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50-599: 841 12370 ENSG00000064012 ENSMUSG00000026029 Q14790 O89110 NM_033357 NM_033358 NM_001372051 NM_001080126 NM_001277926 NM_009812 NP_203522 NP_001358980 NP_001073595 NP_001264855 NP_033942 Caspase-8 is a caspase protein, encoded by the CASP8 gene. It most likely acts upon caspase-3 . CASP8 orthologs have been identified in numerous mammals for which complete genome data are available. These unique orthologs are also present in birds . The CASP8 gene encodes

100-521: A heterodimeric enzyme consisting of the large and small subunits. This protein is involved in the programmed cell death induced by Fas and various apoptotic stimuli. The N-terminal FADD -like death effector domain of this protein suggests that it may interact with Fas-interacting protein FADD. This protein was detected in the insoluble fraction of the affected brain region from Huntington disease patients but not in those from normal controls, which implicated

150-479: A sentence , idea or formula refers to itself. Although statements can be self referential without being paradoxical ("This statement is written in English" is a true and non-paradoxical self-referential statement), self-reference is a common element of paradoxes. One example occurs in the liar paradox , which is commonly formulated as the self-referential statement "This statement is false". Another example occurs in

200-418: A cause of tumor development. Tumor growth can occur by a combination of factors, including a mutation in a cell cycle gene which removes the restraints on cell growth, combined with mutations in apoptotic proteins such as caspases that would respond by inducing cell death in abnormally growing cells. Conversely, over-activation of some caspases such as caspase -3 can lead to excessive programmed cell death. This

250-466: A chain reaction, activating several other executioner caspases. Executioner caspases degrade over 600 cellular components in order to induce the morphological changes for apoptosis. Examples of caspase cascade during apoptosis: Pyroptosis is a form of programmed cell death that inherently induces an immune response. It is morphologically distinct from other types of cell death – cells swell up, rupture and release pro-inflammatory cellular contents. This

300-430: A contradiction, was instrumental in the development of modern logic and set theory. Thought-experiments can also yield interesting paradoxes. The grandfather paradox , for example, would arise if a time-traveler were to kill his own grandfather before his mother or father had been conceived, thereby preventing his own birth. This is a specific example of the more general observation of the butterfly effect , or that

350-417: A distinction between logical paradoxes and semantic paradoxes, with Russell's paradox belonging to the former category, and the liar paradox and Grelling's paradoxes to the latter. Ramsey introduced the by-now standard distinction between logical and semantical contradictions. Logical contradictions involve mathematical or logical terms like class and number , and hence show that our logic or mathematics

400-528: A drug target. For example, inflammatory caspase-1 has been implicated in causing autoimmune diseases ; drugs blocking the activation of Caspase-1 have been used to improve the health of patients. Additionally, scientists have used caspases as cancer therapy to kill unwanted cells in tumors. Most caspases play a role in programmed cell death. These are summarized in the table below. The enzymes are sub classified into three types: Initiator, Executioner and Inflammatory. Note that in addition to apoptosis, caspase-8

450-457: A family of protease enzymes playing essential roles in programmed cell death . They are named caspases due to their specific cysteine protease activity – a cysteine in its active site nucleophilically attacks and cleaves a target protein only after an aspartic acid residue. As of 2009, there are 12 confirmed caspases in humans and 10 in mice, carrying out a variety of cellular functions. The role of these enzymes in programmed cell death

500-482: A large and small subunit. This cleavage allows the active-site loops to take up a conformation favourable for enzymatic activity. Cleavage of Initiator and Executioner caspases occur by different methods outlined in the table below. Caspase-8 Caspase Caspase-3 Apoptosis is a form of programmed cell death where the cell undergoes morphological changes, to minimize its effect on surrounding cells to avoid inducing an immune response. The cell shrinks and condenses -

550-519: A lasting "unity of opposites". In logic , many paradoxes exist that are known to be invalid arguments, yet are nevertheless valuable in promoting critical thinking , while other paradoxes have revealed errors in definitions that were assumed to be rigorous, and have caused axioms of mathematics and logic to be re-examined. One example is Russell's paradox , which questions whether a "list of all lists that do not contain themselves" would include itself and showed that attempts to found set theory on

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600-406: A member of the cysteine - aspartic acid protease ( caspase ) family. Sequential activation of caspases plays a central role in the execution-phase of cell apoptosis . Caspases exist as inactive proenzymes composed of a prodomain , a large protease subunit , and a small protease subunit. Activation of caspases requires proteolytic processing at conserved internal aspartic residues to generate

650-515: A multiprotein complex called the NLRP3 inflammasome . The pro-caspase-1 is brought into close proximity with other pro-caspase molecule in order to dimerise and undergo auto-proteolytic cleavage. Some pathogenic signals that lead to Pyroptosis by Caspase-1 are listed below: Pyroptosis by Caspase-4 and Caspase-5 in humans and Caspase-11 in mice These caspases have the ability to induce direct pyroptosis when lipopolysaccharide (LPS) molecules (found in

