Drug protein binding is the reversible interaction of drugs with proteins in plasma.Protein binding values (% fraction bound) are normally given as the percentage of the total plasma concentration of a drug that is bound to all plasma proteins.
Drug protein binding is the reversible interaction of drugs with proteins in plasma.
Protein binding values (% fraction bound) are normally given as the percentage of the total plasma concentration of a drug that is bound to all plasma proteins.
The total plasma concentration of the drug is expressed as the sum of the percent of free drug and the percent bound.
For A drug moiety there are several tissue components comprising of blood and extravascular tissues available in the body for biological interactions to take place. The molecules indulged in such biological or physiological interactions are said to be macromolecules as they are large in structures and quite complex depending upon the type involved. These macromolecules are proteins, DNA, adipose tissues etc. thus the protein binding process is defined as a phenomenon of complex formation following the interaction of drug moiety and the protein molecule.
The significance of protein binding of drugs is that - As a protein bound drug is neither metabolized nor excreted hence it is pharmacologically inactive due to its pharmacokinetic and Pharmacodynamic inertness. A bound drug always remains confined to a specific tissue or to a particular site with which it possess a greater affinity. The major benefit is the prolonged duration of action of drug as the protein bound-enormous size of drug complex cannot undergo membrane transport.
Usually weak chemical bonds such as ionic bonds, hydrophobic bonds, hydrogen bonds or Vander wall's forces are involved in protein binding of drugs and thus are defined as a reversible process. Covalent bond formation though being very rare may result into permanent or so called irreversible binding with a great potential of portending adverse effects like carcinogenicity, terratogenecity, tissue or organ toxicity etc. this has been widely observed in the therapeutic combination of chloroform and paracetamol whose metabolites gradually lead to hepatotoxicity.
Transient interactions between both proteins and nucleic acids are ubiquitous and fundamental tomany subcellular processes. In recent studies we have shown that protein binding are robust and owing tothe minimal frustration principle, just as for protein folding, are governed primarily by the protein'snative topology (1-3). The native topology based landscape model, which corresponds to a perfectlyfunneled energy landscape, reproduces many of the grosser and finer structural and kinetic aspects ofvarious binding mechanisms found in the laboratory (3). Not only are our computational resultsconsistent with experiments, they also demonstrate that protein plasticity, as envisioned by the fly-castingmechanism, is more fundamental in protein recognition than traditionally imagined. An asymmetricbinding mechanism is often observed for the formation of the symmetric homodimers where one monomer is more structured at the binding transition state; a fact not directly accessible to inference fromkinetic studies at the ensemble level. In addition, models of this class have suggested a new bindingmechanism of the HIV-1 PR and thus a new way of its inhibition (4). The protein topology wassuccessfully implemented to predictsymmetric complexes that are formed via domain-swapping (5).
In a recent study, native topology-based model supplemented by electrostatics was used to study protein-DNA binding. We have found that the heat capacity for folding is shifted to lower temperatures with decreasing the dielectric constant (Fig. 2). This is accompanied with broadening of the heat capacity plots. Accordingly, strong electrostatics destabilizes the protein as the attractive and repulsive forces pull the protein residues. This can result in changing the folding mechanism by stabilizing intermediates. Moreover, similar to protein-protein binding, flexibility was found to be fundamental in protein-DNA binding where protein flexibility acts in concert with electrostatic long-range forces to maximize efficiency of protein-DNA binding (8).
Figure 2. (A) The complex between Sap-1 protein and DNA (positively and negatively charged residues or phosphate atoms are shown by red and yellow beads, respectively). (B) The specific heat profiles for folding for different values of dielectric constants. (C). The effect of protein flexibility on the binding efficiency to DNA (Q equals 1 means a rigid protein).
(a) Physiochemical characteristics of the drug.
intramuscular. Injection of cloxacillin as attributed to greater lipophilicity displays 95% protein binding.
(b) Concentration of drug in the body.
Alteration in the concentration of drug substance as well as the protein molecules or surfaces subsequently brings alteration in the protein binding process.
(c) Drug's affinity towards protein/tissue.
This factor entirely depends upon the degree of attraction or affinity the protein molecule or tissues have towards drug moieties. For Digoxin has more affinity for cardiac muscles proteins as compared to that of proteins of skeletal muscles or those in the plasma like HSA.
(a) Concentration of protein/binding component.
In association to the concentration of proteins molecules available the number of binding sites available in the protein molecules is also significant. Albumin not only possesses large number of binding sites but also has greater potential of carrying out binding process. Numerous drug exhibit multiple site binding with albumin molecules in plasma like fluocloxacillin, ketoprofen, indomethacin etc .
Protein-protein interactions occur between two proteins that are similar in size. The interface between the two molecules tend to be flatter and smoother than those in protein-ligand interactions. Protein-protein interactions are usually more rigid; the interfaces of these interactions do not have the ability to alter their conformation in order to improve binding and ease movement. Conformational changes are limited by steric constraints and thus are said to be rigid.
Also known as the molecular docking technique, protein receptor -ligand docking is used to check the structure, position and orientation of a protein when it interacts with small molecules like ligands. Protein receptor-ligand motifs fit together tightly, and are often referred to as a lock and key mechanism. There is both high specificity and induced fit within these interfaces with specificity increasing with rigidity. Protein receptor-ligand can either have a rigid ligand and a flexible receptor, or a flexible ligand with a rigid receptor.
The native structure of the rigid ligand flexible receptor often maximizes the interface area between the molecules. They move within respect to one another in a perpendicular direction in respect to the interface. This allows for binding of a receptor with a larger than usual ligand. Normally when there is ligand overlap in the docking interface, energy penalties incur. If the van der Waals forces can be decreased, energy loss in the system will be minimized. This can be accomplished by allowing flexibility in the receptor. Flexible receptors allow for docking of a larger ligand than would be allowed for with a rigid receptor.
When the fit between the ligand and receptor does not need to be induced, the receptor can retain its rigidity while maintaining the free energy of the system. For successful docking, the parameters of the ligand need to be constant and the ligand must be slightly smaller in size than that of the receptor interface. No docking is completely rigid though; there is intrinsic movement which allows for small conformational adaptation for ligand binding. When the six degrees of freedom for protein movement are taken into consideration (three rotational, three translational), the amount of inherent flexibility allowed by the receptor is even greater. This further offsets any energy penalty between the receptor and ligand, allowing for easier, more energetically favorable binding between the two.
The search space consists of all possible conformations and configurations. With present computing resources, it would be impossible to exhaustively explore the search space for all possible poses (a pose is the name given to the configuration of the conformation of a molecule in a coordinate system). Needless to say, every docking simulation is a trade-off between accuracy and speed and a good docking tool is expected to maintain a reasonably good balance between the two. See also Protein-Protein Interaction Network Visualization and Prediction Methods for Interactions and Docking.
(a) Competitive binding of drugs.
Displacement interactions are predominant ones among these reactions. In case where two or more drugs have same or identical affinity for a same site then they struggle with one another to bind at the same site. Consider a drug I is bound to a specific site on the molecule and if a second drug called as Drug II is administered now, then the drug meaty having greater affinity towards the bound site would effectively displace th e former drug. This phenomenon is said to be Displacement reaction. The drug which is been removed from its binding site is said to be displaced drug while the one that does the displacement is called as displacer.
The best example for such interactions is the competitive protein binding that occurs between Warfarin and phenylbutazone for HSA, as both are potent binders of HAS, where phenylbutazone is displacer while warfarin is displaced. Clinically such reaction acquire importance when the displaced drug (any) is more than 95% bound to plasma proteins, or occupies small volume of distribution even less than that of 0.15 L/Kg. also when the active drug or the administered pharmacological agent possess narrow therapeutic index. Such situation may also develop in case the displacer drug has greater affinity or at the same time the drug/protein concentration ratio is very high and exhibits a very rapid and significant increase in the plasma concentration of drug.
Patients related factors have their own importance after all the drug has to generate its response on to the administered patient. In this numerous parameters are taken into account like Age, diseased state, pharmacokinetic and Pharmacodynamic characteristics. Protein content and its specific type greatly varies with the age factor. As observed the neonates or newly born babies have very low levels of albumins in the plasma thereby resulting in rebound concentration of drug that is primarily bind to albumin is a major shortcoming. As far as elderly patients are concerned the albumin levels goes down while the concentration of AAG is high enough.
Disease states: the alterations in protein content and thereby the rate and extend of protein binding is greatly influenced by the albumin which is the major drug binding protein. This may ultimately lead to hypoalbuminemia which eventually with the pace of time completely impairs the entire protein drug binding process. For such situations the basic pathological conditions of diseases like trauma, burns, renal, cardiac or hepatic failure etc are largely responsible. Pharmacokinetics as well as Pharmacodynamic of drugs greatly influences the distribution, clearance and thus the biotransformation of drugs to a greater extend. an increased potential of toxicity is observed due to increased concentration of free or the unbound drug.
(B) Binding to extravascular tissues like proteins, fats, bones etc.
There are several blood components for a drug to be exposed to and undergo protein binding process.
Since albumin is basic, acidic and neutral drugs will primarily bind to albumin. If albumin becomes saturated, then these drugs will bind to lipoprotein. Basic drugs will bind to the acidic alpha-1 acid glycoprotein levels of albumin, alpha-1 acid glycoprotein, and lipoprotein.
(a) Binding of drugs to human serum albumins.
The human serum albumin also abbreviated as HSA is a plasma protein with a molecular weight of 650000 and comprises of 59% of total plasma protein content present in the blood. It is most abundantly present in plasma with a very high potential of binding drugs. It has been widely observed that there is no equilibrium between the concentration of drug and that of HSA, as the administered dose is usually smaller as compared to that of plasma proteins present. Almost all types of drugs whether acidic, basic or neutral drugs undergo significant HSA binding.
Experimental studies have postulated that any drug can bind to numerous protein binding site .In such circumstances the primary site is the major binding site and the other as the secondary site; for example, for dicoumarol site I is the primary site while site II is secondary. Those drugs having affinity for the same binding sites compete with one another. But the non-competitively binding drugs either promote or inhibit binding of a drug to another site. This is usually accomplished by mechanism of coupling. There are four different sites for the drugs to bind.
the structures of free drug moiety and their affinity towards the protein molecule.
Site I:To this specific site a large population of drugs bind like Non-Steroidal Anti-Inflammatory Drugs mainly phenylbutazone, indomethacin, many sulfonamides e.g.; sulfamethoxine, sulfamethizole, and even many anti-epileptic drugs like phenytoin etc. this site is also called as Warfarin binding site or as Azapropazone binding site.
so because due to structural changes the following drugs have high and specific affinity for the site. At both the sites I&II many drugs are known to bind.
Site IV:This is referred as Tamoxifen binding site.
At the sites III & IV very few drugs are known to bind.
Protein stability and flexibility are dependent on electrostatic interactions such as hydrogen bonding and van der Waals forces. The energy of the interaction is not evenly distributed between the two proteins at the interface. Rigidity in the interface ensures that the entropy loss is offset and the binding free energy is contributed to in a favorable way by the amino acid residues contained in the interface. Contributions of hot spots to the stability of the protein-protein complex within a hot region is cooperative, however the contributions of independent hot regions are additive.
Hydration is very important for the three dimensional structure and activity of proteins. Surface water molecules are held most strongly by the positively charged basic amino acids. Hydrogen bonding adds conformational flexibility, while the level of hydration determines the degree of flexibility in the internal molecular motions. Water molecules in close proximity to peptide hydrogen bonds cause separation in the bonds and a release of tension in the structure. The presence of water molecules also prevents swift conformational fluctuations from occurring. Water interacts with protein surfaces; the breaking of hydrogen bonds between the water molecules and the amino acids has an unfavorable enthalpic result on the system, effecting the overall energy of the protein. Water molecules act as an adhesive, sealing holes in complementary surfaces that would normally lack shape. Hydrogen bonding drastically reinforces other bonding present in the interface between proteins. This type of bonding occurs when an hydrogen atom proximal to a docking facade interacts across the interface with atoms of another molecule. Hydrogen bonding can occur between side chains, backbone groups, and between the two.
Hydrophobic surfaces located at ligand receptor interfaces have greater ambiguity with bonding. Hydrogen bonding between the peptide atoms decreases the hydrophobicity of the backbone. Coincidentally, hydrophobic surfaces can be sealed with an ordered shell of water molecules, creating an entropically favorable state when water molecules are ejected. Water removal increases the thermodynamic benefit in hydrophobic patches. These patches are uncommon though; the patches found in proteins are more often hydrophilic. The secondary structure of the protein is a result of hydrogen bonding since the residues arrange themselves in such a way so that hydrophobicity of the backbone is reduced. α-helices and β-sheet conformations are the way in which is accomplished.
The hydrogen bonds in the backbone of a protein usually exist in the form of dehydron bonds, which form between two hydrogen atoms bonded that differ in polarity bonds. The proton acceptor in this case is a metal hydride with the donor being OH or NH. Dehydrons attract hydrophobes, their bonding increases the electrostaticity of hydrogen bonds by increases the surrounding dielectric coeffiecient. The dehydron bonds thus create a hydrophobic shell around the backbone increasing the electorstatic interaction; this desolvated environment is condusive for salt bridge formation increasing structural stability.
Salt bridges, also referred to as ionic bonds, are a form of chemical bonding that occur between amino acids of opposite charge. They contribute greatly to the stability of the protein and are usually found in the interior of the protein structure. This stability is dependant on the location of the side chains, and the electrostatic contribution. Hydrophobic environment is conducive to salt bridges. Charged residues within four angstroms to each other have the ability to form salt bridges.
A/(r6) - B/(r12) where r is the distance between A and B.
A protein pocket is a concave surface region containing the active sites of the protein. These areas are solvent accessible, and are characterized as either unfilled or complemented, the partner conformation not being taken under consideration. Compositional difference between complemented pockets and other surface pockets may be useful for predicting complemented pockets from the unbound states. The floor of complemented pockets are often filled with residues that are ionizable and/or polar. In a hydrophobic environment, these residues provide molecules for salt bridge formation and hydrogen bonding which are essential for binding stability. Pockets are crucial for binding site flexibility for large interfaces reduce binding stability, and allow for ligand movement.
Cation-π pairs are frequently present in the interface of proteins, probably due to their low energy conformation. They play an important role in specificity, causing a need for conformational changes to provide the correct orientation for binding. Cation-π interactions are found most frequently in homodimers. The abundance of this form of bonding is tied to the occurrence of specific amino acids. In homodimers, arginine bound to phenylalanine forms the most frequent cation-π bonds, while in the other protein complexes arginine-tyrosine and arginine-tryptophan cation-π bonding is a more likely occurrence.
A hot spot is an area of high energy and binding around an amino acid residue. Surrounded by hydrophobic pockets, hot spots are found in clusters, rather than scattered throughout the interface. This clustering assists with the elimination of water molecules, and increases the bond strength and available bond energy through increases charge-charge relations. Hot spots usually do not include hydrogen bonding, electrostatic interactions, although there is a slight preference of non-polar residues. Packing around hot spots is significantly tighter that the other residues found in the interface. Since hot spots contribute significantly to binding, the association of neighboring residue size, charge, and interaction must be taken under consideration when considering binding affinity and docking. It has been established that a linear relationship between the number of hot spots and the interface size exists; the larger the interface the higher the number of hot spots present.
