title: Inbreeding

text: Meanwhile, milk production per cow per lactation increased from 17,444 lbs to 25,013 lbs from 1978 to 1998 for the Holstein breed. Mean breeding values for milk of Holstein cows increased by 4,829 lbs during this period. High producing cows are increasingly difficult to breed and are subject to higher health costs than cows of lower genetic merit for production (Cassell, 2001).


title: Inbreeding

text: Intensive selection for higher yield has increased relationships among animals within breed and increased the rate of casual inbreeding.


title: Inbreeding

text: Many of the traits that affect profitability in crosses of modern dairy breeds have not been studied in designed experiments. Indeed, all crossbreeding research involving North American breeds and strains is very dated (McAllister, 2001) if it exists at all.


title: Inbreeding

text: The BBC produced two documentaries on dog inbreeding titled "Pedigree Dogs Exposed" and "" that document the negative health consequences of excessive inbreeding.


title: Inbreeding

text: Linebreeding is a form of inbreeding. There is no clear distinction between the two terms, but linebreeding may encompass crosses between individuals and their descendants or two cousins. This method can be used to increase a particular animal's contribution to the population. While linebreeding is less likely to cause problems in the first generation than does inbreeding, over time, linebreeding can reduce the genetic diversity of a population and cause problems related to a too-small gene pool that may include an increased prevalence of genetic disorders and inbreeding depression.


title: Inbreeding

text: Outcrossing is where two unrelated individuals are crossed to produce progeny. In outcrossing, unless there is verifiable genetic information, one may find that all individuals are distantly related to an ancient progenitor. If the trait carries throughout a population, all individuals can have this trait. This is called the founder effect. In the well established breeds, that are commonly bred, a large gene pool is present. For example, in 2004, over 18,000 Persian cats were registered. A possibility exists for a complete outcross, if no barriers exist between the individuals to breed. However, it is not always the case, and a form of distant linebreeding occurs. Again it is up to the assortative breeder to know what sort of traits, both positive and negative, exist within the diversity of one breeding. This diversity of genetic expression, within even close relatives, increases the variability and diversity of viable stock.


title: Inbreeding

text: Systematic inbreeding and maintenance of inbred strains of laboratory mice and rats is of great importance for biomedical research. The inbreeding guarantees a consistent and uniform animal model for experimental purposes and enables genetic studies in congenic and knock-out animals. In order to achieve a mouse strain that is considered inbred, a minimum of 20 sequential generations of sibling matings must occur. With each successive generation of breeding, homozygosity in the entire genome increases, eliminating heterozygous loci. With 20 generations of sibling matings, homozygosity is occurring at roughly 98.7% of all loci in the genome, allowing for these offspring to serve as animal models for genetic studies. The use of inbred strains is also important for genetic studies in animal models, for example to distinguish genetic from environmental effects. The mice that are inbred typically show considerably lower survival rates.


title: Inbreeding

text: Inbreeding increases homozygosity, which can increase the chances of the expression of deleterious or beneficial recessive alleles and therefore has the potential to either decrease or increase the fitness of the offspring. With continuous inbreeding, genetic variation is lost and homozygosity is increased, enabling the expression of recessive deleterious alleles in homozygotes. The coefficient of inbreeding, or the degree of inbreeding in an individual, is an estimate of the percent of homozygous alleles in the overall genome. The more biologically related the parents are, the greater the coefficient of inbreeding, since their genomes have many similarities already. This overall homozygosity becomes an issue when there are deleterious recessive alleles in the gene pool of the family. By pairing chromosomes of similar genomes, the chance for these recessive alleles to pair and become homozygous greatly increases, leading to offspring with autosomal recessive disorders. However, these deleterious effects are common for very close relatives but not for those related on the 3rd cousin or greater level, who exhibit increased fitness.


title: Inbreeding

text: Inbreeding is especially problematic in small populations where the genetic variation is already limited. By inbreeding, individuals are further decreasing genetic variation by increasing homozygosity in the genomes of their offspring. Thus, the likelihood of deleterious recessive alleles to pair is significantly higher in a small inbreeding population than in a larger inbreeding population.


title: Inbreeding

text: The fitness consequences of consanguineous mating have been studied since their scientific recognition by Charles Darwin in 1839. Some of the most harmful effects known from such breeding includes its effects on the mortality rate as well as on the general health of the offspring. Since the 1960s, there have been many studies to support such debilitating effects on the human organism. Specifically, inbreeding has been found to decrease fertility as a direct result of increasing homozygosity of deleterious recessive alleles. Fetuses produced by inbreeding also face a greater risk of spontaneous abortions due to inherent complications in development. Among mothers who experience stillbirths and early infant deaths, those that are inbreeding have a significantly higher chance of reaching repeated results with future offspring. Additionally, consanguineous parents possess a high risk of premature birth and producing underweight and undersized infants. Viable inbred offspring are also likely to be inflicted with physical deformities and genetically inherited diseases. Studies have confirmed an increase in several genetic disorders due to inbreeding such as blindness, hearing loss, neonatal diabetes, limb malformations, disorders of sex development, schizophrenia and several others. Moreover, there is an increased risk for congenital heart disease depending on the inbreeding coefficient (See coefficient of inbreeding) of the offspring, with significant risk accompanied by an F =.125 or higher.


title: Inbreeding

text: The general negative outlook and eschewal of inbreeding that is prevalent in the Western world today has roots from over 2000 years ago. Specifically, written documents such as the Bible illustrate that there have been laws and social customs that have called for the abstention from inbreeding. Along with cultural taboos, parental education and awareness of inbreeding consequences have played large roles in minimizing inbreeding frequencies in areas like Europe. That being so, there are less urbanized and less populated regions across the world that have shown continuity in the practice of inbreeding.


title: Inbreeding

text: The continuity of inbreeding is often either by choice or unavoidably due to the limitations of the geographical area. When by choice, the rate of consanguinity is highly dependent on religion and culture. In the Western world some Anabaptist groups are highly inbred because they originate from small founder populations and until today marriage outside the groups is not allowed for members. Especially the Reidenbach Old Order Mennonites and the Hutterites stem from very small founder populations. The same is true for some Hasidic and Haredi Jewish groups.


title: Inbreeding

text: Of the practicing regions, Middle Eastern and northern Africa territories show the greatest frequencies of consanguinity.


title: Inbreeding

text: Among these populations with high levels of inbreeding, researchers have found several disorders prevalent among inbred offspring. In Lebanon, Saudi Arabia, Egypt, and in Israel, the offspring of consanguineous relationships have an increased risk of congenital malformations, congenital heart defects, congenital hydrocephalus and neural tube defects. Furthermore, among inbred children in Palestine and Lebanon, there is a positive association between consanguinity and reported cleft lip/palate cases. Historically, populations of Qatar have engaged in consanguineous relationships of all kinds, leading to high risk of inheriting genetic diseases. As of 2014, around 5% of the Qatari population suffered from hereditary hearing loss; most were descendants of a consanguineous relationship.


title: Inbreeding

text: Inter-nobility marriage was used as a method of forming political alliances among elites. These ties were often sealed only upon the birth of progeny within the arranged marriage. Thus marriage was seen as a union of lines of nobility and not as a contract between individuals.


title: Inbreeding

text: Royal intermarriage was often practiced among European royal families, usually for interests of state. Over time, due to the relatively limited number of potential consorts, the gene pool of many ruling families grew progressively smaller, until all European royalty was related. This also resulted in many being descended from a certain person through many lines of descent, such as the numerous European royalty and nobility descended from the British Queen Victoria or King Christian IX of Denmark. The House of Habsburg was known for its intermarriages; the Habsburg lip often cited as an ill-effect. The closely related houses of Habsburg, Bourbon, Braganza and Wittelsbach also frequently engaged in first-cousin unions as well as the occasional double-cousin and uncle–niece marriages.


title: Inbreeding

text: In ancient Egypt, royal women were believed to carry the bloodlines and so it was advantageous for a pharaoh to marry his sister or half-sister; in such cases a special combination between endogamy and polygamy is found. Normally, the old ruler's eldest son and daughter (who could be either siblings or half-siblings) became the new rulers. All rulers of the Ptolemaic dynasty uninterruptedly from Ptolemy IV (Ptolemy II married his sister but had no issue) were married to their brothers and sisters, so as to keep the Ptolemaic blood "pure" and to strengthen the line of succession. King Tutankhamun's mother is reported to have been the half-sister to his father, Cleopatra VII (also called Cleopatra VI) and Ptolemy XIII, who married and became co-rulers of ancient Egypt following their father's death, are the most widely known example.


title: Hash table

text: In computing, a hash table, also known as hash map, is a data structure that implements an associative array or dictionary. It is an abstract data type that maps keys to values. A hash table uses a hash function to compute an "index", also called a "hash code", into an array of "buckets" or "slots", from which the desired value can be found. During lookup, the key is hashed and the resulting hash indicates where the corresponding value is stored.


title: Hash table

text: Ideally, the hash function will assign each key to a unique bucket, but most hash table designs employ an imperfect hash function, which might cause hash "collisions" where the hash function generates the same index for more than one key. Such collisions are typically accommodated in some way.


title: Hash table

text: In a well-dimensioned hash table, the average time complexity for each lookup is independent of the number of elements stored in the table. Many hash table designs also allow arbitrary insertions and deletions of key–value pairs, at amortized constant average cost per operation.


title: Hash table

text: Hashing is an example of a space-time tradeoff. If memory is infinite, the entire key can be used directly as an index to locate its value with a single memory access. On the other hand, if infinite time is available, values can be stored without regard for their keys, and a binary search or linear search can be used to retrieve the element.


title: Hash table

text: In many situations, hash tables turn out to be on average more efficient than search trees or any other table lookup structure. For this reason, they are widely used in many kinds of computer software, particularly for associative arrays, database indexing, caches, and sets.


title: Hash table

text: The idea of hashing arose independently in different places. In January 1953, Hans Peter Luhn wrote an internal IBM memorandum that used hashing with chaining. Open addressing was later proposed by A. D. Linh building on Luhn's paper. Around the same time, Gene Amdahl, Elaine M. McGraw, Nathaniel Rochester, and Arthur Samuel of IBM Research implemented hashing for the IBM 701 assembler. Open addressing with linear probing is credited to Amdahl, although Ershov independently had the same idea. The term "open addressing" was coined by W. Wesley Peterson on his article which discusses the problem of search in large files.


