondria and DDX3 inhibition with RK-33 reduced mitochondrial translation. As a consequence, oxygen consumption rates and intracellular ATP concentrations decreased and reactive oxygen species (ROS) increased. RK-33 antagonized the increase in oxygen consumption and ATP production observed after exposure to ionizing radiation and reduced DNA repair. Overall, we conclude that DDX3 inhibition with RK-33 causes radiosensitization in breast cancer through inhibition of mitochondrial translation, which results in reduced oxidative phosphorylation capacity and increased ROS levels, culminating in a bioenergetic catastrophe.

•Cancer survivors who were diagnosed or treated ≥5 years ago, and who had a desirable change in activity since the start of the COVID-19 pandemic reported better perceived cognitive abilities than those who had an undesirable change.•Lifestyle interventions should encourage long-term cancer survivors to break up prolonged periods of sitting and to meet physical activity guidelines to mitigate cancer-related cognitive impairment.•Targeting sedentary behavior and physical activity is an essential health and research priority during the COVID-19 pandemic.

An open structure SIS receiver, used already for astronomy at 345 GHz was tested at 470 and 690 GHz. Receiver noise temperatures considerably better than those of standard systems based on Schottky diode mixers were accomplished. A specific merrit of this system is the option to change the range of input frequencies by simply mounting a specific mixer element in a standard mixer block and by exchange of the output horn at the solid state local ocillator.

Ensuring a supply chain is secure from intentional as well as unintentional incidents is critical in today's global economy. However, some firms place a greater level of strategic importance on supply chain security than others. This research compares firms in the food industry that place a high level of strategic importance on security to firms that do not place a high level of strategic importance on security. The research assesses the measures employed by each group and resulting performance. Findings indicate that firms considering security to be a strategic priority perceive higher levels of security implementation and better security performance. Firms that place a high strategic priority on security show a greater ability to detect and recover from security incidents both inside the firm and across the supply chain in comparison to firms that place a low strategic priority on security. Cluster analysis grouped firms into high and low security performance categories in a manner consistent with the strategic priority construct and demonstrates the security measures that are likely to define high and low security performance.

The transportation function is critical to efficient and effective logistical operations. In order to improve transportation performance, it may be necessary for firms to form closer relationships with their carriers. Unfortunately, there are few studies examining the nuances and outcomes of shipper-carrier relationships. The focus of this work is to delineate the levels of relational closeness found between shippers and carriers and to assess the effects of relational closeness on carrier performance. Based on data and expertise provided by The Hershey Company, a major U.S. confectionary corporation, this research utilizes qualitative and quantitative techniques to accomplish these tasks. Findings indicate that closer relationships between shippers and carriers have no effect on carriers' on-time performance but significantly influence carriers' willingness to commit assets to the shipper and accept loads during times of constrained transportation capacity.

The world has changed a great deal since the most recent installment in the carrier selection criteria literature. The terrorist attacks of September 11th, the recession that followed, and a current business environment characterized by constrained transportation capacity are all likely to have changed the emphasis shippers place on attributes used to select carriers. First, the authors posit three selection criteria have grown more important in the post-September 11th world. Second, the benefits of utilizing the Theory of Reasoned Action to determine the most important selection criteria, and to identify the parties in the shipping organization who value these criteria, are explained. Third, results of an exploratory study demonstrating the usefulness of the Theory of Reasoned Action to predict carrier choice are illustrated. Implications and contributions to academic research and industry practice are then discussed.

The purpose of this study was to determine if the application of tissue harmonic imaging (THI) and real-time spatial compounding (RTSC) would result in a significant difference in the rate of detection and quality of visualization of the normal appendix. Subjects were scanned using the experimental method (the combination of THI and RTSC) and the conventional method (without THI and RTSC). The rate of detection was 85% with the experimental method and 66% with the conventional method. The quality of visualization was measured across three scales—visualized length, walls, and lumen—with a total score equal to the sum of the three scales. The experimental method demonstrated a significant difference in visualized length and total score. The mean score for length using the conventional method was 2.18 compared with 2.56 for the experimental method. The mean score for all three scales for the conventional method was 7.97 compared with 8.67 for the experimental method.

