Protein aggregation is a biological phenomenon in which mis-folded proteins aggregate either intra- or extracellularly. These protein aggregates are correlated with diseases. In fact, protein aggregates have been implicated in a wide variety of disease known as amyloidoses, including ALS, Alzheimer's, Parkinson's and prion disease. After synthesis, proteins fold into a particular three-dimensional conformation, the most thermodynamically favorable: their native state; this folding process is driven by the hydrophobic effect: a tendency for hydrophobic portions of the protein to shield themselves from the hydrophilic environment of the cell by burying into the interior of the protein. Thus, the exterior of a protein is hydrophilic, whereas the interior is hydrophobic. Protein structures are stabilized by non-covalent interactions and disulfide bonds between two cysteine residues; the non-covalent interactions include weak van der waals interactions. Ionic interactions form between an anion and a cation and form salt bridges that help stabilize the protein.
Van der waals interactions include polar interactions. These play an important role in a protein's secondary structure, such as forming an alpha helix or a beta sheet, tertiary structure. Interactions between amino acid residues in a specific protein are important in that protein's final structure; when there are changes in the non-covalent interactions, as may happen with a change in the amino acid sequence, the protein is susceptible to misfolding or unfolding. In these cases, if the cell does not assist the protein in re-folding, or degrade the unfolded protein, the unfolded/misfolded protein may aggregate, in which the exposed hydrophobic portions of the protein may interact with the exposed hydrophobic patches of other proteins. There are three main types of protein aggregates that may form: amorphous aggregates and amyloid fibrils. Protein aggregation can occur due to a variety of causes. There are four classes which are detailed below. Mutations that occur in the DNA sequence may or may not affect the amino acid sequence of the protein.
When the sequence is affected, a different amino acid may change the interactions between the side chains that affect the folding of the protein. This can lead to exposed hydrophobic regions of the protein that aggregate with the same misfolded/unfolded protein or a different protein. In addition to mutations in the affected proteins themselves, protein aggregation could be caused indirectly through mutations in proteins in regulatory pathways such as the refolding pathway or the ubiquitin-proteasome pathway. Chaperones help with protein refolding by providing a safe environment for the protein to fold. Ubiquitin ligases target proteins for degradation through ubiquitin modification. Protein aggregation can be caused by problems that occur during translation. During transcription, DNA is copied into mRNA, forming a strand of pre-mRNA that undergoes RNA processing to form mRNA. During translation, ribosomes and tRNA help translate the mRNA sequence into an amino acid sequence. If problems arise during either step, making an incorrect mRNA strand and/or an incorrect amino acid sequence, this can cause the protein to misfold, leading to protein aggregation.
Environmental stresses such as extreme temperatures and pH or oxidative stress can lead to protein aggregation. One such disease is cryoglobulinemia. Extreme temperatures can weaken and destabilize the non-covalent interactions between the amino acid residues. PHs outside of the protein's pH range can change the protonation state of the amino acids, which can increase or decrease the non-covalent interactions; this can lead to less stable interactions and result in protein unfolding. Oxidative stress can be caused by radicals such as reactive oxygen species; these unstable radicals can attack the amino acid residues, leading to oxidation of side chains and/or cleavage of the polypeptide bonds. This can affect the non-covalent interactions that hold the protein together which can cause protein destabilization, may cause the protein to unfold. Cells have mechanisms that can degrade protein aggregates. However, as cells age, these control mechanisms are weakened and the cell is less able to resolve the aggregates.
The hypothesis that protein aggregation is a causative process in aging is testable now since some models of delayed aging are in hand. If the development of protein aggregates was an aging independent process, slowing down aging will show no effect on the rate of proteotoxicity over time. However, if aging is associated with decline in the activity of protective mechanisms against proteotoxicity, the slow aging models would show reduced aggregation and proteotoxicity. To address this problem several toxicity assays have been done in C. elegans. These studies indicated that reducing the activity of insulin/IGF signaling, a prominent aging regulatory pathway protects from neurodegeneration-linked toxic protein aggregation; the validity of this approach has been tested and confirmed in mammals as reducing the activity of the IGF-1 signaling pathway protected Alzheimer's model mice from the behavioral and biochemical impairments associated with the disease. Several studies have shown that cellular responses to protein aggregation are well-regulated and organized.
Protein aggregates localize to specific areas in the cell, research has been done on these localizations in prokaryotes (E.c
Aggregation was a Canadian online magazine published between 2010 and 2012. Each issue collected together stories and trends from five contributors based on hyperlinks they'd discover on the web, it was one of the first Canadian publications designed for Apple's iPad. Aggregation was published by Gary Campbell, it was released online, for free, on the 15th of the month for six consecutive months, from November 2010 to April 2011. After an eight-month hiatus, Campbell announced; that issue was published in August 2012 while Campbell was living in New York City. There has been no indication; each magazine cover featured a unique piece of interactive artwork by Campbell. The publication's design took advantage of the multimedia nature of tablets by including touch-sensitive and video elements; each issue's contributors were paid for their work through an honorarium to their charity of choice. The publication raised several thousand dollars for Canadian charities far and wide. Other staff involved in the project included Laura Kathleen Maize and Rani Sheen.