Much like DNA microarrays, and gene chips, protein chips have revolutionized the method and speed with which scientists can discover differences in gene expression levels, protein chips are a relatively new addition to proteomics that brings high-throughput efficiency to discovering protein-protein interactions. Earlier protein chips emulated existing proteomic techniques by requiring labeling of proteins, a requirement that resulted in only revealing certain proteins or classes of proteins. Recent developments have put forth label-free techniques that couple the original protein chip idea with MALDI-TOF mass spectrometry, and other forms of mass spectrometry, to produce a protein chip technology that does not require proteins to be labeled, consequently widening the range of protein-protein interactions detected with each chip. While protein chip technology does not directly contribute to binding site characterization, it is a useful method for gaining insight into how proteins and classes of proteins function through their interactions with many other proteins. See chapter on protein chips more more information.
b) Drugs Binding to α1-Acid Glycoprotein.
The acid glycoprotein exists with a 44,000 molecular weight and comprises of 0.04 to 0.1 g% of the total plasma concentration of proteins. It is actually called as the Oromucoid as it mainly binds to basic drugs like Imipramine, Desipramine, lidocaine, Quinidine, etc.
Lipoproteins are those macromolecules present in plasma which portends a greater capacity of forming hydrophobic bonds. The major reason attributed to this is the larger lipid content present in them. But the plasma concentration of lipoproteins is very limited as compared to that of HSA and AAG.
The lipid core of Lipoproteins has their outer core to be made of apoproteins while the internal core is a potpourri containing triglycerides and esters of cholesterol.
The acidic drugs like diclofenac bind extensively to lipoproteins. Similar response are generated by basic drugs like chlorpromazine and neutral drugs like cyclosporine A.
3. High Density Lipoproteins (HDL).
(i) α1-globulins : This is called as CBG elaborated as corticosteroid binding globulin as it largely binds to steroidal drugs such as cortisone, hydrocortisone, prednisone etc. Thyroxin and Cyanocobalamin are also effectively bound to above proteins.
known as Transferring binding site.
(iv) β2-globulins: Carotinoids binding is mainly observed.
(a) Hemoglobin: this has molecular weight & structural similarity to that of HAS but the concentration is much higher than of albumins in blood. Examples of drugs that bind are phenytoin, pentobarbital etc.
(b) Carbonic Anhydrase: Carbonic anhydrase inhibitors mainly bind to the site like chlorthaizine.
(c) Red Blood cell membrane: basic drugs like imipramine are known to bind to RBC membrane.Both the hydrophilic and lipophilic drugs can enter RBCs but the lipophilic drugs can do to a greater extend.
The tissue binding of drugs are also very significant processes occurring in the body. Unlike HSA, the body tissues constitute100 times that of HAS i.e; about 40% of the total body weight . Multiple tissue drug binding are feasible. Tissue drug binding is very essential and vital process as it assists in enhancing the apparent volume of distribution for drugs as this follows a direct relation with the ratio of concentration of drug in body to-free or unbound drug in plasma.
Liver> Kidney> Lung> Muscle.lets have an overview of some tissue drug binding.
1. Liver: Irreversible binding of drugs like paracetamol and their epoxide-metabolites to liver tissues results in hepatotoxicity.
2. Lungs: like imipramine, chlorpromazine and antihistamines accumulation of drugs like imipramine, desipramine or other drugs in lungs eventually leads to congestion in heart or may even produce severe lungs cancer.
3. Kidneys: the protein called as metallothion is widely present in kidneys which have a tendency to undergo complexation with heavy metals such as lead, mercury and cadmium. This gradually paves path for the major renal failures or renal toxicity.
4. Skin: Many drugs are known to accumulate in skin with subsequent reaction with melanin which can ultimately result in skin diseases. Drugs such as chloroquine , phenothiazines are usually involved in this.
5. Eyes: the retinal pigments of the eye also contain melanin. Drugs like chlorquine are responsible for retinopathy as these drugs they interact with the melanin present in the retinal pigments.
6. Bones: bones are made up of calcium and most of the antibiotics mainly like tetracycline exhibits extensive binding to bones and teeth. The permanent brown-yellow discoloration of teeth is an adverse effect of administration of such antibiotics to newly born babies or infants. Similarly lead also generates similar responses with teeth and bones.
A ligand is a small molecule that is able to bind to proteins by weak interactions such as ionic bonds, hydrogen bonds, Van der Waal, and hydrophobic effects. In some cases, a ligand also serves as a signal triggering molecule.
For example, oxygen is the ligand that binds to both hemoglobin and myoglobin.
Binding site: a region of the protein that is complementary to a specific molecule or ion. This site usually exhibits specificity to ligands. The weak interactions of the primary structure of protein, specifically the side chains to the ligand, usually initiates a response. The concentration at which all binding sites are bound to a ligand is termed the point of saturation.
Induced fit is the concept that an enzyme is a flexible rather than a rigid entity. Interactions between the active site and substrate continually reshape the tertiary structure slightly. Instead of the substrate simply binding to the active site, the enzyme and substrate mold to induce a fit similar to that of a lock and key. This allows the substrate to be in the precise position to enable a catalytic response.
Dissociation constant: Kd is the tendency for a ligand to bind to a binding site. It is measured by the ratio of concentrations of the ligand and enzyme over the concentration of the Enzyme-ligand complex. It is equal to the concentration of the ligand at which the total binding sites are half occupied. Association constant is equal to the reciprocal of the dissociation constant.
A molecule, atom, or ion that is charged or neutral and of non-bonding pairs of electrons as electron donors or Lewis bases that form bond to a central metal atom or ion to be as complex ion; it is important for control of chemical reactivity of the complex of ligands and metal; monofunctional ligands are complex ions that have one non-bonding pair of electrons, polyfunctional or known as chelates, two or more. Biological ligands are mostly electron-donating groups; important one of biological system is heme that is of nitrogen donating groups and forms chelate structure.
When a ligand binds to the protein, the chemical conformation of the protein changes. The tertiary structure of the protein is altered. The conformation of the protein determines the function of the protein, as structure often denotes a lot about the function. The tendency in which the ligand binds to the protein is known as the term affinity.
The binding affinity depends on the interaction of the binding site with the ligand. When the interaction of the intermolecular forces between the ligand and binding site are high, the affinity is increased. Similarly, when the intermolecular forces between the ligand and binding site are weak, the affinity is low.
When the affinity is high for the ligand binding, the concentration of the ligand does not need to be high in order for the ligand to bind to its maximum potential. Similarly, when the affinity is low, the concentration of the ligand must be large in order for the ligand to bind properly to the binding site.
A ligand is a substance that has the ability to bind to and form complexes with other biomolecules in order to perform biological processes. Essentially, it is a molecule that triggers signals and binds to the active site of a protein through intermolecular forces (ionic bonds, hydrogen bonds, Van der Waals forces). The docking (association) is usually a reversible reaction (dissociation). Within biological systems, it is rare to find irreversible covalent bonds between the ligand and its target molecule. The chemical conformation is changed when the ligand bonds to its receptors. For example, the three dimensional shape of the receptor protein is change upon the binding of the ligand. Also, the conformational state of a receptor protein will cause variations in the functional state of a receptor. The strength/tendency of the ligand binding is known as affinity. Different types of ligands include substrates, inhibitors, activators, and neurotransmitters.
Binding affinity is the interaction of ligands with their binding sites. A higher affinity ligand binding is usually the result of greater intermolecular force between the ligand and its receptor and involves a longer residence time for the ligand at its receptor binding site. A lower affinity ligand binding, though, involves less intermolecular force between the ligand and its receptor and involves a shorter residence time for the ligand at its receptor binding site. High affinity is essential to the physiology of humans when the binding energy can be used to cause a conformational change in the receptor, which results in altered behavior of an associated ion channel or enzyme. An agonist for any receptor is a ligand that can alter the function of the receptor and cause a physiological response. Agonist binding to a receptor is characterized by how much physiological response can be caused as well as its concentration required to produce the physiological response. High affinity ligand binding means that a relatively low concentration of a ligand will be needed to maximally occupy a ligand binding site and cause a physiological response. Low affinity ligand binding means that a relatively high concentration of a ligand is needed prior to maximizing the occupancy of the binding site and the maximum physiological response to the ligand is achieved. An agonist that is able to partially activate the physiological response is called a "partial agonist." Ligands that bind to a receptor, but do not activate the physiological response, are receptor "antagonists." Ligand binding is usually characterized by the concentration of ligand at which half of the receptor binding sites are occupied, known as the dissociation constant (kd). Binding affinity is usually determined through the use of a radiolabeled ligand called a "hot ligand." Homologous competitive binding experiments use the binding-site competition between a hot and cold ligand.
Targeted drug delivery is the major research area in this era of medical and life sciences. The binding of drugs to lipid containing proteins called as lipoproteins is effectively utilized for controlled and site-specific drug delivery. For this the hydrophilic drug moieties are of great priority. The major application of delivering the drug at a predetermined rate is highly beneficial in treatment and appreciable management of cancer therapies.
The best requirement of site-specific drug delivery is revealed in cancer treatment with that of estramustine. Thus binding of suitable antineoplastic agents like vincristine or vinblastine with the LDL is desirable to prevent the normal cells from damage caused by the administered drug.
The protein drug binding also portends an advantage of efficient drug distribution, absorption and finally prolonged duration of action for longer treatment of chronic diseased conditions.
The absorption equllibrium is attained by transfer of free drug from the site of administration e systemic circulation and when the concentration in these two compartment becomes equal.following equilibrium the process may stop.however binding of the absorbed drug to plasma protein decreases free drug concentration and disturbs such an equilibrium.thus sink condition and the concentration gradiant are reestablished which now act as the driving force for further absorption.thise is particularly useful in case of ionized drugs which are transported with difficulty.
Water insoluble drugs,neutral endogeneous macromolecules such as heparin and several steroids and oil soluble vitamins are circulated and distributed to tissue by binding especially to lipoprotens which act as a vehical for such hydrophobic compound.
Plasma protein binding restricts the entry of drugs that have specific affinity for certain tissues.Thise prevents accumulation of a large fraction of drug in such tissues and thus,subsequent toxic reactions.Plasma protein drug binding thus favors uniform distribution of drug throughout the body by its buffer function.maintains equilibrium between the free and the bound drug.a protein bound drug in particular does not cross the BBB the placental barrier and the glomerulus.
The value of association constant Ka and the number of binding sites N can be obtained by plotting equation (7) in three different ways as shown below.
The pharmacokinetic and pharmacodynamic properties of drugs are largely a function of the reversible binding of drugs to plasma or serum proteins. Such proteins include albumin, α1-acid glycoprotein, lipoproteins and α, ß' and γ globulins. Generally, only the unbound drug is available for diffusion or transport across cell membranes, and for interaction with a pharmacological target (e.g. receptor, ion channel, transporter, enzyme). As a result, the extent of plasma protein binding of a drug influences the drug's action as well as its distribution and elimination. Highly plasma protein bound drugs are confined to the vascular space, thereby having a relatively low volume of distribution. In contrast, drugs that remain largely unbound in plasma are generally available for distribution to other organs and tissues, resulting in large volumes of distribution. The binding of drugs to proteins both in the vascular space and/or the extravascular space results in a decrease in drug clearance and a prolonged drug half-life. Only the unbound drug is available for glomerular filtration and, in some cases, hepatic clearance. However, for high extraction ratio drugs, clearance is relatively independent of protein binding.
system can be used to determine the fraction of a compound bound and unbound to plasma proteins and the effect of concentration on the extent of binding.
• estimation of dose level for in vivo studies.
The assay is performed in a 96-well Teflon dialysis unit. Each well consists of 2 chambers separated by a vertically aligned dialysis membrane of predetermined pore size. Plasma spiked with the compound of interest is added to 1 chamber and buffer to the other chamber. Over time, free compound diffuses from the plasma chamber to the buffer chamber until an equilibrium is reached. The unbound fraction is calculated as the concentration in the buffer side divided by the total concentration in the plasma side.
1) Brahamnkar.D.M, Jaiswal.B.Sunil In "Textbook of Biopharmaceutics and Pharmacokinetics", Edition –I, Vallabh Prakshan, Delhi, 110088, 16-51.
2) Abdou, H.M: Dissolution, Bioavailability and Bioequivalence, Pennsylvania, Mack Publishing Company, 1989.
3) Banakar, U.V: Pharmaceutical Dissolution testing, New York, Marcel Dekker, Inc., 1992.
4) Blanchard, J., Sawchuck, R.J. and Brodie, B.B.: Principles and Perspectives in Drug Bioavailability, New York, S.Karger, 1979.
5) Bourne, D.W.A. and Dittert, LW.: Pharmacokinetics. In: Modern Pharmaceutics, 2nd edition (Banker, G.G and Rhodes, C.T., eds.), NEW York, Marcel Dekker, Inc., 1990.
6) Chasseand, L.F. and Hawkins, D.R.: Biotransformation of the Drugs. In: Encyclopedia of Pharmaceutical Technology, vol. 2(Swarbick, J. and Boylan, JC.,eds.), New York, Marcel Dekker, Inc., 1990.
7) Chein, YW.: Novel Drug Delivery Systems, 2nd edition, New York, Marcel Dekker, Inc., 1992.
8) Florence, AT. And Attwood, D.: Physiochemical Principles of Pharmacy, London, Macmillan, 1981.
9) Ford, J.L.: Dissolution and Dissolution Testing In: Encyclopedia of Pharmaceutical Technology, vol .4 (Swarbick, J. and Boylan, JC.,eds.), New York, Marcel Dekker, Inc., 1991.
10) Gibaldi, M. and Perrier, D: Pharmacokinetics, 2nd edition, New York, Marcel Dekker, Inc., 1982.
11) Gibson, C.G. And Skett, P.: Introduction to Drug Metabolism, London, Chapman and Hall, 1986.
12) Gibaldi, M.: Biopharmaceutic and Clinical Pharmacokinetics, 4th edition, Philadelphia, Lea and Febiger, 1991.
13) Griffin, J.P., D'Arcy, P.F. and Spiers, C.J.: A Manual of Drug Interactions, 4th edition, Bombay, K.M.Varghese Company, 1988.
14) Hoener, B.A.Benet, L.Z.: Factors Influencing Drug Absorption and Drug Availability. In: Modern Pharmaceutics, 2nd edition (Banker, G.G and Rhodes, C.T., eds.), New York, Marcel Dekker, Inc., 1990.
15) Jolles, J. and Woolridge, K.R.H.: Drug Design- Fact Fantasy?, London, Academic Press, 1984.
16) Kydoneus, A.: Treatise on Controlled Drug Delivery, New York, Marcel Dekker, Inc., 1992.
17) La Du B.N., Mandel, H.G. and Way, E.L.: Fundamentals of Drug Metabolism and Drug Disposition, Baltimore, Williams and Wilkins, 1971.
18) Loper, A.E. and Gardener, C.R.: Gastrointestinal Absorption of Drugs. In: Encyclopedia of Pharmaceutical Technology, vol. 6 (Swarbick, J. and Boylan, JC.,eds.), New York, Marcel Dekker, Inc., 1992.
19) Low, L.K. and Castagnoli, N.Jr.: Metabolic Changes of Drugs and Related Organic Compounds. In: Wilson and Griswold's Textbook of Organic, Medicinal Pharmaceutical Chemistry, 9th edition (Delado, J.N. and Remers, W.A.., eds), Philadelphia, J.B. Lippincott Company, 1991.
20) Meyer, M.C.: Bioavailability of Drugs and Bioequivalence. In : Encyclopedia of Pharmaceutical Technology, vol. 1(Swarbick, J. and Boylan, JC.,eds.), New York, Marcel Dekker, Inc., 1988.
21) Niazi, S.: Textbook of Biopharmaceutic and Clinical Pharmacokinetics, New York, Appleton Century Crofts, 1979.
22) Notari, R.E.: Biopharmaceutic and Clinical Pharmacokinetics: An Introduction, 4th edition, New York, Marcel Dekker, Inc., 1987.
23) Reindenburg, M.M. and Erill, S.: Drug-Protein Binding, New York, Praeger, 1986.
24) Ritschel, W.A.: Handbook of Clinical Pharmacokinetics, 3rd edition, Illinois, Drug Intelligence Publications, Inc., 1986.
25) Robinson, J.R. and Lee, V.H.: Controlled Drug Delivery: Fundamentals and Applications, 2nd edition, New York, Marcel Dekker, Inc., 1987.
26) Rowland, M. and Tozer, T.N.: Clinical Pharmacokinetics: Concepts and Applications, 2nd edition, Philadelphia, Lea and Febiger, 1989.
27) Sloan, K.B.: Prodrugs: Topical and Ocular Drug Delivery, New York, Marcel Dekker, Inc., 1992.
28) Sharjel, L.Yu, A.B.C.: Applied Biopharmaceutics and Pharmacokinetics, 2nd edition, Connecticut, Appleton Century Croffts, 1985.
29) Mc Elany, J.C.: Buccal Absorption of Drugs. In: Encyclopedia of Pharmaceutical Technology, vol. 2(Swarbick, J. and Boylan, JC.,eds.), New York, Marcel Dekker, Inc., 1990.
Reindenburg, M. and Erill, S. (1986). Drug-protein binding, new york, praeger.