Elevated levels of tumor necrosis factor-α (TNF-α) have been associated with several inflammatory diseases, and therefore, strategies for its suppression have become important targets in drug discovery. Our efforts to suppress TNF-α have centered on the inhibition of TNF-α converting enzyme (TACE) through the use of hydroxamate inhibitors. Starting from broad-spectrum matrix metalloproteinase (MMP) inhibitors, we have designed and synthesized novel benzothiadiazepines as potent and selective TACE inhibitors. The benzothiadiazepines were synthesized with variation in P1 and P1‘ in order to effect potency and selectivity. The inhibitors were evaluated versus porcine TACE (pTACE), and the initial selectivity was assessed with counterscreens of MMP-1, -2, and -9. Several potent and selective inhibitors were discovered with compound 41 being the most active against pTACE (Ki = 5 nM) while still maintaining good selectivity versus the MMP's (at least 75-fold). Most compounds were assessed in the human peripheral blood mononuclear cell assay (PBMC) and the human whole blood assay (WBA) to determine their ability to suppress TNF-α. Compound 32 was the most potent compound in the PBMC assay (IC50 = 0.35 μM), while compound 62 was the most active in the WBA (IC50 = 1.4 μM).

Abstract. Purpose: The recombination factor Rad51 is highly expressed in human pancreatic adenocarcinoma. In this study we asked whether high-level expression of Rad51 antigen stimulates a B-cell response leading to Rad51-specific autoantibodies in human pancreatic cancer patients. Methods: Sera of patients suffering from pancreatic cancer (57) as well as sera of healthy donors (86) were screened for Rad51 autoantibodies by Western-blot analysis. Rad51 over-expressing cell lines were used as antigen source. Results: Four out of 57 (7%) sera tested were found positive for Rad51 autoantibodies of IgG subclass, while all 86 control sera were negative. Conclusion: This observation identifies Rad51 as a tumour-associated antigen in pancreatic adenocarcinoma. Since high-level expression of Rad51 is restricted to tumour cells, Rad51 is also a tumour-specific antigen. Further analyses should reveal whether Rad51 might also function as a tumour-specific transplantation antigen (TSTA) and whether it might serve as a target for new immunotherapeutical approaches.

Mitral valve combined with coronary artery surgery is associated with a higher hospital mortality than each operation in particular. Controversy exists regarding the predictive value of ischemic mitral valve disease (MVD) on outcome.

To search for TNF-α (tumor necrosis factor α) converting enzyme (TACE) inhibitors, we designed a new class of macrocyclic hydroxamic acids by linking the P1 and P2‘ residues of acyclic anti-succinate-based hydroxamic acids. A variety of residues including amide, carbamate, alkyl, sulfonamido, Boc-amino, and amino were found to be suitable P1−P2‘ linkers. With an N-methylamide at P3‘, the 13−16-membered macrocycles prepared exhibited low micromolar activities in the inhibition of TNF-α release from LPS-stimulated human whole blood. Further elaboration in the P3‘−P4‘ area using the cyclophane and cyclic carbamate templates led to the identification of a number of potent analogues with IC50 values of ≤0.2 μM in whole blood assay (WBA). Although the P3‘ area can accommodate a broad array of structurally diversified functional groups including polar residues, hydrophobic residues, and amino and carboxylic acid moieties, in both the cyclophane series and the cyclic carbamate series, a glycine residue at P3‘ was identified as a critical structural component to achieve both good in vitro potency and good oral activity. With a glycine residue at P3‘, an N-methylamide at P4‘ provided the best cyclophane analogue, SL422 (WBA IC50 = 0.22 μM, LPS-mouse ED50 = 15 mg/kg, po), whereas a morpholinylamide at P4‘ afforded the most potent and most orally active cyclic carbamate analogue, SP057 (WBA IC50 = 0.067 μM, LPS-mouse ED50 = 2.3 mg/kg, po). Further profiling for SL422 and SP057 showed that these macrocyclic compounds are potent TACE inhibitors, with Ki values of 12 and 4.2 nM in the porcine TACE assay, and are broad-spectrum MMP inhibitors. Pharmacokinetic studies in beagle dogs revealed that SL422 and SP057 are orally bioavailable, with oral bioavailabilities of 11% and 23%, respectively.

