title: D. B. Weiss

text: Weiss collaborated with Benioff on the HBO television series "Game of Thrones", based on George R. R. Martin's book series "A Song of Ice and Fire". Benioff and Weiss also directed three episodes together. For the first two, they flipped a coin to decide who would get the credit on the show. Weiss received directing credit for "Two Swords", Season 4 episode 1, while Benioff was credited for "Walk of Punishment", Season 3 episode 3. Benioff and Weiss were both credited for co-directing the series finale, "The Iron Throne".


title: D. B. Weiss

text: On July 19, 2017, Weiss announced that he and Benioff were going to begin production on another HBO series, "Confederate", after the final season of "Game of Thrones". Weiss and Benioff said, "We have discussed "Confederate" for years, originally as a concept for a feature film, but our experience on "Thrones" has convinced us that no one provides a bigger, better storytelling canvas than HBO." In January 2020, HBO President Casey Bloys confirmed that the project had been officially canceled.


title: D. B. Weiss

text: On February 6, 2018, Disney announced that Weiss and Benioff would write and produce a new series of "Star Wars" films after the last season of "Game of Thrones" ended in 2019. Toward the end of the last season, a petition to HBO was started on Change.org. It described showrunners Benioff and Weiss as "woefully incompetent writers" and demanded "competent writers" to remake the eighth season of "Game of Thrones" in a manner "that makes sense". The petition eventually amassed over 1.5 million signatures. In the "Chicago Sun Times", Richard Roeper wrote that the backlash to the eighth season was so great that he doubted he had "ever seen the level of fan (and to a lesser degree, critical) vitriol leveled at" "Game of Thrones".


title: D. B. Weiss

text: In early 2019, Weiss and Benioff entered into an exclusive $200 million deal with Netflix to produce several films and television shows exclusively for it. In late October 2019, it was reported that Weiss and Benioff had exited their deal with Disney due to their commitments to Netflix.


title: D. B. Weiss

text: Weiss and Benioff's first project on Netflix were as directors of Leslie Jones's stand-up comedy special "Time Machine".


title: D. B. Weiss

text: In September 2020, it was announced that Weiss, Benioff and Alexander Woo would write and executive produce a Netflix series based on "The Three-Body Problem" trilogy in a four-part series.


title: Mutation

text: In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, mitosis, or meiosis or other types of damage to DNA (such as pyrimidine dimers caused by exposure to ultraviolet radiation), which then may undergo error-prone repair (especially microhomology-mediated end joining), cause an error during other forms of repair, or cause an error during replication (translesion synthesis). Mutations may also result from insertion or deletion of segments of DNA due to mobile genetic elements.


title: Mutation

text: Mutations may or may not produce detectable changes in the observable characteristics (phenotype) of an organism. Mutations play a part in both normal and abnormal biological processes including: evolution, cancer, and the development of the immune system, including junctional diversity. Mutation is the ultimate source of all genetic variation, providing the raw material on which evolutionary forces such as natural selection can act.


title: Mutation

text: Mutation can result in many different types of change in sequences. Mutations in genes can have no effect, alter the product of a gene, or prevent the gene from functioning properly or completely. Mutations can also occur in non-genic regions. A 2007 study on genetic variations between different species of "Drosophila" suggested that, if a mutation changes a protein produced by a gene, the result is likely to be harmful, with an estimated 70% of amino acid polymorphisms that have damaging effects, and the remainder being either neutral or marginally beneficial. Due to the damaging effects that mutations can have on genes, organisms have mechanisms such as DNA repair to prevent or correct mutations by reverting the mutated sequence back to its original state.


title: Mutation

text: Mutations can involve the duplication of large sections of DNA, usually through genetic recombination. These duplications are a major source of raw material for evolving new genes, with tens to hundreds of genes duplicated in animal genomes every million years. Most genes belong to larger gene families of shared ancestry, detectable by their sequence homology. Novel genes are produced by several methods, commonly through the duplication and mutation of an ancestral gene, or by recombining parts of different genes to form new combinations with new functions.


title: Mutation

text: Here, protein domains act as modules, each with a particular and independent function, that can be mixed together to produce genes encoding new proteins with novel properties. For example, the human eye uses four genes to make structures that sense light: three for cone cell or color vision and one for rod cell or night vision; all four arose from a single ancestral gene. Another advantage of duplicating a gene (or even an entire genome) is that this increases engineering redundancy; this allows one gene in the pair to acquire a new function while the other copy performs the original function. Other types of mutation occasionally create new genes from previously noncoding DNA.


title: Mutation

text: Changes in chromosome number may involve even larger mutations, where segments of the DNA within chromosomes break and then rearrange. For example, in the Homininae, two chromosomes fused to produce human chromosome 2; this fusion did not occur in the lineage of the other apes, and they retain these separate chromosomes. In evolution, the most important role of such chromosomal rearrangements may be to accelerate the divergence of a population into new species by making populations less likely to interbreed, thereby preserving genetic differences between these populations.