Home / Deals / Just Play Peanuts Ice-Skating Rink | 50% Cartwheel Today ONLY at Target!
Just Play Peanuts Ice-Skating Rink | 50% Cartwheel Today ONLY at Target!
Now through 12/24 Target is offering a 50% Cartwheel on a specific toy everyday! Today's HOT Cartwheel deal is 50% off Just Play Peanuts Ice-Skating Rink! Regularly $17.99 you can pick it up today for ONLY $8.99 when you use your 50% off Cartwheel! This offer is only available in store, today only and one per person!
Kohls Early Birds Sale ends at 3pm CST + 25% Off Coupon!


text:
WARRIORS SIGN PRO-BOWLER HALOTI NGATA – (April Fools)
Former Highland HS Rugby All-American signs with Major League Rugby's Utah Warriors just two weeks after announcing his retirement from the NFL
(Salt Lake City, Utah) – Haloti Ngata, the 5-time NFL Pro-Bowler and Super Bowl champion with the Baltimore Ravens, announced this morning that he has signed an Associate Player Contract with Major League Rugby and will start immediately with the Utah Warriors. Ngata, who played high school rugby at Salt Lake City's Highland High School, had just announced his retirement from the NFL on March 18th on top Mt. Kilimanjaro with a banner which read, 'I'm retiring on top'. He matched that by hiking Utah's Ensign Peak this weekend with a banner that reads, 'I'm Going Back To Rugby', making the statement that this is the place, rugby is the place that molded him to be the football player he is known to be.
Ngata, 35, was selected in the first round of the 2006 NFL draft and played defensive tackle for the Baltimore Ravens, where he earned his Super Bowl ring in 2013. Ngata also played with the Detroit Lions, and most recently with the Philadelphia Eagles. In college, Ngata was a consensus All-American at the University or Oregon but his athletic dominance was first evident on the rugby pitch.
"Rugby was always my first love, it taught me how to be a better football player which proved out in my college and pro career. I am honored to sign with the Warriors and hope to make an impact this Friday night versus Seattle" said Ngata.
Haloti Discusses Importance of Rugby
"I wanted to move my family back to Utah but do not want to stop competing and want to bring another rugby championship home to Utah. The Warriors have done an amazing job in bringing professional rugby to Utah and the Warriors fan base is loud and loyal" Ngata continued. "Whether its the Washington Huskies, the Seattle Seahawks, or now the Seattle Seawolves, I've never been fond of teams from Seattle."
As a rugby player for Highland High School, Ngata played the eightman position and weighing in at over 250 pounds at the time, helped lead Highland to a National Championship. His explosive running and hitting on the rugby pitch carried over into his college and professional football career. Haloti Discusses Importance of Rugby "We are excited to have Haloti join the team, he will be a huge asset to our forwards and eightman position and his professional experience will be an added gift on the field and in the locker room with the team. We will make sure he is in rugby shape for the rest of the season," said Warriors Head Coach Alf Daniels.
Warriors Forwards Coach, Stevie Scott responded to the signing of Ngata, "Being from Scotland, I don't know a thing about American Football or the NFL but if he is ready to play rugby again, and can help us scrum our way to victory, and does what I say then I am happy to have him on our pitch. I understand he's about 18 stones, that should be plenty to scare the other teams not to mention his athletic prowess."
It is anticipated that Ngata will start this Friday night as the Warriors take on the defending Major League Rugby Champions the Seattle Seawolves starting at 7:00pm MST at Zions Bank Stadium in Herriman, Utah.
For more information about Ngata's signing, the Haloti Ngata Family Foundation or about receiving '2 for 1' priced tickets to this Friday's game for reading this all the way through, call the Utah Warriors Front Office at 801-935-4045.