The serine/threonine kinase Rho-kinase was recently identified as a downstream effector of the small GTPase Rho, mediating effects of Rho on the actin cytoskeleton. Also phosphatidylinositol 4,5-bisphosphate (PI(4,5)P(2)) has been implicated in the regulation of actin polymerization. As the synthesis of PI(4,5)P(2) has been suggested to be affected by Rho proteins, we investigated whether Rho-kinase is involved in the control of PI(4,5)P(2) levels. Overexpression of RhoA in HEK-293 cells increased phosphatidylinositol 4-phosphate (PI4P) 5-kinase activity and concomitantly enhanced cellular PI(4,5)P(2) levels, whereas overexpression of the Rho-inactivating C3 transferase decreased both PI4P 5-kinase activity and PI(4,5)P(2) levels. These effects of RhoA could be mimicked by overexpression of wild-type Rho-kinase and of the constitutively active catalytic domain of Rho-kinase, Rho-kinase-CAT. In contrast, a kinase-deficient mutant of Rho-kinase had no effect on PI4P 5-kinase activity. Importantly, the increase in PI4P 5-kinase activity and PI(4,5)P(2) levels by wild-type Rho-kinase, but not by Rho-kinase-CAT, was completely prevented by coexpression of C3 transferase, indicating that the effect of Rho-kinase was under the control of endogenous Rho. In cell lysates, addition of recombinant RhoA and Rho-kinase-CAT stimulated PI4P 5-kinase activity. Finally, the increase in PI(4,5)P(2) levels induced by both Rho-kinase-CAT and RhoA was reversed by the Rho-kinase inhibitor HA-1077. Our data suggest that Rho-kinase is involved in the Rho-controlled synthesis of PI(4,5)P(2) by PI4P 5-kinase.

The Baltic Sea catchment area has seen considerable agricultural and industrial development over the last century, but observational evidence of eutrophication is ambiguous. We examined organic carbon accumulation rates and the stable isotope signature of δ13C and δ15N in organic matter in four 210Pb-dated short sediment cores from the southern and central Baltic Sea to search for sedimentary records of increased nutrient input and biological production. Organic carbon accumulation rates vary little through time in the cores from the Oder estuary and the Arkona Basin, but increase significantly in the Bornholm Basin and in the Gotland Deep records over the last 40years.

Stimulation of phospholipase D (PLD) by membrane receptors is now recognized as a major signal transduction pathway involved in diverse cellular functions. Rho proteins control receptor signaling to PLD, and these GTPases have been shown to directly stimulate purified recombinant PLD1 enzymes in vitro. Here we report that stimulation of PLD activity, measured in the presence of phosphatidylinositol 4,5-bisphosphate, by RhoA in membranes of HEK-293 cells expressing the m3 muscarinic acetylcholine receptor (mAChR) is phosphorylation-dependent. Therefore, the possible involvement of the RhoA-stimulated serine/threonine kinase, Rho-kinase, was investigated. Overexpression of Rho-kinase and constitutively active Rho-kinase (Rho-kinase-CAT) but not of kinase-deficient Rho-kinase-CAT markedly increased m3 mAChR-mediated but not protein kinase C-mediated PLD stimulation, similar to overexpression of RhoA. Expression of the Rho-inactivating C3 transferase abrogated the stimulatory effect of wild-type Rho-kinase, but not of Rho-kinase-CAT. Recombinant Rho-kinase-CAT mimicked the phosphorylation-dependent PLD stimulation by RhoA in HEK-293 cell membranes. Finally, the Rho-kinase inhibitor HA-1077 largely inhibited RhoA-induced PLD stimulation in membranes as well as PLD stimulation by the m3 mAChR but not by protein kinase C in intact HEK-293 cells. We conclude that Rho-kinase is involved in Rho-dependent PLD stimulation by the G protein-coupled m3 mAChR in HEK-293 cells. Thus, our findings identify Rho-kinase as a novel player in the receptor-controlled PLD signaling pathway.