700-457: A range of pathogenic ligands. Some mediators of Caspase-1 activation are: NOD-like Leucine Rich Repeats (NLRs), AIM2 -Like Receptors (ALRs), Pyrin and IFI16 . These proteins allow caspase-1 activation by forming a multiprotein activating complex called Inflammasomes. For example, a NOD Like Leucine Rich Repeat NLRP3 will sense an efflux of potassium ions from the cell. This cellular ion imbalance leads to oligomerisation of NLRP3 molecules to form

750-431: A result that appears counter to intuition , but is demonstrated to be true nonetheless: A falsidical paradox establishes a result that appears false and actually is false, due to a fallacy in the demonstration. Therefore, falsidical paradoxes can be classified as fallacious arguments : An antinomy is a paradox which reaches a self-contradictory result by properly applying accepted ways of reasoning. For example,

800-421: A role in inflammation, whereby it directly processes pro-inflammatory cytokines such as pro- IL1β . These are signalling molecules that allow recruitment of immune cells to an infected cell or tissue. There are other identified roles of caspases such as cell proliferation, tumor suppression, cell differentiation, neural development and axon guidance and ageing. Caspase deficiency has been identified as

850-430: A time-traveler killing his own grandfather, it is the inconsistency of defining the past to which he returns as being somehow different from the one that leads up to the future from which he begins his trip, but also insisting that he must have come to that past from the same future as the one that it leads up to. W. V. O. Quine (1962) distinguished between three classes of paradoxes: A veridical paradox produces

900-410: A time-traveller's interaction with the past—however slight—would entail making changes that would, in turn, change the future in which the time-travel was yet to occur, and would thus change the circumstances of the time-travel itself. Often a seemingly paradoxical conclusion arises from an inconsistent or inherently contradictory definition of the initial premise. In the case of that apparent paradox of

950-487: Is a logically self-contradictory statement or a statement that runs contrary to one's expectation. It is a statement that, despite apparently valid reasoning from true or apparently true premises, leads to a seemingly self-contradictory or a logically unacceptable conclusion. A paradox usually involves contradictory-yet-interrelated elements that exist simultaneously and persist over time. They result in "persistent contradiction between interdependent elements" leading to

1000-458: Is also required for the inhibition of another form of programmed cell death called necroptosis. Caspase-14 plays a role in epithelial cell keratinocyte differentiation and can form an epidermal barrier that protects against dehydration and UVB radiation. Caspases are synthesised as inactive zymogens (pro-caspases) that are only activated following an appropriate stimulus. This post-translational level of control allows rapid and tight regulation of

1050-411: Is an example of the well-known liar paradox : it is a sentence that cannot be consistently interpreted as either true or false, because if it is known to be false, then it can be inferred that it must be true, and if it is known to be true, then it can be inferred that it must be false. Russell's paradox , which shows that the notion of the set of all those sets that do not contain themselves leads to

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1100-443: Is done in response to a range of stimuli including microbial infections as well as heart attacks (myocardial infarctions). Caspase-1, Caspase-4 and Caspase-5 in humans, and Caspase-1 and Caspase-11 in mice play important roles in inducing cell death by pyroptosis. This limits the life and proliferation time of intracellular and extracellular pathogens. Caspase-1 activation is mediated by a repertoire of proteins, allowing detection of

1150-443: Is induced by caspases and in fungi and plants, apoptosis is induced by arginine and lysine-specific caspase like proteases called metacaspases. Homology searches revealed a close homology between caspases and the caspase-like proteins of Reticulomyxa (a unicellular organism). The phylogenetic study indicates that divergence of caspase and metacaspase sequences occurred before the divergence of eukaryotes. Paradox A paradox

1200-409: Is initiated by dimerisation, which is facilitated by binding to adaptor proteins via protein–protein interaction motifs that are collectively referred to as death folds . The death folds are located in a structural domain of the caspases known as the pro-domain, which is larger in those caspases that contain death folds than in those that do not. The pro-domain of the intrinsic initiator caspases and

1250-602: Is minimal and lymphoma has not been observed in the CEDS patients. CEDS is inherited in an autosomal recessive manner. The clinical phenotype of CEDS patients represented a paradox since caspase-8 was considered to be chiefly a proapoptotic protease , that was mainly involved in signal transduction from Tumor necrosis factor receptor family death receptors such as Fas. The defect in lymphocyte activation and protective immunity suggested that caspase-8 had additional signaling roles in lymphocytes . Further work revealed that caspase-8