redpajama_set_name: RedPajamaCommonCrawl


Not sure if this fits better under social or tech. It's sure about my perceived science.
By re-reading that post, I thought it would fit better here in buffer given its size. But, instead of moving it I decided to just clarify it and link here, with a more descriptive title.


text:
Category 4 Kyarr is the strongest cyclone over the Arabian Sea in 12 years
It has also helped make 2019 the most active North Indian cyclone season on record.
Extremely severe cyclonic storm Kyarr is a Category 4-equivalent cyclone churning through the Arabian Sea. (NASA)
By Matthew Cappucci
Matthew Cappucci
Meteorologist, Capital Weather Gang
On the brink of Category 5 status, Cyclone Kyarr is a monster. The Indian Ocean beast — dubbed a top-tier "super cyclonic storm" by the India Meteorological Department — is the first storm of such intensity to rage in the Arabian Sea in 12 years.
While Kyarr will remain largely out to sea, it's "very likely to maintain" intensity through Monday night before beginning to curve west-southwest. It has also helped propel 2019 into the top spot for most active North Indian cyclone season on record.
The storm now
A multi-day satellite loop shows the rapid organization and intensification of Kyarr. (NASA)
Now, Kyarr has maximum one-minute sustained winds of 150 mph, with gusts approaching 185 mph in the storm's eyewall, the zone of most extreme winds. That puts it 7 mph below the threshold of equivalent Category 5 status.
Satellite imagery captured its stunning symmetry Monday morning, Kyarr exhibiting its well-structured banding and translucent, mistily veiled eye. Crystal-clear skies can be seen to the northwest of the storm, where sinking outflow air suppresses any cloud growth. Outflow channels are also visible in the banded, wispy tendrils of cloud protruding like fingers out of the storm's southern tier.
It will probably begin weakening within the next 24 hours beginning Tuesday morning, expending its massive energy as it ticks down to tropical storm or Category 1 strength over the weekend.
Where it's going
The Joint Typhoon Warning Center calls for Kyarr to meander westward while slowly weakening as it approaches the Gulf of Aden. (JTWC)
Forecast agencies began tracking the incipient cyclone as early as Oct. 20, when a weak area of low pressure began to materialize over the southeast Arabian Sea. On Oct. 2, it organized into a tropical storm; between Oct. 25 and 26, Kyarr lurched in strength, rapidly intensifying into a Category 3-equivalent storm. Studies have documented an increase in these rapid intensification events likely tied to climate change.
On the forecast track, Kyarr's destructive wind field will evade land for the time being, though waves over the open ocean could top 50 or 60 feet.
The system will pass north of Yemen-owned Socotra before meandering into the Gulf of Aden. Its then rapidly decaying remnants will thread the needle between Somalia and Yemen but could throw a bit of moisture to the ordinarily water-starved landscape to the north.
If any rain does occur there from this oddly tracking cyclone, it would be highly unusual: Bosaso, Somalia, and Al Mukalla, Yemen, average less than 1 and 2 inches of rain annually per year, respectively.
Coastal Oman could also see a few showers. Otherwise, Kyarr by then should have lost most of its strength, its circulation largely dissipating as it churns westward. Wind is not expected to be a threat on land.
The significance
It has been a landmark year for hurricanes in the North Indian Ocean. In fact, it has been the Indian Ocean's most energetic cyclone season on record, with reliable, satellite-based bookkeeping dating back to 1972.
Thus far, 2019 Accumulated Cyclone Energy, or "ACE," has hit 53.9 units. ACE is a measure of how much kinetic energy a cyclone is dishing out through its winds. Consider that the average year-to-date ACE for the North Indian Ocean is no more than 10 units. 2019 has exceeded that benchmark by a landslide; the previous seasonal record was 46.1 ACE units in 2007.
Large inter-annual variability is expected from year to year, with a "normal" season very abnormal. Kyarr is the North Indian Ocean's seventh named storm this season, marking the first time more than half a dozen had spun up in a single season since 1998.
2019 could also claim one more top spot: the most "major hurricane days" in a given season.
Though hurricanes are called "cyclones" in the Indian Ocean (and "typhoons" in the North Pacific), a figure called "major hurricane days" tracks the number of days for which one major hurricane-equivalent cyclone roams the North Indian Ocean each season. If two major hurricanes do so simultaneously, each day they both exist would go down as two major hurricane days.
The record — 5.25 days, achieved in 2007 and 1999 — may come close to falling. As of Monday morning Eastern time, the 2019 tally was up to 4.5 major hurricane days, 18 hours short of the record, with Kyarr forecast to remain at major hurricane status through at least Tuesday morning.
Kyarr also set the record for the lowest barometric pressure ever observed in the Arabian Sea. Its 915 millibar sea-level air pressure is what you would expect in a "typical" atmosphere if you climbed more than a half mile high. That "deficit" of air draws air inward like a vacuum, fueling the system's strong spiral winds.
Super Cyclonic Storm #Kyarr has the lowest pressure on record in the Arabian Sea, with a central pressure of just 915hPa.
Estimated winds are joint strongest on record, alongside Cyclone #Gonu pic.twitter.com/JPBwQ77yh7
— Met Office (@metoffice) October 27, 2019
The Indian Ocean Dipole
The banner year for Indian Ocean storms may have gotten a little help from the Indian Ocean Dipole (IOD), a large overturning circulation in the tropical atmosphere over the Indian Ocean.
When the feature is in its positive phase, anomalously warm water pools in the Arabian Sea and west North Indian Ocean, which may help fuel more intense storms. Cooler sea surface temperatures exist farther east, over Australia and the Maritime Continent. This fosters broad rising motion to the west, with subsidence — or sinking — to the east. That rising motion enhances convection, shower and thunderstorm activity, with the relatively weak upper-level winds allowing that convective activity to more easily aggregate into a tropical disturbance.
Recently, the Indian Ocean Dipole's positive amplitude has been at near-record strength. Western waters have been baking, helping spur an active monsoon season across India, as well. Meanwhile, the scales have tipped farther east in Australia, where scant rainfall heralds prolonged drought that has been parching the continent.
The Australian Bureau of Meteorology expects the Dipole strength to grow even more before breaking some in the next one to two months.
The Indian Ocean Dipole (temperature gradient across the tropical indian ocean) that is causing half of our drought) is nearing record territory: https://t.co/lB8jHzKCW4 pic.twitter.com/U5TH3d6Nch
— Tamworth Weather (@2340weather) October 23, 2019
Meanwhile, another tropical wave south of Sri Lanka may develop into a tropical cyclone by Saturday.
Matthew Cappucci Matthew Cappucci is a meteorologist for Capital Weather Gang. He earned a B.A. in atmospheric sciences from Harvard University in 2019, and has contributed to The Washington Post since he was 18. He is an avid storm chaser and adventurer, and covers all types of weather, climate science, and astronomy. Follow
Washington, D.C., Snow Tracker
Current snow:
Average season-to-date snow:
Average seasonal snow:
Record most snow:
Record least snow:
(1997-98, 1972-73)
Last year's snow:
by @capitalweather


