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Technical Solutions for Bio-Measurements

Technical Solutions for Bio-Measurements Biological processes are controlled automatically. Registration of signals and measuring their relative strength is hence a key problem. Receptors may be relatively simple or complex. The complexity is the direct response to ambiguity of signals. If there is however a common feature of diverse signals a construction of generic receptor mechanism is usually observed. Combinatorial technique is commonly used in biological systems to decrease the complexity in reception of highly ambiguous signals. KEYWORDS: information entropy, signalling, biological clock The mechanisms of biology are founded upon the principles of physics and chemistry. We should therefore expect signal receptors to resemble their technological counterparts, possibly with some unique properties related to their biological nature. The primary difference lies in the materials which make up living organisms, a significant portion of which consists of proteins. Accordingly, proteins are often encountered as components of detector and effector systems in living tissues, while the role of signals falls to simple molecules, including ions (usually calcium, but also sodium, potassium and other elements). The great diversity of proteins has enabled evolution to perfect many different protein-based receptors, enzymes, motive structures, framework lattices and other constructs. Proteins are polymers which consist of amino acids and fold into solidlike shapes (called native forms) with binding pockets to facilitate their intended function. In order for a protein to fold properly, the presence of water is necessary ­ this fact is of great importance to many different biological systems. Detector subunits often employ allosteric proteins whose structure changes as a result of interaction with a ligand, enabling the signal to propagate. Such proteins exhibit two distinct (but similarly stable) conformations. Transition from one conformation to another is triggered by interaction with a ligand which, in turn, depends on the concentration of ligands in the protein's environment. The most frequently observed use of allosteric proteins is to measure the concentrations of various components in cellular metabolic pathways. This phenomenon enables the cell (as well as the organism as a whole) to regulate and control its own metabolism. A single-signal receptor is usually a simple structure, with an activation threshold dependent on its affinity for a particular ligand. However, as signals become more ambiguous, the complexity of detector subunits increases (note that unambiguous signal detection is a crucial concern given the potential consequences of misinterpretation and the need to ensure efficient operation of cellular machinery). A quantitative measure of information ambiguity can be derived from Shannon's formula: I i log 2 pi [bit] where: Ii ­ amount of information (bit) carried by event of the probability pi. Logarithm with the base "2" makes bit the unit of I. The amount of information measured in bits is assumed to be dependent on probability of the event under consideration. The event of low probability is carrying more information than the event which is more probable proportionally according to logarithmic dependency. The event of probability =1 (the sure event) is carrying 0 bits. The limited information capacity of genomes makes it difficult to effectively store the enormous quantity of information required by living organisms. Perhaps unsurprisingly, evolution has shaped effective (though generic) information storage solutions which are shared across multiple branches of animal and plant taxonomy. Information entropy and its influence on the properties of measurement systems Most intracellular and intercellular signals are characterized by three key properties: unambiguity, predetermination and predictability. As a result, registering and measuring the relative strength of each signal may be performed using relatively simple mechanisms. Unambiguity is a result of operation in a well-defined environment under homeostatic conditions, characteristic of most biological processes. If the signal grows more ambiguous, the system used to register and measure its strength needs to increase in complexity. Two solutions are possible in such circumstances: A ­ further development of the receptor/detector unit (usually by increasing the number of subunits capable of identifying signal carriers); B ­ seeking common properties among various signals to simplify the signal detection process through the use of generic mechanisms. As it turns out, the latter solution is more attractive and has been preferentially selected by evolution. It should also be noted that detection of internal signals (triggered by the organism itself) follows somewhat different principles than detection of external signals (arriving from beyond the organism). This distinction is presented in more detail below. Internal signal detection Internal signals are typically characterized by low ambiguity, although there are exceptions ­ some signals can become quite ambiguous as a result of the natural fallibility of biological systems. Internal signal detection often relies on exploiting common properties of various signal carriers. One example is identification of misfolded proteins by detecting fragments of polypeptide chains rich in nonpolar residues and basic amino acids ­ such residues are usually internalized and therefore not available for detection in properly folded molecules [1-5] (Figure 1). In this case the signal is triggered by aggregation of detectors suspended in the endoplasmic reticulum. Similarly to many other detection processes, the pathway exhibits an activation threshold (dependent on the degree of oligomerization), which protects the cell from undesirable and potentially harmful overreaction to random stimuli. Another interesting solution can be observed in the process of detecting and purging proteolytic enzymes which penetrate into the bloodstream from the digestive tract or are released by dying cells. The defining property of these enzymes, i.e. their ability to degrade proteins, can be exploited to detect and neutralize them, preventing harmful interactions with living tissues. To this end, special proteins called serpins are present in blood. The serpin molecule lies dormant until it comes into contact with a proteolytic enzyme, at which point it acts like a mousetrap: the enzyme cleaves a specially exposed peptide bond within the protein body, converting it to its active form. Once activated, the serpin responds by forming a complex with the enzyme, resulting in its deactivation [6]. Figure 1. Conveying information about the strength of the signal and/or determining the tolerance threshold by controlling the density of signal receptors in the cellular membrane: the receptor detects misfolded proteins and measures their concentration. Inset: model view of receptor oligomerization. Black dot: chaperone protein which prevents receptors from aggregating when no pathological proteins are present. Another mechanism worth mentioning is DNA repair, which proceeds in a similar fashion regardless of the sequences involved and the location of strand breaks. Once a break is created (which is a fairly common occurrence), the presence of "dangling" ends triggers repair mechanisms which act to correct the problem [7-10]. Of note are also blood coagulation mechanisms which represent an interesting middle ground between universality and specificity: they can respond to a perceived discontinuity of the tunica media layer (intrinsic pathway) or to signals released by traumatized tissue (extrinsic pathway) [1113]. Receptors and measurement systems interacting with the external environment Signals arriving from beyond the organism are typically characterized by high information entropy, necessitating more complex receptors. In shaping ever more sophisticated detection mechanisms nature seems to rely on the principles of combinatorial optimization wherein a large set of specific interactions replaces a single "catch-all" solution. One example of this process is the sense of smell, where the structure of olfactory receptors depends on a very large pool of genes (approximately 1,000-1,300). Individual olfactory receptors transmit their signals to specific clusters of neurons with very little overlap, resulting in a mosaic-like "smell projection" emerging in the brain. There is a great variety of potential smells, each dependent on different chemicals (such as can be found in e.g. fruit or flowers) and each corresponding to a different projection pattern [12,13]. Unlike a simple receptor attuned to one specific signal, the perception of smell relies on combinations of diverse stimuli, resulting in a vast range of possible results (especially given the genetic diversity of olfactory receptors). A similar "mosaic" model can be discerned in taste perception. While the selectivity of taste buds is narrower than that of olfactory receptors, the subjective sensation is additionally dependent on the perceived smell, appearance and temperature of food, all of which contributes to increased diversity of tastes. Still, both presented examples pale in comparison to the flexibility of immunological response systems which must account for the indeterminate nature of antigens entering the organism. Here, combinatorial principles are applied to gene fragments rather than entire genes, resulting in an even greater diversity of proteins. Evolution has succeeded in devising a mechanism which can produce arbitrary antibodies without the need to store corresponding genetic sequences for each and every antibody. This mechanism enables the immune system to effectively counter various antigens without imposing undue burden on the genome (Figure 2). Antibody synthesis is a highly dynamic process. Unlike in smell perception, recombinant genes are not permanently stored. Instead, they are immediately consumed to produce small but diverse populations of lymphocytes. Those lymphocytes which prove capable of interacting with the target antigen begin to multiply and produce antibodies. Coupled with the sharply upregulated mutagenesis inherent in antibody production this phenomenon yields approximately 109 ­ 1011 distinct immunological response modes, covering the entire spectrum of potential antigens. Figure 2. Combinatorial optimization as applied to stochastic selection of DNA fragments in the light and heavy chain assembly process, as well as in the synthesis of immunoglobulins. Biological specificity of sensory organs Sensory organs, such as the nose, eye or ear, possess structural properties related to their function. For example, the structure of the nose must prevent mucus membranes from drying up as a result of permanent contact with air while ensuring that its sensory cells can continue to register volatile (and mostly nonpolar) information carriers. This is why interaction between receptors and ligands is mediated by nonspecific carrier proteins suspended in the mucus which typically covers nasal membranes [14,15]. A