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 Enzyme_inhibitor : définition de Enzyme_inhibitor et synonymes de Enzyme_inhibitor (anglais)

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Enzyme inhibitor

  HIV protease in a complex with the protease inhibitor ritonavir. The structure of the protease is shown by the red, blue and yellow ribbons. The inhibitor is shown as the smaller ball-and-stick structure near the centre. Created from PDB 1HXW.

An enzyme inhibitor is a molecule that binds to enzymes and decreases their activity. Since blocking an enzyme's activity can kill a pathogen or correct a metabolic imbalance, many drugs are enzyme inhibitors. They are also used as herbicides and pesticides. Not all molecules that bind to enzymes are inhibitors; enzyme activators bind to enzymes and increase their enzymatic activity, while enzyme substrates bind and are converted to products in the normal catalytic cycle of the enzyme.

The binding of an inhibitor can stop a substrate from entering the enzyme's active site and/or hinder the enzyme from catalysing its reaction. Inhibitor binding is either reversible or irreversible. Irreversible inhibitors usually react with the enzyme and change it chemically (e.g. via covalent bond formation). These inhibitors modify key amino acid residues needed for enzymatic activity. In contrast, reversible inhibitors bind non-covalently and different types of inhibition are produced depending on whether these inhibitors bind to the enzyme, the enzyme-substrate complex, or both.

Many drug molecules are enzyme inhibitors, so their discovery and improvement is an active area of research in biochemistry and pharmacology. A medicinal enzyme inhibitor is often judged by its specificity (its lack of binding to other proteins) and its potency (its dissociation constant, which indicates the concentration needed to inhibit the enzyme). A high specificity and potency ensure that a drug will have few side effects and thus low toxicity.

Enzyme inhibitors also occur naturally and are involved in the regulation of metabolism. For example, enzymes in a metabolic pathway can be inhibited by downstream products. This type of negative feedback slows flux through a pathway when the products begin to build up and is an important way to maintain homeostasis in a cell. Other cellular enzyme inhibitors are proteins that specifically bind to and inhibit an enzyme target. This can help control enzymes that may be damaging to a cell, such as proteases or nucleases; a well-characterised example is the ribonuclease inhibitor, which binds to ribonucleases in one of the tightest known protein–protein interactions.[1] Natural enzyme inhibitors can also be poisons and are used as defences against predators or as ways of killing prey.

  Reversible inhibitors

  Types of reversible inhibitors

Reversible inhibitors bind to enzymes with non-covalent interactions such as hydrogen bonds, hydrophobic interactions and ionic bonds. Multiple weak bonds between the inhibitor and the active site combine to produce strong and specific binding. In contrast to substrates and irreversible inhibitors, reversible inhibitors generally do not undergo chemical reactions when bound to the enzyme and can be easily removed by dilution or dialysis.

  Competitive inhibition: substrate (S) and inhibitor (I) compete for the active site.

There are four kinds of reversible enzyme inhibitors. They are classified according to the effect of varying the concentration of the enzyme's substrate on the inhibitor.[2]

  • In competitive inhibition, the substrate and inhibitor cannot bind to the enzyme at the same time, as shown in the figure on the left. This usually results from the inhibitor having an affinity for the active site of an enzyme where the substrate also binds; the substrate and inhibitor compete for access to the enzyme's active site. This type of inhibition can be overcome by sufficiently high concentrations of substrate (Vmax remains constant), i.e., by out-competing the inhibitor. However, the apparent Km will increase as it takes a higher concentration of the substrate to reach the Km point, or half the Vmax. Competitive inhibitors are often similar in structure to the real substrate (see examples below).
  • In uncompetitive inhibition, the inhibitor binds only to the substrate-enzyme complex, it should not be confused with non-competitive inhibitors. This type of inhibition causes Vmax to decrease (maximum velocity decreases as a result of removing activated complex) and Km to decrease (due to better binding efficiency as a result of Le Chatelier's principle and the effective elimination of the ES complex thus decreasing the Km which indicates a higher binding affinity).
  • In mixed inhibition, the inhibitor can bind to the enzyme at the same time as the enzyme's substrate. However, the binding of the inhibitor affects the binding of the substrate, and vice versa. This type of inhibition can be reduced, but not overcome by increasing concentrations of substrate. Although it is possible for mixed-type inhibitors to bind in the active site, this type of inhibition generally results from an allosteric effect where the inhibitor binds to a different site on an enzyme. Inhibitor binding to this allosteric site changes the conformation (i.e., tertiary structure or three-dimensional shape) of the enzyme so that the affinity of the substrate for the active site is reduced.
  • Non-competitive inhibition is a form of mixed inhibition where the binding of the inhibitor to the enzyme reduces its activity but does not affect the binding of substrate. As a result, the extent of inhibition depends only on the concentration of the inhibitor. Vmax will decrease due to the inability for the reaction to proceed as efficiently, but Km will remain the same as the actual binding of the substrate, by definition, will still function properly.

  Quantitative description of reversible inhibition

Reversible inhibition can be described quantitatively in terms of the inhibitor's binding to the enzyme and to the enzyme–substrate complex, and its effects on the kinetic constants of the enzyme. In the classic Michaelis–Menten scheme below, an enzyme (E) binds to its substrate (S) to form the enzyme–substrate complex ES. Upon catalysis, this complex breaks down to release product P and free enzyme. The inhibitor (I) can bind to either E or ES with the dissociation constants Ki or Ki', respectively.

  • Competitive inhibitors can bind to E, but not to ES. Competitive inhibition increases Km (i.e., the inhibitor interferes with substrate binding), but does not affect Vmax (the inhibitor does not hamper catalysis in ES because it cannot bind to ES).
  • Non-competitive inhibitors have identical affinities for E and ES (Ki = Ki'). Non-competitive inhibition does not change Km (i.e., it does not affect substrate binding) but decreases Vmax (i.e., inhibitor binding hampers catalysis).
  • Mixed-type inhibitors bind to both E and ES, but their affinities for these two forms of the enzyme are different (KiKi'). Thus, mixed-type inhibitors interfere with substrate binding (increase Km) and hamper catalysis in the ES complex (decrease Vmax).
  Kinetic scheme for reversible enzyme inhibitors

When an enzyme has multiple substrates, inhibitors can show different types of inhibition depending on which substrate is considered. This results from the active site containing two different binding sites within the active site, one for each substrate. For example, an inhibitor might compete with substrate A for the first binding site, but be a non-competitive inhibitor with respect to substrate B in the second binding site.[3]

  Measuring the dissociation constants of a reversible inhibitor

  Lineweaver–Burk plots of different types of reversible enzyme inhibitors. The arrow shows the effect of increasing concentrations of inhibitor.

As noted above, an enzyme inhibitor is characterised by its two dissociation constants, Ki and Ki', to the enzyme and to the enzyme-substrate complex, respectively. The enzyme-inhibitor constant Ki can be measured directly by various methods; one extremely accurate method is isothermal titration calorimetry, in which the inhibitor is titrated into a solution of enzyme and the heat released or absorbed is measured.[4] However, the other dissociation constant Ki' is difficult to measure directly, since the enzyme-substrate complex is short-lived and undergoing a chemical reaction to form the product. Hence, Ki' is usually measured indirectly, by observing the enzyme activity under various substrate and inhibitor concentrations, and fitting the data[5] to a modified Michaelis–Menten equation

V = \frac{V_{max}[S]}{\alpha K_{m} + \alpha^{\prime}[S]} = \frac{(1/\alpha^{\prime})V_{max}[S]}{(\alpha/\alpha^{\prime}) K_{m} + [S]}

where the modifying factors α and α' are defined by the inhibitor concentration and its two dissociation constants

\alpha = 1 + \frac{[I]}{K_{i}}

\alpha^{\prime} = 1 + \frac{[I]}{K_{i}^{\prime}}.

Thus, in the presence of the inhibitor, the enzyme's effective Km and Vmax become (α/α')Km and (1/α')Vmax, respectively. However, the modified Michaelis-Menten equation assumes that binding of the inhibitor to the enzyme has reached equilibrium, which may be a very slow process for inhibitors with sub-nanomolar dissociation constants. In these cases, it is usually more practical to treat the tight-binding inhibitor as an irreversible inhibitor (see below); however, it can still be possible to estimate Ki' kinetically if Ki is measured independently.

The effects of different types of reversible enzyme inhibitors on enzymatic activity can be visualized using graphical representations of the Michaelis–Menten equation, such as Lineweaver–Burk and Eadie-Hofstee plots. For example, in the Lineweaver–Burk plots at the right, the competitive inhibition lines intersect on the y-axis, illustrating that such inhibitors do not affect Vmax. Similarly, the non-competitive inhibition lines intersect on the x-axis, showing these inhibitors do not affect Km. However, it can be difficult to estimate Ki and Ki' accurately from such plots,[6] so it is advisable to estimate these constants using more reliable nonlinear regression methods, as described above.