text:
Find or Sell any Parts for Your Vehicle in USA
Add New Used Part
Skoda Yeti stars at the 2013 Frankfurt Motor Show
Wed, 11 Sep 2013 00:00:00 -0700
Is there an award Skoda hasn't won recently? The rate the Czech brand is going, there'll be a special ceremony at Frankfurt 2013 to give Skoda an award for picking up the most awards. In the meantime, we can bring you news of a fresh face for the Skoda Yeti.
And it's more than just a cosmetic refresh. For the first time ever, the Skoda Yeti compact-SUV will be available in two variants - one for the town and one for the country. We're in Frankfurt at the IAA show to get the lowdown on the new Skoda Yeti.
By Gavin Braithwaite-Smith, contributor, MSN Cars
Motos Cars
2040Parts.com © 2012-2022. All Rights Reserved.
Use of this Web site constitutes acceptance of the 2040Parts User Agreement and Privacy Policy.


text:
Home / Featured /Podcasts-Drills / Podcast: Jason Lange 2
Free Podcast! This is actually our second podcast with Jason Lange, now at Montevallo, It is kind of amazing how he has changed his practice planning in just four years since we spoke last,
Montevallo Career Highlights (2nd Year)
Two Great Lakes Valley Goal Keeper of the Year awards
Seven Great Lakes Valley All-Conference selections
One Great Lakes Valley Conference Tournament appearance
14 Great Lakes Valley Conference All-Academic Team selections
Coaching Experience
University Montevallo Head Coach (2018-present)
Pfeiffer University Head Coach (2014-16)
Mars Hill University Assistant Coach (2010-13)
Coaching Highlights
Helped lead Mars Hill to three consecutive Deep South Conference Championships
Jason Lange is entering his third season as the first ever head coach of the men's lacrosse program at the University of Montevallo.
Lange arrived at Montevallo after serving as the head coach for three seasons at Pfeiffer University in Misenheimer, North Carolina, a NCAA Division II school in the Conference Carolinas.
Lange compiled a career record of 27-17 in his three seasons at Pfeiffer, including a 10-6 mark in Conference Carolinas play.
Prior to his arrival at Pfeiffer, Lange served as a member of the Mars Hill University coaching staff for four seasons. In his final season at Mars Hill in 2013, Lange helped guide the team to a program-best 11-3 record. Lange also helped lead the team to three consecutive Deep South Conference regular season championships during his time as an assistant coach at Mars Hill.
In six seasons combined as an assistant coach and a head coach, Lange has coached five All-Americans, 22 All-Conference standouts, three Conference Players of the Year, and one Conference Freshman of the Year. He also coached three players that were drafted into the National Lacrosse League, and one player that signed with a Major League Lacrosse team.
Prior to joining the Lions' coaching staff, Lange was a standout on the field for Mars Hill. He served as a defenseman from 2004-09 where he helped lead the team to a Deep South Conference tournament championship in 2008 and a regular season title in 2009. Following the 2009 season, Lange represented the United States Athletes International at the Berlin Open in Germany and helped lead the team to the championship game.
Lange holds a bachelor's degree in physical education with a minor in coaching.
Montevallo announced men's lacrosse as the University's 18th intercollegiate sport in May. The Falcons' inaugural season was spring of 2018.
In the full podcast for our Premium Members, Coach shares his thoughts on dramatic changes major changes to his practice plans, from just 4 yrs ago, and so much more,
His Prospect Camp information can be found just click here…
http://www.laxcoachmike.com/fullmembers/wp-content/interviews/171%20Jason%20Lange%202020.mp3
Read the entire article just click here,
Download (right-click -> Save As)


text:
Announcement, Research Update
Five Key Takeaways from the 2021 ASCO Annual Meeting
You could call it the Super Bowl of the cancer world. The American Society of Clinical Oncology Annual Meeting, traditionally drawing tens of thousands of people from all over the world to Chicago, is one of the biggest showcases of the year for the latest and most promising treatments and approaches to curing cancer. The meeting was held virtually once again this year due to the COVID pandemic, and that wasn't the only impact current events had on the program.
"This year's meeting not only featured cutting edge research, but also thought-provoking discussions about some of the biggest issues facing global health care systems and new drug development, including how we close the gaps that exist in access to clinical trials and innovative cancer medicines," said Ute Dugan, MD, PICI's Chief Medical Officer.
From reducing disparities to expanding immunotherapy options, here are five key takeaways from the 2021 ASCO Annual Meeting.
Diversity, Equity and Inclusion Takes Center Stage
Efforts to boost diversity, equity, inclusion and belonging are rightfully emerging as a key priority for many organizations, and the oncology world is no exception. The theme of this year's meeting was "Equity: Every Patient. Every Day. Everywhere." That meant more diversity on panels, greater scrutiny around disparities and a focus on access to care to ensure all cancer patients can benefit from the latest breakthroughs.
Importantly, this year's meeting also focused on objectively analyzing the areas where the field is making progress, as well as where it's still falling short. In 2018 and 2019, the U.S. Food and Drug Administration approved 28 new cancer treatments based on trial data from 8,700 patients. FDA reports show just four percent of those patients on study were Black. That's in line with historical data. According to the FDA, just five percent of Black cancer patients are enrolled in clinical trials.
Researchers from the Abramson Cancer Center of the University of Pennsylvania presented data showing they were able to double the number of Black patients enrolled in their clinical trials. Importantly, they laid out the steps they took to make it happen, including changes in marketing strategies and an increased focus on community relations.
"Aligning the number of Black patients with cancer we care for with the number enrolled in our trials is how we can help bring more equitable care to the community, close gaps in disparities, and sustain trust," said the study's senior author Robert Vonderheide, MD, DPhil, director of the Abramson Cancer Center and a PICI member researcher. "There's more work to be done to improve access and inclusion of minority groups, and the impact of this outreach and engagement effort is an important step forward."
Progress for New Checkpoint Inhibitor LAG-3
Checkpoint inhibitors, which work by blocking certain signals in the body and allowing the immune system to attack cancer, have been revolutionary in many different disease types. Historically, the two most effective inhibitors have targeted proteins called PD-1 or CTLA-4. This year's meeting included news of a groundbreaking new checkpoint option targeting a protein called LAG-3.
Bristol Myers Squibb reported data on a Phase 3 trial combining a LAG-3 inhibitor called relatlimab with the PD-1 inhibitor nivolumab in patients with melanoma. The global study found the median progression-free survival of patients who received both drugs was 10 months, compared to just four and a half months for patients who received nivolumab alone.
There were also significantly more serious side effects in the combination arm. The data showed adverse events serious enough to require hospitalization occurred in almost 19 percent of patients on both checkpoint inhibitors, compared to just under 10 percent on nivolumab alone. More patients in the combination arm had to stop treatment because of these issues – 14 percent, compared with less than 7 percent in the nivolumab group.
"This is encouraging progress that can expand immunotherapy treatment options for cancer patients, but there's still work to do to better understand who is most likely to benefit," said Lisa Butterfield, PhD, Vice President, Research and Development at PICI.
Drugging the "Undruggable" KRAS Mutation
Certain genetic mutations are known to be associated with cancer growth, which theoretically makes them attractive targets for new therapies. However, designing a treatment that hits its target is a complex challenge. That's especially true of a gene called KRAS. It's one of the most common genetic drivers of certain disease types like lung cancer, but it has historically been an evasive target, leading many to refer to it as "undruggable."
That's just one of the reasons why new data on a recently approved KRAS inhibitor called sotorasib are so encouraging. A Phase 2 study led by researchers at The University of Texas MD Anderson Cancer Center showed sotorasib, which targets a specific mutation called KRAS-G12C, led to a 37 percent objective response rate and a median overall survival of 12.5 months in non-small cell lung cancer patients who have undergone previous treatments.
"This is the first time a study has shown that a KRAS inhibitor may help cancer patients live longer. It's especially encouraging in patients who had failed a previous therapy, which is a group of patients who generally have poor outcomes and who need options," said Marko Spasic, MD, PICI's Medical Director.
The FDA approved sotorasib in May based on previously reported data.
Moving Immunotherapy Earlier in Treatment
Figuring out who to treat with checkpoint inhibitors and expanding those options is only part of the equation. There's also a question of timing. In most cases, like the KRAS inhibitor study, patients receive immunotherapy after failing a previous treatment like chemotherapy. But research presented at this year's meeting showed the potential benefit of using immunotherapy earlier in a patient's course.
Researchers treated kidney cancer patients with a PD-1 inhibitor following surgery to remove their tumors and found it cut the rate of disease returning or death by almost a third over a two-year period. The study, led by the Dana-Farber Cancer Institute and funded by Merck, was presented as part of the meeting's plenary session, during which reviewers called it practice changing.
A separate study found adding a PD-1 inhibitor to pre-surgical chemotherapy can enhance responses in esophageal cancer patients. A third showed the benefit of adding PD-1 as a first-line therapy for patients with gastric cancers.
Radioactive Medicine in Prostate Cancer
The fast-growing field of nuclear medicine and cancer therapy saw a groundbreaking presentation at this year's meeting. A Novartis-funded trial added a radioligand called Lu-PSMA-617, which uses a radioactive molecule that can kill cancer combined with a protein that can guide it toward tumors. That drug was added to standard of care treatments in prostate cancer patients who had exhausted all other treatment options. The combination improved median overall survival from 11 months to 15 months and progression free survival from 3.4 months to 8.7 months.
"This is a group of patients with a common cancer who need more options, and this study shows a potential new way to target their tumors," said Theresa LaVallee, PhD, Vice President of Translational Medicine and Regulatory Affairs at PICI.
Novartis is studying the drug in other cancer types.
Keep up to date with the latest PICI news by signing up to receive email updates.