title: Hash table

text: The first published work on hashing with chaining is credited to Arnold Dumey, who discussed the idea of using remainder module a prime as a hash function. The word "hashing" was first published by an article by Robert Morris. A theoretical analysis of linear probing was submitted originally by Konheim and Weiss.


title: Hash table

text: An associative array stores a set of (key, value) pairs and allows insertion, deletion, and lookup (search), with the constraint of unique keys. In the hash table implementation of associative arrays, an array formula_1 of length formula_2 is partially filled with formula_3 elements, where formula_4. A value formula_5 gets stored at an index location formula_6, where formula_7 is a hash function, and formula_8. Under reasonable assumptions, hash tables have better time complexity bounds on search, delete, and insert operations in comparison to self-balancing binary search trees.


title: Hash table

text: Hash tables are also commonly used to implement sets, by omitting the stored value for each key and merely tracking whether the key is present.


title: Hash table

text: The performance of the hash table deteriorates in relation to the load factor formula_9. Therefore a hash table is resized or "rehashed" if the load factor formula_9 approaches 1. A table is also resized if the load factor drops below formula_15. Acceptable figures of load factor formula_9 include 0.6 and 0.75.


title: Hash table

text: A hash function formula_7 maps the universe formula_18 of keys formula_19 to array indices or slots within the table for each formula_20 where formula_21 and formula_22. The conventional implementations of hash functions are based on the "integer universe assumption" that all elements of the table stem from the universe formula_23, where the bit length of formula_24 is confined within the word size of a computer architecture.


title: Hash table

text: A perfect hash function formula_7 is defined as an injective function such that each element formula_5 in formula_27 maps to a unique value in formula_28. A perfect hash function can be created if all the keys are known ahead of time.


title: Hash table

text: The schemes of hashing used in "integer universe assumption" include hashing by division, hashing by multiplication, universal hashing, dynamic perfect hashing, and static perfect hashing. However, hashing by division is the commonly used scheme.


title: Hash table

text: Where formula_1 is a real-valued constant. An advantage of the hashing by multiplication is that the formula_2 is not critical. Although any value formula_1 produces a hash function, Donald Knuth suggests using the golden ratio.


title: Hash table

text: Uniform distribution of the hash values is a fundamental requirement of a hash function. A non-uniform distribution increases the number of collisions and the cost of resolving them. Uniformity is sometimes difficult to ensure by design, but may be evaluated empirically using statistical tests, e.g., a Pearson's chi-squared test for discrete uniform distributions.


title: Hash table

text: The distribution needs to be uniform only for table sizes that occur in the application. In particular, if one uses dynamic resizing with exact doubling and halving of the table size, then the hash function needs to be uniform only when the size is a power of two. Here the index can be computed as some range of bits of the hash function. On the other hand, some hashing algorithms prefer to have the size be a prime number.


title: Hash table

text: For open addressing schemes, the hash function should also avoid "clustering", the mapping of two or more keys to consecutive slots. Such clustering may cause the lookup cost to skyrocket, even if the load factor is low and collisions are infrequent. The popular multiplicative hash is claimed to have particularly poor clustering behavior.


title: Hash table

text: K-independent hashing offers a way to prove a certain hash function does not have bad keysets for a given type of hashtable. A number of K-independence results are known for collision resolution schemes such as linear probing and cuckoo hashing. Since K-independence can prove a hash function works, one can then focus on finding the fastest possible such hash function.


title: Hash table

text: A search algorithm that uses hashing consists of two parts. The first part is computing a hash function which transforms the search key into an array index. The ideal case is such that no two search keys hashes to the same array index. However, this is not always the case and is impossible to guarantee for unseen given data. Hence the second part of the algorithm is collision resolution. The two common methods for collision resolution are separate chaining and open addressing.


title: Hash table

text: In separate chaining, the process involves building a linked list with key–value pair for each search array index. The collided items are chained together through a single linked list, which can be traversed to access the item with a unique search key. Collision resolution through chaining with linked list is a common method of implementation of hash tables. Let formula_37 and formula_5 be the hash table and the node respectively, the operation involves as follows:


title: Hash table

text: If the element is comparable either numerically or lexically, and inserted into the list by maintaining the total order, it results in faster termination of the unsuccessful searches.


title: Hash table

text: If the keys are ordered, it could be efficient to use "self-organizing" concepts such as using a self-balancing binary search tree, through which the theoretical worst case could be brought down to formula_39, although it introduces additional complexities.


title: Hash table

text: In dynamic perfect hashing, two-level hash tables are used to reduce the look-up complexity to be a guaranteed formula_40 in the worst case. In this technique, the buckets of formula_12 entries are organized as perfect hash tables with formula_42 slots providing constant worst-case lookup time, and low amortized time for insertion. A study shows array based separate chaining to be 97% more performant when compared to the standard linked list method under heavy load.


title: Hash table

text: Techniques such as using fusion tree for each buckets also result in constant time for all operations with high probability.


title: Hash table

text: The linked list of separate chaining implementation may not be cache-conscious due to spatial locality—locality of reference—when the nodes of the linked list are scattered across memory, thus the list traversal during insert and search may entail CPU cache inefficiencies.


title: Hash table

text: In cache-conscious variants, a dynamic array found to be more cache-friendly is used in the place where a linked list or self-balancing binary search trees is usually deployed for collision resolution through separate chaining, since the contiguous allocation pattern of the array could be exploited by hardware-cache prefetchers—such as translation lookaside buffer—resulting in reduced access time and memory consumption.


title: Hash table

text: Open addressing is another collision resolution technique in which every entry record is stored in the bucket array itself, and the hash resolution is performed through probing. When a new entry has to be inserted, the buckets are examined, starting with the hashed-to slot and proceeding in some "probe sequence", until an unoccupied slot is found. When searching for an entry, the buckets are scanned in the same sequence, until either the target record is found, or an unused array slot is found, which indicates an unsuccessful search.


title: Hash table

text: The performance of open addressing may be slower compared to separate chaining since the probe sequence increases when the load factor formula_9 approaches 1. The probing results in an infinite loop if the load factor reaches 1, in the case of a completely filled table. The average cost of linear probing depends on the hash function's ability to distribute the elements uniformly throughout the table to avoid clustering, since formation of clusters would result in increased search time.


title: Hash table

text: Since the slots are located in successive locations, linear probing could lead to better utilization of CPU cache due to locality of references resulting in reduced memory latency.


title: Hash table

text: Coalesced hashing is a hybrid of both separate chaining and open addressing in which the buckets or nodes link within the table. The algorithm is ideally suited for fixed memory allocation. The collision in coalesced hashing is resolved by identifying the largest-indexed empty slot on the hash table, then the colliding value is inserted into that slot. The bucket is also linked to the inserted node's slot which contains its colliding hash address.


title: Hash table

text: Cuckoo hashing is a form of open addressing collision resolution technique which guarantees formula_40 worst-case lookup complexity and constant amortized time for insertions. The collision is resolved through maintaining two hash tables, each having its own hashing function, and collided slot gets replaced with the given item, and the preoccupied element of the slot gets displaced into the other hash table. The process continues until every key has its own spot in the empty buckets of the tables; if the procedure enters into infinite loop—which is identified through maintaining a threshold loop counter—both hash tables get rehashed with newer hash functions and the procedure continues.


title: Hash table

text: Hopscotch hashing is an open addressing based algorithm which combines the elements of cuckoo hashing, linear probing and chaining through the notion of a "neighbourhood" of buckets—the subsequent buckets around any given occupied bucket, also called a "virtual" bucket. The algorithm is designed to deliver better performance when the load factor of the hash table grows beyond 90%; it also provides high throughput in concurrent settings, thus well suited for implementing resizable concurrent hash table. The neighbourhood characteristic of hopscotch hashing guarantees a property that, the cost of finding the desired item from any given buckets within the neighbourhood is very close to the cost of finding it in the bucket itself; the algorithm attempts to be an item into its neighbourhood—with a possible cost involved in displacing other items.


title: Hash table

text: Each bucket within the hash table includes an additional "hop-information"—an "H"-bit bit array for indicating the relative distance of the item which was originally hashed into the current virtual bucket within "H"-1 entries. Let formula_12 and formula_46 be the key to be inserted and bucket to which the key is hashed into respectively; several cases are involved in the insertion procedure such that the neighbourhood property of the algorithm is vowed: if formula_46 is empty, the element is inserted, and the leftmost bit of bitmap is set to 1; if not empty, linear probing is used for finding an empty slot in the table, the bitmap of the bucket gets updated followed by the insertion; if the empty slot is not within the range of the "neighbourhood," i.e. "H"-1, subsequent swap and hop-info bit array manipulation of each bucket is performed in accordance with its neighbourhood invariant properties.


title: Hash table

text: Robin hood hashing is an open addressing based collision resolution algorithm; the collisions are resolved through favouring the displacement of the element that is farthest—or longest "probe sequence length" (PSL)—from its "home location" i.e. the bucket to which the item was hashed into. Although robin hood hashing does not change the theoretical search cost, it significantly affects the variance of the distribution of the items on the buckets, i.e. dealing with cluster formation in the hash table. Each node within the hash table that uses robin hood hashing should be augmented to store an extra PSL value. Let formula_5 be the key to be inserted, formula_49 be the (incremental) PSL length of formula_5, formula_37 be the hash table and formula_52 be the index, the insertion procedure is as follows:


title: Hash table

text: Repeated insertions cause the number of entries in a hash table to grow, which consequently increases the load factor; to maintain the amortized formula_40 performance of the lookup and insertion operations, a hash table is dynamically resized and the items of the tables are "rehashed" into the buckets of the new hash table, since the items cannot be copied over as varying table sizes results in different hash value due to modulo operation. If a hash table becomes "too empty" after deleting some elements, resizing may be performed to avoid excessive memory usage.