1300-399: Is no contradiction, the doctor is the boy's mother.). Paradoxes that are not based on a hidden error generally occur at the fringes of context or language , and require extending the context or language in order to lose their paradoxical quality. Paradoxes that arise from apparently intelligible uses of language are often of interest to logicians and philosophers . "This sentence is false"

1350-548: Is non-terminating recursion , in the form of circular reasoning or infinite regress . When this recursion creates a metaphysical impossibility through contradiction, the regress or circularity is vicious . Again, the liar paradox is an instructive example: "This statement is false"—if the statement is true, then the statement is false, thereby making the statement true, thereby making the statement false, and so on. The barber paradox also exemplifies vicious circularity: The barber shaves those who do not shave themselves, so if

1400-579: Is problematic. Semantical contradictions involve, besides purely logical terms, notions like thought , language , and symbolism , which, according to Ramsey, are empirical (not formal) terms. Hence these contradictions are due to faulty ideas about thought or language, and they properly belong to epistemology . A taste for paradox is central to the philosophies of Laozi , Zeno of Elea , Zhuangzi , Heraclitus , Bhartrhari , Meister Eckhart , Hegel , Kierkegaard , Nietzsche , and G.K. Chesterton , among many others. Søren Kierkegaard, for example, writes in

1450-449: Is seen in several neurodegenerative diseases where neural cells are lost, such as Alzheimer's disease . Caspases involved with processing inflammatory signals are also implicated in disease. Insufficient activation of these caspases can increase an organism's susceptibility to infection, as an appropriate immune response may not be activated. The integral role caspases play in cell death and disease has led to research on using caspases as

1500-476: The Philosophical Fragments that: But one must not think ill of the paradox, for the paradox is the passion of thought, and the thinker without the paradox is like the lover without passion: a mediocre fellow. But the ultimate potentiation of every passion is always to will its own downfall, and so it is also the ultimate passion of the understanding to will the collision, although in one way or another

1550-535: The Grelling–Nelson paradox points out genuine problems in our understanding of the ideas of truth and description. Sometimes described since Quine's work, a dialetheia is a paradox that is both true and false at the same time. It may be regarded as a fourth kind, or alternatively as a special case of antinomy. In logic, it is often assumed, following Aristotle , that no dialetheia exist, but they are allowed in some paraconsistent logics . Frank Ramsey drew

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1600-409: The barber paradox , which poses the question of whether a barber who shaves all and only those who do not shave themselves will shave himself. In this paradox, the barber is a self-referential concept. Contradiction , along with self-reference, is a core feature of many paradoxes. The liar paradox, "This statement is false," exhibits contradiction because the statement cannot be false and true at

1650-530: The cytoskeleton will collapse, and the nuclear envelope disassembles the DNA fragments up. This results in the cell forming self-enclosed bodies called ' blebs ', to avoid release of cellular components into the extracellular medium. Additionally, the cell membrane phospholipid content is altered, which makes the dying cell more susceptible to phagocytic attack and removal. Apoptotic caspases are subcategorised as: Once initiator caspases are activated, they produce

1700-401: The addition of an immunodeficient phenotype. Thus, the clinical manifestations include splenomegaly and lymphadenopathy , in addition to recurrent sinopulmonary infections, recurrent mucocutaneous herpesvirus , persistent warts and molluscum contagiosum infections, and hypogammaglobulinemia . There is sometimes lymphocytic infiltrative disease in parenchymal organs, but autoimmunity

1750-401: The barber does not shave himself, then he shaves himself, then he does not shave himself, and so on. Other paradoxes involve false statements and half-truths ("'impossible' is not in my vocabulary") or rely on hasty assumptions (A father and his son are in a car crash; the father is killed and the boy is rushed to the hospital. The doctor says, "I can't operate on this boy. He's my son." There

1800-625: The cell wall of gram negative bacteria) are found in the cytoplasm of the host cell. For example, Caspase 4 acts as a receptor and is proteolytically activated, without the need of an inflammasome complex or Caspase-1 activation. A crucial downstream substrate for pyroptotic caspases is Gasdermin D (GSDMD) Inflammation is a protective attempt by an organism to restore a homeostatic state, following disruption from harmful stimulus, such as tissue damage or bacterial infection. Caspase-1, Caspase-4, Caspase-5 and Caspase-11 are considered 'Inflammatory Caspases'. H. Robert Horvitz initially established

1850-421: The collision must become its downfall. This, then, is the ultimate paradox of thought: to want to discover something that thought itself cannot think. A paradoxical reaction to a drug is the opposite of what one would expect, such as becoming agitated by a sedative or sedated by a stimulant . Some are common and are used regularly in medicine, such as the use of stimulants such as Adderall and Ritalin in

1900-465: The enzyme. Activation involves dimerization and often oligomerisation of pro-caspases, followed by cleavage into a small subunit and large subunit. The large and small subunit associate with each other to form an active heterodimer caspase. The active enzyme often exists as a heterotetramer in the biological environment, where a pro-caspase dimer is cleaved together to form a heterotetramer. The activation of initiator caspases and inflammatory caspases