Bubble clouds forming in an extended volume of liquid in acoustic cavitation show a slowly varying filamentary structure, whose origin is still not completely understood. Experimental observations are reported that provide some characteristics of the phenomenon, such as bubble distributions and sound–field measurements. A discussion of relevant physical interactions in bubbly liquids is comprised of wave dynamics, Bjerknes and drag forces, nucleation and coalescence. For describing the structure formation process, continuum and particle approaches are employed. In the framework of the continuum model it is shown that homogeneous bubble distributions are unstable, and regions with high bubble concentration emerge in the course of a self–concentration process. In the particle model, all bubbles are treated as interacting objects that move in the liquid. This approach is complementary to the continuum model. It allows the inclusion of some particular features, for instance Bjerknes forces based on nonlinear bubble oscillations. Both models are discussed and results are compared with experimentally observed patterns.

Using a plug-flow and a batch reactor the hydrogenation of mixtures of carbon dioxide and ethene over unsupported cobalt has been studied. The results show that the hydrogenation of carbon dioxide is totally blocked as long as ethene is present in the gas phase. In contrast carbon dioxide does not at all influence the hydrogenation of ethene, which leads to a complex mixture of hydrocarbons. This reaction can be explained as a copolymerisation proceeding via two different monomers (C1 and C2 fragments). The observed oscillatory molar product distribution in dependence on the number of C atoms can exactly be described by means of a numerical model.

Abstract: The present study was designed to test the hypothesis that in hypertrophied myocardium of patients with hypertrophic obstructive cardiomyopathy (HOCM) a reduced contractile reserve provided by frequency dependent potentiation of force of contraction contributes to the myocardial dysfunction. Myectomy was performed in 8 HOCM patients with normal systolic left ventricular function at rest. Nonfailing myocardium from the hearts of three multiorgan donors was investigated for comparison. In thin myocardial strips we measured the inotropic effects of different stimulation frequencies (0,5–3.0Hz) at different extracellular Ca2+ concentrations (1.8–16.2 mmol/l). At 1.8 mmol/l extracellular Ca2+ concentration, increasing stimulation rates had no positive inotropic effect in HOCM myocardium, whereas in nonfailing myocardium force of contraction increased up to 3 Hz. Increasing extracellular Ca2+ concentrations induced a positive force-frequency relation in HOCM with a maximum at 5.4 mmol/l Ca2+. A further increase to 16.2 mmol/l Ca2+ resulted in a negative force-frequency relation in these specimens. The time to peak tension and the time to relaxation decreased at increasing stimulation frequencies at all Ca2+ concentrations investigated. In conclusion, in hypertrophied myocardium of HOCM patients increasing stimulation frequencies failed to have a positive inotropic effect at physiological extracellular Ca2+ concentrations. The induction of a positive force-frequency relation by higher Ca2+ concentrations suggests that an abnormal cellular Ca2+ handling may play an important pathophysiological role.