peculiar ­ and seemingly paradoxical ­ solution manifests itself in the structure of the eye, where photoreceptors are positioned distally with respect to the direction of incoming photons. There is an intervening layer of nerve fibers and auxiliary cells between the source of light and the retinal receptor layer [16]. This structure, while counterintuitive, results from the nature of biological receptors, which ­ unlike manmade technologies ­ are in fact living tissues. The photoreceptive layer must be constantly replenished on one side, while its used-up fragments must be accordingly disposed of on the opposite side. This task falls to the so-called pigmented layer, placed distally with respect to the path of light. Live receptors are "paradoxically" overlaid by another layer of tissue involved in propagation of optical signals (Figure 3). Light reaches receptor cells having passed through an occluding layer of support cells and is preferentially absorbed by freshly synthesized pigment layers. In turn, old receptor cells are found near the bottom of the retina, close to another support layer which degrades residual pigment and attenuates any remaining light so as not to confuse active receptors. Figure 3. Schematic cross-section of the retina, indicating cell layers which occlude the receptor layer. Special constructs as an adaptation to special biological requirements The flexibility of biological constructs manifests itself whenever adaptation to unusual environmental conditions is necessary. Consider the spider Hasarius Adansoni, which captures its prey as a result of a precisely measured leap. Judging the leap distance requires keen depth perception which, in turn, calls for specialized ocular receptors. Unlike most insect species which possess relatively primitive eyes, the spider has evolved a complex eye, with a retina composed of four distinct layers and a lens which exhibits significant chromatic aberration. The aberration separates incoming light into spectral bands, one of which (the green band) is registered by the second and fourth layers of the retina as a means of judging distance. Light is initially focused in the fourth layer but the image becomes blurry in the second layer. Consequently, the degree to which such blurring can be counteracted by refocusing the image in the second layer provides a useful measure of distance [17]. When illuminated by pure red light the spider becomes incapable of capturing its prey. Another example of a specialized detection system can be found in plants which have evolved UV light detectors (note that ultraviolet radiation is potentially harmful to nucleic acids). Most plants exploit the visible spectrum as an energy source and information carrier, employing detectors which consists of proteins bound to various chromophores. UV detection is, however, mediated by amino acids alone, and more specifically ­ by a special bond between an aromatic and a basic aminoacid, known as the cation- interaction. This interaction can be broken as a result of photon absorption by the aromatic component of the complex. As a result, a dimeric protein may decompose into its constituent subunits, triggering an actionable signal [18]. Other examples of environmental adaptation in biological systems include e.g. the IR-sensitive parietal eye in reptiles and magnetic field receptors in birds [19-22]. Measuring time Time measurement in biology is usually discussed in the context of aging and senescence. However, a far more precise time base is required for processes which depend on the circadian rhythm, both within individual cells and in the organism as a whole. The need to measure the passage of time has resulted in biological clocks. At the core of each clock lies an oscillator with a stable, predetermined frequency and a reset feature. Biological clocks are needed to synchronize processes whose intensity varies along with the alertness level of the organism, ensuring that these processes do not accidentally contravene one another. Biological oscillators rely on two protein synthesis process which occur out of phase with each other but remain correlated in such a way that the product of one process ­ having reached a predetermined concentration threshold ­ triggers the opposite process while at the same time downregulating its own synthesis [23,24]. It should be noted that individual molecules of each product do not directly function as signal carriers ­ rather, the signal is a consequence of the product reaching a predetermined concentration in the surrounding environment (Figure 4). The specific conditions under which both complexes can emerge enable rapid generation and degradation of signals, thus satisfying the unambiguity criterion. The entire mechanism can therefore be described as a self-controlling process. Circadian clocks can also be reset by perceived changes in ambient light, associated with the day-night cycle. Figure 4. Model view of a biological clock as compared to the action of a pendulum. Bars indicate changes in the concentrations of products of coupled synthesis processes (labeled I and II). The phase displacement of both processes is also illustrated. Rhythmic oscillations are commonly found in technical and biological systems as the fundamental element in synchronisation of different processes. It seems however that only circadian rhythms correspond fully to the clock mechanism as only in this case resetting based on independent timerelated signals is involved [24-26]. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Bio-Algorithms and Med-Systems de Gruyter

