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By U. Ingvar. Life University.

The -zein subunit consists of two major protein subunits of about 210 to 245 amino acid residues buy cialis black 800mg visa erectile dysfunction drugs egypt, each with a molecular weight of 23 and 27 kDa buy cheap cialis black 800 mg line erectile dysfunction treatment garlic, respectively (35). It has been used to prepare particulate systems for drug delivery and food applica- tions (34,36). Gliadin Gliadin is a gluten protein found in wheat and also belongs to the prolamine protein family. Most of the gliadins exist as monomers and are classified into (25–35 kDa), (30–35 kDa), (35–40 kDa), and (55–70 kDa) fractions in the order of decreasing electrophoretic mobility (37). This is attributed to the presence of interpolypeptide disulphide bonds and to the cooperative hydrophobic interactions (38). Gliadins exhibit bioadhesive property and have been explored for oral and topical drug delivery applications (39,40). It belongs to the group of 11S globulins, with sedimentation coefficients between 11S and 14S (molec- ular weight = 300–400 kDa). Legumin has a complex globular structure that is made up of six pairs of subunits, with each subunit consisting of disulphide-linked acid (molecular weight = 40 kDa) and basic (molecular weight = 20 kDa) polypeptides (41). The composition of the protein depends on the source from which it is derived and can have a signifi- cant influence on the preparation of nanoparticles. Therefore, batch-to-batch variation can have a significant influence on the nanoparticle characteristics. The batches with higher molecular weight fractions resulted in larger particle size and higher polydispersity. This can be overcome by using a two-step desolvation process to remove the large molecular weight aggregates (43). Similar to animal/human proteins, the plant proteins also contains various molecular weight fractions. In addition, the presence of pigments can also interfere with the preparation of nanoparticles. This necessitates a purification of the protein polymers before the preparation of nanoparticles (37). Protein Solubility The solubility of the protein in aqueous or organic solvent dictates the choice of the method and the nanoparticle characteristics. Protein nanoparticles are prepared by utilizing the differential solubility of the protein in aqueous and nonaqueous solvents, as proteins can fold or unfold depending on the polarity of the solvent (1). The pH value of the aqueous solution was found to have a significant influence on the size of the albumin nanoparticles (45). At a pH away from the pI, the hydrophobic interactions in the protein are reduced, result- ing in lesser aggregation (26). Type A gelatin has a pI of 7 to 9, whereas type B gelatin has a pI of 4 to 7 (Table 1). Hence, the source of gelatin can influence the size, zeta-potential, and drug loading in gelatin nanoparticles (46, 47). For type A gelatin and type B gelatin, pH 7 and pH 3, respectively, were found to be critical for the preparation of nanoparticles (48). At these pH values, the strengths of electrostatic interactions are maximized for obtaining stable particles with optimal drug loading. Furthermore, in the case of gelatin, due to its high viscosity, a preheating (40◦C) step was used to prepare smaller size nanoparticles (48). However, a higher temperature (50◦C) was found to increase the particle size, due to the excessive unfolding of the protein (48). In a comparative study between different strengths of gelatin (75, 175, and 300 bloom strength), it was found that 300 bloom strength was optimal in terms of particle size, polydispersity index, and drug encapsulation (48). Surface Properties One of the significant advantages of protein polymers is the presence of numerous surface functional groups that can be used for modifying the surface of the pro- tein nanoparticles to alter their biodistribution or biocompatibility or drug loading and/or improve their enzymatic stability (Fig. Particle size and surface proper- ties of protein nanoparticles depend on the number of disulfide bonds, number of thiol groups, degree of unfolding, electrostatic repulsion among protein molecules, pH, and ionic strength. The surface amine groups can be cross-linked using cross-linkers such as glutaraldehyde (Fig. The protonation or deprotonation of the surface amine groups can influence the degree of cross-linking (46). An increase in cross-linker concentration generally decreases the particle size of protein nanoparticles due to the formation of denser particles (48). Cross-linking helps in controlling the drug release from protein nanoparticles, as well as stabilizing the particles against prote- olytic breakdown. The surface functional groups can also be used to load drugs by electrostatic interactions (47). Kommareddy and Amiji (50) thiolated the surface amine groups to form disulfide bonds in gelatin nanoparticles. These nanoparticles can release their cargo under the highly reduc- ing environment in the tumor cells (50). Similarly, ligands have been attached to the surface of protein nanoparticles for drug targeting to specific tissues in the body (51,52). The surface functional groups in the protein can also directly interact with the biological membrane. Gliadin nanoparticles have been reported to show bioad- hesive property in the intestinal membrane, where the surface amino acids adhered to the intestinal membrane through hydrogen bonding and hydrophobic interac- tions (39). Drug Properties The physicochemical properties of the drug, such as solubility, log P, and molec- ular weight, influence the drug loading in protein nanoparticles. The drugs can be loaded through encapsulation in the nanoparticle or by the interaction of drug with the protein through covalent or noncovalent interactions.