In a year-end article in Masthead magazine, Canadian Living magazine editor-in-chief Jennifer Reynolds cited Aggregation, alongside other digital magazines The Kit and Covet Garden, as one of the most fascinating moments in Canadian magazine publishing in 2010. Toronto's Eye Weekly included it in a list of required reading, as did Torontoist and numerous other blogs. Aggregation was a finalist for best tablet magazine at the 2011 Canadian Online Publishing AwardsIn 2012, Campbell was invited to speak about the magazine as an example of the changing the media landscape at the Toronto Digifest conference. Aggregation magazine web site
Particle agglomeration refers to formation of assemblages in a suspension and represents a mechanism leading to destabilization of colloidal systems. During this process, particles dispersed in the liquid phase stick to each other, spontaneously form irregular particle clusters, flocs, or aggregates; this phenomenon is referred to as coagulation or flocculation and such a suspension is called unstable. Particle aggregation can be induced by adding salts or an other chemical referred to as coagulant or flocculant; some people refer to flocculation when aggregation is induced by addition of polymers or polyelectrolytes, while coagulation is used in a broader sense. Particle aggregation is an irreversible process. Once particle aggregates have formed, they will not disrupt. In the course of aggregation, the aggregates will grow in size, as a consequence they may settle to the bottom of the container, referred to as sedimentation. Alternatively, a colloidal gel may form in concentrated suspensions which changes its rheological properties.
The reverse process whereby particle aggregates are disrupted and dispersed as individual particles, referred to as peptization, hardly occurs spontaneously, but may occur under stirring or shear. Colloidal particles may remain dispersed in liquids for long periods of time; this phenomenon is referred to as colloidal stability and such a suspension is said to be stable. Stable suspensions are obtained at low salt concentrations or by addition of chemicals referred to as stabilizers or stabilizing agents. Similar aggregation processes occur in other dispersed systems too. In emulsions, they may be coupled to droplet coalescence, not only lead to sedimentation but to creaming. In aerosols, airborne particles may aggregate and form larger clusters. A well dispersed colloidal suspension consists of individual, separated particles and is stabilized by repulsive inter-particle forces; when the repulsive forces weaken or become attractive through the addition of a coagulant, particles start to aggregate.
Particle doublets A2 will form from singlets A1 according to the scheme A1 + A1 → A2In the early stage of the aggregation process, the suspension contains particle monomers and some dimers. The rate of this reaction is characterized by the aggregation rate coefficient k. Since doublet formation is a second order rate process, the units of this coefficients are m3s−1 since particle concentrations are expressed as particle number per unit volume. Since absolute aggregation rates are difficult to measure, one refers to the dimensionless stability ratio W = kfast/k where kfast is the aggregation rate coefficient in the fast regime, k the coefficient at the conditions of interest; the stability ratio is close to unity in the fast regime, increases in the slow regime, becomes large when the suspension is stable. When the interaction potential between the particles is purely attractive, the aggregation process is limited by mutual diffusion of the particles, one refers to fast, rapid or diffusion limited aggregation.
When the interaction potential shows an intermediate barrier, the aggregation is slowed down by the fact that numerous attempts will be necessary to overcome this barrier, one refers to slow or reaction limited aggregation. The aggregation can be tuned from fast to slow by varying the concentration of salt, pH, or an other additive. Since the transition from fast to slow aggregation occurs in a narrow concentration range, one refers to this range as the critical coagulation concentration. Colloidal particles are suspended in water. In this case, they accumulate a surface charge and an electrical double layer forms around each particle; the overlap between the diffuse layers of two approaching particles results in a repulsive double layer interaction potential, which leads to particle stabilization. When salt is added to the suspension, the electrical double layer repulsion is screened, van der Waals attraction become dominant and induce fast aggregation; the figure on the right shows the typical dependence of the stability ratio W versus the electrolyte concentration, whereby the regimes of slow and fast aggregation are indicated.
The table below summarizes CCC ranges for different net charge of the counter ion. The charge is expressed in units of elementary charge; this dependence reflects the Schulze-Hardy rule, which states that the CCC varies as the inverse sixth power of the counter ion charge. The CCC depends on the type of ion somewhat if they carry the same charge; this dependence may reflect different particle properties or different ion affinities to the particle surface. Since particles are negatively charged, multivalent metal cations thus represent effective coagulants. Adsorption of oppositely charged species may destabilize a particle suspension by charge neutralization or stabilize it by buildup of charge, leading to a fast aggregation near the charge neutralization point, slow aggregation away from it. Quantitative interpretation of colloidal stability was first formulated within the DLVO theory; this theory confirms the existence slow and fast aggregation regimes though in the slow regime the dependence on the salt concentration is predicted to be much stronger than observed experimentally.