  Special cases

  • The mechanism of partially competitive inhibition is similar to that of non-competitive, except that the EIS complex has catalytic activity, which may be lower or even higher (partially competitive activation) than that of the enzyme–substrate (ES) complex. This inhibition typically displays a lower Vmax, but an unaffected Km value.[7]
  • Uncompetitive inhibition occurs when the inhibitor binds only to the enzyme–substrate complex, not to the free enzyme; the EIS complex is catalytically inactive. This mode of inhibition is rare and causes a decrease in both Vmax and the Km value.[7]
  • Substrate and product inhibition is where either the substrate or product of an enzyme reaction inhibit the enzyme's activity. This inhibition may follow the competitive, uncompetitive or mixed patterns. In substrate inhibition there is a progressive decrease in activity at high substrate concentrations. This may indicate the existence of two substrate-binding sites in the enzyme. At low substrate, the high-affinity site is occupied and normal kinetics are followed. However, at higher concentrations, the second inhibitory site becomes occupied, inhibiting the enzyme.[8] Product inhibition is often a regulatory feature in metabolism and can be a form of negative feedback.
  • Slow-tight inhibition occurs when the initial enzyme–inhibitor complex EI undergoes isomerisation to a second more tightly held complex, EI*, but the overall inhibition process is reversible. This manifests itself as slowly increasing enzyme inhibition. Under these conditions, traditional Michaelis–Menten kinetics give a false value for Ki, which is time–dependent. The true value of Ki can be obtained through more complex analysis of the on (kon) and off (koff) rate constants for inhibitor association. See irreversible inhibition below for more information.

  Examples of reversible inhibitors

  Peptide-based HIV-1 protease inhibitor ritonavir

As enzymes have evolved to bind their substrates tightly, and most reversible inhibitors bind in the active site of enzymes, it is unsurprising that some of these inhibitors are strikingly similar in structure to the substrates of their targets. An example of these substrate mimics are the protease inhibitors, a very successful class of antiretroviral drugs used to treat HIV.[9] The structure of ritonavir, a protease inhibitor based on a peptide and containing three peptide bonds, is shown on the right. As this drug resembles the protein that is the substrate of the HIV protease, it competes with this substrate in the enzyme's active site.

Enzyme inhibitors are often designed to mimic the transition state or intermediate of an enzyme-catalysed reaction. This ensures that the inhibitor exploits the transition state stabilising effect of the enzyme, resulting in a better binding affinity (lower Ki) than substrate-based designs. An example of such a transition state inhibitor is the antiviral drug oseltamivir; this drug mimics the planar nature of the ring oxonium ion in the reaction of the viral enzyme neuraminidase.[10]

  Nonpeptidic HIV-1 protease inhibitor tipranavir

However, not all inhibitors are based on the structures of substrates. For example, the structure of another HIV protease inhibitor tipranavir is shown on the left. This molecule is not based on a peptide and has no obvious structural similarity to a protein substrate. These non-peptide inhibitors can be more stable than inhibitors containing peptide bonds, because they will not be substrates for peptidases and are less likely to be degraded.[11]

In drug design it is important to consider the concentrations of substrates to which the target enzymes are exposed. For example, some protein kinase inhibitors have chemical structures that are similar to adenosine triphosphate, one of the substrates of these enzymes. However, drugs that are simple competitive inhibitors will have to compete with the high concentrations of ATP in the cell. Protein kinases can also be inhibited by competition at the binding sites where the kinases interact with their substrate proteins, and most proteins are present inside cells at concentrations much lower than the concentration of ATP. As a consequence, if two protein kinase inhibitors both bind in the active site with similar affinity, but only one has to compete with ATP, then the competitive inhibitor at the protein-binding site will inhibit the enzyme more effectively.[12]

  Irreversible inhibitors

  Types of irreversible inhibition

  Reaction of the irreversible inhibitor diisopropylfluorophosphate (DFP) with a serine protease

Irreversible inhibitors usually covalently modify an enzyme, and inhibition can therefore not be reversed. Irreversible inhibitors often contain reactive functional groups such as nitrogen mustards, aldehydes, haloalkanes, alkenes, Michael acceptors, phenyl sulfonates, or fluorophosphonates. These electrophilic groups react with amino acid side chains to form covalent adducts. The residues modified are those with side chains containing nucleophiles such as hydroxyl or sulfhydryl groups; these include the amino acids serine (as in DFP, right), cysteine, threonine or tyrosine.[13]

Irreversible inhibition is different from irreversible enzyme inactivation. Irreversible inhibitors are generally specific for one class of enzyme and do not inactivate all proteins; they do not function by destroying protein structure but by specifically altering the active site of their target. For example, extremes of pH or temperature usually cause denaturation of all protein structure, but this is a non-specific effect. Similarly, some non-specific chemical treatments destroy protein structure: for example, heating in concentrated hydrochloric acid will hydrolyse the peptide bonds holding proteins together, releasing free amino acids.[14]

Irreversible inhibitors display time-dependent inhibition and their potency therefore cannot be characterised by an IC50 value. This is because the amount of active enzyme at a given concentration of irreversible inhibitor will be different depending on how long the inhibitor is pre-incubated with the enzyme. Instead, kobs/[I] values are used,[15] wherekobs is the observed pseudo-first order rate of inactivation (obtained by plotting the log of % activity vs. time) and [I] is the concentration of inhibitor. The kobs/[I] parameter is valid as long as the inhibitor does not saturate binding with the enzyme (in which case kobs = kinact).

  Analysis of irreversible inhibition

  Kinetic scheme for irreversible inhibitors

As shown in the figure to the left, irreversible inhibitors form a reversible non-covalent complex with the enzyme (EI or ESI) and this then reacts to produce the covalently modified "dead-end complex" EI*. The rate at which EI* is formed is called the inactivation rate or kinact. Since formation of EI may compete with ES, binding of irreversible inhibitors can be prevented by competition either with substrate or with a second, reversible inhibitor. This protection effect is good evidence of a specific reaction of the irreversible inhibitor with the active site.

The binding and inactivation steps of this reaction are investigated by incubating the enzyme with inhibitor and assaying the amount of activity remaining over time. The activity will be decrease in a time-dependent manner, usually following exponential decay. Fitting these data to a rate equation gives the rate of inactivation at this concentration of inhibitor. This is done at several different concentrations of inhibitor. If a reversible EI complex is involved the inactivation rate will be saturable and fitting this curve will give kinact and Ki.[16]

Another method that is widely used in these analyses is mass spectrometry. Here, accurate measurement of the mass of the unmodified native enzyme and the inactivated enzyme gives the increase in mass caused by reaction with the inhibitor and shows the stoichiometry of the reaction.[17] This is usually done using a MALDI-TOF mass spectrometer. In a complementary technique, peptide mass fingerprinting involves digestion of the native and modified protein with a protease such as trypsin. This will produce a set of peptides that can be analysed using a mass spectrometer. The peptide that changes in mass after reaction with the inhibitor will be the one that contains the site of modification.

  Special cases

  Chemical mechanism for irreversible inhibition of ornithine decarboxylase by DFMO. Pyridoxal 5'-phosphate (Py) and enzyme (E) are not shown. Adapted from[18]

Not all irreversible inhibitors form covalent adducts with their enzyme targets. Some reversible inhibitors bind so tightly to their target enzyme that they are essentially irreversible. These tight-binding inhibitors may show kinetics similar to covalent irreversible inhibitors. In these cases, some of these inhibitors rapidly bind to the enzyme in a low-affinity EI complex and this then undergoes a slower rearrangement to a very tightly bound EI* complex (see figure above). This kinetic behaviour is called slow-binding.[19] This slow rearrangement after binding often involves a conformational change as the enzyme "clamps down" around the inhibitor molecule. Examples of slow-binding inhibitors include some important drugs, such methotrexate,[20] allopurinol,[21] and the activated form of acyclovir.[22]

  Examples of irreversible inhibitors

  Trypanothione reductase with the lower molecule of an inhibitor bound irreversibly and the upper one reversibly. Created from PDB 1GXF.