Subfamilies are color- coded according to ligand type whereby the broad ligand types applied by 17 Gloriam et al buy cialis black 800 mg with amex erectile dysfunction studies. Legend: red – receptor with aminergic ligands; pink – peptide ligands; green – lipid ligands; dark blue – purinergic P2Y ligands; light blue – adenosine ligands; brown – melatonin ligands order 800mg cialis black mastercard erectile dysfunction treatment delhi. Subfamilies in this tree are more scattered; however, most subfamilies cluster together. This may imply that ligands for these receptor subtypes are non-selective, such as the adenosine receptor antagonists caffeine and theophylline. Additionally, receptor selectivity may vary with relatively small changes in ligand structure: an 8-cycloalkyl substituent on theophylline confers A1 receptor selectivity, whereas a phenylstyryl substituent on the same position in caffeine renders these compounds selective for the A2A receptor. The purinergic receptor P2Y12 is found near the adenosine receptors owing to the purine core typical for ligands of both these subfamilies. In agreement with the ligand selectivity reported for the α1-, α2-, and β-adrenoceptor subfamilies, these receptors form three distinct 26 clusters; furthermore, the α1B and α1D receptors are the closest in the distance matrix. This indicates the presence of distinct chemical classes in the ligand set of the M2 receptor, which may be the result of inclusion of allosteric ligands. In general, the remaining aminergic receptors (serotonergic, dopaminergic, histaminergic and cholinergic) are more scattered throughout the substructure tree. The grouping of the eight prostanoid receptors (Figure 2) indicates similarity in substructure profiles of the ligands. This is based on the fact that 35, 36 most prostanoid receptor ligands are direct derivatives of the endogenous ligands, the so-called eicosanoids. These ligands are highly similar, all consisting of large aliphatic, lipophilic alkyl chains. The presence of the leukotriene and cannabinoid receptors in this lipid cluster may seem strange at first. Leukotrienes are however also eicosanoids, which clarifies the position of the leukotriene B4 and cysteinyl-leukotriene 37, 38 receptors in this cluster. In addition, arachidonic acid is the common precursor for eicosanoids and two derivatives of arachidonic acid, anandamide and 2- arachidonylglycerol, both of which are endogenous ligands (‘endocannabinoids’) of the cannabinoid receptors. The relationship between target clustering in the substructure tree (Figure 2) and ligand promiscuity suggests that the substructure tree may be used to identify possible side effects on receptors that are close neighbors in this tree. If inspection reveals a ligand to bind to receptor(s) that are phylogenetically related to the target of interest, a more detailed experimental follow-up with respect to receptor selectivity would be worthwhile. For instance, with the exclusion of the glycoprotein, P2Y, angiotensin, and bradykinin receptors, all other receptors represented by two subtypes occur in pairs in both the ligand tree and the sequence tree. In addition, the prostanoid receptors largely group together in both trees, as do most of the aminergic receptors. D1 and D5 (D1-like) versus D2, D3, and D4 (D2-like), exists both in the sequence-based classification and 39 ligand-based classification. This is in agreement with a previous study and also known from drugs on the market such as the benzazepines that favor D1–like over D2-like dopamine receptors. Similarly, antipsychotics such as chlorpromazine have a higher 40 affinity for the D2-like subtypes than D1-like receptors. The fact that many clusters arise in both trees indicates that the receptors in these clusters have similar sequences and similar ligands, that is, ligands with substantially overlapping substructure sets. The (qualitative) similarities and differences among sequence and substructure trees are discussed in the following. This plot, provided in Figure 3 (and described in detail in the Materials and Methods section), visualizes how receptor distances deviate between the sequence-based tree and the ligand-based classification of receptors. In sequence space, receptor distances indicate the (dis)similarly between protein sequences, while in ligand space, receptor distances reflect the overlap in structural features found in ligands for these receptors. From the delta-delta plot, it becomes