1950-580: The form of images or other media. For example, M.C. Escher featured perspective-based paradoxes in many of his drawings, with walls that are regarded as floors from other points of view, and staircases that appear to climb endlessly. Informally, the term paradox is often used to describe a counterintuitive result. Self-reference , contradiction and infinite regress are core elements of many paradoxes. Other common elements include circular definitions , and confusion or equivocation between different levels of abstraction . Self-reference occurs when

2000-433: The identification of sets with properties or predicates were flawed. Others, such as Curry's paradox , cannot be easily resolved by making foundational changes in a logical system. Examples outside logic include the ship of Theseus from philosophy, a paradox that questions whether a ship repaired over time by replacing each and all of its wooden parts one at a time would remain the same ship. Paradoxes can also take

2050-409: The importance of caspases in apoptosis and found that the ced-3 gene is required for the cell death that took place during the development of the nematode C. elegans . Horvitz and his colleague Junying Yuan found in 1993 that the protein encoded by the ced-3 gene is cysteine protease with similar properties to the mammalian interleukin-1-beta converting enzyme (ICE) (now known as caspase 1). At

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2100-639: The induction of nuclear translocation of NF-κB. Moreover, the biochemical form of caspase-8 differed in the two pathways. For the death pathway, the caspase-8 zymogen is cleaved into subunits that assemble to form the mature, highly active caspase heterotetramer whereas for the activation pathway, the zymogen appears to remain intact perhaps to limit its proteolytic function but enhance its capability as an adapter protein. Caspase-8 has been shown to interact with: Caspase Caspases ( c ysteine- asp artic prote ases , c ysteine asp art ases or c ysteine-dependent asp artate-directed prote ases ) are

2150-483: The inflammatory caspases contains a single death fold known as caspase recruitment domain (CARD), while the pro-domain of the extrinsic initiator caspases contains two death folds known as death effector domains (DED). Multiprotein complexes often form during caspase activation. Some activating multiprotein complexes includes: Once appropriately dimerised, the Caspases cleave at inter domain linker regions, forming

2200-468: The role in neurodegenerative diseases. Many alternatively spliced transcript variants encoding different isoforms have been described, although not all variants have had their full-length sequences determined. A very rare genetic disorder of the immune system can also be caused by mutations in this gene. This disease, called CEDS, stands for “ Caspase eight deficiency state .” CEDS has features similar to ALPS , another genetic disease of apoptosis , with

2250-471: The same time. The barber paradox is contradictory because it implies that the barber shaves himself if and only if the barber does not shave himself. As with self-reference, a statement can contain a contradiction without being a paradox. "This statement is written in French" is an example of a contradictory self-referential statement that is not a paradox and is instead false. Another core aspect of paradoxes

2300-428: The time, ICE was the only known caspase. Other mammalian caspases were subsequently identified, in addition to caspases in organisms such as fruit fly Drosophila melanogaster . Researchers decided upon the nomenclature of the caspase in 1996. In many instances, a particular caspase had been identified simultaneously by more than one laboratory; each would then give the protein a different name. For example, caspase 3

2350-399: The treatment of attention deficit hyperactivity disorder (also known as ADHD), while others are rare and can be dangerous as they are not expected, such as severe agitation from a benzodiazepine . The actions of antibodies on antigens can rarely take paradoxical turns in certain ways. One example is antibody-dependent enhancement (immune enhancement) of a disease's virulence; another

2400-418: Was essential for the induction of the transcription factor “nuclear factor κB” ( NF-κB ) after stimulation through antigen receptors, Fc receptors, or Toll-like receptor 4 in T, B, and natural killer cells . Biochemically, caspase-8 was found to enter the complex of the inhibitor of NF-κB kinase (IKK) with the upstream Bcl10-MALT1 (mucosa-associated lymphatic tissue) adapter complex which were crucial for

2450-630: Was first identified in 1993, with their functions in apoptosis well characterised. This is a form of programmed cell death, occurring widely during development, and throughout life to maintain cell homeostasis . Activation of caspases ensures that the cellular components are degraded in a controlled manner, carrying out cell death with minimal effect on surrounding tissues . Caspases have other identified roles in programmed cell death such as pyroptosis , necroptosis and PANoptosis . These forms of cell death are important for protecting an organism from stress signals and pathogenic attack. Caspases also have

2500-414: Was variously known as CPP32, apopain and Yama. Caspases, therefore, were numbered in the order in which they were identified. ICE was, therefore, renamed as caspase 1. ICE was the first mammalian caspase to be characterised because of its similarity to the nematode death gene ced-3, but it appears that the principal role of this enzyme is to mediate inflammation rather than cell death. In animals apoptosis

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