A trifluoromethyl ketone analogue of arachidonic acid in which the COOH group is replaced with COCF3 (AACOCF3) was prepared and found to be a tight- and slow-binding inhibitor of the 85-kDa cytosolic human phospholipase A2 (cPLA2). Enzyme inhibition was observed when AACOCF3 was tested in assays using either phospholipid vesicles or phospholipid/Triton X-100 mixed micelles. The fact that the inhibition developed over several minutes in both assays establishes that AACOCF3 inhibits by direct binding to the enzyme rather than by decreasing the fraction of enzyme bound to the substrate interface. From the measured values of the inhibitor association and dissociation rate constants, an upper limit of the equilibrium dissociation constant for the Ca(2+).AACOCF3.PLA2 complex of 5 x 10(-5) mole fraction was obtained. Thus, detectable inhibition of cPLA2 by AACOCF3 occurs when this compound is present in the assay at a level of one inhibitor per several thousand substrates. Arachidonic acid analogues in which the COOH group is replaced by COCH3, CH(OH)CF3, CHO, or CONH2 did not detectably inhibit the cPLA2. The arachidonyl ketones AACOCF2CF3 and AACOCF2Cl were found by 19F NMR to be less hydrated than AACOCF3 in phospholipid/Triton X-100 mixed micelles, and compared to AACOCF3 these compounds are also weaker inhibitors of cPLA2. In keeping with the fact that cPLA2 displays substrate specificity for arachidonyl-containing phospholipids, the arachidic acid analogue C19H39COCF3 is a considerably less potent inhibitor compared to AACOCF3.(ABSTRACT TRUNCATED AT 250 WORDS)

Nicotinic acid (NA) is commonly used to treat dyslipidemia, but it elicits an adverse effect, termed flushing, which consists of cutaneous vasodilation with associated discomfort. An animal model of NA-induced flushing has been established in mice. As in humans, NA stimulated vasodilation in a dose-dependent manner, was associated with an increase of the vasodilatory prostaglandin (PG) D2 in plasma and could be blocked by pretreatment with aspirin. Two PGD2 receptors have been identified: PGD2 receptor 1 (DP1, also called DP) and PGD2 receptor 2 (DP2, sometimes termed CRTH2). DP2 does not mediate NA-induced vasodilation; the DP2-specific agonist DK-PGD2 (13,14-dihydro-15-keto-PGD2) did not induce cutaneous vasodilation, and DP2 ؊/؊ mice had a normal vasodilatory response to NA. By contrast, BW245C, a DP1-selective agonist, induced vasodilation in mice, and MK-0524, a DP1-selective antagonist, blocked both PGD2-and NA-induced vasodilation. NA-induced vasodilation was also studied in DP1 ؉/؉ , DP1 ؉/؊ , and DP1 ؊͞؊ mice; although NA-induced vasodilation depended almost completely on DP1 in female mice, it depended only partially on DP1 in male mice. The residual NA-induced vasodilation in male DP ؊͞؊ mice was aspirin-sensitive. Thus, in the mouse, DP1 appears to be an important component involved in NA-induced vasodilation, but other cyclooxygenase-dependent mechanisms also may be involved. A clinical study in healthy men and women demonstrated that treatment with MK-0524 reduced the symptoms of flushing and the increase in skin perfusion after the administration of NA. These studies suggest that DP1 receptor antagonism may be an effective means to suppress NA-induced flushing in humans.aspirin ͉ prostaglandin D2 receptor 1 antagonist ͉ MK-0524 ͉ niacin ͉ flushing N icotinic acid (NA), sometimes called niacin, is a watersoluble B vitamin that has been used to treat dyslipidemia for almost 50 years (1, 2). Used in high doses, it reduces plasma low-density lipoprotein cholesterol, apolipoprotein B, triglycerides, and lipoprotein(a) and increases high-density lipoprotein cholesterol and apolipoprotein A-I (3, 4). NA has been shown to have cardiovascular benefit when used alone or in combination with statins (hydroxymethylglutaryl-CoA reductase inhibitors) in several clinical trials (5-7).Despite these demonstrated beneficial effects, widespread use of NA for dyslipidemia has been limited by symptoms of flushing, which is associated with cutaneous vasodilation of the face, neck, and torso that occurs in nearly all patients (5, 8). Administration of cyclooxygenase (COX) inhibitors, such as aspirin and indomethacin, before ingestion of NA can attenuate the NA-induced cutaneous reactions in most patients (9-13) without affecting its plasma free fatty acid-lowering effect (14). However, doses of aspirin of 325 mg or higher are generally required to significantly block flushing (15), which compromises the utility of this approach for the chronic suppression of flushing. Although the mechanism of action of NA-induced flushi...