apparent that the prostanoid receptors and P2Y1 receptor are on average the most distant receptors from the rest of the classes. This may be a reflection of the evolutionary relationship between sequences, which results in coverage of a small region of the overall sequence space. The ligands for these targets do not have such a direct relationship and thus cover a broader range in overall substructure space. The difference between ligand-based and target-based classifications may be due to 43 convergent evolution. Functional convergence denotes how proteins that differ in sequence may fulfill the same protein function. These may therefore have a different selectivity profile compared to the endogenous ligand. Delta-delta plot visualization of receptor distances in sequence and substructure space. The average distance towards the other targets is plotted for sequence and substructure space. Targets that are, on average, more distant from the rest are plotted further away from the origin; targets plotted above the diagonal are more distant in sequence space, while targets plotted below the diagonal are more distant in substructure space. This indicates that this receptor is, in general, more distant from the other receptors, most prominent in sequence space. Example plots expressing the performance of the simulated receptor de-orphanization. The full set of plotted scores is provided in Additional file 2 – Plotted scores for the leave-one-out validation. For each plot, receptors are ordered along the x-axis (labeled “Number of included receptors”) in order of increasing distance in sequence space to the receptor under study. On the y-axis (labeled “Ligands identified”), the cumulative number of retrieved ligands is depicted, normalized linearly to the interval [0;1]. The red curve indicates the number of active ligands that are retrieved when including all (closest) receptors that are listed along the x-axis up to that point.

The effects of sensory deprivation and sensory bombardment on apparent movement thresholds cheap 800mg cialis black amex what causes erectile dysfunction cure. Effects of interruption of the visual pathway on the response to geniculate stimulation cialis black 800 mg free shipping erectile dysfunction caused by spinal stenosis. The Chinese indoctrination program for prisoners of war; A study of attempted brainwashing. This problem in communication is not an unfamiliar one to the psychiatrist, who often aims to recover unconscious conflicts or memories from the neurotic or psychotic patient in the hope of producing therapeutic benefit. Coercion may be used, however, if the patient is considered to be behaving in a manner that is destructive to himself (e. Furthermore, the code of ethics, particularly of the psychiatrist, ordinarily binds the physician to keep -96- confidential the secrets that his patients impart to him, whether or not the patient has been aware or unaware of their nature. In the practice of psychiatry, the code of respecting and keeping the confidences of a patient is considered to be a tool that facilitates the confession or expression of otherwise taboo material from the patient. In this position the physician may be forced to disqualify himself as a continuing confidant for the patient until the patient has remedied his social obligation to the state. Mentioning these situations and the customary attitude of the medical profession has a bearing on the substance of this report. The use of drugs in obtaining a confession from a criminal, or in obtaining information that a source may consciously wish to keep confidential for fear of repercussion to himself or his group, is fraught with ethical conflicts for the physician. This explains in part why there is a relative paucity of systematized published scientific investigation by physiciaits on this matter. The general feeling in western countries regarding the employment of chemical agents to "make people do things against their will" has precluded serious systematic study of the potentialities of drugs for interrogation. It has not, however, precluded considerable speculation on the subject, some of it rather unrealistic. Much relevant scientific information has been published on the therapeutic employment of drugs. The bulk of the medical articles of the last few years on the effects of drugs on behavior deals with the use and effects of these drugs on the mentally ill population. In fact, a growing avalanche of articles of