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de Gruyter
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Abstract

Biological processes are controlled automatically. Registration of signals and measuring their relative strength is hence a key problem. Receptors may be relatively simple or complex. The complexity is the direct response to ambiguity of signals. If there is however a common feature of diverse signals a construction of generic receptor mechanism is usually observed. Combinatorial technique is commonly used in biological systems to decrease the complexity in reception of highly ambiguous signals. KEYWORDS: information entropy, signalling, biological clock The mechanisms of biology are founded upon the principles of physics and chemistry. We should therefore expect signal receptors to resemble their technological counterparts, possibly with some unique properties related to their biological nature. The primary difference lies in the materials which make up living organisms, a significant portion of which consists of proteins. Accordingly, proteins are often encountered as components of detector and effector systems in living tissues, while the role of signals falls to simple molecules, including ions (usually calcium, but also sodium, potassium and other elements). The great diversity of proteins has enabled evolution to perfect many different protein-based receptors, enzymes, motive structures, framework lattices and other constructs. Proteins are polymers which consist of amino acids and fold into solidlike shapes (called native forms) with binding pockets to facilitate their intended function. In order for a protein to fold properly, the presence of water is necessary ­ this fact is of great importance to many different biological systems. Detector subunits often employ allosteric proteins whose structure changes as a result of interaction with a ligand, enabling the signal to propagate. Such proteins exhibit two distinct (but similarly stable) conformations. Transition from one conformation to another is triggered by interaction with a ligand which, in turn, depends on the concentration of ligands in the protein's environment. The most frequently observed use of allosteric proteins is to measure the concentrations of various components in cellular metabolic pathways. This phenomenon enables the cell (as well as the organism as a whole) to regulate and control its own metabolism. A single-signal receptor is usually a simple structure, with an activation threshold dependent on its affinity for a particular ligand. However, as signals become more ambiguous, the complexity of detector subunits increases (note that unambiguous signal detection is a crucial concern given the potential consequences of misinterpretation and the need to ensure efficient operation of cellular machinery). A quantitative measure of information ambiguity can be derived from Shannon's formula: I i log 2 pi [bit] where: Ii ­ amount of information (bit) carried by event of the probability pi. Logarithm with the base "2" makes bit the unit of I. The amount of information measured in bits is assumed to be dependent on probability of the event under consideration. The event of low probability is carrying more information than the event which is more probable proportionally according to logarithmic dependency. The event of probability =1 (the sure event) is carrying 0 bits. The limited information capacity of genomes makes it difficult to effectively store the enormous quantity of information required by living organisms. Perhaps unsurprisingly, evolution has shaped effective (though generic) information storage solutions which are shared across multiple branches of animal and plant taxonomy. Information entropy and its influence on the properties of measurement systems Most intracellular and intercellular signals are characterized by three key properties: unambiguity, predetermination and predictability. As a result, registering and measuring the relative strength of each signal may be performed using relatively simple mechanisms. Unambiguity is a result of operation in a well-defined environment under homeostatic conditions, characteristic of most biological processes. If the signal grows more ambiguous, the system used to register and measure its strength needs to increase in complexity. Two solutions are possible in such circumstances: A ­ further development of the receptor/detector unit (usually by increasing the number of subunits capable of identifying signal carriers); B ­ seeking common properties among various signals to simplify the signal detection process through the use of generic mechanisms. As it turns out, the latter solution is more attractive and has been preferentially selected by evolution. It should also be noted that detection of internal signals (triggered by the organism itself) follows somewhat different principles than detection of external signals (arriving from beyond the organism). This distinction is presented in more detail below. Internal signal detection Internal signals are typically characterized by low ambiguity, although there are exceptions ­ some signals can become quite ambiguous as a result of the natural fallibility of biological systems. Internal signal detection often relies on exploiting common properties of various signal carriers. One example is identification of misfolded proteins by detecting fragments of polypeptide chains rich in nonpolar residues and basic amino acids ­ such residues are usually internalized and therefore not available for detection in properly folded molecules [1-5] (Figure 1). In