After activation, agonist-occupied G protein-coupled receptors are phosphorylated by G protein-coupled receptor kinases and bind cytosolic beta-arrestins, which uncouple the receptors from their cognate G proteins. Recent studies on the beta2-adrenergic receptor have demonstrated that beta-arrestin also targets the receptors to clathrin-coated pits for subsequent internalization and activation of mitogen-activated protein kinases. We and others have previously shown that muscarinic acetylcholine receptors (mAChRs) of the m1, m3, and m4 subtype require functional dynamin to sequester into HEK-293 tsA201 cells, whereas m2 mAChRs sequester in a dynamin-independent manner. To investigate the role of beta-arrestin in mAChR sequestration, we determined the effect of overexpressing beta-arrestin-1 and the dominant-negative inhibitor of beta-arrestin-mediated receptor sequestration, beta-arrestin-1 V53D, on mAChR sequestration and function. Sequestration of m1, m3, and m4 mAChRs was suppressed by 60-75% in cells overexpressing beta-arrestin-1 V53D, whereas m2 mAChR sequestration was affected by less than 10%. In addition, overexpression of beta-arrestin-1 V53D as well as dynamin K44A significantly suppressed m1 mAChR-mediated activation of mitogen-activated protein kinases. Finally, we investigated whether mAChRs sequester into clathrin-coated vesicles by overexpressing Hub, a dominant-negative clathrin mutant. Although sequestration of m1, m3, and m4 mAChRs was inhibited by 50-70%, m2 mAChR sequestration was suppressed by less than 10%. We conclude that m1, m3, and m4 mAChRs expressed in HEK-293 tsA201 cells sequester into clathrin-coated vesicles in a beta-arrestin- and dynamin-dependent manner, whereas sequestration of m2 mAChRs in these cells is largely independent of these proteins.

Stimulation of phospholipase D (PLD) in HEK-293 cells expressing the M(3) muscarinic receptor by phorbol ester-activated protein kinase C (PKC) apparently involves Ral GTPases. We report here that PKC, but not muscarinic receptor-induced PLD stimulation in these cells, is strongly and specifically reduced by expression of dominant-negative RalA, G26A RalA, as well as dominant-negative Ras, S17N Ras. In contrast, overexpression of the Ras-activated Ral-specific guanine nucleotide exchange factor, Ral-GDS, specifically enhanced PKC-induced PLD stimulation. Moreover, recombinant Ral-GDS potentiated Ral-dependent PKC-induced PLD stimulation in membranes. Epidermal growth factor, platelet-derived growth factor, and insulin, ligands for receptor tyrosine kinases (RTKs) endogenously expressed in HEK-293 cells, apparently use the PKC- and Ras/Ral-dependent pathway for PLD stimulation. First, PLD stimulation by the RTK agonists was prevented by PKC inhibition and PKC down-regulation. Second, expression of dominant-negative RalA and Ras mutants strongly reduced RTK-induced PLD stimulation. Third, overexpression of Ral-GDS largely potentiated PLD stimulation by the RTK agonists. Finally, using the Ral binding domain of the Ral effector RLIP as an activation-specific probe for Ral proteins, it is demonstrated that endogenous RalA is activated by phorbol ester and RTK agonists. Taken together, strong evidence is provided that RTK-induced PLD stimulation in HEK-293 cells is mediated by PKC and a Ras/Ral signaling cascade.

ADP-ribosylation factor-related protein (ARP) is a membrane-associated GTPase with remote similarity to the family of ADP-ribosylation factors (ARF). In a yeast two-hybrid screen designed to identify proteins interacting with ARP, we isolated a partial cDNA of the ARF-specific guanine nucleotide exchange factor mSec7-1/cytohesin encoding its N terminus and most of the Sec7 domain (codons 1-200). ARP and ARP-Q79L (GTPase-negative ARP) exhibited a higher affinity to mSec7-1-(1-200) than ARP-T31N (nucleotide exchange-defective ARP) in the two-hybrid assay. Similarly, full-length [35S]mSec7-1/cytohesin was specifically adsorbed to glutathione-Sepharose loaded with glutathione S-transferase (GST)-ARP-Q79L, GST-ARP, or GST-ARP-T31N, the latter exhibiting the lowest binding affinity. Overexpression of ARP-Q79L, but not of ARP-T31N, in COS-7 cells reduced the fluorescence from co-expressed green fluorescent protein fused with mSec7-1/cytohesin or mSec7-2/ARNO in plasma membranes as detected by deconvolution microscopy. Recombinant ARP and ARP-Q79L, but not ARP-T31N, inhibited the phospholipase D (PLD) activity stimulated by mSec7-2/ARNO and ARF in a system of isolated membranes. Furthermore, transfection of HEK-293 cells with ARP or ARP-Q79L, but not ARP-T31N, inhibited the muscarinic acetylcholine receptor-3 induced PLD stimulation and translocation of ARF from cytosol to membranes. These data suggest that the GTP-bound form of ARP specifically binds mSec7-1/cytohesin, and that ARP may be involved in a pathway inhibiting the ARF-controlled activity of PLD.