this type sprang up with the advent of tranquilizing drugs. From this large body of publications, the reviewer aims to extrapolate to the problems of interrogation. Then, there is a notably smaller group of studies that deals principally wiih explorations in methods of assessing the psychopharma- -97- cologic effects of drugs on relatively normal individuals. From these studies, too, the reviewer aims to transfer what has been learned to the problems of interrogation. Finally, there are the relatively rare published investigations on the use of drugs for purposes of interrogation in police or security procedures; these are reviewed carefully because of their direct relevance. No published reports have come to the attention of this author detailing the scientific application of drugs by intelligence agencies of any nation as a means of obtaining information. Apparently, what knowledge is available, whether derived from haphazard experience or systematic study, is not accessible in open sources. Rolin (112) casually claims that the Nazis used mescaline to get information from prisoners at Dachau. In discussing the methods of communist indoctrination of Americans who have fallen into the hands of communists or communist-controlled countries, Hinkle (62) has stated that the methods of Russian interrogation and indoctrination are derived from age-old police methods that have been systematized, and are not dependent on drugs, 1 hypnotism, or any other special procedure designed by scientists. Methodological Problems in Determining the Applicability of Drugs to Interrogation Procedures: Nonspecific Effects of Drugs on Verbal Behavior One of the crucial questions arising in evaluating the use of a drug for interrogation techniques is what responses are related to the pharmacologic activity of the drug administered and what responses are related to some other aspects of the transactions taking place when a person receives medication from another person. A large variety of nonpharmacologic factors can affect the responses of an individual after getting a dose of medication (see also Masserman and Pechtel, 102). In fact, one of the major problems plaguing investigators of 1 Popular literature contains a number of accounts alleging the use of drugs in interrogations. Recent well-publicized examples include the alleged use of mescaline against Cardinal Mindszenty (S. Ryan, I came back from a Red death cell, Saturday Evening Post, January 17, 24, 31, and February 7, 1953); and the account by the Communist editor, Henri Alleg, of an alleged use of sodium pentothal in interrogations he received while held by French forces in Algeria (H. A series of nonpharmacologic factors within the total transaction of a person giving another person a drug has been found to be more or less capable of contributing to the responses occurring with administration of the drug. These factors may be listed and what is known about each will be taken up separately. Reactions to attitudes or motivations of the person administering the medication and interacting with the informant. The studies of Beecher and his group (7, 8) indicate that 30 to 50 per cent of individuals are placebo reactors, that is, respond with symptomatic relief to taking an inert substance. If one is interested in the pharmacology of a new drug and tries it out on a group of patients, a third to a half of this group will be relieved of their symptoms by a placebo; they react favorably to the syringe, pills or capsule, regardless of what it contains. Thus they dilute the significant data derived from the half or two-thirds of the group that react only to the active ingredient in the syringe or capsule. In studying a new drug-whether one is interested in applying its pharniacologic effect toward the alleviation of pain, amelioration of emotional distress, or the facilitation of communication of covert information-the scientist is not primarily interested in the subjective and behavioral effects of syringes and pills. Thus the scientist is obliged to take into account the placebo reactors, who must be screened out if one is to get an accurate idea of what the drug itself does. Of course, to relieve pain or facilitate communication in a patient or prisoner, the "placebo phenomenon" can be made use of itself and -99- the investigator can expect that in 30 to 50 per cent of trials pain may be relieved or interrogation may be facilitated.

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