title: Hash table

text: Generally, a new hash table with a size double that of the original hash table gets allocated privately and every item in the original hash table gets moved to the newly allocated one by computing the hash values of the items followed by the insertion operation. Rehashing is computationally expensive despite its simplicity.


title: Hash table

text: Some hash table implementations, notably in real-time systems, cannot pay the price of enlarging the hash table all at once, because it may interrupt time-critical operations. If one cannot avoid dynamic resizing, a solution is to perform the resizing gradually to avoid storage blip—typically at 50% of new table's size—during rehashing and to avoid memory fragmentation that triggers heap compaction due to deallocation of large memory blocks caused by the old hash table. In such case, the rehashing operation is done incrementally through extending prior memory block allocated for the old hash table such that the buckets of the hash table remain unaltered. A common approach for amortized rehashing involves maintaining two hash functions formula_63 and formula_64. The process of rehashing a bucket's items in accordance with the new hash function is termed as "cleaning", which is implemented through command pattern by encapsulating the operations such as formula_65, formula_66 and formula_67 through a formula_68 wrapper such that each element in the bucket gets rehashed and its procedure involve as follows:


title: Hash table

text: Linear hashing is an implementation of the hash table which enables dynamic growths or shrinks of the table one bucket at a time.


title: Hash table

text: The performance of a hash table is dependent on the hash function's ability in generating quasi-random numbers (formula_71) for entries in the hash table where formula_72, formula_3 and formula_74 denotes the key, number of buckets and the hash function such that formula_75. If the hash function generates same formula_71 for distinct keys (formula_77), this results in "collision", which should be dealt with in several ways. The constant time complexity (formula_40) of the operation in a hash table is presupposed on the condition that the hash function doesn't generate colliding indices; thus, the performance of the hash table is directly proportional to the chosen hash function ability to disperse the indices. However, construction of such a hash function is practically unfeasible, that being so, implementations depend on case-specific collision resolution techniques in achieving higher performance.


title: Hash table

text: Hash tables are commonly used to implement many types of in-memory tables. They are used to implement associative arrays.


title: Hash table

text: Hash tables may also be used as disk-based data structures and database indices (such as in dbm) although B-trees are more popular in these applications.


title: Hash table

text: Hash tables can be used to implement caches, auxiliary data tables that are used to speed up the access to data that is primarily stored in slower media. In this application, hash collisions can be handled by discarding one of the two colliding entries—usually erasing the old item that is currently stored in the table and overwriting it with the new item, so every item in the table has a unique hash value.


title: Hash table

text: Hash tables can be used in the implementation of set data structure, which can store unique values without any particular order; set is typically used in testing the membership of a value in the collection, rather than element retrieval.


title: Hash table

text: A transposition table to a complex Hash Table which stores information about each section that has been searched.


title: Hash table

text: Many programming languages provide hash table functionality, either as built-in associative arrays or as standard library modules.


title: Hash table

text: In JavaScript, every value except for 7 "primitive" data types is called an "object", which uses either integers, strings, or guaranteed-unique "symbol" primitive values as keys for a hash map. ECMAScript 6 also added codice_1 and codice_2 data structures.


title: Hash table

text: Java programming language includes the codice_4, codice_5, codice_6, and codice_7 generic collections.


title: Forza Horizon 5

text: Forza Horizon 5 is a 2021 racing video game developed by Playground Games and published by Xbox Game Studios. It is the fifth "Forza Horizon" title and twelfth main instalment in the "Forza" series. The game is set in a fictionalised representation of Mexico. It was released on 9 November 2021 for Microsoft Windows, Xbox One, and Xbox Series X/S.


title: Forza Horizon 5

text: The game received critical acclaim and became a commercial success upon release; it launched to over ten million players in the first week, the biggest-ever launch for an Xbox Game Studios game. The game was nominated for three jury-voted awards at The Game Awards 2021, winning all three of its nominations and tying with Hazelight's "It Takes Two" for most wins, and was also nominated for the public-voted Players' Voice award, which went to fellow Xbox Game Studios title "Halo Infinite".


title: Forza Horizon 5

text: "Forza Horizon 5" is a racing video game set in an open world environment based in a fictional representation of Mexico. The game has the largest map in the entire "Forza Horizon" series, being 50% larger than its predecessor, "Forza Horizon 4", while also having the highest point in the "Horizon" series. The map was described by creative director Mike Brown as one of the most diverse "Forza Horizon" maps the team has built. The map contains an active caldera volcano, jungles and beaches, ancient Mayan temples, and towns and cities such as Guanajuato. Players can explore the open world freely, though they can also compete in multiplayer races and complete the campaign mode. Both the cars featured in the game and the player character can be extensively customised. Players are able to create custom liveries and tunes for cars, and perform engine swaps, drivetrain swaps, or install body kits on certain vehicles. The game is the first in the franchise to support ray tracing on cars (although this is only available in Forzavista).


title: Forza Horizon 5

text: The game introduces a new weather system (local weather) in which players can visit one side of the map and can visibly see a storm. Because Mexico is such a vast nation with such a wide range of elevations, multiple climates would appear in the game at around the same time. The four seasons still exist but would affect the eleven unique biomes around the map. For example, in the dry season, dust storms will appear, while tropical storms occur throughout the fall storm season. Another detail is in the jungle, in which the environment would now react to the weather; an example of this is leaves flying everywhere.


title: Forza Horizon 5

text: "Forza Horizon 5" also introduces a brand new Horizon Arcade. This consists of a series of mini-multiplayer games strewn across the map. One of these mini-multiplayer games is called "Piñata pop" where the Horizon Festival's cargo plane drops piñatas. The goal is to pop as many piñatas as they can with the help of other players. It also introduces the "EventLab", a toolset in which players can create custom games, races, and more depending on their personal preference. A new feature called "Forza Link" was introduced. According to Brown, it is an AI assistant that tracks the current statuses of players, helping them to link with other players online and play together. Forza Link can also link players' GPS systems if they accept the invitation from another player. Accolades, new to the "Forza Horizon" series, allow players to collect points and prizes for completing certain tasks. Some vehicles can only be unlocked through the completion of the Accolades. There are over 1,800 accolades for the player to achieve.


title: Forza Horizon 5

text: The Eliminator battle royale game mode introduced in "Forza Horizon 4" returns, albeit with players starting in a 1963 Volkswagen Beetle rather than a 1965 Mini. The world is designed for the mode unlike the previous game, which received The Eliminator after launch. As in the previous game, players can buy in-game houses ranging from small beachside cabanas to even a hotel, which can unlock rewards such as Wheelspins and the right to Fast Travel. The game features over 600 licensed vehicles.


title: Forza Horizon 5

text: Due to licensing issues, vehicles from Alfa Romeo, Fiat (including Abarth marque) and Lancia were not present in the base game. Prior to the release of "Forza Horizon 5", the Stratos HF Stradale was shown in a video covering car audio but it was scrapped in the released game.


title: Forza Horizon 5

text: "Forza Horizon 5" has seen many content updates and bug fixes since its release. Monthly content updates include new cars, collectibles, horns, clothing, etc. These updates typically have a specific theme; for example, the Series 2 update in December 2021 was based around Christmas. Many updates also include series-specific map changes, for example, the Series 5 update introduced a stunt park located in the stadium on the map. This game is the first in the franchise to introduce new map changes, aside from seasons.


title: Forza Horizon 5

text: On 1 March 2022, American and British Sign language interpreter videos in a picture-in-picture format for cinematics were added.


title: Forza Horizon 5

text: The Series 13 update, released on 11 October 2022, celebrated the tenth anniversary of the "Forza Horizon" series, adding new content to the game in celebration. This included a new radio station titled "Horizon Mixtape", featuring a total of fifteen music tracks from the previous four entries (six tracks available from the start, five unlockable tracks via accolades by completing each chapter of the Horizon Story "Horizon Origins", and four tracks unlockable via completing limited-time seasonal championships in the Festival Playlist) along with recreations of key moments of the five games' initial drive sequences in the new Horizon Story "Horizon Origins"—with Horizon Bass Arena DJ and Horizon Mixtape host Scott Tyler (voiced by Ronan Summers), the only "Forza Horizon" series character to have appeared in every game so far, joining the player—the return of Midnight Battles from "Forza Horizon 3", and new achievements, accolades, and badges. Each of the previous four entries' title screens was also recreated by Playground Games within the game world of "Forza Horizon 5", with each season (week) of Series 13 using a recreated title screen corresponding to a different game; "Forza Horizon" in summer, "Forza Horizon 2" in autumn, "Forza Horizon 3" in winter, and "Forza Horizon 4" in spring.


title: Forza Horizon 5

text: The Series 14 update, released on 10 November 2022, added a new Horizon Story featuring the members of Donut Media. In November 2022, after a money-making exploit was discovered in the game's "Super7" mode, Playground Games disabled the game's auction house and later released a patch to fix the exploit. However, they announced that the auction house would remain closed for the time being to rebalance the game's economy.


title: Forza Horizon 5

text: The game's first expansion, "Forza Horizon 5: Hot Wheels", a follow-up to a similar expansion for "Forza Horizon 3", was released on 19 July 2022. This announcement was accidentally leaked via a Steam listing three days before its official announcement.


title: Forza Horizon 5

text: "Forza Horizon 5" was developed by Playground Games. The goal for the team was to create a game whose scale was significantly larger than its predecessors. The team chose Mexico as the game's setting due to its diverse and varied landscape. The team partnered with Mexican artists to create the in-game murals, and Mexican musicians to create the in-game soundtracks. It also sent a team to visit Mexico to capture real-world light and sky data. The game utilised photogrammetry data extensively in order to make the game's virtual environment to look similar to its real-life counterpart. An example of this is the rocks in the side of the caldera volcano where they can be viewed with such detail. Individual objects, such as the needles of cholla cacti, can also be displayed by the game (although this is only available for the Xbox Series consoles as of now).


title: Forza Horizon 5

text: "Forza Horizon 5" was announced during Microsoft and Bethesda's showcase at E3 2021. The game was released for Microsoft Windows, Xbox One, and Xbox Series X and Series S on 9 November 2021.