Abstract Background:: Altered Ca2+ metabolism of the sarcoplasmic reticulum results in changes of the contractile behavior in failing human myocardium. The ryanodine-sensitive Ca2+ release channel of the sarcoplasmic reticulum plays a key role in the intracellular Ca2+ handling in cardiac myocytes. Recently, we showed that the density of 3H-ryanodine binding sites which correspond to the SR Ca2+ release channel in human myocardial homogenates is unchanged in failing human myocardium. However, the sensitivity of the channel towards Ca2+, which acts as the trigger signal of channel activation and thereby initiates contraction, has not yet been investigated in failing and nonfailing myocardium. Methods: Homogenates (100 μg protein) from hearts with dilated (DCM, n = 10) or ischemic (ICM, n = 9) cardiomyopathy were incubated with a saturating concentration of 3H-ryanodine (12 nM) in the presence of different Ca2+ concentrations ranging from 1 nM to 10 mM. For comparison, myocardium of 8 nonfailing hearts which could not be transplanted for technical reasons was investigated. Nonspecific binding was determined in the presence of a high concentration (10 μM) of unlabeled ryanodine. Results: 3H-ryanodine binding to the Ca2+ release channel showed a bell-shaped pattern with an increase in specific binding at submicromolar Ca2+ concentrations and a decrease at higher Ca2+ concentrations than 0.5 mM, whereas nonspecific binding was not influenced by different Ca2+ concentrations. In nonfailing myocardium, maximal 3H-ryanodine binding (Bmax) was 85.2 ± 3.1 fmol/mg protein and half-maximal binding was reached at a free Ca2+ concentration of 0.25 (0.22 – 0.30)μM (EC50). Neither EC50 values nor maximal specific 3H-ryanodine binding differed between nonfailing and failing myocardium of both etiologies. EC50 values were 0.24 (0.23 – 0.26)μM (DCM, n = 10) or 0.28 (0.25 – 0.31)μM (ICM, n = 9), respectively. Caffeine (2 mM) and the ATP-analogon AMP-PCP (1 mM) led to a shift towards lower Ca2+ concentrations consistent with an activation of the channel by these compounds, whereas Mg2+ (0.7 mM) shifted the Ca2+-dependence of 3H-ryanodine binding towards higher Ca2+ concentrations indicating inhibition of channel opening. After activation of the Ca2+ release channel by caffeine or AMP-PCP as well as after the inhibition with MG2+ EC50 values were the same in failing and nonfailing myocardium. Conclusion: Caffeine and AMP-PCP sensitize, whereas Mg2+ desensitizes the myocardial Ca2+ release channel to Ca2+. The determination of Ca2+-dependent 3H-ryanodine binding to the human myocardial Ca2+ release channel is a useful tool to investigate its open probability. Furthermore, the Ca2+-sensitivity and the pharmacological behavior of the human SR Ca2+ release channel are similar in failing and nonfailing myocardium.

A number of individual, ergonomic, and organizational factors of presumed importance for the occurrence of musculoskeletal disorders were investigated in a group of 260 visual display terminal (VDT) workers. The cross-sectional study utilized medical and workplace investigations as well as questionnaires. The results were subjected to a multivariate analysis in order to find the major factors associated with various upper-body muscular problems. Several such factors were identified for each investigated type of musculoskeletal problem. Some were related to the individual: age, gender, woman with children at home, use of spectacles, smoking, stomach-related stress reactions, and negative affectivity. Organizational variables of importance were opportunities for flexible rest breaks, extreme peer contacts, task flexibility, and overtime. Identified ergonomic variables were static work posture, hand position, use of lower arm support, repeated work movements, and keyboard or VDT vertical position.