Carbon materials on the nanoscale exhibit diverse outstanding properties, rendering them extremely suitable for the fabrication of electrochemical biosensors. Over the past two decades, advances in this area have continuously emerged. In this review, we attempt to survey the recent developments of electrochemical biosensors based on six types of carbon nanomaterials (CNs), i.e., graphene, carbon nanotubes, carbon dots, carbon nanofibers, nanodiamonds and buckminsterfullerene. For each material, representative samples are introduced to expound the different roles of the CNs in electrochemical bioanalytical strategies. In addition, remaining challenges and perspectives for future developments are also briefly discussed.

5-Lipoxygenase-activating protein (FLAP) is an 1 S-kDa integral membrane protein which is essential for cellular leukotriene (LT) synthesis, and is the target of LT biosynthesis inhibitors. However, the mechanism by which FLAP activates S-LO has not been determined. We have expressed high levels of human FLAP in Spodopteru frugiperda (39) insect cells infected with recombinant baculovirus, and used this system to demonstrate that FLAP specifically binds ['2sI]L-739,059, a novel photoaffinity analog of arachidonic acid. This binding is inhibited by both arachidonic acid and MK-886, an LT biosynthesis inhibitor which specifically interacts with FLAP. These studies suggest that FLAP may activate 5-LO by specifically binding arachidonic acid and transferring this substrate to the enzyme.5-Lipoxygenase-activating protein; 5-Lipoxygenase; Arachidonic acid; Photoaffinity labeling; Baculovirus

The sediment budget is a method to study the distribution of sediment in different parts of a river basin. This paper studies the sediment budget of the Yangtze River by analyzing the data on soil erosion, size distributions of sediment deposits, sediment load, and fluvial process. A method to determine the sediment budget for the Yangtze River is proposed in which the total soil erosion from the upstream reaches and tributaries is divided into two parts: sediment load transported to the Yichang station and sediment storage in the tributaries and gullies. Furthermore, the sediment load is divided into three parts: bed material load deposited in the middle and lower reaches for the fluvial process, wash load transported to the estuary, and sediment deposition in Tongting Lake. The sediment transported into the estuary is further divided into two parts: very fine sediment drifting to the ocean and sediment deposition in the estuary for land creation. There is a large sediment demand for (1) the fluvial process to reach the minimum stream power in the middle and lower reaches; (2) sediment mining for building material; and (3) land creation in the estuary. The riverbed profile in the middle and lower reaches is developing toward the equilibrium profile defined by the minimum stream power, but the impoundment of the Three Gorges Reservoir interrupts and modifies this fluvial process. The annual sediment load in the Yangtze River has reduced due to various human activities by about 100 × 106 t in the past 15 years. Thus there is a sediment shortage for land creation in the river mouth.

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A novel concept is proposed for converting liquid-phase colorimetric assay into enhanced surface-tethered electrochemical analysis, which is based on the analyte-induced formation of a network architecture of metal nanoparticles (MNs). In a proof-of-concept trial, thymine-functionalized silver nanoparticle (Ag-T) is designed as the sensing unit for Hg(2+) determination. Through a specific T-Hg(2+)-T coordination, the validation system based on functionalized sensing units not only can perform well in a colorimetric Hg(2+) assay, but also can be developed into a more sensitive and stable electrochemical Hg(2+) sensor. In electrochemical analysis, the simple principle of analyte-induced aggregation of MNs can be used as a dual signal amplification strategy for significantly improving the detection sensitivity. More importantly, those numerous and diverse colorimetric assays that rely on the target-induced aggregation of MNs can be augmented to satisfy the ambitious demands of sensitive analysis by converting them into electrochemical assays via this approach.

[1] Reservoir sedimentation management is of critical importance for the sustainable development of surface water resources. Sanmenxia Dam, located on the middle reach of the Yellow River, in China, is notorious for its severe sedimentation problems. Because of the alarming rate of loss of reservoir storage capacity and the unacceptable negative impact induced by the rapid upstream extension of sediment deposited in the river's backwater region, the dam has been reconstructed to provide high sediment releasing capacity, and the dam operation has been changed in order to achieve a balance between sediment inflow and outflow. As a result, the dam is still providing the basin with flood control, irrigation, and hydropower generation, even though some benefits are lower than the original design. Complex sedimentation processes in response to the dam reconstruction and changes of dam operation are discussed in this paper. The engineering experiences and management practices of Sanmenxia Dam are valuable assets to the sustainable use of reservoirs built on sediment-laden rivers.