A summer evening's barbeque is the setting for a meeting of the local Operatic Society. Next season's play is to be announced but Nick, the director, has promised four different people the lead in four different shows, under the pressure of blackmail, financial crisis, family loyalty and sexual favours.
As the evening progresses the tension between the ridiculously diverse set of characters is stretched to breaking point. Which show will be picked? Who will get the coveted lead? Will friendships, marriages and the group itself survive? Will they ever light the damn barbeque?


Caiden is 21mths, Lana is 4, life is about to get busy here!
like she did on holiday, but was struggling to keep her eyes open.
covers them all up... she lasted five minutes before sleep found her!!
dirty in any way, shape or form.
And the boy even got in on the act at the water's edge.
The rest of today will be full of moving-the-spare-bed-downstairs, and go-to-the-supermarket-to-buy-food-cause-now-we're-feeding-8-people, and tidy-the-scraproom-up-to-keep-the-kids-out, and plan-what-to-do-with-the-kids cause it's school holidays here, too!!
Glad to see they arrived safely.


text:
Wolfgang Fremuth (* 1954 in Leonberg) ist ein deutscher Biologe. Er war Leiter der Fachabteilung Europa der Zoologischen Gesellschaft Frankfurt (ZGF), ist Mitglied im BUND und Unterstützer und Förderer von EuroNatur.

Leben
Fremuth studierte an der Universität Tübingen und Universität Hohenheim Biologie. Er war Mitarbeiter an der Landesanstalt für Bienenkunde in Hohenheim (BaWü). Anschließend wurde er Naturschutzreferent beim BUND-Bundesverband und war von 1985 bis 1992 dessen stellvertretender Bundesgeschäftsführer. Von 2001 bis 2011 war er Leiter der Europa-Abteilung der ZGF.

Von 2011 bis 2016 leitete Wolfgang Frehmuth ein Expertenteam zur Entwicklung des Prespa Nationalparks in Albanien und zur Schaffung des grenzüberschreitenden Biosphärenreservates (Prespa-Ohrid-Seenland). Dieses wurde am 14. Juni 2014 von der UNESCO anerkannt.

Fremuth war bis Oktober 2016 Präsident der europäischen EECONET Stiftung.

Werke (Auswahl)

Einzelnachweise

Biologe
Deutscher
Geboren 1954
Mann

redpajama_set_name: RedPajamaWikipedia


Ehlmann Farms by Fischer and Frichtel offers a limited edition of just 10 gorgeous home sites ranging from ½ acre to nearly a full acre in size in an amazing location! This serene and private setting offers incredibly easy access to Highways 364, 94, 64/40, Chesterfield Valley and is located in the desirable AAA-rated Francis Howell School District. Offering single family homes from the elegant Estate Collection, these executive homes include high end finishes, 3 car side entry garages, distinctive brick and stone elevations, James Hardie fiber cement siding, deluxe Kitchens with granite countertops, designer cabinetry, hardwood flooring, luxurious master retreats with spa like baths and more. The Woodside is a 3 bedroom, 2 bath, 2,662 square foot, split bedroom ranch. Features include a Study-Flex Room, Formal Dining Room, Bonus Room-Optional Bedroom 4 and center Kitchen open to the Breakfast Room and Great Room. A professional design consultant will assist you in designing your dream home to reflect your individual tastes and needs. There are walkout and in-grade home-sites to choose from, some of which back to a large common ground area. Build to your specifications, 8 fantastic plans, 1/2 to nearly 1acre home sites, fantastic St. Charles location…a rare and limited opportunity!
1 TBB-Woodside @ Ehlmann Farms (MLS #16005082) is a 1 story single family home located in Weldon Spring, MO. This single family home is 2,662 sqft with 3 bedrooms and 2 baths. This property was listed on 02/04/2016 and has been priced for sale at $525,900.
The 4 bedroom single family home at 146 Cross Timbers Lane in St Charles is comparable and sold for $404,000 on 04/26/2018. Another comparable 4 bedroom single family home, 188 Shortleaf Pine in St Charles sold for $499,999 on 07/12/2018.


text:
Krispy Kreme Goes Krispy Scream For Halloween
Krispy Kreme scares up something sweet this Halloween
Krispy Kreme and Sony Pictures Consumer Products Celebrate Ghostbusters 30th Milestone Anniversary with Ghostbusters and Stay Puft Marshmallow Doughnuts
Krispy Kreme Doughnuts® and Sony Pictures Consumer Products have joined together to mark the 30th anniversary of the iconic Ghostbusters blockbuster motion picture franchise with two new exclusive marshmallow Kreme™-filled Ghostbuster treats inspired by the supernatural comedy's sweetest villains.
Ghostbusters Doughnut: A marshmallow Kreme-filled shell topped with white icing, a decorative green "splat" inspired by Slimer, and a Ghostbusters logo sugar piece.
Stay Puft Marshmallow: A marshmallow Kreme-filled shell topped with white icing, decorated with Stay Puft Marshmallow Man's familiar face and a sugar piece hat.
The Ghostbusters and Stay Puft Marshmallow Doughnuts join Krispy Skremes seasonal favorites – the Jack-o-Lantern, Spider Web, and Halloween Sprinkles doughnuts – for a Halloween assortment so good it's spooky!
Jack-o-Lantern Doughnut: A pumpkin-shaped doughnut wearing a mask of orange icing and a jack-o-lantern face.
Halloween Sprinkles Doughnut: A festive orange and black sprinkled doughnut.
Spider Web Doughnut: A chocolate-iced doughnut with Kreme™ filling caught in a tasty web of white icing.
These Halloween-themed treats are available now through October 31, 2014 at the following Central Florida locations while supplies last.
Krispy Kreme Winter Park – Drive thru Open 24 hours
1031 S. Orlando Avenue (17-92), Winter Park, FL 32789
Open 5:30 a.m. to 10 p.m. (Sunday–Thursday) and
5:30 a.m. to 11 p.m. (Friday and Saturday)
Krispy Kreme Millenia – Open 24 hours
4080 Millenia Blvd., Orlando, FL 32939
Krispy Kreme Kissimmee – Open 24 hours
(192 / Mile Marker 11.5), Kissimmee, FL 34746
Make sure that you connect with Krispy Kreme and Ghostbusters!
KrispyKreme.com, www.Ghostbusters.com, HotLightApp.com, Facebook, foursquare and Twitter, and KrispyKremeDoughnuts on YouTube.
Author ShelleyPosted on October 7, 2014 October 7, 2014 Categories Orlando PlacesLeave a comment on Krispy Kreme Goes Krispy Scream For Halloween
Sketchbook Ornaments From The Disney Store
The Disney Store has a new set of Sketchbook Ornaments this year that I am absolutely obsessed with, and my 'wish list' of ornaments is crazy!
The Sketchbook Ornaments are so wonderful, because each ornament really captures an iconic character moment using quality finishes at a really reasonable price!
The price point of the ornaments in the line are between $12.95 and $16.95, and the price reflects if an ornament has light and sound features and if it can be personalized.
These resin ornaments are really beautiful, and no detail has been skipped and the colors used are the same as they are in the movies or shorts. Also, all of the Sketchbook Ornaments feature a 2014 Disney Store Logo Charm.
They even have an exclusive set of on-line Disney Sketchbook Ornaments that are released monthly, and capture 'Moments that made Disney'. You can see them here. October's release will celebrate the 1932 release of Flowers and Trees in the Silly Symphonies Series.
So enough talking, lets look at some of my favorites!
2014 Disney Store Sketchbook Ornaments
The Disney Store's site is always offering great deals, and you can get free shipping everyday for orders over $75 when you use the code SHIPMAGIC at checkout. Make sure that you sign up for their email list for even more offers!
So what do you think of the new Sketchbook Ornaments from the Disney Store? Will you be picking one up for the holidays?
Also, I just wanted to add a note that this post is not sponsored. I really love these ornaments and wanted to share them with you!
Author ShelleyPosted on October 7, 2014 October 7, 2014 Categories #DisneySide, Christmas, Disney Store Features, ShoppingLeave a comment on Sketchbook Ornaments From The Disney Store
Marvel's Guardians Of The Galaxy Coming to Blu-ray
Marvel's GUARDIANS OF THE GALAXY arrives on Digital HD plus Disney Movies Anywhere November 18th and on Blu-ray™ 3D Combo Pack, Blu-ray, DVD and On-Demand December 9th!
The comedic adventure is packed with never-before-seen deleted scenes, gag reel, and an exclusive look at "Marvel's The Avengers: Age of Ultron" and more!
Marvel's Guardians of the Galaxy film has earned over $645 million worldwide and recently passed the $300 million mark at both the domestic and international box offices. Guardians of the Galaxy opened domestically August 1 with $94.3 million to become the biggest August debut of all time and ultimately the biggest August release ever; it's also the highest grossing film of the year and the first to surpass $300 million in 2014 domestically. After becoming the 10th straight Marvel Studios film to open at #1, Guardians of the Galaxy occupied the top spot domestically for four of its first six weekends in release.
If you haven't seen Guardians of the Galaxy…WHAT ARE YOU WAITING FOR???
Synopsis: From Marvel, the studio that launched the epic franchises of "Iron Man," "Thor," "Captain America" and "Marvel's The Avengers," comes an unlikely new team—the "Guardians of the Galaxy." The Marvel Cinematic Universe expands into the cosmos when brash space adventurer Peter Quill steals a coveted orb and becomes the object of a relentless bounty hunt. To evade his enemies, Quill forges an uneasy truce with Rocket, a gun-toting raccoon; Groot, a tree-like humanoid; the deadly assassin Gamora; and the revenge-driven Drax. But when Quill discovers the true power of the orb, he must rally his ragtag band of misfits for a desperate battle that will decide the fate of the galaxy. Featuring amazing new characters and exclusive bonus features, this must-own blockbuster will have you hooked on a feeling… of pure adrenaline!
Cast: Chris Pratt ("The Lego Movie," TV's "Parks and Recreation") as Peter Quill, Zoe Saldana ("Avatar," "Star Trek") as Gamora, Dave Bautista ("Riddick," "The Man with the Iron Fists") as Drax, Vin Diesel ("Fast and the Furious" series, "Riddick") as Groot, Bradley Cooper ("American Hustle," "Silver Linings Playbook") as Rocket, Lee Pace ("The Hobbit" series, "Lincoln") as Ronan, Michael Rooker (TV's "The Walking Dead") as Yondu Udonta, Karen Gillan ("Oculus," TV's "Doctor Who") as Nebula, Djimon Hounsou ("How to Train Your Dragon 2," "Gladiator") as Korath, John C. Reilly ("Wreck-It Ralph," "Talladega Nights: The Ballad of Ricky Bobby") as Corpsman Dey, Glenn Close (TV's "Damages," "Tarzan") as Nova Prime and Benicio Del Toro("Traffic," "The Usual Suspects") as The Collector.
I know that I can't wait to pick up a copy of Guardians of the Galaxy, can you?
Author ShelleyPosted on October 7, 2014 October 6, 2014 Categories Disney Movie News, Disney Movies Anywhere, Guardians of the Galaxy, MarvelLeave a comment on Marvel's Guardians Of The Galaxy Coming to Blu-ray