Diisopropylfluorophosphate (DFP) is shown as an example of an irreversible protease inhibitor in the figure above right. The enzyme hydrolyses the phosphorus–fluorine bond, but the phosphate residue remains bound to the serine in the active site, deactivating it.[23] Similarly, DFP also reacts with the active site of acetylcholine esterase in the synapses of neurons, and consequently is a potent neurotoxin, with a lethal dose of less than 100 mg.[24]

Suicide inhibition is an unusual type of irreversible inhibition where the enzyme converts the inhibitor into a reactive form in its active site. An example is the inhibitor of polyamine biosynthesis, α-difluoromethylornithine or DFMO, which is an analogue of the amino acid ornithine, and is used to treat African trypanosomiasis (sleeping sickness). Ornithine decarboxylase can catalyse the decarboxylation of DFMO instead of ornithine, as shown above. However, this decarboxylation reaction is followed by the elimination of a fluorine atom, which converts this catalytic intermediate into a conjugated imine, a highly electrophilic species. This reactive form of DFMO then reacts with either a cysteine or lysine residue in the active site to irreversibly inactivate the enzyme.[18]

Since irreversible inhibition often involves the initial formation of a non-covalent EI complex, it is sometimes possible for an inhibitor to bind to an enzyme in more than one way. For example, in the figure showing trypanothione reductase from the human protozoan parasite Trypanosoma cruzi, two molecules of an inhibitor called quinacrine mustard are bound in its active site. The top molecule is bound reversibly, but the lower one is bound covalently as it has reacted with an amino acid residue through its nitrogen mustard group.[25]

  Discovery and design of inhibitors

  Robots used for the high-throughput screening of chemical libraries to discover new enzyme inhibitors

New drugs are the products of a long drug development process, the first step of which is often the discovery of a new enzyme inhibitor. In the past the only way to discover these new inhibitors was by trial and error: screening huge libraries of compounds against a target enzyme and hoping that some useful leads would emerge. This brute force approach is still successful and has even been extended by combinatorial chemistry approaches that quickly produce large numbers of novel compounds and high-throughput screening technology to rapidly screen these huge chemical libraries for useful inhibitors.[26]

More recently, an alternative approach has been applied: rational drug design uses the three-dimensional structure of an enzyme's active site to predict which molecules might be inhibitors.[27] These predictions are then tested and one of these tested compounds may be a novel inhibitor. This new inhibitor is then used to try to obtain a structure of the enzyme in an inhibitor/enzyme complex to show how the molecule is binding to the active site, allowing changes to be made to the inhibitor to try to optimise binding. This test and improve cycle is then repeated until a sufficiently potent inhibitor is produced.[28] Computer-based methods of predicting the affinity of an inhibitor for an enzyme are also being developed, such as molecular docking[29] and molecular mechanics.

  Uses of inhibitors

Enzyme inhibitors are found in nature and are also designed and produced as part of pharmacology and biochemistry. Natural poisons are often enzyme inhibitors that have evolved to defend a plant or animal against predators. These natural toxins include some of the most poisonous compounds known. Artificial inhibitors are often used as drugs, but can also be insecticides such as malathion, herbicides such as glyphosate, or disinfectants such as triclosan.

  The structure of sildenafil (Viagra)
  The coenzyme folic acid (left) compared to the anti-cancer drug methotrexate (right)
  The structure of a complex between penicillin G and the Streptomyces transpeptidase. Generated from PDB 1PWC.

The most common uses for enzyme inhibitors are as drugs to treat disease. Many of these inhibitors target a human enzyme and aim to correct a pathological condition. However, not all drugs are enzyme inhibitors. Some, such as anti-epileptic drugs, alter enzyme activity by causing more or less of the enzyme to be produced. These effects are called enzyme induction and inhibition and are alterations in gene expression, which is unrelated to the type of enzyme inhibition discussed here. Other drugs interact with cellular targets that are not enzymes, such as ion channels or membrane receptors.

An example of a medicinal enzyme inhibitor is sildenafil (Viagra), a common treatment for male erectile dysfunction. This compound is a potent inhibitor of cGMP specific phosphodiesterase type 5, the enzyme that degrades the signalling molecule cyclic guanosine monophosphate.[30] This signalling molecule triggers smooth muscle relaxation and allows blood flow into the corpus cavernosum, which causes an erection. Since the drug decreases the activity of the enzyme that halts the signal, it makes this signal last for a longer period of time.

Another example of the structural similarity of some inhibitors to the substrates of the enzymes they target is seen in the figure comparing the drug methotrexate to folic acid. Folic acid is a substrate of dihydrofolate reductase, an enzyme involved in making nucleotides that is potently inhibited by methotrexate. Methotrexate blocks the action of dihydrofolate reductase and thereby halts the production of nucleotides. This block of nucleotide biosynthesis is more toxic to rapidly growing cells than non-dividing cells, since a rapidly-growing cell has to carry out DNA replication, therefore methotrexate is often used in cancer chemotherapy.[31]

Drugs also are used to inhibit enzymes needed for the survival of pathogens. For example, bacteria are surrounded by a thick cell wall made of a net-like polymer called peptidoglycan. Many antibiotics such as penicillin and vancomycin inhibit the enzymes that produce and then cross-link the strands of this polymer together.[32] This causes the cell wall to lose strength and the bacteria to burst. In the figure, a molecule of penicillin (shown in a ball-and-stick form) is shown bound to its target, the transpeptidase from the bacteria Streptomyces R61 (the protein is shown as a ribbon-diagram).

Drug design is facilitated when an enzyme that is essential to the pathogen's survival is absent or very different in humans. In the example above, humans do not make peptidoglycan, therefore inhibitors of this process are selectively toxic to bacteria. Selective toxicity is also produced in antibiotics by exploiting differences in the structure of the ribosomes in bacteria, or how they make fatty acids.

  Metabolic control

Enzyme inhibitors are also important in metabolic control. Many metabolic pathways in the cell are inhibited by metabolites that control enzyme activity through allosteric regulation or substrate inhibition. A good example is the allosteric regulation of the glycolytic pathway. This catabolic pathway consumes glucose and produces ATP, NADH and pyruvate. A key step for the regulation of glycolysis is an early reaction in the pathway catalysed by phosphofructokinase-1 (PFK1). When ATP levels rise, ATP binds an allosteric site in PFK1 to decrease the rate of the enzyme reaction; glycolysis is inhibited and ATP production falls. This negative feedback control helps maintain a steady concentration of ATP in the cell. However, metabolic pathways are not just regulated through inhibition since enzyme activation is equally important. With respect to PFK1, fructose 2,6-bisphosphate and ADP are examples of metabolites that are allosteric activators.[33]

Physiological enzyme inhibition can also be produced by specific protein inhibitors. This mechanism occurs in the pancreas, which synthesises many digestive precursor enzymes known as zymogens. Many of these are activated by the trypsin protease, so it is important to inhibit the activity of trypsin in the pancreas to prevent the organ from digesting itself. One way in which the activity of trypsin is controlled is the production of a specific and potent trypsin inhibitor protein in the pancreas. This inhibitor binds tightly to trypsin, preventing the trypsin activity that would otherwise be detrimental to the organ.[34] Although the trypsin inhibitor is a protein, it avoids being hydrolysed as a substrate by the protease by excluding water from trypsin's active site and destabilising the transition state.[35] Other examples of physiological enzyme inhibitor proteins include the barstar inhibitor of the bacterial ribonuclease barnase[36] and the inhibitors of protein phosphatases.[37]

  Pesticides and herbicides

Many herbicides and pesticides are enzyme inhibitors. Acetylcholinesterase (AChE) is an enzyme found in animals from insects to humans. It is essential to nerve cell function through its mechanism of breaking down the neurotransmitter acetylcholine into its constituents, acetate and choline. This is somewhat unique among neurotransmitters as most, including serotonin, dopamine, and norepinephrine, are absorbed from the synaptic cleft rather than cleaved. A large number of AChE inhibitors are used in both medicine and agriculture. Reversible competitive inhibitors, such as edrophonium, physostigmine, and neostigmine, are used in the treatment of myasthenia gravis and in anaesthesia. The carbamate pesticides are also examples of reversible AChE inhibitors. The organophosphate insecticides such as malathion, parathion, and chlorpyrifos irreversibly inhibit acetylcholinesterase.

The herbicide glyphosate is an inhibitor of 3-phosphoshikimate 1-carboxyvinyltransferase,[38] other herbicides, such as the sulfonylureas inhibit the enzyme acetolactate synthase. Both these enzymes are needed for plants to make branched-chain amino acids. Many other enzymess are inhibited by herbicides, including enzymes needed for the biosynthesis of lipids and carotenoids and the processes of photosynthesis and oxidative phosphorylation.[39]

  To discourage seed predators, pulses contain trypsin inhibitors that interfere with digestion.