title: Forza Horizon 5

text: "Game Informer" appreciated the social interactions in the game, especially the score comparisons, "More times than I could count, I noticed my friend hit a higher top speed, causing me to turn around and try the challenge again". "Ars Technica" liked the visuals of the title, praising how it looked "next-gen", "I seriously cannot keep track of how many times "FH5" made my eyes bulge. The game takes special care to emphasize massive vistas... with screen-bursting HDR effects doing wonders for a richly saturated canvas of cities, sunsets, and scenery". While criticizing the car handling for making the game too easy, "Rock Paper Shotgun" enjoyed the new additions to the formula like the EventLab creator and Super7 events, "If you’ve played a Forza Horizon game before then you might feel a slight sense of deja vu, but you won’t care as the formula has been perfected at last". "Eurogamer" praised "Horizon 5"'s open world of Mexico, writing that "The map is an absolute wonder, backed by a game engine which can deliver staggering views across the whole thing from the summit of the volcano that towers over it. The environments are rich and saturated with colour and atmosphere, from humid swamps to arid dunes, from deep, verdant canyons to pastel-striped barrios".


title: Forza Horizon 5

text: "Polygon" liked the settings to tune difficulty and handling, but felt the game bombarded you with too many events and activities at once, "I feel constantly pinged with mentions and suggestions, from all directions, like two teenagers are blowing up my DMs". "The Verge" felt the progression systems were less confusing overall compared to "3", and praised how the player could choose what to do next, "You’re able to choose which specific types of events to unlock as you progress... I feel like if I stopped playing the game and came back to it weeks later, I’d have a much better sense of what I’d been doing".


title: Forza Horizon 5

text: Before the game's release on 9 November, over 1.2 million players had accessed the game by buying either the premium edition of the game or the premium add-ons bundle as an Xbox Game Pass subscriber, with "Video Game Chronicle" estimating gross revenue between $54 million and $118 million before release. The game also reached 1 on the Steam weekly charts for the week of 1 to 7 November 2021. Phil Spencer, head of Xbox, announced on 9 November that more than 4.5 million people have played the game in less than 24 hours after launch, the largest launch for an Xbox Game Studios game, while it also held three times more concurrent players than "Forza Horizon 4". On 18 November, the official "Forza Horizon" Twitter account announced that over ten million people have played the game during its first week of release, the largest amount of players for a game's first week in the Xbox brand's history. Writing for "Forbes", Erik Kain attributes the game's success to its at-launch availability on Xbox Game Pass, cross-platform play between Xbox One, Xbox Series X/S, and PC, its cloud gaming support via Xbox Cloud Gaming, and the high quality of the game itself. On 9 January 2022, two months after its release, the game passed the 15 million player mark, breaking the record for the previous game in the series in less than a year since it was released. The game attracted more than 20 million players seven months after its initial release.


title: Bella Heathcote

text: Isabella Heathcote (born 27 May 1987) is an Australian actress and model. She began her acting career in 2008. The following year, she had a recurring role as Amanda Fowler on the television soap opera "Neighbours".


title: Bella Heathcote

text: Heathcote has since portrayed governess Victoria Winters in Tim Burton's film adaptation of "Dark Shadows", Jane Bennett in "Pride and Prejudice and Zombies", model Gigi in "The Neon Demon", Nicole Dörmer in the dystopian alternate history thriller series "The Man in the High Castle", Leila Williams, a deranged ex-lover of Christian Grey, in "Fifty Shades Darker" and Olive Byrne in "Professor Marston and the Wonder Women".


title: Bella Heathcote

text: Heathcote was born in Melbourne, Australia. Her father was a lawyer. She attended Korowa Anglican Girls' School. She began her career in 2008. In May 2010, she was a recipient of a Heath Ledger Scholarship.


title: Bella Heathcote

text: In December 2010, Heathcote was cast in David Chase's film "Not Fade Away". In February 2011, Tim Burton selected Heathcote to play Victoria Winters and Josette du Pres in his film adaptation of "Dark Shadows", starring opposite Johnny Depp, Michelle Pfeiffer, and Helena Bonham Carter. She was later cast in Nicolas Winding Refn's thriller film "The Neon Demon", which was released in 2016.


title: Bella Heathcote

text: Heathcote was named as one of the 10 Actors to Watch: Breakthrough Performances of 2012 at the 20th Hamptons International Film Festival. The following year, she starred alongside Max Minghella in The Killers' music video for "Shot at the Night". Heathcote was part of the Spring/Summer 2014 campaign for Miu Miu alongside fellow actresses Lupita Nyong'o, Elle Fanning and Elizabeth Olsen.


title: Bella Heathcote

text: In 2017, Heathcote played Leila Williams in the film "Fifty Shades Darker", the sequel to "Fifty Shades of Grey". She also joined the season 2 cast of television drama "The Man in the High Castle", as Nicole Dörmer, a Berlin-born filmmaker. Heathcote starred as Olive Byrne, partner of psychologists and comic book authors William Moulton Marston and Elizabeth Holloway Marston, in the 2017 biographical film "Professor Marston and the Wonder Women".


title: Bella Heathcote

text: Heathcote played Susan Parsons in the CBS All Access drama "Strange Angel". The show is an adaptation of George Pendle's book "Strange Angel: The Otherworldly Life of Rocket Scientist John Whiteside Parsons". The series was cancelled after two seasons in November 2019. Heathcote appears in the second season of Australian web television series "Bloom" as a younger incarnation of Loris Webb, played by Anne Charleston.


title: Bella Heathcote

text: Heathcote appeared in the independent drama "Relic", alongside Emily Mortimer and Robyn Nevin. The film follows a daughter, a mother and a grandmother who are "haunted by a manifestation of dementia that consumes their family's home". The movie was produced by AGBO Films, the Russo Brothers production company and Jake Gyllenhaal, while co-written and directed by Natalia Erika James. In February 2020, it was announced that Heathcote will star alongside Toni Collette in the Netflix thriller series "Pieces of Her", which is adapted from the Karin Slaughter novel of the same name.


title: Orlando Brown (actor)

text: Orlando Brown (born December 4, 1987) is an American actor, rapper, and singer. He is best known for his roles as Cadet Kevin 'Tiger' Dunne in "Major Payne", 3J Winslow in "Family Matters", Max in "Two of a Kind", Damey Wayne "Waynehead" in "Waynehead", Sticky Webb in "The Proud Family", Cornelius Fillmore in "Fillmore!", Eddie Thomas in "That's So Raven", and Frankie in "Eddie's Million Dollar Cook-Off".


title: Orlando Brown (actor)

text: Orlando Brown made his acting debut in 1995 as Cadet Kevin 'Tiger' Dunne in "Major Payne". In 1998, he co-starred with Mary-Kate Olsen and Ashley Olsen in "Two of a Kind". In 1996, he was cast as 3J Winslow in "Family Matters". He began voice acting in 1996 when he starred as a childhood version of Damon Wayans in "Waynehead". For Disney he starred in "That's So Raven", "Max Keeble's Big Move", "Eddie's Million Dollar movie "Bloody Hands". After leaving Disney in 2007, Orlando decided to concentrate on his music career.


title: Orlando Brown (actor)

text: On February 28, 2016, in Torrance, California, Brown was arrested and later charged with domestic battery, obstruction of justice, drug possession with intent to sell, and possession of contraband in jail, following an altercation with his then-girlfriend in public. Police were called to the scene after he struck her in the parking lot of a police station and he was found by officers to be in possession of methamphetamine, a stimulant drug, at the time of the incident. Brown failed to appear for a scheduled court date in relation to the charges and a warrant was issued for his arrest; he was ultimately taken into custody by police on March 18, 2016, in Barstow, California, after police were called to a private residence in response to complaints of a domestic disturbance between Brown, his girlfriend, and his girlfriend's mother and subsequently faced additional charges of domestic battery, drug possession, and resisting arrest.


title: Orlando Brown (actor)

text: Following his release from jail in Barstow, he again failed to appear for a scheduled court date and a warrant was again issued for his arrest; he fled California for Nevada and was eventually apprehended by bounty hunters in Las Vegas, who found him hiding in the closet of a private homeowner on April 13, 2016.


title: Orlando Brown (actor)

text: On June 5, 2016, Brown was arrested in Las Vegas by police while leaving a local hotel known for prostitution and illegal drug sale and use. He refused to cooperate with officers after they stopped his taxicab, and a subsequent search found him to be in possession of methamphetamine and a pipe, and that he had an outstanding warrant for his arrest, in relation to one of his unresolved domestic battery charges. He was charged with drug possession, possession of drug paraphernalia, and resisting arrest.


title: Orlando Brown (actor)

text: Several months later, on September 2, 2016, Brown, recently released from a medical facility where he'd been hospitalized for undisclosed reasons, was arrested after breaking into Legends Restaurant & Venue, a Las Vegas establishment owned by his childhood friend Danny Boy, and attempting to change the locks. Police found Brown on the roof of the building, after security cameras showed him entering the building without permission.


title: Orlando Brown (actor)

text: In early 2016, Brown debuted to the public a new tattoo, that of his former "That's So Raven" co-star Raven-Symoné, on his neck. Later that year, he entered rehab, after an intervention from friends and family, but remained in the program only one week, and was photographed shortly after his release walking down the street barefoot, carrying a box of wine.


title: Orlando Brown (actor)

text: In 2018, Brown appeared on an episode of "Dr. Phil", and made false claims, among them that he was the son of musical icon Michael Jackson, saying his full name was Orlando Brown Prince Michael Jackson Jr., and that he had four children, two of whom he had never met and whose names he did not know. He claimed the oldest of his children is between the ages of 16 and 18, meaning Brown would have been between 13 and 15 at the time of their birth. He additionally claimed he had been sober for four years. The episode aired on December 21, 2018.


title: Orlando Brown (actor)

text: Since his appearance on the Dr. Phil show, Brown has admitted to his past addictions and opened up about his struggles at a church fundraising event in 2020.


title: Statute of limitations

text: A statute of limitations, known in civil law systems as a prescriptive period, is a law passed by a legislative body to set the maximum time after an event within which legal proceedings may be initiated. In most jurisdictions, such periods exist for both criminal law and civil law such as contract law and property law, though often under different names and with varying details.