text:
Little Mermaid Backlash: A 'Cultural Appropriation' Outrage Tragedy
Today, I'm going to talk about the controversy surrounding the casting of singer and actress Halle Bailey as Ariel in the upcoming Disney remake of the Little Mermaid. Mainly, those complains have centered around the fact that Halle Bailey, who is black and doesn't have red hair, doesn't look anything like the cartoon version of Ariel. However, the Woke crowd have predictably screamed racism. They seem to have forgotten that racism is a strong charge, as in for example how black Americans were treated before desegregation, and it's not to be used lightly without adequate evidence, lest the real history becomes forgotten.
Personally, I'm fine with a black Ariel. I agree that The Little Mermaid is just a story, mermaids aren't even real so they can be anything you want them to be. However, I also understand a lot of people, especially those around my age who watched the cartoon back when they were very young, do have an attachment to how Ariel was portrayed in that particular production. So these emotions are jusitifiable, even if not entirely rational, and they certainly do not represent racism. In fact, I even suspect that some of the people pushing the racism angle here may have an agenda, for example to create culture war style conflict for political ends, or to justify a further increase in political correctness. Call me paranoid, but the world has gotten quite strange in recent years, so anything is possible.
Of course, another reason why people are so upset about this is the 'Woke' push against so-called 'cultural approriation' in recent years. Starting a few years ago, the Woke crowd have deemed every instance of someone adopting elements of another culture an injustice akin to blackface. For example, last year's Eurovision winner was accused of appropriating Asian culture in her performance. There was also this pointless outrage about a white young woman who wore a Chinese dress to her prom. And then, again just last year, Scarlett Johannson was forced to quit a trans role in an upcoming movie, because SJWs demanded a real trans person be cast instead. I mean, if you ridigly uphold cultural boundaries like this, you would expect to get a negative reaction towards a black actress being cast as Ariel. To expect anything else would just be a double standard.
While BreadTube itself in general has not cared to comment on this latest controversy, the idea of 'cultural appropriation' has deep roots in the pool of theory that Breadists draw their ideas from. For there to be 'cultural appropriation', culture has to be seen to belong to one group in the first place, which means its use by another group would hence be seen as appropriation, and hence exploitation. This worldview is fundamentally rooted in the systems of oppression view, which hypothesizes that there are interlinking systems of cultural oppression in capitalist society. Both classical liberals and classical Marxists have disputed this view, and I have in the past made my case as to why I believe there simply cannot be interlocking systems of cultural oppression as the Breadists believe. Anyway, what I want to say is that, parts of intersectional theory can have rather divisive consequences for society, which also undermines solidarity between everyday individuals and ultimately serves the establishment's continued economic privilege above the 99%.
I think we need to put this 'cultural appropration' thing to bed, once and for all. While I agree that blackface is certainly wrong because of its particular historical associations, there is actually no reason why most other forms of cultural appropriation are bad, and in my experience even very progressive people secretly agree with me on this. For example, a white woman wearing an Asian dress doesn't actually hurt anybody.
By Team Tara - July 12, 2019
Little Mermaid Backlash: A 'Cultural Appropriation...


text:
Q: Oracle SQL - Using SysDate to create a specific date I need to automate a report that will always the first day of the current month and year in the WHERE caluses.
"YYYY-MM-01"
I am trying to achieve the following but sadly, I can't get anything to work using To_Char/ To_Date/SysDate.
    to_date(SYSDATE('YYYY-MM') + '-01', 'yyyy-mm-dd')

Thank you

A: To get the first day of the current month (as a DATE), simply:
trunc(sysdate,'MON')

or, formatted:
to_char(trunc(sysdate,'MON'),'yyyy-mm-dd')

A: The string concatenation operator in Oracle is ||, not +.  And SYSDATE is a constant not a function:
to_date(to_char(SYSDATE, 'YYYY-MM') || '-01', 'yyyy-mm-dd')

By the way, you can also do this calculation as:
trunc(sysdate - extract(day from sysdate) + 1)

That is, subtract the day of the month and add one.  That way, you don't have to mess with fiddly date/character formats.

redpajama_set_name: RedPajamaStackExchange


text:
Waffle House Waitress Earns College Scholarship
posted by Todd Robbins - Mar 13, 2018
A photo went viral last week of a Waffle House waitress in La Marque,Texas helping a 78-year-old customer cut his food. (La Marque is just outside Houston.)
Apparently he said his hands were a little weak, because he recently got out of the hospital. So she helped him out . . . cut his ham for him . . . and acted like it was no big deal.
But the reaction it's gotten HAS been a big deal. The waitress is an 18-year-old named Evoni Williams.
After the photo blew up on Facebook, the mayor of La Marque honored her by declaring March 8th Evoni Williams Day.
Then the president of Texas Southern University saw the photo . . . found out Evoni has been waiting tables to save up for college . . . and offered her a $16,000 scholarship.
A spokeswoman for the university says Evoni showed the type of character they wish all their students had. Evoni says she's planning to study business administration and hopes to own her own restaurant or salon someday.
(CNN)


text:
Odisha's first Business Research Fair organized by KSOM
KSOM conducted its inaugural Business Research Fair on 16th-17th March'2018. The first of its kind fair in Odisha was inaugurated by Dr. Hrushikesha Mohanty, Vice Chancellor, KIIT. and Prof. Debasish Das, Director, KSOM. Other top officials of the University also visited and participated in the fair that spanned over two days.
KURIOCITY is an innovative platform for conducting research and analyzing behaviour of individuals (consumers, influencers and others) and how those impact business processes. Research problems provided by corporates were gamified to obtain participant's responses. Encompassing all management parameters, Kuriocity had several Marketing Research Games, Personality Tests and Financial Simulations.
The inaugural fair had over 40 stalls where research data was collected in the form of challenging games. Several corporates across industry verticals participated in the Business Research Fair. Notable market players like Big Bazaar, MayFair Chain of Hotels,, Vodafone along with several startups were part of the fair. The event also had popular retailers like Habib, Unisex, Dugout, Hub etc. as gifting partners.
KSOM students put up an impressive display of talent and creativity in the two days. With more than 2000 footfalls from Bhubaneswar and surrounding areas, the event was a grand success. The fair saw huge participation from various demographics including school students, entrepreneurs, corporates, graduates and academicians and received widespread appreciation and positive feedback.


In single phase electric power, the double-subscript notation eliminates the need for both the polarity markings for voltages and direction arrows for currents. It is even more useful for representing voltages and currents in three-phase circuits, resulting in greater clarity and less confusion.
The voltage phasor with double subscripts represents the voltage across the two nodes identified by the two subscripts. The voltage is positive during the half-cycle in which the node named by the first subscript is at a higher potential than the node named by the second subscript.
The current phasor with the double subscripts represents the current flowing between two nodes of a circuit. The current is considered positive when it flows in the direction from the node identified by the first subscript toward the node identified by the second subscript.
In this article, we shall find extremely useful the double subscript notation. In this case of phasors, the notation is Vab for the voltage of point a with respect to point b. we shall also use a double subscript notation for current, taking, for example, Iab as the current flowing in the direct path from point a to point b. these quantities are illustrated in figure (1), where the direct path from a to b is distinguished from the alternative path from a to b through c.
These steps are shown graphically in figure 2(b).
This is a common arrangement in a normal house supplied with both 115 V and 230 V rms, since if |Van|=|V1|=115V, then |Vab|=|2V1|=230V.
Let us now consider the source of figure 3 loaded with two identical loads, both having an impedance Z1, as shown in figure 4.
Thus the neutral could be removed without changing any current or voltage in the system.
If the lines aA and bB are not perfect conductors but have equal impedances Z2, then InN is still zero because we simply add the series impedances Z1 and Z2 and have essentially the same situation as in figure 4. Indeed, in the more general case shown in figure 5, the neutral current InN is still zero. This may be seen by writing the two mesh equations.
Since by KCL the left member of the last equation is –InN, the neutral current is zero. This is, of course, a consequence of the symmetry of figure 5.
If the symmetry of figure 5 is destroyed by having unequal loads at terminals A-N and N-B or unequal line impedances in lines aA and bB, then there will be a neutral current.
And, of course, is not zero.


The next generation of science thought leaders are gearing up to lead America's energy efforts. And biodiesel, our nation's only commercially available advanced biofuel, is front and center.
Student scientists from Dartmouth College in New Hampshire to Oregon State University in Corvallis are leading the initiative. The group has formed to demonstrate and grow support for biodiesel among tomorrow's scientific leaders.
We, the undersigned student scientists, believe that biodiesel can reduce dependence on petroleum, help address climate change and boost domestic economies.
Biodiesel from a variety of feedstocks can meet contemporary needs for environmental stewardship, economic prosperity, and quality of life without compromising the ability of future generations to meet these needs for themselves.
We support increased investment in research and development and higher education to train future scientists by public and private sources that will enhance biodiesel as a sustainable fuel for transportation and other uses. We are confident that scientific advancements can demonstrate, preserve, and enhance biodiesel's ability to help meet the food, feed, fiber, and energy needs of the future.
Sign the declaration to Join the Next Generation Scientists, today!
Find more information on the Sustainability Blog!