  Natural poisons

Animals and plants have evolved to synthesise a vast array of poisonous products including secondary metabolites, peptides and proteins that can act as inhibitors. Natural toxins are usually small organic molecules and are so diverse that there are probably natural inhibitors for most metabolic processes.[40] The metabolic processes targeted by natural poisons encompass more than enzymes in metabolic pathways and can also include the inhibition of receptor, channel and structural protein functions in a cell. For example, paclitaxel (taxol), an organic molecule found in the Pacific yew tree, binds tightly to tubulin dimers and inhibits their assembly into microtubules in the cytoskeleton.[41]

Many natural poisons act as neurotoxins that can cause paralysis leading to death and have functions for defence against predators or in hunting and capturing prey. Some of these natural inhibitors, despite their toxic attributes, are valuable for therapeutic uses at lower doses.[42] An example of a neurotoxin are the glycoalkaloids, from the plant species in the Solanaceae family (includes potato, tomato and eggplant), that are acetylcholinesterase inhibitors. Inhibition of this enzyme causes an uncontrolled increase in the acetylcholine neurotransmitter, muscular paralysis and then death. Neurotoxicity can also result from the inhibition of receptors; for example, atropine from deadly nightshade (Atropa belladonna) that functions as a competitive antagonist of the muscarinic acetylcholine receptors.[43]

Although many natural toxins are secondary metabolites, these poisons also include peptides and proteins. An example of a toxic peptide is alpha-amanitin, which is found in relatives of the death cap mushroom. This is a potent enzyme inhibitor, in this case preventing the RNA polymerase II enzyme from transcribing DNA.[44] The algal toxin microcystin is also a peptide and is an inhibitor of protein phosphatases.[45] This toxin can contaminate water supplies after algal blooms and is a known carcinogen that can also cause acute liver hemorrhage and death at higher doses.[46]

Proteins can also be natural poisons or antinutrients, such as the trypsin inhibitors (discussed above) that are found in some legumes, as shown in the figure above. A less common class of toxins are toxic enzymes: these act as irreversible inhibitors of their target enzymes and work by chemically modifying their substrate enzymes. An example is ricin, an extremely potent protein toxin found in castor oil beans. This enzyme is a glycosidase that inactivates ribosomes. Since ricin is a catalytic irreversible inhibitor, this allows just a single molecule of ricin to kill a cell.[47]

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Review: Diamonds in the Rough (PC)

Now thats a manly jaw!
Diamonds in the Rough
Genre: Adventure
Developer: Atropos Studios
Publisher: Atropos Studios
Release Date: 03/18/2008

Today I feel like a true member of the Diehard Gamefan writing staff for the first time. Yes, I’m going through that traditional rite of passage all writers here must be a part of by reviewing my first obscure low-budget adventure game! Ahhh, I’m misting up a bit as I type this.

Anyways, Diamonds in the Rough is the first game from new Greek developer Atropos Studios and is written/designed by the guy who single-handedly developed the cult favorite freeware adventure Other Worlds. So far a small handful of sites devoted to adventure games have bestowed largely glowing reviews upon this title, but is this merely a case of people being pleasantly surprised that a game made with very limited resources is actually decent or have Atropos Studios managed to produce a true top-level adventure game?

1) Story

Near the end of DitR (which I’ll refer to the game as from now on so as to limit finger strain) your main character takes a dose of yellow phosphorous leaving him with only a couple torturous hours to live. Re-checking the beginning of this paragraph to see if you missed a spoiler warning? There’s not one there because this is actually the first thing you learn when you start up the a new game, as right from the beginning DitR announces it’s intention to present a story that’s a little different. Maybe even a bit challenging.

The rest of the game takes place in flashback form as you take control of Jason Hart, a young man from a rough background who happens to have limited psychic abilities. If presented with a question with multiple answers, Jason has the ability to always choose the answer the person who asked the question wants him to choose. Jason is recruited by Diamonds in the Rough, an organization lead by a William Hungerton and relocated to a small, isolated compound/town whose residents all posses special abilities. All Jason has to do is take part in occasional tests of his powers and he’s provided with anything he could possibly want, except information about Diamonds in the Rough’s true purpose that is. That information quickly becomes Jason’s number one desire when he discovers a vaguely sinister message carved into an old desk by the man who lived in his house before him…

“We aren’t diamonds, we’re only pieces of coal.”Â

The set-up for DitR is quite unique, the little town is populated by an interesting cast characters and despite being written by someone for whom English isn’t a first language, and the dialogue is pretty sharp. It’s not perfect, most people from non-English speaking countries that try to write in English don’t realize that North Americans speak a formless mush of contractions, half pronounced, blended-together words and stupid phrases we picked up from rap videos, and as such the dialog in DitR sounds a bit inauthentic at times. Whether that’s a good or bad thing is up to you.

Where DitR’s story succeeds best though is in creating a constant lingering sense of unease. There’s no intestine chomping zombies, no cackling villains or shambling genital shaped abominations and yet right from the beginning there’s a palatable sense there’s something not right about this seemingly idyllic town. Discovering the aforementioned “pieces of coal”Â message is a genuinely off-putting moment, and later in the game when you find a couple drops of blood on a bathroom floor you’ll feel like you’ve been punched in the gut. Games like Ninja Gaiden can spend countless hours and dollars developing the perfect blood-spurting neck wound and gamers simply shrug their shoulders then move onto the next hyper-violent action game, while DitR manages to create a truly disturbing moment with a couple red dots on a bathroom floor. Now that’s the power of a well-built story.

A lot of other reviews of this game mention a twist ending, leading me to question whether these reviewers actually know what “twist ending”Â means. Granted the ending of the game is definitely surprising, even a bit shocking, but it’s in a “wow, are they really going there with this story?”Â sense, not because of any twist. I wasn’t sure what I thought about the ending at first. Given the somewhat surreal feeling of most of the story I guess I was expecting the DitR organization’s sinister motivations to be more cosmic or supernatural in nature, when instead they’re rooted in our real and sometimes very ugly world. In retrospect though, I have to give the writer of DitR credit for tackling such challenging subject matter. You simply wouldn’t see anything like this in a mainstream game. In an interesting move the writer even includes a message you can read after you beat the game explaining his motivations, writing processes and research methods, which puts the ending in the proper context (and at the same time will scare the shit out of you with the information that some of the characters in the game were actually based on real people).

Bottomline Diamonds in the Rough’s storyline is one of the most intriguing I’ve experienced in years and is without a doubt the most worthwhile aspect of the game.

Story Rating: Classic

2) Graphics

Now I know I just wrote that this game creates a sense of unease mostly through it’s well crafted story rather than packing the game with hideous freaks, but I may have to take that back…

Get the children out of the room!

Argh, God! Kill it, kill it with fire! Yes, this game is filled with such abominations. Characters with strange, twisted, anatomically incorrect appendages that bend and flex in ways human limbs weren’t intended to. Dead soulless eyes stare out at you; their bodies remaining eerily stalk still as they talk, as if they’re waiting to strike. Brrrrrr.

Just in case I’m not making this clear enough, the DitR character models? Really, really, really ugly. Like, really. The environments are comparatively much better looking in that they’re merely static, bland and low-res as opposed to a borderline heath hazard.

Graphics Rating: Dreadful

3) Sound

Now unlike the visuals the audio in DitR is actually pretty good. The music is simple and often seems to be incongruous to the settings or situation, but that actually adds to the vaguely off-putting, surreal vibe of the game.

Surprisingly given this is a Greek game the English voice acting is also solidly done, or at least the male voices are. The female voices are largely lousy, the most noticeable poor performance being the girl doing your best friend Sydelle’s voice. She’s a major character who you hear from a lot and the performance is mostly stilted with the actress doing a poor job of concealing some sort of accent (it doesn’t sound Greek, but then I’m no linguist). This seems to be a common issue with video games actually. When it comes to the male voice actors they hire guys who can actually, you know, act, but when it comes to casting the female parts they just grab anyone with boobs who works in the office then plunk them in front of a microphone. Maybe it’s some sort of desperate game designer seduction technique.

“Hey sweetheart, why don’t you come over to my place? We can have a few drinks then if the mood strikes you maybe we can, well you know…record some lines for my indy adventure game. I’ll make you a star honey, a star!”Â

Ahem, what were we talking about again? Oh right. DitR music = very good, voice acting = average. Moving on.

Sound Rating: Good

4) Control and Gameplay

Diamonds in the Rough is a point-and-click adventure game, but even though you interact with everything simply by clicking on it this game is presented in a 3rd person perspective instead of 1st person style like Myst. This is kind of needless, as having Jason wandering around onscreen accomplishes nothing other than to slow down the gameplay and offend gamers’ eyes with his ugliness. A 1st person perspective would have allowed them to streamline things and hide their severe limitations where creating 3D models is concerned, but oh well.