Relationships between visual display terminal (VDT) use and musculoskeletal problems were examined in a group of 353 office workers, using data from medical and workplace investigations as well as questionnaires. There were no general differences between VDT and non-VDT users as to the occurrence of muscle problems. Combinations of specific VDT work situations such as data entry work or work with a VDT for more than 20 h/week and the presence of some other factors were, however, associated with excess risks of certain muscle problems. The extraneous factors involved in the definitions of such risk groups were: use of bifocal or progressive glasses at a VDT; stomach-related stress reactions; limited rest break opportunity, repetitive movements; non-use of lower arm support; and possibly the vertical position of the keyboard; and presence of specular glare.

Three families segregating for X-linked ichthyosis (XLI) were analysed using the full-length STS cDNA probe and an anonymous polymorphic DNA sequence closely linked to the STS gene. In patients from two of the families, submicroscopic chromosomal deletions could be detected using both the STS and the GMGX9 (DXS237 locus) probes. Patients in the third family showed the same hybridization pattern as healthy males following molecular hybridization with either of the probes. The results of DNA analysis (indirect geno-type diagnosis) agree well with those based on the arylsulfatase C/ß-gal determination and prove the reliability of the biochemical test. Both methods are discussed for carrier detection, prenatal diagnosis, and genetic conselling.

Digital luminescent radiography enables dual-energy subtraction imaging, because this computed system allows susbtraction of imaging data and image post processing, as for example special windowing or edge enhancement. In a special cassette a copper filter is placed between two imaging plates for energy separation by a single X-ray exposure. Image post-processing with subtraction of imaging data permits the elimination of either skeleton or soft tissue structures. The influence of filter thickness, tube voltage and the X-ray exposure dosage on image quality is examined by the use of an anthropomorphic quality is examined by the use of an anthropomorphic phantom of the chest. According to our initial results dual energy subtraction imaging in one-shot-technique seems to be useful in the diagnostics of skeletal lesions and especially pulmonary nodules.

A novel synthesis of symmetric and nonsymmetric 9,9-disubstituted 4,5-diazafluorenes has been developed. These compounds have activity in both an in vitro acetylcholine release assay and in vivo rodent models of learning and memory. Preparation of these compounds involves a unique aldol condensation between 4,5-diazafluoren-9-one (4) and 4-picoline. Reduction of aldol product 5 (5-(4-pyridinylmethylene)-5H-cyclopenta[2,1-b:3,4-b‘]dipyridine) provides monoalkylated diazafluorene 6 (5-(4-pyridinylmethyl)-5H-cyclopenta[2,1-b:3,4-b‘]dipyridine) which proved to be a key intermediate for synthesis of nonsymmetric analogs.

We report a facile, low-temperature reaction between condensed-phase NO2 and H2O that leads ultimately to the formation of a large concentration (θ0 = 0.42 monolayers) of adsorbed oxygen adatoms on a Au(111) surface. This reaction represents a novel route to generate surface oxygen on Au that can be utilized in fundamental studies of oxidation catalysis over Au such as low-temperature CO oxidation and the operation of Au converter tubes used in redox chemiluminesence detectors for atmospheric NOx. Also, this reaction may be relevant to heterogeneous processes occurring on ice particles in stratospheric clouds. This reaction is not specifically catalyzed by the Au(111) surface or by the defects present on the Au surface, and so this reaction may have some general utility for facile oxidation of unreactive surfaces.

The "ALI" (Autofahrer-Leit- und Informationssystem) guidance and information system for highways has been developed in the Federal Republic of Germany. It is the aim of the research described here to analyze the driver's information processing behaviour with the ALI display in real traffic and to evaluate possible consequences for driving safety. Extensive field experiments and additional experiments in a driving simulator were conducted. To analyze the temporal structure of information perception and processing the measurement of eye movements was an essential tool. The time budget derived from these data shows no overload by time-pressure. The eye movement patterns measured lead to the hypothesis that the information obtained through ALI is processed by queuing. Related to the attention allocation this is not an optimal strategy and should be improved. To minimize false route decisions, the compatibility of ALI symbols with traffic signs should be improved as well.