Whole Groundnut kernels free of bruises attract foreign exchange earnings. The appropriate selection and the interactions between the processing parameters in groundnut decortication produces clean kernels. Therefore, the focus of this study was to establish mathematical equations in order to explore and predict the possible relationships between the process inputs (grading, moisture content and screen apertures) and the measured output (clean kernels, bruised kernels and split kernels) in decorticating three selected varieties of groundnut in-shell commonly cultivated in Nigeria with a view of maximizing their kernel quality. The varieties were Samnuts 10, 14 and 18. In doing this, individual relationships were explored one at a time by keeping other process parameters constant to ensure clear interpretations. The relationships between grading, moisture content and screen apertures versus the response (efficiency of clean, bruised and split kernels) were approximated using a linear and nonlinear (quadratic or polynomials) functions. Regression analysis and design expert software (multivariate) were used to develop the mathematical models that describe the relationships between these inputs and the measured outputs.
AMINU, S.; AKANDE, F. B.; OLA, F. A.. MODELING THE RELATIONSHIP BETWEEN GRADING, MOISTURE CONTENT AND SCREEN APERTURES IN GROUNDNUT DECORTICATION. Arid Zone Journal of Engineering, Technology and Environment, [S.l.], v. 14, n. SPi4, p. 185-193, dec. 2018. ISSN 2545-5818. Available at: <http://azojete.com.ng/index.php/azojete/article/view/530>. Date accessed: 22 apr. 2019.


Bruxism: habitual teeth grinding eventually impacts bone health and can lead to gum recession.
Trauma: if the teeth and gum tissue has been damaged by an accident, it may lead to gum recession if not treated promptly with proper dental care.
Genetics: certain medical conditions or a genetic predisposition for gum recession or weak gum tissue.
Maintaining gum health through good oral hygiene and routine dental care are the keys to avoiding gum recession. If you have receding gums, it is important to seek the advice of your local AACD dentist to identify the underlying cause and discuss how to address your oral health and cosmetic needs. There are surgical treatment options that can restore the aesthetics of your smile.
The first step in addressing receding gums is to evaluate the condition of your gums and overall oral health. Minimal gum recession that is the result of existing periodontal disease may require only conservative treatments, such as scaling and root planing, to halt further recession and restore health. Your AACD dentist will discuss your oral hygiene and make personalized recommendations for the appropriate type of tooth brush and other oral care products for gum disease.
If gum recession is affecting the health and/or aesthetics of your smile, a gum graft may be the best long-term solution to meet your needs. Your dentist will discuss the expected results of oral surgery to correct gum recession and the necessary steps in the process. A gum graft can cover exposed tooth roots and stabilize bone deterioration that is affecting your oral health. In addition to restoring symmetry to the aesthetics of your smile, a successful gum graft can reduce the side effects of gum recession such as increased sensitivity and the risk of advanced tooth decay.
Your dentist will go over all aspects of a gum graft procedure including aftercare for the best recovery. Most patients tolerate a gum graft well and will experience only minor discomfort and short-term dietary restriction.


text:
Lottie Dod ha battuto nel challenge round la detentrice del titolo Blanche Bingley 6-2, 6-0.

Tabellone

Challenge Round

Fase preliminare

Collegamenti esterni

Torneo di Wimbledon 1887


text:
Silent Hill HD Collection | Zombiegamer Review
– April 10, 2012Posted in: Featured Articles, Games, Playstation 3, Reviews, Xbox 360
The Silent Hill HD Collection brings the "genre-defining" survival horror games Silent Hill 2 and Silent Hill 3 up-to-date with "true high-definition graphics" and… not much else.
Developer: Hijinx Studios
Publisher: Konami
S.A. Distributor: Ster Kinekor Entertainment
For fans of: Scary games. Old scary games.
Reviewed on: PlayStation 3.
Also available on: Xbox 360.
If we had to give it a numerical score: 5.0 out of 10 (for story and nostalgia's sake).
Pretty cheap.
Were great games when they were originally released…
… maybe they should've been left untouched for nostalgia's sake.
The controls and camera.
HD graphic update? Still looks like a four year old game.
Silent Hill as a series has much to be credited for – especially the first three games in the series. Silent Hill, Silent Hill 2 and Silent Hill 3 (released in 1999, 2001 and 2003 respectively) were quality survival horror games which featured a great atmosphere and story. You would think that with a graphic re-skin, those two elements would still find a way a shine through, but I'm sorry to say that something has gone terribly wrong here. This update has sadly ruined a perfectly great memory.
Gameplay, features, visuals and sound
The two games featured in this HD Collection – Silent Hill 2 and Silent Hill 3 – are still the third person slow paced fright fest that made many love them originally. Sadly, the poor controls have been left untouched to frustrate the experience for a second time. If you played the games originally, I would like to think you know what I'm talking about. If you hoped the graphical update meant fixing the controls and wonky camera, you will be a very, very sad panda.
Movement – considering the developments made by other games in the genre – is archaic. It's slow and completely cumbersome. The combat still feels like a button push made last century is only reacting now. And while fans are probably screaming at me for picking on an issue that existed on original release (although I'm willing to bet it didn't bother back then), I expect a little more from an HD update than simply a pretty new skin and some new voices.
Even the graphic update is a disappointment. Apparently, the game has been updated to feature "true high-definition graphics". Unless I missed a setting somewhere, both games still look like they were produced years ago at the end of the PS2 cycle. Silent Hill 3 comes off much better than Silent Hill 2 does in this regard, but both still look dated. Sadly, the effect of this, is that elements with volume like the fog in Silent Hill 2 – which are part of the game's fantastic psychological atmosphere – are so poorly updated that they are just not realistic enough and effectively suspend believe in the environment surrounding you. To add to this, the general lack of claustrophobia that the fog should have introduced appears to have been further nullified by the fog seemingly parting in front of you like it was afraid of you. The creatures and textures have not been updated nearly enough to measure up to any other more recently released survival horror games.
The sound has been updated too. An all new set of voices have been recorded (which might bewilder some), but you can always choose to still play with the original voices. The new ones are perfectly adequate in driving the story along, but they're not going for Oscar glory. Unfortunately, the sound effects still sound untouched from the around ten year old versions and once again make it hard to enjoy the atmosphere being created. Ten years ago those sounds would've caused bowel movements. Now they're pretty laughable. Make no mistake, there are still enough moments that will make you jump, it's just that they (for me at least) were few and far between.
I am not going to detail the stories in the two games – my suspicion is that anyone considering this collection would've played the games in their original versions. Suffice to say that the stories remain thankfully untouched. There are some framerate dips at times and there is a lack of additional content – although the latter is not a requirement, but more of a nice to have had.
Re-visiting "classics" is turning a little into heartbreak for me. The memories were great. Sadly, when an update feels this… lazy, the memory gets ruined. Yes, they look better (just), but the gameplay has been comfortably surpassed by modern games with working mechanics and probably just as brilliant atmosphere and story. I find it really hard to recommend this to anyone – except for the story. If you played Silent Hill 2 on release and can replay the game without wondering why it didn't get a complete overall, you may just love it. I couldn't.
Zombiegamer rating:
Silent Hill | HD Collection PS3 exclusive "right now" Silent Hill HD Collection Gets New Release Date and Trailer Silent Hill HD Collection | Launch Trailer Silent Hill HD Collection Xbox 360 bound
Tags: Review, Silent Hill HD


Interxion's Dublin-based data center business continues to grow as an increasing number of American and European companies see Ireland as a strategic connection hub.
Ireland has risen to be one of Europe's most strategic data center hubs, and with favorable tax laws and a large pool of young, well-educated workers, the country has attracted a formidable group of data center providers, including Amazon, Google and Microsoft along with several capable local competitors, including Equinix and Digital Realty.
In this Q&A, Tanya Duncan, managing director of Interxion's Dublin campus and 17-year veteran of the company discusses the burgeoning Irish data center market and the unique connectivity services that help Interxion's enterprise and SaaS customers tie together cloud and traditional data center services.
What has made Ireland perhaps the biggest hub for data centers in Europe over the past decade or more?
Tanya Duncan: Part of it is our geographical location. Some 20% of the TransAtlantic cables that go from North America to northern Europe land in Ireland, and that's an ever-increasing number given the proliferation of hyperscale data centers here. [Ireland] seems to be a natural trading point between the United States and Europe. And it helps that the connectivity is secure and the latency is low.
What other advantages does Ireland have to attract both American and European companies?
Duncan: There are several. I mentioned connectivity as one. There are the power sources we have such as wind and an established track record when it comes to sustainability. We have a renewable energy target of 40% by 2020. We also have a long history of high-tech companies investing in Ireland and a lot of that is tied to the government's pro-business attitude vis-à-vis the corporate tax rate. And we have a young, high-tech savvy worker base with skills [that] international high-tech companies are looking for. About 55% of our population is under 35 and a third is under 25. But we are as much a victim to the global skills shortages as anywhere else. So we also must try to keep up with the momentum and demand.
How will the new U.S. tax policy undercut some of Ireland's advantages?
Duncan: We are still analyzing what the implications for companies might be. It is hard to answer.
What technology advantages can you offer customers that your competitors don't have in Ireland?
We see ourselves as a hybrid facilitator enabling clients to utilize both the cloud and traditional data center services.
Duncan: First, we are carrier neutral and provide connectivity to multiple carriers (Tier 1, localized ISPs). [We also] set up direct connections to multiple cloud services providers, so users have the choice of whatever cloud service provider they want. This gives clients more security, reliability and improved throughput and performance [versus] an internet connection from their on-premises location. We see ourselves as a hybrid facilitator enabling clients to utilize both the cloud and traditional data center services.
You've been following the issue involving the U.S. Department of Justice trying to access information residing on servers in Ireland as part of a criminal investigation. How could the outcome of the case affect your business?
Duncan: The implications of the outcome could be very far reaching. For instance, if you look at one of the more extreme possible outcomes, it could mean that you couldn't send an email between the U.S. and Europe because of the requirements that could come out of this decision. People are trying to understand the technology involved, the data and the legalities around it. I am not an expert on this, but I think they are looking at all the right things and hope they reach a decision which protects everyone.
Who are your competitors either in Ireland or in Europe in general for the services you provide?
Duncan: We have the hyperscale providers like Amazon, Google and Microsoft. Then there are the self-builds, or the guys who build for the hyperscalers. There has been a big proliferation of the hyperscalers in Ireland. In fact, when you take the hyperscalers into account, Ireland is the third highest DC market in terms of megawatts in Europe. On the multi-tenant side the usual suspects are all here like Equinix and Digital Realty along with a few local players.
Would you consider colocating your data center to Ireland?