If you’ve used a computer sometime within the last 15 years you should be able to get your head around controlling DitR just fine. You simply use the left mouse key to click on anything you want to interact with and the right mouse key to scroll through your pointer’s various functions (walk, examine, use, talk, use item/thought). The game requires you to constantly scroll through the functions and it starts to become rather annoying quickly, particularly since many of the functions could have been combined (there’s really no reason examine, use and talk had to be separate functions). This incessant scrolling through the functions is exacerbated by the fact that you can’t simply open up your inventory and click on an item to select it, you have to switch to the “use”Â function in order to grab it. This is completely needless.

The gameplay here will be pretty familiar to anyone who’s played an adventure game before. You wander around a smallish world, pump people for information and haul a backbreaking load of trinkets around that you’ll use and combine to solve puzzles in order to progress. It’s pretty standard stuff with the one major addition to the mix being the Thoughts Panel.

Note - Order more post-it notes.

Occasionally while talking to someone, reading something or examining an item a light bulb will appear over your head and a new thought will be added to your Thoughts Panel. By selecting one of these it will become Jason’s current thought, but unfortunately the mechanic is not quite as interesting as you might hope. Your current thought has no effect on how you act or respond to people, you’ll reply to other characters in the same way regardless of if you’re thinking about the sinister doings of the Diamonds in the Rough organization or cupcakes. Instead the thoughts are simply used as a 2nd inventory. Once you select a thought it will be represented as a sticky note which you can show to people to trigger new conversations, apply to items or areas on screen to help solve puzzles or even combine with inventory items or other thoughts to create new thoughts. So there’s a fair amount of depth to it, but honestly the Thoughts Panel often just makes the game more complicated rather than more fun. As just one example, in most current adventure games if you have a new objective new conversation branches will simply automatically appear when you talk to people. Not here, instead you have to fish around in your Thoughts Panel for the right thought to show them in order to get some new information, which makes me think “pain in the ass”Â more than “innovative”Â.

This “make things needlessly complicated”Â approach is really applied to the majority of the game’s puzzles. This game doesn’t really serve up much in the way of satisfyingly clever mind teasers, most of the challenge in DitR comes from the game simply withholding information or being frustratingly vague about things. For instance at one point in the game you have to get an object out of your closet which should be easy for anyone who isn’t, you know, a bug-eating moron. But of course this is an adventure game, so your main character is a bug-eating moron and can’t find anything in his own closet because the light is burned out. Okay fine, I’m used to adventure games where the guy tasked with saving the world is barely smart enough to dress himself, so I’ll accept he needs to order a light bulb to locate things a foot in front of his face in his own closet. No hint about how to order said light bulb is given, you’re simply sent off to randomly scour the area in a process that’s more frustrating than fun. This kind of thing happens a lot in the game. Also in order to trigger events you often have to complete totally unrelated tasks the game doesn’t inform you of. Want to get a guy to appear in the park for a clandestine meeting? Well, make sure you combined two thoughts in the Thoughts Panel, talked to some random kid, and delivered a specific envelope (none of which has much of anything to do with meeting this guy). The makers of the game simply decided you had to have this, this and that done in order to progress to the next step in the game. Would be lovely if they’d actually tell players that.

Now I’m sure a small selection of old-school adventure game fanatics may enjoy this kind of stuff, but those of us who don’t think adventure games should stay forever mired in the same needlessly obtuse gameplay we were putting up with in the 20 years ago will mostly be annoyed.

Control and Gameplay Rating: Mediocre

5) Replayability

As with most adventure titles, if you know what you’re doing you could probably blow through this game in an hour or two. That said the game’s vagueness and relatively high level of challenge will significantly lengthen your experience (personally it took me around 10 hours to complete the game). 10 hours is actually pretty decent for an adventure game, but once you’re done you’re done. There’s no incentive to play through again and I expect most people won’t, as the game’s annoyances will only be more noticeable when you’re no longer distracted by wondering what’s going to happen next in the story.

Replayability Rating: Mediocre

6) Balance

DitR is definitely more difficult than your average current day adventure game, but for the most part it chugs along at a pretty steady high, but manageable level of difficulty. That is, until you careen headfirst into the brick wall that is the password puzzle. This brain breaking frustration-fest requires a migraine-inducing array of steps and questionable leaps of logic to complete. Good puzzles should stimulate you and make your feel smart when you solve them. This puzzle makes you feel stupid and when you finally slog through it you mainly just feel like punching the guy who designed it. So yeah, the game’s actually pretty well balanced with one big glaring pimple-on-prom-night exception.

Balance Rating: Mediocre

7) Originality

Gameplay-wise this game is mostly very standard stuff, with the Thoughts Panel sounding interesting but not adding a whole lot to the game. I do have to give it points for it’s unique and challenging storyline though even if the actual gameplay is strictly by the book.

Originality Rating: Mediocre

8) Addictiveness

This game is very hot and cold when it comes to addictiveness. When you’re on a roll, knocking down the puzzles and revealing the story at a decent rate the game will grab you and hours will disappear without you noticing. On the other hand, when you find yourself lost due to the game’s stubborn insistence on denying you guidance all the game’s flaws become much more noticeable. If I hadn’t sworn a solemn blood oath to Gamefan cult leader Alex Lucard to review this game on time it definitely would have been put on the backburner after a few of the more brain breaking sections.

Addictiveness Rating: Decent

The town square...of EVIL.

9) Appeal Factor

Most people are going to take one look at this game and not give it the slightest chance. Everything about it screams low-budget indy game and just like most people would rather watch the latest “Adam Sandler makes a funny voice for 90 minutes”Â movie than a quality independent film, the vast majority won’t give this one a 2nd look. It doesn’t help that it’s an adventure game either, as it’s a cult genre at best these days. I don’t expect this one to spread much beyond the community of true adventure game fanatics.

Appeal Factor Rating: Awful

10) Miscellaneous

You feel kind of bad beating up on a low-budget independent game like this. It’s like that poor kid in elementary school…sure he sported a bowl-cut, wore the same clothes for 2 months straight and his lunch each day was nothing but an old hot dog bun and a slice of processed cheese, but it’s wasn’t really his fault. I respect the makers of Diamonds in the Rough for telling a challenging story, attempting to do something a little bit different and just generally trying to make a fairly ambitious game without a lot of resources. In some respects they actually succeeded big time and I’d like to see what Alkis Polyrakis and the folks at Atropos Studios cook up in the future.

Miscellaneous Rating: Enjoyable

The Scores
Story: Classic
Graphics: Dreadful
Sound: Good
Control and Gameplay: Mediocre
Replayability: Mediocre
Balance: Mediocre
Originality: Mediocre
Addictiveness: Decent
Appeal Factor: Awful
Miscellaneous: Enjoyable

Final Score: Mediocre Game

Short Attention Span Summary

You know it’s one thing to review a Grand Theft Auto IV or Smash Bros. Brawl and report that, shock of shocks, these games are in fact good. It’s another and more satisfying thing altogether I think to discover that great obscure game, that diamond in the rough (see what I did there?) and help give it some much-needed exposure. I was hoping this would be that game, but despite an excellent story it just has too many issues weighing it down to recommend to anyone but the most dedicated of adventure game fans. Then again, they’re probably the only people who would go out of their way to track this game down anyways, so I suppose it all works out in the end.

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What Is Your Security Canary?

April 13, 2017 Added by:Jesse McKenna

Although traditional anti-malware approaches tend to focus on looking deep within each endpoint for suspicious activity, in the case of ransomware particularly, this equates to monitoring the coal miners and when an event happens, you’ve just lost a miner.

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Bracing for the Future of Information Security Threats

April 04, 2017 Added by:Steve Durbin

New attacks will impact both business reputation and shareholder value, and cyber risk exists in every aspect of the enterprise. Here are the top nine threats to information security over the next two years.

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When Ransomware Strikes: Does Your Company Have a Data Disaster Recovery Plan?

February 16, 2017 Added by:Jeff Erramouspe

Ransomware is rampant and those who commit the attacks aren’t discriminating against any industry, company size, or company location.

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DynA-Crypt Ransomware Steals and Deletes User Data

February 11, 2017 Added by:Ionut Arghire

A newly observed piece of ransomware doesn’t merely focus on encrypting user’s files, but also attempts to steal data from the infected machine, and to delete files, researchers warn.

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Tuesday, March 19, 2013

Spring is HERE! Let's Organize!!

I love Spring.  The newest of things!! What better time than to re-organize your products, hair accessories, and all those other in-between stuff. Don't forget to throw away anything that has expired! Yes, hair products do expire. Read all about it by clicking HERE.

Watch how I organize my products.

How do you organize your products?