title: Statute of limitations

text: When the time which is specified in a statute of limitations runs out, a claim might no longer be filed or, if it is filed, it may be subject to dismissal if the defense against that claim is raised that the claim is time-barred as having been filed after the statutory limitations period. When a statute of limitations expires in a criminal case, the courts no longer have jurisdiction. Most common crimes, misconducts and wrongdoings that have statutes of limitations are distinguished from particularly serious crimes because these claims may be brought at any time.


title: Statute of limitations

text: In civil law systems, such provisions are typically part of their civil and criminal codes. The cause of action dictates the statute of limitations, which can be reduced or extended in order to ensure a full and fair trial. The intention of these laws is to facilitate resolution within a "reasonable" period of time. What amount of time is considered "reasonable" varies from country to country. In the United States, it may vary from jurisdiction to jurisdiction and state to state. Internationally, the statute of limitations may vary from one civil or criminal action to another. Some countries have no statute of limitations whatsoever.


title: Statute of limitations

text: Analysis of a statute of limitations also requires the examination of any associated statute of repose, tolling provisions, and exclusions.


title: Statute of limitations

text: Common law legal systems can include a statute specifying the length of time within which a claimant or prosecutor must file a case. In some civil jurisdictions (e.g., California), a case cannot begin after the period specified, and courts have no jurisdiction over cases filed after the statute of limitations has expired. In some other jurisdictions (e.g., New South Wales, Australia), a claim can be filed which may prove to have been brought outside the limitations period, but the court will retain jurisdiction in order to determine that issue, and the onus is on the defendant to plead it as part of their defence, or else the claim will not be statute barred.


title: Statute of limitations

text: Once they are filed, cases do not need to be resolved within the period specified in the statute of limitations.


title: Statute of limitations

text: The purpose and effect of statutes of limitations are to protect defendants. There are three reasons for their enactment:


title: Statute of limitations

text: In Classical Athens, a five-year statute of limitations was established for almost all cases, exceptions being such as the prosecution of non-constitutional laws (which had no limitation). Demosthenes wrote that these statutes of limitations were adopted to control "sycophants" (professional accusers).


title: Statute of limitations

text: The limitation period generally begins when the plaintiff's cause of action accrues, meaning the date upon which the plaintiff is first able to maintain the cause of action in court, or when the plaintiff first becomes aware of a previous injury (for example, occupational lung diseases such as asbestosis).


title: Statute of limitations

text: A statute of repose limits the time within which an action may be brought based upon when a particular event occurred (such as the completion of construction of a building or the date of purchase of manufactured goods), and does not permit extensions. A statute of limitations is similar to a statute of repose, but may be extended for a variety of reasons (such as the minority of the victim).


title: Statute of limitations

text: For example, most U.S. jurisdictions have passed statutes of repose for construction defects. If a person receives an electric shock due to a wiring defect that resulted from the builder's negligence during construction of a building, the builder is potentially liable for damages if the suit is brought within the time period defined by the statute, normally starting with the date that construction is substantially completed. After the statutory time period has passed, without regard to the nature or degree of the builder's negligence or misconduct, the statute of repose presents an absolute defense to the claim.


title: Statute of limitations

text: Statutes of repose are sometimes controversial; manufacturers contend that they are necessary to avoid unfair litigation and encourage consumers to maintain their property. Alternatively, consumer advocates argue that they reduce incentives to manufacture durable products and disproportionately affect the poor, because manufacturers will have less incentive to ensure low-cost or "bargain" products are manufactured to exacting safety standards.


title: Statute of limitations

text: Many jurisdictions toll or suspend the limitation period in exceptional circumstances such as if the aggrieved person (plaintiff, appellant or petitioner) was a minor, or has filed a bankruptcy proceeding. In those instances, the running of limitations is tolled or paused, until the condition ends. Equitable tolling may also be applied if an individual may intimidate a moving party into not reporting or has been promised a suspended period.


title: Statute of limitations

text: The statute of limitations may begin when the harmful event, such as fraud or injury, occurs or it may begin when the harmful event is discovered. The U.S. Supreme Court has described the "standard rule" of when the time begins as "when the plaintiff has a complete and present cause of action." The rule has existed since the 1830s. A "discovery rule" applies in other cases (including medical malpractice), or a similar effect may be applied by tolling.


title: Statute of limitations

text: According to U.S. district judge Sean J. McLaughlin, the discovery rule does not apply to mass media such as newspapers and the Internet; the statute of limitations begins to run at the date of publication. In 2013, the U.S. Supreme Court unanimously ruled in "Gabelli v. SEC" that the discovery rule does not apply to U.S. Securities and Exchange Commission's investment-advisor-fraud lawsuits since one of the purposes of the agency is to root out fraud.


title: Statute of limitations

text: In private civil matters, the limitation period may generally be shortened or lengthened by agreement of the parties. Under the Uniform Commercial Code, the parties to a contract for sale of goods may reduce the limitation period to one year but not extend it.


title: Statute of limitations

text: Limitation periods that are known as laches may apply in situations of equity; a judge will not issue an injunction if the requesting party waited too long to ask for it. Such periods are subject to broad judicial discretion.


title: Statute of limitations

text: For US military cases, the Uniform Code of Military Justice (UCMJ) states that all charges except those facing court-martial on a capital charge have a five-year statute of limitations. If the charges are dropped in all UCMJ proceedings except those headed for general court-martial, they may be reinstated for six months after which the statute of limitations has run out.


title: Statute of limitations

text: In civil law countries, almost all lawsuits must be brought within a legally-determined period at the end of which the right of action is extinguished. This is known as liberative or extinctive prescription. Under Italian and Romanian law, criminal trials must be ended within a time limit.


title: Statute of limitations

text: In criminal cases, the public prosecutor must lay charges within a time limit which varies by jurisdiction and varies based on the nature of the charge, whose directives vary from country to country. Over the last decade of the 20th century, many United States jurisdictions significantly lengthened the statute of limitations for sex offenses, particularly against children, as a response to research and popular belief that a variety of causes can delay the recognition and reporting of crimes of this nature.


title: Statute of limitations

text: Common triggers for suspending the prescription include a defendant's fugitive status or the commission of a new crime. In some jurisdictions, a criminal may be convicted "in absentia". Prescription should not be confused with the need to prosecute within "a reasonable delay" as obligated by the European Court of Human Rights.


title: Statute of limitations

text: Under international law, genocide, crimes against humanity and war crimes are usually not subject to the statute of limitations as codified in a number of multilateral treaties. States ratifying the Convention on the Non-Applicability of Statutory Limitations to War Crimes and Crimes Against Humanity agree to disallow limitations claims for these crimes. In Article 29 of the Rome Statute of the International Criminal Court, genocide, crimes against humanity and war crimes "shall not be subject to any statute of limitations".


title: Statute of limitations

text: In Australia, the statutes of limitation are prescribed separately by each state or territory jurisdiction for civil matters. In criminal proceedings the statute of limitations is normally defined by statute.


title: Statute of limitations

text: The Limitations Act of 1958 allows 12 years for victims of child abuse to make a claim, with age 37 the latest at which a claim can be made. The police submitted evidence to a commission, the Victorian Inquiry into Church and Institutional Child Abuse (in existence since 2012) indicating that it takes an average of 24 years for a victims of child sexual abuse to go to the police. According to Attorney General Robert Clark, the government will remove statutes of limitations on criminal child abuse; victims of violent crime should be given additional time, as adults, to deal with the legal system. Offenders of minors and the disabled have used the statute of limitations to avoid detection and prosecution, moving from state to state and country to country; an example which was presented to the Victorian Inquiry was the Christian Brothers.


title: Statute of limitations

text: An argument for abolishing statutes of limitations for civil claims by minors and people under guardianship is ensuring that abuse of vulnerable people would be acknowledged by lawyers, police, organisations and governments, with enforceable penalties for organisations which have turned a blind eye in the past. Support groups such as SNAP Australia, Care Leavers Australia Network and Broken Rites have submitted evidence to the Victoria inquiry, and the Law Institute of Victoria has advocated changes to the statute of limitations.


title: Statute of limitations

text: Indictable (serious) offences such as fraud, serious theft, murder, kidnapping, aggravated assault, sexual assault, arson, bribery, perjury, do not have a limitation period. A defendant can be charged at any future date. In sexual abuse cases in particular, men and women have been charged and convicted up to five decades after the abuse had been committed.


title: Statute of limitations

text: In Finland, the authority of a prosecuting official to bring charges for a crime expires after a set period of time has passed since the act. This period is 20, 10, 5, or 2, years depending on the seriousness of the offence. Offences punishable with life imprisonment, such as murder and treason, do not expire. Sexual offences committed against minors do not expire before the victim reaches 23 or 28 years of age, depending on the nature of the offence.


title: Statute of limitations

text: In Germany, the statute of limitations on crimes varies by type of crime, with the highest statute of limitation being 30 years for voluntary manslaughter (). Murder, genocide, crimes against humanity, war crimes and the crime of aggression have no statute of limitations.


title: Statute of limitations

text: In Germany, the crime of murder used to have a 20 year statute of limitations. In 1969, the statute of limitations for murder was extended from twenty to 30 years. The limitations were abolished altogether in 1979, in order to prevent Nazi criminals from avoiding criminal liability.


title: Statute of limitations

text: For most other criminal offences, the statute of limitations is set by Section 78(3) of the Criminal Code () as follows:


title: Statute of limitations

text: In the civil code (), the regular statute of limitations is three years (plus the time until the end of the calendar year); however, different terms between two and thirty years may apply in specific situations. For example, the term is only two years for claims for alleged defects of purchased goods, but 30 years for claims resulting from a court judgement (such as awarded damages).


title: Statute of limitations

text: The statute of limitations for criminal offences is governed by Sec. 468 of the Criminal Procedure Code.


title: Statute of limitations

text: The statutes of limitations in New Zealand are defined by section 25 of the Criminal Procedure Act 2011. For offences committed by body corporates, the statutes of limitation are determined as if they were a natural person. The limits are as follows:


title: Statute of limitations

text: The statute of limitations on murder was abolished by a change in law on 1 July 2014, causing any murders committed after 1 July 1989 to have no statute of limitations. This led to the national police force implementing a new investigation group for old cases called the "Cold Case" group. The law was also changed to let cases involving domestic violence, forced marriage, human trafficking and genital mutilation to count from the day the defendant turns 18 years old. Cases where the statute of limitations has already passed can not be extended due to the constitution preventing it.