title: Mutation

text: Sequences of DNA that can move about the genome, such as transposons, make up a major fraction of the genetic material of plants and animals, and may have been important in the evolution of genomes. For example, more than a million copies of the Alu sequence are present in the human genome, and these sequences have now been recruited to perform functions such as regulating gene expression. Another effect of these mobile DNA sequences is that when they move within a genome, they can mutate or delete existing genes and thereby produce genetic diversity.


title: Mutation

text: Nonlethal mutations accumulate within the gene pool and increase the amount of genetic variation. The abundance of some genetic changes within the gene pool can be reduced by natural selection, while other "more favorable" mutations may accumulate and result in adaptive changes.


title: Mutation

text: For example, a butterfly may produce offspring with new mutations. The majority of these mutations will have no effect; but one might change the color of one of the butterfly's offspring, making it harder (or easier) for predators to see. If this color change is advantageous, the chances of this butterfly's surviving and producing its own offspring are a little better, and over time the number of butterflies with this mutation may form a larger percentage of the population.


title: Mutation

text: Neutral mutations are defined as mutations whose effects do not influence the fitness of an individual. These can increase in frequency over time due to genetic drift. It is believed that the overwhelming majority of mutations have no significant effect on an organism's fitness. Also, DNA repair mechanisms are able to mend most changes before they become permanent mutations, and many organisms have mechanisms for eliminating otherwise-permanently mutated somatic cells.


title: Mutation

text: Four classes of mutations are (1) spontaneous mutations (molecular decay), (2) mutations due to error-prone replication bypass of naturally occurring DNA damage (also called error-prone translesion synthesis), (3) errors introduced during DNA repair, and (4) induced mutations caused by mutagens. Scientists may also deliberately introduce mutant sequences through DNA manipulation for the sake of scientific experimentation.


title: Mutation

text: One 2017 study claimed that 66% of cancer-causing mutations are random, 29% are due to the environment (the studied population spanned 69 countries), and 5% are inherited.


title: Mutation

text: Humans on average pass 60 new mutations to their children but fathers pass more mutations depending on their age with every year adding two new mutations to a child.


title: Mutation

text: "Spontaneous mutations" occur with non-zero probability even given a healthy, uncontaminated cell. Naturally occurring oxidative DNA damage is estimated to occur 10,000 times per cell per day in humans and 100,000 times per cell per day in rats. Spontaneous mutations can be characterized by the specific change:


title: Mutation

text: There is increasing evidence that the majority of spontaneously arising mutations are due to error-prone replication (translesion synthesis) past DNA damage in the template strand. In mice, the majority of mutations are caused by translesion synthesis. Likewise, in yeast, Kunz et al. found that more than 60% of the spontaneous single base pair substitutions and deletions were caused by translesion synthesis.


title: Mutation

text: Although naturally occurring double-strand breaks occur at a relatively low frequency in DNA, their repair often causes mutation. Non-homologous end joining (NHEJ) is a major pathway for repairing double-strand breaks. NHEJ involves removal of a few nucleotides to allow somewhat inaccurate alignment of the two ends for rejoining followed by addition of nucleotides to fill in gaps. As a consequence, NHEJ often introduces mutations.


title: Mutation

text: Induced mutations are alterations in the gene after it has come in contact with mutagens and environmental causes.


title: Mutation

text: Whereas in former times mutations were assumed to occur by chance, or induced by mutagens, molecular mechanisms of mutation have been discovered in bacteria and across the tree of life. As S. Rosenberg states, "These mechanisms reveal a picture of highly regulated mutagenesis, up-regulated temporally by stress responses and activated when cells/organisms are maladapted to their environments—when stressed—potentially accelerating adaptation." Since they are self-induced mutagenic mechanisms that increase the adaptation rate of organisms, they have some times been named as adaptive mutagenesis mechanisms, and include the SOS response in bacteria, ectopic intrachromosomal recombination and other chromosomal events such as duplications.


title: Mutation

text: The sequence of a gene can be altered in a number of ways. Gene mutations have varying effects on health depending on where they occur and whether they alter the function of essential proteins.


title: Mutation

text: Small-scale mutations affect a gene in one or a few nucleotides. (If only a single nucleotide is affected, they are called point mutations.) Small-scale mutations include:


title: Mutation

text: The effect of a mutation on protein sequence depends in part on where in the genome it occurs, especially whether it is in a coding or non-coding region. Mutations in the non-coding regulatory sequences of a gene, such as promoters, enhancers, and silencers, can alter levels of gene expression, but are less likely to alter the protein sequence. Mutations within introns and in regions with no known biological function (e.g. pseudogenes, retrotransposons) are generally neutral, having no effect on phenotype – though intron mutations could alter the protein product if they affect mRNA splicing.


title: Mutation

text: Mutations that occur in coding regions of the genome are more likely to alter the protein product, and can be categorized by their effect on amino acid sequence:


title: Mutation

text: A mutation becomes an effect on function mutation when the exactitude of functions between a mutated protein and its direct interactor undergoes change. The interactors can be other proteins, molecules, nucleic acids, etc. There are many mutations that fall under the category of by effect on function, but depending on the specificity of the change the mutations listed below will occur.