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In cart 0 items
to the amount of 0 r.

440/3 3D Namba champion propeller stainless steel

Code: NAMBA440/3

Price: $54.95

Stainless steel propeller

This series of propellers showed the best result in the competition NAMBA USA.
3D Namba champion serie is a new breakthrough in 3D technologies.
We have primed the most advanced and latest technologies in the manufacture of RC propellers for boat models.
Propeller manufacturing on 3D equipment using stainless steel.
Diameter: 1.57" (40 mm)
Pitch: 1.4
Shaft: 3/16" (4.75 mm)
Balanced RTR
Material: Stainless Steel
Surface -  mirror shine
 Manufactured by Doctorprops.

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Download NetSpeedMonitor (64 bit)

NetSpeedMonitor (64 bit)

Views: 1787310

With NetSpeedMonitor you can monitor the current speed (up- and downstream) of your Network Interfaces and the amount of data transferred. In addition to the Connection Table with all TCP/UDP endpoints and the Toolbar Tooltip with a quick and short traffic overview, you can also see detailed daily and monthly Traffic Statistics. NetSpeedMonitor toolbar requires no additional drivers like other Network Monitoring tools do.

blogger counters


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Home Page

This has ben an ongoing restoration, it was decided when the car was first obtained that the best way to complete the resto was to do it in sections, so spreading the cost and effort over a few years. The plan has been working well and now the car is back from the paint shop in its new colour ready to be assembled.

mgb jim 08

This is the car before I started to remove the Chorme, Lights etc. ready for the painting.

mgb jim 07

You can see the Dent in the Bumper and the Hood, also the push back on the front of the Fender has bowed out the section over the wheel arch. The Hood is the original Alumimum, the dent will be hard to remove as the back side is covered by the supporting section that goes across the front of the Hood.

mgb jim 05

I have the front of the car stripped and also the rear

mgb jim 06

The car went off to the paint shop have its new colour and the body dents and dings removed.

mgb jim 01

As you can see the body is now free of the dents on the Front and the bow in the Front fender has been fixed

mgb jim 04

All the door steps and inside door edges have been painted

mgb jim 03

So now all I have to do is put everything back, making sure it all works.


WARC-Identified-Payload-Type: application/xml

text: 박형곤 2016-08-28T12:08:50Z 2016-08-28T12:08:50Z 2010 1053-587X OAK-6278 http://dspace.ewha.ac.kr/handle/2015.oak/220538 In this paper, we consider the resource reciprocation among self-interested peers in peer-to-peer (P2P) networks, which is modeled as a stochastic game. Peers play the game by determining their optimal strategies for resource distributions using a Markov decision process (MDP) framework. The optimal strategies enable the peers to maximize their long-term utility. Unlike in conventional MDP frameworks, we consider heterogeneous peers that have different and limited ability to characterize their resource reciprocation with other peers. This is due to the large complexity requirements associated with their decision making processes. We analytically investigate these tradeoffs and show how to determine the optimal number of state descriptions, which maximizes each peer's average cumulative download rates given a limited time for computing the optimal strategies. We also investigate how the resource reciprocation evolves over time as peers adapt their reciprocation strategies by changing the number of state descriptions. Then, we study how resulting download rates affect their performance as well as that of the other peers with which they interact. Our simulation results quantify the tradeoffs between the number of state descriptions and the resulting utility. We also show that evolving resource reciprocation can improve the performance of peers which are simultaneously refining their state descriptions. © 2009 IEEE. English Evolution of resource reciprocation strategies in P2P networks Article 3 PART 1 58 SCI SCIE SCOPUS 1205 1218 IEEE Transactions on Signal Processing 10.1109/TSP.2009.2033731 WOS:000274472600022 2-s2.0-79955625536 Park H. Van Der Schaar M. 박형곤(16744100700) 20170922132145


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2013A concentration of organic compounds of alcoholic distillate under bioethanol productionIvanov, Sergey; Shiyan, Peter; Buliy, Yuri; Kuts, Anatoly
2015A conceptual metaphoric analysis of poverty in Marie Corelli’s novel The Sorrows of SatanMolozhon, Maria
2000A convergence class for entire Dirichlet series of slow growthMulyava, Oksana
2013A mathematical model for calculating the saturator of the sugar productionOvcharuk, Vladimir; Yushchuk, Inna; Metlov, Sergei
1993A method for determining the mass-molecular composition of microbial exopolysaccharidesVotselko, S.; Pirog, Tatiana; Malashenko, Yuri; Grinberg, Tamara
2016A new approach for controlling steam turbine of thermal power plantLymar, Victor; Shevchenko, Sviatoslav; Smirnova, Elizabeth
2013A new form of beet cossettes – the way to get and benefitsLulka, Alexander; Mironchuk, Valeriy; Adamenko, Andriy
1999A new method for construction of solutions nonlinear wave equationsBarannyk, Anatoliy; Yuryk, Ivan
2013A new method of analysis of granulated hopsLitvynchuk (Vorontsova), Svitlana; Nosenko, Volodymyr; Meletyev, Anatoly; Hutsalo, Inna
2014A New Prototype of a Food 3D PrinterCherednik, Alexander
2013A perfect product in a feel-good containerVerzhak, Victoria; Korenchuk, Catherine
1998A possible general mechanism of the signal transfer on the α/β-interferons expression. 1. The local cell membrane deformation as the first induction stageKarpov, Alexander
1999A possible general mechanism of the signal transfer switching on the α/β-interferons expression. 2. The role of the cAMP in the process of the interferon inductionKarpov, Alexander
2017A retrospective analysis of the concept of "self-regulating learning" in the philosophical and psychological-pedagogical literature of the West European educational spaceHerasymova, Olga
2016A study of the viscosity of water solutions of inulin – the functional food ingredientZinchenko, Natalia; Simurova, Natalia; Shelakov, Andrei
2016A study of water ice formation and melting processes on vertical cooled pipesZasiadko, Yaroslav; Pilipenko, Alexey; Forsyuk, Andriy; Gryschenko, Roman
2001A two-stage cultivation technique for producing microbial exopolysaccaride ethapolan with improved rheological propertiesPirog, Tatiana; Malashenko, Yuri; Votselko, S.
2014About pore structure of sugar beet pulpIvashchenko, Natalia; Bulyandra, Alexey; Verbitckiy, Boris; Lutsyk, Yuriy; Bernic, M.; Ciobanu, E.
2013About Some Physical Properties of Water in Nanosistems and the Possible Mechanism of Superconductivity Induction by Water in Compounds andMartseniuk, Oleksandr; Martseniuk, Liudmyla; Kurik, Mikhail
2004Absorption anisotropy studies of polymethine dyesLepkowicz, R.; Przhonska, Olga; Stryland, E.; Slominsky, Yu.; Kachkovski, A.; Mayboroda, Elena; Bondar, Nikolai


text:
Court Service

Court Service

East Bay Messenger and Attorney Service is here to serve all your legal needs. These are just some of the court services our experienced court runners can provide:

  • File and lodge documents at Superior Court.
  • Print and prep court documents to meet the standards of the court.
  • Record your Deed, Lien, PCOR, and other documents.
  • Research at the assessors office in your county.
  • Conduct background checks at criminal courts.
  • Open eviction files with the sheriff in your county.

I can do what you need to achieve your legal goals, if you have a project contact me about it.

Rates for (Berkeley / Oakland / Emeryville )

Rates are determined by the time we have to get your job done. Most courts in the Bay Area close at 3PM. Chamber’s copy preparation and delivery are available as well, please contact me with your request.

  • Routine (4-hour): $45 (includes courtesy copies)
  • Rush (2-hour): $55 (includes courtesy copies)
  • ASAP (1 hour): $65 (includes courtesy copies)
  • Waiting time: $0.75/minute
  • Printing and doc prep: $0.30/page
  • Pick-up: Free for Oakland / Berkeley / Emeryville; $15 outside
  • Email: $.30/page if more than 12 pages

Other courthouse? Contact Me


text:
Filling the Talent Pool

Dearduff, Jeff
July 2006
Snack Food & Wholesale Bakery;Jul2006, Vol. 95 Issue 7, p72
Trade Publication
The article provides information on various critical and direct influences that contribute to the manager's ability in executing responsibility towards work.

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  • Corporate Board Composition, Protocols, and Voting Behavior: Experimental Evidence. Gillette, Ann B.; Noe, Thomas H.; Rebello, Michael J. // Working Paper Series (Federal Reserve Bank of Atlanta);Aug2000, Vol. 2000 Issue 10, p1

    Presents an experiment model of the governance of an institution. Dependence of the management of the institution on the information possessed by insiders; Multiagent mechanisms that impose penalties for conflicting recommendations; Implementation of the intuitionally preferred allocation in...