title: Statute of limitations

text: In the Philippines, the Revised Penal Code has different limitation periods, based on the penalty of the crime:


title: Statute of limitations

text: Other special laws have their own limitation periods. For crimes punished under the Revised Penal Code, the limitation period won't run if the offender is outside the Philippines, while for those punished under other laws, it does. Municipal ordinances have a limitation period of 2 months.


title: Statute of limitations

text: In July 2015, the National Assembly abolished a 25-year limit on first degree murder; it had previously been extended from 15 to 25 years in December 2007.


title: Statute of limitations

text: Turkish Code of Obligations sets the general limitation period to ten years, which applies where the law does not provide a specific limitation period.


title: Statute of limitations

text: There is no statute of limitations for sexual offenses committed against minors, however, under both the Turkish Penal Code (article 99) and Turkish Civil Code (Law No. 2827).


title: Statute of limitations

text: Unlike many countries, the United Kingdom has no statute of limitations for criminal offences above summary offences (offences tried exclusively in the magistrates’ court). In these cases, criminal proceedings must be brought within six months according to the Magistrates' Courts Act 1980. To obtain a conviction in "some road traffic offences" (i.e., speeding) the driver must be notified, within 14 days of the offence, of the intention to prosecute them according to the Road Traffic Offenders Act 1988.


title: Statute of limitations

text: For civil claims, the statue of limitations varies depending on the type of claim. For example, a claim (debt) from a simple contract can no longer be pursued after six years.


title: Statute of limitations

text: In the United States, statutes of limitations may apply in criminal procedures and civil lawsuits. Statutes of limitations vary significantly among U.S. jurisdictions.


title: Statute of limitations

text: A government agency is permitted by the Congress to create under federal regulations its own statute of limitations.


title: Statute of limitations

text: The U.S. Supreme Court held in "Stogner v. California" (by a 5–4 majority) that California's retroactive extension of the statute of limitations for sexual offenses committed against minors was an unconstitutional ex post facto law.


title: Statute of limitations

text: A civil statute of limitations applies to a non-criminal legal action, including a tort or contract case. If the statute of limitations expires before a lawsuit is filed, the defendant may raise the statute of limitations as an affirmative defense to seek dismissal of the charge. The exact time period depends on both the state and the type of claim (contract claim, personal injury, fraud etc.). Most fall in the range of one to ten years, with two to three years being most common.


title: Statute of limitations

text: A criminal statute of limitations defines a time period during which charges must be initiated for a criminal offense. If a charge is filed after the statute of limitations expires, the defendant may obtain dismissal of the charge.


title: Statute of limitations

text: The statute of limitations in a criminal case only runs until a criminal charge is filed and a warrant issued, even if the defendant is a fugitive. When the identity of a defendant is not known, some jurisdictions provide mechanisms to initiate charges and thus stop the statute of limitations from running. For example, some states allow an indictment of a John Doe defendant based upon a DNA profile derived from evidence obtained through a criminal investigation. Although rare, a grand jury can issue an indictment in absentia for high-profile crimes to get around an upcoming statute of limitations deadline. One example is the skyjacking of Northwest Orient Airlines Flight 305 by D. B. Cooper in 1971. The identity of D. B. Cooper remains unknown to this day, and he was indicted under the name "John Doe, aka Dan Cooper."


title: Statute of limitations

text: Crimes which are widely considered heinous have no statute of limitations. Although there is usually no statute of limitations for murder (particularly first-degree murder), judges have been known to dismiss murder charges in cold cases if they feel that the delay violates the defendant's right to a speedy trial. For example, waiting many years for an alibi witness to die before commencing a murder trial would be unconstitutional.


title: Statute of limitations

text: Under 46 U.S. Code § 30106, "Except as otherwise provided by law, a civil action for damages for personal injury or death arising out of a maritime tort must be brought within 3 years after the cause of action arose." There are some exceptions to this, primarily with regard to Jones Act cases filed against the government, in which case the statute of limitations can be less than 2 years.


title: Statute of limitations

text: U.S. jurisdictions recognize exceptions to statutes of limitation that may allow for the prosecution of a crime or civil lawsuit even after the statute of limitations would otherwise have expired. Some states stop the clock for a suspect who is not residing within the state or is purposely hiding. Kentucky, North Carolina, and South Carolina have no statutes of limitation for felonies, while Wyoming includes misdemeanors as well. However, the right to speedy trial may derail any prosecution after many years have passed.


title: Statute of limitations

text: When an officer of the court is found to have fraudulently presented facts to impair the court's impartial performance of its legal task, the act (known as "fraud upon the court") is not subject to a statute of limitation: "This concept that the inherent power of federal courts to vacate a fraudulently obtained judgment—even years after the judgment was entered—has long been recognized by the Supreme Court." Fraud on the court can be done many ways and in any court. One of which can be "where the court or a member is corrupted or influenced or influence is attempted or where the judge has not performed his judicial function — thus where the impartial functions of the court have been directly corrupted." Officer of the court includes any judge, law clerk, court clerk, lawyer, investigator, probation officer, referee, legal guardian, parenting-time expeditor, mediator, evaluator, administrator, special appointee, and/or anyone else whose influence is part of the judicial mechanism.


title: Statute of limitations

text: In tort law, if any person or entity commits a series of illegal acts against another person or entity (or in criminal law if a defendant commits a continuing crime) the limitation period may begin to run from the last act in the series. The entire chain of events can be tolled if the violations were continuing. Courts have explained that the continuing-violations doctrine "tolls the statute of limitations in situations where a continuing pattern forms due to discriminatory acts which have been occurring over a period of time, as long as at least one incident of discrimination occurred within the limitations period." Whether the continuing-violations doctrine applies to a particular violation is subject to judicial discretion; it was said to apply to copyright infringement in the jurisdiction of the Seventh Circuit, but not in the jurisdiction of the Second Circuit.


title: Glycolysis

text: Glycolysis is the metabolic pathway that converts glucose () into pyruvate (). The free energy released in this process is used to form the high-energy molecules adenosine triphosphate (ATP) and reduced nicotinamide adenine dinucleotide (NADH). Glycolysis is a sequence of ten reactions catalyzed by enzymes.


title: Glycolysis

text: Glycolysis is a metabolic pathway that does not require oxygen (In anaerobic conditions pyruvate is converted to lactic acid). The wide occurrence of glycolysis in other species indicates that it is an ancient metabolic pathway. Indeed, the reactions that make up glycolysis and its parallel pathway, the pentose phosphate pathway, occur in the oxygen-free conditions of the Archean oceans, also in the absence of enzymes, catalyzed by metal.


title: Glycolysis

text: In most organisms, glycolysis occurs in the liquid part of cells, the cytosol. The most common type of glycolysis is the "Embden–Meyerhof–Parnas (EMP) pathway", which was discovered by Gustav Embden, Otto Meyerhof, and Jakub Karol Parnas. Glycolysis also refers to other pathways, such as the "Entner–Doudoroff pathway" and various heterofermentative and homofermentative pathways. However, the discussion here will be limited to the Embden–Meyerhof–Parnas pathway.


title: Glycolysis

text: The use of symbols in this equation makes it appear unbalanced with respect to oxygen atoms, hydrogen atoms, and charges. Atom balance is maintained by the two phosphate (P) groups:


title: Glycolysis

text: Charges are balanced by the difference between ADP and ATP. In the cellular environment, all three hydroxyl groups of ADP dissociate into −O and H, giving ADP, and this ion tends to exist in an ionic bond with Mg, giving ADPMg. ATP behaves identically except that it has four hydroxyl groups, giving ATPMg. When these differences along with the true charges on the two phosphate groups are considered together, the net charges of −4 on each side are balanced.


title: Glycolysis

text: For simple fermentations, the metabolism of one molecule of glucose to two molecules of pyruvate has a net yield of two molecules of ATP. Most cells will then carry out further reactions to "repay" the used NAD and produce a final product of ethanol or lactic acid. Many bacteria use inorganic compounds as hydrogen acceptors to regenerate the NAD.


title: Glycolysis

text: Cells performing aerobic respiration synthesize much more ATP, but not as part of glycolysis. These further aerobic reactions use pyruvate, and NADH + H from glycolysis. Eukaryotic aerobic respiration produces approximately 34 additional molecules of ATP for each glucose molecule, however most of these are produced by a mechanism vastly different from the substrate-level phosphorylation in glycolysis.


title: Glycolysis

text: The lower-energy production, per glucose, of anaerobic respiration relative to aerobic respiration, results in greater flux through the pathway under hypoxic (low-oxygen) conditions, unless alternative sources of anaerobically oxidizable substrates, such as fatty acids, are found.


title: Glycolysis

text: The pathway of glycolysis as it is known today took almost 100 years to fully elucidate. The combined results of many smaller experiments were required in order to understand the pathway as a whole.


title: Glycolysis

text: The first steps in understanding glycolysis began in the nineteenth century with the wine industry. For economic reasons, the French wine industry sought to investigate why wine sometimes turned distasteful, instead of fermenting into alcohol. French scientist Louis Pasteur researched this issue during the 1850s, and the results of his experiments began the long road to elucidating the pathway of glycolysis. His experiments showed that fermentation occurs by the action of living microorganisms, yeasts, and that yeast's glucose consumption decreased under aerobic conditions of fermentation, in comparison to anaerobic conditions (the Pasteur effect).


title: Glycolysis

text: Insight into the component steps of glycolysis were provided by the non-cellular fermentation experiments of Eduard Buchner during the 1890s. Buchner demonstrated that the conversion of glucose to ethanol was possible using a non-living extract of yeast, due to the action of enzymes in the extract. This experiment not only revolutionized biochemistry, but also allowed later scientists to analyze this pathway in a more controlled laboratory setting. In a series of experiments (1905-1911), scientists Arthur Harden and William Young discovered more pieces of glycolysis. They discovered the regulatory effects of ATP on glucose consumption during alcohol fermentation. They also shed light on the role of one compound as a glycolysis intermediate: fructose 1,6-bisphosphate.