The Schulze-Hardy rule can be derived from DLVO theory as well. Other mechanisms of colloid stabilization are possible involving polymers. Adsorbed or grafted polymers may form a protective layer around the particles, induce steric repulsive forces, lead to steric stabilization at it
A pheromone is a secreted or excreted chemical factor that triggers a social response in members of the same species. Pheromones are chemicals capable of acting like hormones outside the body of the secreting individual, to impact the behavior of the receiving individuals. There are alarm pheromones, food trail pheromones, sex pheromones, many others that affect behavior or physiology. Pheromones are used from basic unicellular prokaryotes to complex multicellular eukaryotes, their use among insects has been well documented. In addition, some vertebrates and ciliates communicate by using pheromones; the portmanteau word "pheromone" was coined by Peter Karlson and Martin Lüscher in 1959, based on the Greek φερω pheroo and ὁρμων hormon. Pheromones are sometimes classified as ecto-hormones, they were researched earlier by various scientists, including Jean-Henri Fabre, Joseph A. Lintner, Adolf Butenandt, ethologist Karl von Frisch who called them various names, like for instance "alarm substances".
These chemical messengers are transported outside of the body and affect neurocircuits, including the autonomous nervous system with hormone or cytokine mediated physiological changes, inflammatory signaling, immune system changes and/or behavioral change in the recipient. They proposed the term to describe chemical signals from conspecifics that elicit innate behaviors soon after the German biochemist Adolf Butenandt had characterized the first such chemical, bombykol, a chemically well-characterized pheromone released by the female silkworm to attract mates. Aggregation pheromones function in mate selection, overcoming host resistance by mass attack, defense against predators. A group of individuals at one location is referred to as an aggregation, whether consisting of one sex or both sexes. Male-produced sex attractants have been called aggregation pheromones, because they result in the arrival of both sexes at a calling site and increase the density of conspecifics surrounding the pheromone source.
Most sex pheromones are produced by the females. Aggregation pheromones have been found in members of the Coleoptera, Hemiptera and Orthoptera. In recent decades, the importance of applying aggregation pheromones in the management of the boll weevil, stored product weevils, Sitophilus granarius, Sitophilus oryzae, pea and bean weevil has been demonstrated. Aggregation pheromones are among the most ecologically selective pest suppression methods, they are nontoxic and effective at low concentrations. Some species release a volatile substance when attacked by a predator that can trigger flight or aggression in members of the same species. For example, Vespula squamosa use alarm pheromones to alert others to a threat. In Polistes exclamans, alarm pheromones are used as an alert to incoming predators. Pheromones exist in plants: Certain plants emit alarm pheromones when grazed upon, resulting in tannin production in neighboring plants; these tannins make the plants less appetizing for the herbivore.
Epideictic pheromones are different from territory pheromones. Fabre observed and noted how "females who lay their eggs in these fruits deposit these mysterious substances in the vicinity of their clutch to signal to other females of the same species they should clutch elsewhere." It may be helpful to note that the word epideictic, having to do with display or show, has a different but related meaning in rhetoric, the human art of persuasion by means of words. Releaser pheromones are pheromones. For example, some organisms use powerful attractant molecules to attract mates from a distance of two miles or more. In general, this type of pheromone elicits a rapid response, but is degraded. In contrast, a primer pheromone has a longer duration. For example, rabbit release mammary pheromones that trigger immediate nursing behavior by their babies. Signal pheromones cause short-term changes, such as the neurotransmitter release that activates a response. For instance, GnRH molecule functions as a neurotransmitter in rats to elicit lordosis behavior.
Primer pheromones trigger a change of developmental events. Laid down in the environment, territorial pheromones mark the boundaries and identity of an organism's territory. In cats and dogs, these hormones are present in the urine, which they deposit on landmarks serving to mark the perimeter of the claimed territory. In social seabirds, the preen gland is used to mark nests, nuptial gifts, territory boundaries with behavior described as'displacement activity'. Social insects use trail pheromones. For example, ants mark their paths with pheromones consisting of volatile hydrocarbons. Certain ants lay down an initial trail of pheromones; this trail serves as a guide. As long as the food source remains available, visiting ants will continuously renew the pheromone trail; the pheromone requires continuous renewal. When the food supply begins to dwindle, the trail-making ceases. In at least one species of ant, trails that no longer lead to food are marked with a repellent pheromone; the Eciton burchellii species provides an example of using pheromones to mark and maintain foraging paths.
When species of wasps such as Polybia sericea found new nests, they use pheromones to lead the rest of the