  • Measuring the Quality of Corporate Governance: In Search of a Tailormade Approach? Van den Berghe, L.A.A.; Levrau, Abigail // Journal of General Management;Spring2003, Vol. 28 Issue 3, p71

    Focuses on the measurement of the quality of corporate governance. Impact of corporate governance mechanisms on company performance; Comparison of main corporate governance rating systems; Critical analysis of the underlying principles and criteria used by the rating systems; Proposed...

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    Focuses on important developments in the corporate governance debate in 1998 in Great Britain. Details on the report published by Hampel Committee; List of plans set out by the committee; Comments from Margaret Beckett, president of the Board of Trade; Key goals of Beckett's consultation document.

  • Corporate Governance Is Key. Kelly, Bruce // Pensions & Investments;12/14/1998, Vol. 26 Issue 25, p16

    Discusses the changes in global corporate governance, according to the report titled `Corporate Governance 1998: An International Comparison.' Ranking of the world's leading economies which includes the United States, Great Britain and France; Board structure, voting rights, disclosure and...

  • Governance is a Global Challenge.  // Bank Loan Report;10/7/2002, Vol. 17 Issue 39, p1

    Focuses on the discussion on corporate governance during the 2002 Annual Meeting of the Institute of International Finance. Globalization of the concept of corporate governance; Actions banks and corporations have to take to restore investor confidence; Call for regulations that will keep a...

  • 1998 was a dynamic year for governance. Reynolds, Jr.,, Russell S. // NACD Directorship;Feb99, Vol. 25 Issue 2, p1

    Assesses corporate governance in the United States in 1998. Examples of board revolts that resulted in chief executive changes; Guidelines on corporate governance; Challenge to shareholder rights.

  • Corporate governance in the new millennium: More work and evaluation. Koppes, Richard H. // NACD Directorship;Apr99, Vol. 25 Issue 4, p11

    Discusses the advantages and disadvantages of corporate governance. Importance for corporations and their directors to be aware of their duty to shareholders; Views on the future of corporate governance in the United States; Significance of effective governance to the healthy growth of capitalism.

  • INFOLINE.  // NACD Directorship;Apr2001, Vol. 27 Issue 4, p18

    Presents updates on corporate governance. Overall assets held by United States institutions by the end of 1999; Percentage of chief executive officers whose salaries are stock-based; Overview of the guide `Transactional Accounting' Second Edition.

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Make it Monday: Quick and easy bows!

Hello friends! I wanted to make a special bow to decorate Emily’s 10th birthday present and was so happy when I found this YouTube video by Margaret Meyer. The instructions are easy to follow and the bow is so easy to make 🙂 All you need are 9 lengths of wrapping paper (measurements on video), all 3/4 of an inch wide (less than perfectly cut by me!) and some glue:

The less than perfectly cut paper didn’t matter once the bow was made!

Of course, it coordinated perfectly with the paper:

And looked fantastic on the wrapped present:

Next time you need a bow, give it a try! Thanks so much for visiting today; I’ll pop back soon to share a little about Emily’s Slime Party, organised by the amazing Ruby 🙂 Megan xo

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text:
ElAnsar Chairman Message

It is well know that success never immigrate out of nothing …but the exerted hard efforts & the continues planning & development the success keys in any field of work. Our customers have to get their residence with the feature they ever dream .for that reasons we make our ever first priority aim “customer satisfaction” setting for that goal all our powers & the intelligent minds.This would clearly appear in our project service.

Eng . Mohamed el Sokaily

ElAnsar Group

  • AL ansar group was founded in 1996. We were able to dig our name, over the past 17 years, between the growing up real estate companies in Egypt, where we had established a number of large and distinctive projects in the Alexandrya City. Our mission is to provide the best luxurious apartments and attention to every details to give our customers inside and outside Egypt the best home he is looking for. We have earned the trust and credibility of our customers, all over the years.
  • AL ansar group has an ambitious plan to increase its market share in the Egypt ian market after the great successes that was achieved during the past few years which were hailed our customers.
  • AL ansar group is always keen to achieve the requirements and needs of its clients providing them with the highest degree of quality and commitment..

The activities of our group of companies are

685 El Horya Ave . Louran . Alex . Egypt


text:
Home » Showroom »
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Pt. Sumber Makmur

Street Address: Jl. Boulevard Raya Gd. Demarker Otomotif Centre Bl. G14

Country/Region: Indonesia

View Contact Details
I want to learn and understand all product parts Toyota and I am now studying independently selling spare parts toyota start all over again .

Company Profile

Business Type:Agent
Main Products:Toyota
Market Type:After Market

Send your message to this supplier

Enter between 20 to 3,000 characters, English only.


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Global Logistics
Efficient professional, customer service, innovation and development
Ocean Shipping FCL

Service overview：

We have all over the world service agent network and sound branches, and MSK, MSC, cma-cgm, APL, OOCL, EMC, NYK, HMM and other world-renowned shipping companies cooperation experience and establish a good relationship is to provide you with the most efficient transport, the lowest freight strong guarantee!

Advantage routes：

West American line, East American line, South America line, Japan line, European ground line, southeast Asia line, etc

Service scope

Shipping import and export FCL business;Ocean freight inquiry;Inquiry of maritime customs clearance fees;Maritime import and export declaration/inspection declaration, warehousing/distribution business;Port to port, port to door, door to door, door to port transport;Other shipping related services.

Service  details:

Our shipping services cover nearly 1200 ports and cities around the world, more than 200 countries, 53 shipping companies, transparent, fair, within reach!

Provide diversified and personalized services for amazon sellers, act as an agent for amazon FBA customs clearance, label change, overseas warehousing and other one-stop services.

Shipping double customs clearance service creates a new era of DDU/DDP service, solves the problem of customs clearance and delivery for small and medium-sized enterprises, and makes international logistics easier!

Main receiving places in China: shenzhen, dongguan humen, guangzhou huangpu, zhongshan, zhuhai, shunde, foshan, jiangmen, huizhou, shantou, zhaoqing, yangjiang, heyuan, xiamen, fuzhou, chengdu, chongqing, changsha, wuhan, nanchang, nanning, guizhou, kunming, Hong Kong.

At present, the airline service can be provided: central and American, South America, the United States, Canada, red sea, Mediterranean, black sea, Australia, New Zealand, Africa, Egypt, Lebanon, Middle East, India and Pakistan, southeast Asia, northeast Asia, Hong Kong, Macao and Taiwan.

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text:
Boho Wedding // Ashley & David

Have you noticed this Boho Wedding?

Ashley and David’s wedding was a dream! These two have such a stunning relationship and they had been beyond excited to be obtaining married! Their whole wedding day radiated with joy. You could see it on their faces and the face of every single single individual there. Take a couple of moments to watch their film and you will see (and hear) why. We are nonetheless swooning more than their gorgeous sunset session! And their dance floor was so gorgeous! Congratulations Ashley and David! We loved celebrating with you and your households! Get pleasure from the rest of your honeymoon!

// Venue: Rock Hurst Farm Wedding Venue and Events
// Organizing & Florals: BKWed
// Videography: Hampton Road Studios
// Photography: Rylee Hitchner Photography
// Dress: Heidi Elnora
// Bridesmaids : Bella Bridesmaids
// Hair & Makeup: Hair & Make Up by BBM
// Band: The A-Town A-List
// Caterer: Savoie Catering
// Cakes: Olexa’s Cafe, Cakes, & Catering
// Popsicles: Steel City Pops
// Doughnuts: We Have Doughnuts
// Rentals: PropHouse Birmingham & Chelsea Antique Mall

Discover us right here:

Music // An individual by Future of Forestry, Our Time Is Now by Lights & Motion, and Moment By Moment by Phillip Cuccias.