title: Glycolysis

text: The elucidation of fructose 1,6-bisphosphate was accomplished by measuring levels when yeast juice was incubated with glucose. production increased rapidly then slowed down. Harden and Young noted that this process would restart if an inorganic phosphate (Pi) was added to the mixture. Harden and Young deduced that this process produced organic phosphate esters, and further experiments allowed them to extract fructose diphosphate (F-1,6-DP).


title: Glycolysis

text: Arthur Harden and William Young along with Nick Sheppard determined, in a second experiment, that a heat-sensitive high-molecular-weight subcellular fraction (the enzymes) and a heat-insensitive low-molecular-weight cytoplasm fraction (ADP, ATP and NAD and other cofactors) are required together for fermentation to proceed. This experiment begun by observing that dialyzed (purified) yeast juice could not ferment or even create a sugar phosphate. This mixture was rescued with the addition of undialyzed yeast extract that had been boiled. Boiling the yeast extract renders all proteins inactive (as it denatures them). The ability of boiled extract plus dialyzed juice to complete fermentation suggests that the cofactors were non-protein in character.


title: Glycolysis

text: In the 1920s Otto Meyerhof was able to link together some of the many individual pieces of glycolysis discovered by Buchner, Harden, and Young. Meyerhof and his team were able to extract different glycolytic enzymes from muscle tissue, and combine them to artificially create the pathway from glycogen to lactic acid.


title: Glycolysis

text: In one paper, Meyerhof and scientist Renate Junowicz-Kockolaty investigated the reaction that splits fructose 1,6-diphosphate into the two triose phosphates. Previous work proposed that the split occurred via 1,3-diphosphoglyceraldehyde plus an oxidizing enzyme and cozymase. Meyerhoff and Junowicz found that the equilibrium constant for the isomerase and aldoses reaction were not affected by inorganic phosphates or any other cozymase or oxidizing enzymes. They further removed diphosphoglyceraldehyde as a possible intermediate in glycolysis.


title: Glycolysis

text: With all of these pieces available by the 1930s, Gustav Embden proposed a detailed, step-by-step outline of that pathway we now know as glycolysis. The biggest difficulties in determining the intricacies of the pathway were due to the very short lifetime and low steady-state concentrations of the intermediates of the fast glycolytic reactions. By the 1940s, Meyerhof, Embden and many other biochemists had finally completed the puzzle of glycolysis. The understanding of the isolated pathway has been expanded in the subsequent decades, to include further details of its regulation and integration with other metabolic pathways.


title: Glycolysis

text: The first five steps of Glycolysis are regarded as the preparatory (or investment) phase, since they consume energy to convert the glucose into two three-carbon sugar phosphates (G3P).


title: Glycolysis

text: The first step is phosphorylation of glucose by a family of enzymes called hexokinases to form glucose 6-phosphate (G6P). This reaction consumes ATP, but it acts to keep the glucose concentration low, promoting continuous transport of glucose into the cell through the plasma membrane transporters. In addition, it blocks the glucose from leaking out – the cell lacks transporters for G6P, and free diffusion out of the cell is prevented due to the charged nature of G6P. Glucose may alternatively be formed from the phosphorolysis or hydrolysis of intracellular starch or glycogen.


title: Glycolysis

text: In animals, an isozyme of hexokinase called glucokinase is also used in the liver, which has a much lower affinity for glucose (K in the vicinity of normal glycemia), and differs in regulatory properties. The different substrate affinity and alternate regulation of this enzyme are a reflection of the role of the liver in maintaining blood sugar levels.


title: Glycolysis

text: G6P is then rearranged into fructose 6-phosphate (F6P) by glucose phosphate isomerase. Fructose can also enter the glycolytic pathway by phosphorylation at this point.


title: Glycolysis

text: The change in structure is an isomerization, in which the G6P has been converted to F6P. The reaction requires an enzyme, phosphoglucose isomerase, to proceed. This reaction is freely reversible under normal cell conditions. However, it is often driven forward because of a low concentration of F6P, which is constantly consumed during the next step of glycolysis. Under conditions of high F6P concentration, this reaction readily runs in reverse. This phenomenon can be explained through Le Chatelier's Principle. Isomerization to a keto sugar is necessary for carbanion stabilization in the fourth reaction step (below).


title: Glycolysis

text: The energy expenditure of another ATP in this step is justified in 2 ways: The glycolytic process (up to this step) becomes irreversible, and the energy supplied destabilizes the molecule. Because the reaction catalyzed by phosphofructokinase 1 (PFK-1) is coupled to the hydrolysis of ATP (an energetically favorable step) it is, in essence, irreversible, and a different pathway must be used to do the reverse conversion during gluconeogenesis. This makes the reaction a key regulatory point (see below).


title: Glycolysis

text: Furthermore, the second phosphorylation event is necessary to allow the formation of two charged groups (rather than only one) in the subsequent step of glycolysis, ensuring the prevention of free diffusion of substrates out of the cell.


title: Glycolysis

text: The same reaction can also be catalyzed by pyrophosphate-dependent phosphofructokinase (PFP or PPi-PFK), which is found in most plants, some bacteria, archea, and protists, but not in animals. This enzyme uses pyrophosphate (PPi) as a phosphate donor instead of ATP. It is a reversible reaction, increasing the flexibility of glycolytic metabolism. A rarer ADP-dependent PFK enzyme variant has been identified in archaean species.


title: Glycolysis

text: Destabilizing the molecule in the previous reaction allows the hexose ring to be split by aldolase into two triose sugars: dihydroxyacetone phosphate (a ketose), and glyceraldehyde 3-phosphate (an aldose). There are two classes of aldolases: class I aldolases, present in animals and plants, and class II aldolases, present in fungi and bacteria; the two classes use different mechanisms in cleaving the ketose ring.


title: Glycolysis

text: Electrons delocalized in the carbon-carbon bond cleavage associate with the alcohol group. The resulting carbanion is stabilized by the structure of the carbanion itself via resonance charge distribution and by the presence of a charged ion prosthetic group.


title: Glycolysis

text: Triosephosphate isomerase rapidly interconverts dihydroxyacetone phosphate with glyceraldehyde 3-phosphate (GADP) that proceeds further into glycolysis. This is advantageous, as it directs dihydroxyacetone phosphate down the same pathway as glyceraldehyde 3-phosphate, simplifying regulation.


title: Glycolysis

text: The second half of glycolysis is known as the pay-off phase, characterised by a net gain of the energy-rich molecules ATP and NADH. Since glucose leads to two triose sugars in the preparatory phase, each reaction in the pay-off phase occurs twice per glucose molecule. This yields 2 NADH molecules and 4 ATP molecules, leading to a net gain of 2 NADH molecules and 2 ATP molecules from the glycolytic pathway per glucose.


title: Glycolysis

text: The aldehyde groups of the triose sugars are oxidised, and inorganic phosphate is added to them, forming 1,3-bisphosphoglycerate.


title: Glycolysis

text: The hydrogen is used to reduce two molecules of NAD, a hydrogen carrier, to give NADH + H for each triose.


title: Glycolysis

text: Hydrogen atom balance and charge balance are both maintained because the phosphate (P) group actually exists in the form of a hydrogen phosphate anion (), which dissociates to contribute the extra H ion and gives a net charge of -3 on both sides.


title: Glycolysis

text: Here, arsenate (), an anion akin to inorganic phosphate may replace phosphate as a substrate to form 1-arseno-3-phosphoglycerate. This, however, is unstable and readily hydrolyzes to form 3-phosphoglycerate, the intermediate in the next step of the pathway. As a consequence of bypassing this step, the molecule of ATP generated from 1-3 bisphosphoglycerate in the next reaction will not be made, even though the reaction proceeds. As a result, arsenate is an uncoupler of glycolysis.


title: Glycolysis

text: This step is the enzymatic transfer of a phosphate group from 1,3-bisphosphoglycerate to ADP by phosphoglycerate kinase, forming ATP and 3-phosphoglycerate. At this step, glycolysis has reached the break-even point: 2 molecules of ATP were consumed, and 2 new molecules have now been synthesized. This step, one of the two substrate-level phosphorylation steps, requires ADP; thus, when the cell has plenty of ATP (and little ADP), this reaction does not occur. Because ATP decays relatively quickly when it is not metabolized, this is an important regulatory point in the glycolytic pathway.


title: Glycolysis

text: Enolase next converts 2-phosphoglycerate to phosphoenolpyruvate. This reaction is an elimination reaction involving an E1cB mechanism.


title: Glycolysis

text: "Cofactors:" 2 Mg, one "conformational" ion to coordinate with the carboxylate group of the substrate, and one "catalytic" ion that participates in the dehydration.


title: Glycolysis

text: A final substrate-level phosphorylation now forms a molecule of pyruvate and a molecule of ATP by means of the enzyme pyruvate kinase. This serves as an additional regulatory step, similar to the phosphoglycerate kinase step.


title: Glycolysis

text: The existence of more than one point of regulation indicates that intermediates between those points enter and leave the glycolysis pathway by other processes. For example, in the first regulated step, hexokinase converts glucose into glucose-6-phosphate. Instead of continuing through the glycolysis pathway, this intermediate can be converted into glucose storage molecules, such as glycogen or starch. The reverse reaction, breaking down, e.g., glycogen, produces mainly glucose-6-phosphate; very little free glucose is formed in the reaction. The glucose-6-phosphate so produced can enter glycolysis "after" the first control point.


title: Glycolysis

text: In the second regulated step (the third step of glycolysis), phosphofructokinase converts fructose-6-phosphate into fructose-1,6-bisphosphate, which then is converted into glyceraldehyde-3-phosphate and dihydroxyacetone phosphate. The dihydroxyacetone phosphate can be removed from glycolysis by conversion into glycerol-3-phosphate, which can be used to form triglycerides. Conversely, triglycerides can be broken down into fatty acids and glycerol; the latter, in turn, can be converted into dihydroxyacetone phosphate, which can enter glycolysis "after" the second control point.