this case the signal is triggered by aggregation of detectors suspended in the endoplasmic reticulum. Similarly to many other detection processes, the pathway exhibits an activation threshold (dependent on the degree of oligomerization), which protects the cell from undesirable and potentially harmful overreaction to random stimuli. Another interesting solution can be observed in the process of detecting and purging proteolytic enzymes which penetrate into the bloodstream from the digestive tract or are released by dying cells. The defining property of these enzymes, i.e. their ability to degrade proteins, can be exploited to detect and neutralize them, preventing harmful interactions with living tissues. To this end, special proteins called serpins are present in blood. The serpin molecule lies dormant until it comes into contact with a proteolytic enzyme, at which point it acts like a mousetrap: the enzyme cleaves a specially exposed peptide bond within the protein body, converting it to its active form. Once activated, the serpin responds by forming a complex with the enzyme, resulting in its deactivation [6]. Figure 1. Conveying information about the strength of the signal and/or determining the tolerance threshold by controlling the density of signal receptors in the cellular membrane: the receptor detects misfolded proteins and measures their concentration. Inset: model view of receptor oligomerization. Black dot: chaperone protein which prevents receptors from aggregating when no pathological proteins are present. Another mechanism worth mentioning is DNA repair, which proceeds in a similar fashion regardless of the sequences involved and the location of strand breaks. Once a break is created (which is a fairly common occurrence), the presence of "dangling" ends triggers repair mechanisms which act to correct the problem [7-10]. Of note are also blood coagulation mechanisms which represent an interesting middle ground between universality and specificity: they can respond to a perceived discontinuity of the tunica media layer (intrinsic pathway) or to signals released by traumatized tissue (extrinsic pathway) [1113]. Receptors and measurement systems interacting with the external environment Signals arriving from beyond the organism are typically characterized by high information entropy, necessitating more complex receptors. In shaping ever more sophisticated detection mechanisms nature seems to rely on the principles of combinatorial optimization wherein a large set of specific interactions replaces a single "catch-all" solution. One example of this process is the sense of smell, where the structure of olfactory receptors depends on a very large pool of genes (approximately 1,000-1,300). Individual olfactory receptors transmit their signals to specific clusters of neurons with very little overlap, resulting in a mosaic-like "smell projection" emerging in the brain. There is a great variety of potential smells, each dependent on different chemicals (such as can be found in e.g. fruit or flowers) and each corresponding to a different projection pattern [12,13]. Unlike a simple receptor attuned to one specific signal, the perception of smell relies on combinations of diverse stimuli, resulting in a vast range of possible results (especially given the genetic diversity of olfactory receptors). A similar "mosaic" model can be discerned in taste perception. While the selectivity of taste buds is narrower than that of olfactory receptors, the subjective sensation is additionally dependent on the perceived smell, appearance and temperature of food, all of which contributes to increased diversity of tastes. Still, both presented examples pale in comparison to the flexibility of immunological response systems which must account for the indeterminate nature of antigens entering the organism. Here, combinatorial principles are applied to gene fragments rather than entire genes, resulting in an even greater diversity of proteins. Evolution has succeeded in devising a mechanism which can produce arbitrary antibodies without the need to store corresponding genetic sequences for each and every antibody. This mechanism enables the immune system to effectively counter various antigens without imposing undue burden on the genome (Figure 2). Antibody synthesis is a highly dynamic process. Unlike in smell perception, recombinant genes are not permanently stored. Instead, they are immediately consumed to produce small but diverse populations of lymphocytes. Those lymphocytes which prove capable of interacting with the target antigen begin to multiply and produce antibodies. Coupled with the sharply upregulated mutagenesis inherent in antibody production this phenomenon yields approximately 109 ­ 1011 distinct immunological response modes, covering the entire spectrum of potential antigens. Figure 2. Combinatorial optimization as applied to stochastic selection of DNA fragments in the light and heavy chain assembly process, as well as in the synthesis of immunoglobulins. Biological specificity of sensory organs Sensory organs, such as the nose, eye or ear, possess structural properties related to their function. For example, the structure of the nose must prevent mucus membranes from drying up as a result of permanent contact with air while ensuring that its sensory cells can continue to register volatile (and mostly nonpolar) information carriers. This is why interaction between receptors and ligands is mediated by nonspecific carrier proteins suspended in the mucus which typically covers nasal membranes [14,15]. A peculiar ­ and seemingly