Gear used:

Major Cameras –
3rd Angle Ceremony Camera –
4th Angle Ceremony Camera –
Slider –
Stabilizer –
Tripods – &
Monopods –
Reception Lights –
Audio Recorder –
Shotgun Mics –
Lavalier Mics –
Recorder for Lav Mics –

Canon 24 mm 1.four L –
Canon 35 mm 1.4 L –
Canon 50 mm 1.2 L –
Canon 100 mm 2.8L –
Canon 24-105 mm 4.0L –
Canon 70-200 2.8 L IS I –
Canon 70-200 4. L IS –

** Some affiliate hyperlinks above. **

From: Hampton Road Studios

  1. yogatharshini shanmugam

    One of the best wedding vdeos i hv watched😁….its simple yet beautiful and elegant😍..the outdoor location looked nice with the weather/season…and beautiful wedding gown…can’t wait for mine

  2. okky. HISCORP

    Hello capengrs , masih bingung pilih venue dan vendor untuk hari bahgaia kalia ??? kami memiliki wedding package all in one dengan banyak bonus menarik yg bisa langsung dia bawa pulang . more infp OKKY 087885829119

  3. my legit dream wedding!!! and glad to see such a happy couple that not only has a great relationship with eachother but with god too

  4. stephanie perrotti

    Hi Guys! Would you be open to sharing your process for backing up your footage from the start of the day to the end? Do you keep everything on it’s cards until you dump them in numerous places? Or do you dump footage as you go on? I have not been able to find a flawless process when it comes to transferring footage! HELP 🙂

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Aiyza Designer Wedding Fashion

Aiyza Designer Wedding Fashion Wedding Gowns, Bridesmaid Dresses, Tuxedos, Wedding Jewelry, Wedding Rings & the Latest Wedding Designer Fashions!
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Last Update 13:59
Monday, 25 May 2020

Turkey slams Armenia for halting deal to improve ties

AFP , Tuesday 17 Feb 2015
Views: 1166
Views: 1166

Turkey lashed out Tuesday at Armenian President Serzh Sarkisian for his decision to withdraw from parliament a landmark deal aimed at repairing relations between the two nations.

"We don't think this is the right approach by Armenia, it is an erroneous and baseless step," said Turkish foreign ministry spokesman Tanju Bilgic in Ankara, quoted by Turkish media.

Sarkisian said on Monday he was recalling the protocols both countries signed in 2009 from parliament due to the "absence of political will" on the Turkish side.

The deal was brokered under US, French and Russian supervision in Zurich but the accords have since languished without ratification in both nations' parliaments.

Sarkisian's decision appears to have for now buried the deal, which would have led to the opening up of the border between the two neighbours.

Relations between Turkey and Armenia remain blocked as Ankara refuses to cede to Yerevan's demands that it acknowledge the mass killing of Armenians by Ottoman forces in World War I was a genocide.

Sarkisian's decision to recall the accords comes at a particularly critical moment, as Armenians prepare to mark the 100th anniversary of the start of the massacres on April 24.

Armenians have angrily accused Turkey of trying to overshadow the ceremonies planned in Yerevan by advancing its advancing its commemorations of the 1915 Ottoman resistance against the Allied landing in Gallipoli to the same day.

Bilgic in turn accused Armenia of using the anniversary year as a pretext for renewing accusations against Turkey over the killings.

Yerevan says around 1.5 million Armenians were slaughtered in a deliberate campaign against them.

Turkey disputes that figure.

Short link:

© 2010 Ahram Online.


text:
Kiev 2005: more information for the delegations

by Sietse Bakker 63 views

Host broadcaster NTU revealed more information about their services for the press and the fans of the contest. Meanwhile, the hosts have been chosen and preparations for the official reception started. Things are speeding up in Kiev!

Though several national broadcasters already started with pre-accreditation, accreditation itself through NTU has not yet started. The current plan is to kick off with the accreditation procedure on 23rd of March. We advise journalists to contact their national public broadcaster to obtain accreditation. If you have already done so, there is nothing to worry about.

NTU's website
A Ukrainian and English website focussed on the 2005 Eurovision Song Contest will be launched on 21st of March by NTU. The website will be produced by NTU and exists next to the EBU's official Eurovision Song Contest website eurovision.tv.

Press facilities
The press centre will, like last year, most likely be a special tent within a 30-second walking distance of the Palats Sportu. “This tent will have all the facilities modern journalists need in it”, 2005 Eurovision Song Contest press officer Marko Markovic said.

The hosts
The hosts of the Eurovision Song Contest have been chosen! You will find out their names on 23rd of March!

Official reception
In a formal request to President Yushchenko, the organisation of the 2005 Eurovision Song Contest requested permission to use Marijins'kyj Palats and its territory for the official reception, scheduled on 16th of May. Marijins'kyj Palats is one of the most beautiful historical buildings in Kiev, dating from 18th century, and is being used by the Ukrainian government for the reception of foreign delegations and meetings on an international level. Last year's Eurovision Song Contest winner Ruslana Lyzhychko is supporting this idea and personally asked President Yushchenko about this issue.

ESCToday is growing and always looks for new members to join our team! Feel free to drop us a line if you're interested! Use the Contact Us page or send us an email at vacancies@esctoday.com!


text:
Skip to main content
Top Tips for Working From Home

Top Tips for Working From Home

Top Tips for Working From Home

To say it has been an adjustment might be a bit of an understatement but the brands of Covent Garden have come together to help you feel your best whilst working from home.

Atelier Cologne – Fragrance your Space

Atelier Cologne is known for creating vivid stories from all their scents and they want to help you make the most out of your scent whilst at home.

The first tip from the team is moisturise with the coordinating smell prior to applying your scent as it can help the fragrance last longer on your skin.

They also recommend every morning, light your favourite Atelier Cologne candle, the one that makes you the happiest, and let the smell of the beautiful natural oils fulfil your home.

Atelier Cologne

Molton Brown

Molton Brown - Stay Hydrated

We all know how important handwashing is but with everyone stepping up their washing game it is causing a lot of dry hands. Did you know moisturising is known to improve skin health and reduces the risk of irritating the skin?

The team at Molton Brown recommend taking the time once a day to give your hands some TLC. Using something like their recharging black pepper hand lotion, which the scent aims to invigorate whilst delivering a surge of moisture to the skin, take the time to work in the cream from the forearm down paying special attention to the backs of hands.

A great way to relax and treat the hands is beginning with the pinky finger, pinch the top of the finger for a moment then moving on to using short strokes with your thumb massage the finger towards the knuckle. Finally, gently squeeze the finger all over. Repeat the process with each finger, and finish with the thumb.

For Art’s Sake – Fight the Glare

With our screen time being higher than ever we need to protect our peepers and For Art’s Sake has the best tip for that.

This oh-so-cool brand doesn’t just do sun glasses, they also have an amazing range of For those who have their prescription at the ready, get your new lenses fitted with a blue light filter which will protect your eyes from all the screen.

Even if you don’t need a prescription lenses you can still get the blue filter and wear them as something stylish but sensible.

For Art’s Sake

Jo Malone London

Jo Malone London – Get Some Good Sleep

Getting a good night’s sleep is at the top of everyone’s to do list but sometimes it isn’t that easy. Thankfully, Jo Malone London has released a new limited-edition collection, offering a fresh perspective on an iconic ingredient: English lavender.

Included in the new collection are two limited-edition home products, both infused with the scent of Lavender & Musk. Making the journey to dreams that little bit easier, Jo Malone London’s limited-edition Pillow Mist is infused with aromatic English lavender which mingles with a cocooning note of musk to create a soft and sensual scent that helps you relax and unwind ready for a good night’s sleep.

VyTA – Cheers to you!

You might not be able to spend your Friday night drinks sitting on top of the Market Building people watching across the Piazza below but don’t let that stop you in indulging in one of VyTA’s signature drinks.

The wonderful team has shared their recipe for their signature La VyTA en Rose cocktail:

10ml of Lime Juice

20ml of Lemon Juice

20ml of Yuzu Liquore

20ml of Vodka

10ml of Gomme Syrup

10ml of Cointreau

30ml of Blood Orange Juice

All the ingredients need to be shaken, then poured in to coupette glass with a blood orange garnish – cheers!

Jigsaw – Fashionably Comfy

If there was ever a time to invest in cashmere, now would be the time. Jigsaw’s  is the perfect piece to wear around the house to feel stylishly comfortable. Jigsaw’s best tip for loungewear? Coordinate it.

Partner your lambswool blend with a brush of cashmere with coordinating coloured for that perfect pairing.

When changing from daytime loungewear to nightwear it is important each piece feels special, it is all about those little pleasures so invest in a two piece like this


text:
Ethics. Research. Community.

Review of transplantation in HIV patients during the HAART era.

Clinical transplants.
[Record Source: PubMed]
Human immunodeficiency virus (HIV) infection was once thought to be a relative or even absolute contraindication to transplantation. With the recent advent of highly active antiretroviral therapy (HAART), those infected with HIV are now living longer and dying from illnesses other than acquired immunodeficiency syndrome (AIDS). Although studies prior to the HAART era suggested poor outcomes might occur with transplantation in those infected with HIV, more recent studies have demonstrated results comparable to those of recipients without HIV infection. A number of issues persist regarding ethics, patient selection, post-operative management, and drug interactions between antiretroviral and immunosuppression agents. In this review, kidney, liver, and heart transplantation in the HIV-positive population were analyzed using data from the Organ Procurement and Transplantation Network/ Scientific Registry of Transplant Recipients.
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