title: Glycolysis

text: The change in free energy, Δ"G", for each step in the glycolysis pathway can be calculated using Δ"G" = Δ"G"°' + "RT"ln "Q", where "Q" is the reaction quotient. This requires knowing the concentrations of the metabolites. All of these values are available for erythrocytes, with the exception of the concentrations of NAD and NADH. The ratio of NAD to NADH in the cytoplasm is approximately 1000, which makes the oxidation of glyceraldehyde-3-phosphate (step 6) more favourable.


title: Glycolysis

text: Using the measured concentrations of each step, and the standard free energy changes, the actual free energy change can be calculated. (Neglecting this is very common - the delta G of ATP hydrolysis in cells is not the standard free energy change of ATP hydrolysis quoted in textbooks).


title: Glycolysis

text: From measuring the physiological concentrations of metabolites in an erythrocyte it seems that about seven of the steps in glycolysis are in equilibrium for that cell type. Three of the steps — the ones with large negative free energy changes — are not in equilibrium and are referred to as "irreversible"; such steps are often subject to regulation.


title: Glycolysis

text: Step 5 in the figure is shown behind the other steps, because that step is a side-reaction that can decrease or increase the concentration of the intermediate glyceraldehyde-3-phosphate. That compound is converted to dihydroxyacetone phosphate by the enzyme triose phosphate isomerase, which is a catalytically perfect enzyme; its rate is so fast that the reaction can be assumed to be in equilibrium. The fact that Δ"G" is not zero indicates that the actual concentrations in the erythrocyte are not accurately known.


title: Glycolysis

text: The enzymes that catalyse glycolysis are regulated via a range of biological mechanisms in order to control overall flux though the pathway. This is vital for both homeostatsis in a static environment, and metabolic adaptation to a changing environment or need. The details of regulation for some enzymes are highly conserved between species, whereas others vary widely.


title: Glycolysis

text: In animals, regulation of blood glucose levels by the pancreas in conjunction with the liver is a vital part of homeostasis. The beta cells in the pancreatic islets are sensitive to the blood glucose concentration. A rise in the blood glucose concentration causes them to release insulin into the blood, which has an effect particularly on the liver, but also on fat and muscle cells, causing these tissues to remove glucose from the blood. When the blood sugar falls the pancreatic beta cells cease insulin production, but, instead, stimulate the neighboring pancreatic alpha cells to release glucagon into the blood. This, in turn, causes the liver to release glucose into the blood by breaking down stored glycogen, and by means of gluconeogenesis. If the fall in the blood glucose level is particularly rapid or severe, other glucose sensors cause the release of epinephrine from the adrenal glands into the blood. This has the same action as glucagon on glucose metabolism, but its effect is more pronounced. In the liver glucagon and epinephrine cause the phosphorylation of the key, regulated enzymes of glycolysis, fatty acid synthesis, cholesterol synthesis, gluconeogenesis, and glycogenolysis. Insulin has the opposite effect on these enzymes. The phosphorylation and dephosphorylation of these enzymes (ultimately in response to the glucose level in the blood) is the dominant manner by which these pathways are controlled in the liver, fat, and muscle cells. Thus the phosphorylation of phosphofructokinase inhibits glycolysis, whereas its dephosphorylation through the action of insulin stimulates glycolysis.


title: Glycolysis

text: The three regulatory enzymes are hexokinase (or glucokinase in the liver), phosphofructokinase, and pyruvate kinase. The flux through the glycolytic pathway is adjusted in response to conditions both inside and outside the cell. The internal factors that regulate glycolysis do so primarily to provide ATP in adequate quantities for the cell's needs. The external factors act primarily on the liver, fat tissue, and muscles, which can remove large quantities of glucose from the blood after meals (thus preventing hyperglycemia by storing the excess glucose as fat or glycogen, depending on the tissue type). The liver is also capable of releasing glucose into the blood between meals, during fasting, and exercise thus preventing hypoglycemia by means of glycogenolysis and gluconeogenesis. These latter reactions coincide with the halting of glycolysis in the liver.


title: Glycolysis

text: In addition hexokinase and glucokinase act independently of the hormonal effects as controls at the entry points of glucose into the cells of different tissues. Hexokinase responds to the glucose-6-phosphate (G6P) level in the cell, or, in the case of glucokinase, to the blood sugar level in the blood to impart entirely intracellular controls of the glycolytic pathway in different tissues (see below).


title: Glycolysis

text: When glucose has been converted into G6P by hexokinase or glucokinase, it can either be converted to glucose-1-phosphate (G1P) for conversion to glycogen, or it is alternatively converted by glycolysis to pyruvate, which enters the mitochondrion where it is converted into acetyl-CoA and then into citrate. Excess citrate is exported from the mitochondrion back into the cytosol, where ATP citrate lyase regenerates acetyl-CoA and oxaloacetate (OAA). The acetyl-CoA is then used for fatty acid synthesis and cholesterol synthesis, two important ways of utilizing excess glucose when its concentration is high in blood. The regulated enzymes catalyzing these reactions perform these functions when they have been dephosphorylated through the action of insulin on the liver cells. Between meals, during fasting, exercise or hypoglycemia, glucagon and epinephrine are released into the blood. This causes liver glycogen to be converted back to G6P, and then converted to glucose by the liver-specific enzyme glucose 6-phosphatase and released into the blood. Glucagon and epinephrine also stimulate gluconeogenesis, which coverts non-carbohydrate substrates into G6P, which joins the G6P derived from glycogen, or substitutes for it when the liver glycogen store have been depleted. This is critical for brain function, since the brain utilizes glucose as an energy source under most conditions. The simultaneously phosphorylation of, particularly, phosphofructokinase, but also, to a certain extent pyruvate kinase, prevents glycolysis occurring at the same time as gluconeogenesis and glycogenolysis.


title: Glycolysis

text: All cells contain the enzyme hexokinase, which catalyzes the conversion of glucose that has entered the cell into glucose-6-phosphate (G6P). Since the cell membrane is impervious to G6P, hexokinase essentially acts to transport glucose into the cells from which it can then no longer escape. Hexokinase is inhibited by high levels of G6P in the cell. Thus the rate of entry of glucose into cells partially depends on how fast G6P can be disposed of by glycolysis, and by glycogen synthesis (in the cells which store glycogen, namely liver and muscles).


title: Glycolysis

text: Glucokinase, unlike hexokinase, is not inhibited by G6P. It occurs in liver cells, and will only phosphorylate the glucose entering the cell to form glucose-6-phosphate (G6P), when the glucose in the blood is abundant. This being the first step in the glycolytic pathway in the liver, it therefore imparts an additional layer of control of the glycolytic pathway in this organ.


title: Glycolysis

text: Phosphofructokinase is an important control point in the glycolytic pathway, since it is one of the irreversible steps and has key allosteric effectors, AMP and fructose 2,6-bisphosphate (F2,6BP).


title: Glycolysis

text: Fructose 2,6-bisphosphate (F2,6BP) is a very potent activator of phosphofructokinase (PFK-1) that is synthesized when F6P is phosphorylated by a second phosphofructokinase (PFK2). In the liver, when blood sugar is low and glucagon elevates cAMP, PFK2 is phosphorylated by protein kinase A. The phosphorylation inactivates PFK2, and another domain on this protein becomes active as fructose bisphosphatase-2, which converts F2,6BP back to F6P. Both glucagon and epinephrine cause high levels of cAMP in the liver. The result of lower levels of liver fructose-2,6-bisphosphate is a decrease in activity of phosphofructokinase and an increase in activity of fructose 1,6-bisphosphatase, so that gluconeogenesis (in essence, "glycolysis in reverse") is favored. This is consistent with the role of the liver in such situations, since the response of the liver to these hormones is to release glucose to the blood.


title: Glycolysis

text: ATP competes with AMP for the allosteric effector site on the PFK enzyme. ATP concentrations in cells are much higher than those of AMP, typically 100-fold higher, but the concentration of ATP does not change more than about 10% under physiological conditions, whereas a 10% drop in ATP results in a 6-fold increase in AMP. Thus, the relevance of ATP as an allosteric effector is questionable. An increase in AMP is a consequence of a decrease in energy charge in the cell.


title: Glycolysis

text: Citrate inhibits phosphofructokinase when tested "in vitro" by enhancing the inhibitory effect of ATP. However, it is doubtful that this is a meaningful effect "in vivo", because citrate in the cytosol is utilized mainly for conversion to acetyl-CoA for fatty acid and cholesterol synthesis.


title: Glycolysis

text: TIGAR, a p53 induced enzyme, is responsible for the regulation of phosphofructokinase and acts to protect against oxidative stress. TIGAR is a single enzyme with dual function that regulates F2,6BP. It can behave as a phosphatase (fructuose-2,6-bisphosphatase) which cleaves the phosphate at carbon-2 producing F6P. It can also behave as a kinase (PFK2) adding a phosphate onto carbon-2 of F6P which produces F2,6BP. In humans, the TIGAR protein is encoded by "C12orf5" gene. The TIGAR enzyme will hinder the forward progression of glycolysis, by creating a build up of fructose-6-phosphate (F6P) which is isomerized into glucose-6-phosphate (G6P). The accumulation of G6P will shunt carbons into the pentose phosphate pathway.


title: Glycolysis

text: The final step of glycolysis is catalysed by pyruvate kinase to form pyruvate and another ATP. It is regulated by a range of different transcriptional, covalent and non-covalent regulation mechanisms, which can vary widely in different tissues. For example, in the liver, pyruvate kinase is regulated based on glucose availability. During fasting (no glucose available), glucagon activates protein kinase A which phosphorylates pyruvate kinase to inhibit it. An increase in blood sugar leads to secretion of insulin, which activates protein phosphatase 1, leading to dephosphorylation and re-activation of pyruvate kinase. These controls prevent pyruvate kinase from being active at the same time as the enzymes that catalyze the reverse reaction (pyruvate carboxylase and phosphoenolpyruvate carboxykinase), preventing a futile cycle. Conversely, the isoform of pyruvate kinasein found in muscle is not affected by protein kinase A (which is activated by adrenaline in that tissue), so that glycolysis remains active in muscles even during fasting.