paradoxical ­ solution manifests itself in the structure of the eye, where photoreceptors are positioned distally with respect to the direction of incoming photons. There is an intervening layer of nerve fibers and auxiliary cells between the source of light and the retinal receptor layer [16]. This structure, while counterintuitive, results from the nature of biological receptors, which ­ unlike manmade technologies ­ are in fact living tissues. The photoreceptive layer must be constantly replenished on one side, while its used-up fragments must be accordingly disposed of on the opposite side. This task falls to the so-called pigmented layer, placed distally with respect to the path of light. Live receptors are "paradoxically" overlaid by another layer of tissue involved in propagation of optical signals (Figure 3). Light reaches receptor cells having passed through an occluding layer of support cells and is preferentially absorbed by freshly synthesized pigment layers. In turn, old receptor cells are found near the bottom of the retina, close to another support layer which degrades residual pigment and attenuates any remaining light so as not to confuse active receptors. Figure 3. Schematic cross-section of the retina, indicating cell layers which occlude the receptor layer. Special constructs as an adaptation to special biological requirements The flexibility of biological constructs manifests itself whenever adaptation to unusual environmental conditions is necessary. Consider the spider Hasarius Adansoni, which captures its prey as a result of a precisely measured leap. Judging the leap distance requires keen depth perception which, in turn, calls for specialized ocular receptors. Unlike most insect species which possess relatively primitive eyes, the spider has evolved a complex eye, with a retina composed of four distinct layers and a lens which exhibits significant chromatic aberration. The aberration separates incoming light into spectral bands, one of which (the green band) is registered by the second and fourth layers of the retina as a means of judging distance. Light is initially focused in the fourth layer but the image becomes blurry in the second layer. Consequently, the degree to which such blurring can be counteracted by refocusing the image in the second layer provides a useful measure of distance [17]. When illuminated by pure red light the spider becomes incapable of capturing its prey. Another example of a specialized detection system can be found in plants which have evolved UV light detectors (note that ultraviolet radiation is potentially harmful to nucleic acids). Most plants exploit the visible spectrum as an energy source and information carrier, employing detectors which consists of proteins bound to various chromophores. UV detection is, however, mediated by amino acids alone, and more specifically ­ by a special bond between an aromatic and a basic aminoacid, known as the cation- interaction. This interaction can be broken as a result of photon absorption by the aromatic component of the complex. As a result, a dimeric protein may decompose into its constituent subunits, triggering an actionable signal [18]. Other examples of environmental adaptation in biological systems include e.g. the IR-sensitive parietal eye in reptiles and magnetic field receptors in birds [19-22]. Measuring time Time measurement in biology is usually discussed in the context of aging and senescence. However, a far more precise time base is required for processes which depend on the circadian rhythm, both within individual cells and in the organism as a whole. The need to measure the passage of time has resulted in biological clocks. At the core of each clock lies an oscillator with a stable, predetermined frequency and a reset feature. Biological clocks are needed to synchronize processes whose intensity varies along with the alertness level of the organism, ensuring that these processes do not accidentally contravene one another. Biological oscillators rely on two protein synthesis process which occur out of phase with each other but remain correlated in such a way that the product of one process ­ having reached a predetermined concentration threshold ­ triggers the opposite process while at the same time downregulating its own synthesis [23,24]. It should be noted that individual molecules of each product do not directly function as signal carriers ­ rather, the signal is a consequence of the product reaching a predetermined concentration in the surrounding environment (Figure 4). The specific conditions under which both complexes can emerge enable rapid generation and degradation of signals, thus satisfying the unambiguity criterion. The entire mechanism can therefore be described as a self-controlling process. Circadian clocks can also be reset by perceived changes in ambient light, associated with the day-night cycle. Figure 4. Model view of a biological clock as compared to the action of a pendulum. Bars indicate changes in the concentrations of products of coupled synthesis processes (labeled I and II). The phase displacement of both processes is also illustrated. Rhythmic oscillations are commonly found in technical and biological systems as the fundamental element in synchronisation of different processes. It seems however that only circadian rhythms correspond fully to the clock mechanism as only in this case resetting based on independent timerelated signals is involved [24-26].

Journal

Bio-Algorithms and Med-Systemsde Gruyter

Published: Dec 1, 2012

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