title: Mutation

text: In genetics, it is sometimes useful to classify mutations as either harmful or beneficial (or neutral):


title: Mutation

text: Large-scale quantitative mutagenesis screens, in which thousands of millions of mutations are tested, invariably find that a larger fraction of mutations has harmful effects but always returns a number of beneficial mutations as well. For instance, in a screen of all gene deletions in "E. coli", 80% of mutations were negative, but 20% were positive, even though many had a very small effect on growth (depending on condition). Note that gene "deletions" involve removal of whole genes, so that point mutations almost always have a much smaller effect. In a similar screen in "Streptococcus pneumoniae", but this time with transposon insertions, 76% of insertion mutants were classified as neutral, 16% had a significantly reduced fitness, but 6% were advantageous.


title: Mutation

text: This classification is obviously relative and somewhat artificial: a harmful mutation can quickly turn into a beneficial mutations when conditions change. Also, there is a gradient from harmful/beneficial to neutral, as many mutations may have small and mostly neglectable effects but under certain conditions will become relevant. Also, many traits are determined by hundreds of genes (or loci), so that each locus has only a minor effect. For instance, human height is determined by hundreds of genetic variants ("mutations") but each of them has a very minor effect on height, apart from the impact of nutrition. Height (or size) itself may be more or less beneficial as the huge range of sizes in animal or plant groups shows.


title: Mutation

text: Attempts have been made to infer the distribution of fitness effects (DFE) using mutagenesis experiments and theoretical models applied to molecular sequence data. DFE, as used to determine the relative abundance of different types of mutations (i.e., strongly deleterious, nearly neutral or advantageous), is relevant to many evolutionary questions, such as the maintenance of genetic variation, the rate of genomic decay, the maintenance of outcrossing sexual reproduction as opposed to inbreeding and the evolution of sex and genetic recombination. DFE can also be tracked by tracking the skewness of the distribution of mutations with putatively severe effects as compared to the distribution of mutations with putatively mild or absent effect. In summary, the DFE plays an important role in predicting evolutionary dynamics. A variety of approaches have been used to study the DFE, including theoretical, experimental and analytical methods.


title: Mutation

text: One of the earliest theoretical studies of the distribution of fitness effects was done by Motoo Kimura, an influential theoretical population geneticist. His neutral theory of molecular evolution proposes that most novel mutations will be highly deleterious, with a small fraction being neutral. A later proposal by Hiroshi Akashi proposed a bimodal model for the DFE, with modes centered around highly deleterious and neutral mutations. Both theories agree that the vast majority of novel mutations are neutral or deleterious and that advantageous mutations are rare, which has been supported by experimental results. One example is a study done on the DFE of random mutations in vesicular stomatitis virus. Out of all mutations, 39.6% were lethal, 31.2% were non-lethal deleterious, and 27.1% were neutral. Another example comes from a high throughput mutagenesis experiment with yeast. In this experiment it was shown that the overall DFE is bimodal, with a cluster of neutral mutations, and a broad distribution of deleterious mutations.


title: Mutation

text: Though relatively few mutations are advantageous, those that are play an important role in evolutionary changes. Like neutral mutations, weakly selected advantageous mutations can be lost due to random genetic drift, but strongly selected advantageous mutations are more likely to be fixed. Knowing the DFE of advantageous mutations may lead to increased ability to predict the evolutionary dynamics. Theoretical work on the DFE for advantageous mutations has been done by John H. Gillespie and H. Allen Orr. They proposed that the distribution for advantageous mutations should be exponential under a wide range of conditions, which, in general, has been supported by experimental studies, at least for strongly selected advantageous mutations.


title: Mutation

text: In general, it is accepted that the majority of mutations are neutral or deleterious, with advantageous mutations being rare; however, the proportion of types of mutations varies between species. This indicates two important points: first, the proportion of effectively neutral mutations is likely to vary between species, resulting from dependence on effective population size; second, the average effect of deleterious mutations varies dramatically between species. In addition, the DFE also differs between coding regions and noncoding regions, with the DFE of noncoding DNA containing more weakly selected mutations.


title: Mutation

text: In multicellular organisms with dedicated reproductive cells, mutations can be subdivided into germline mutations, which can be passed on to descendants through their reproductive cells, and somatic mutations (also called acquired mutations), which involve cells outside the dedicated reproductive group and which are not usually transmitted to descendants.


title: Mutation

text: Diploid organisms (e.g., humans) contain two copies of each gene—a paternal and a maternal allele. Based on the occurrence of mutation on each chromosome, we may classify mutations into three types. A wild type or homozygous non-mutated organism is one in which neither allele is mutated.


title: Mutation

text: A germline mutation in the reproductive cells of an individual gives rise to a "constitutional mutation" in the offspring, that is, a mutation that is present in every cell. A constitutional mutation can also occur very soon after fertilisation, or continue from a previous constitutional mutation in a parent. A germline mutation can be passed down through subsequent generations of organisms.


title: Mutation

text: The distinction between germline and somatic mutations is important in animals that have a dedicated germline to produce reproductive cells. However, it is of little value in understanding the effects of mutations in plants, which lack a dedicated germline. The distinction is also blurred in those animals that reproduce asexually through mechanisms such as budding, because the cells that give rise to the daughter organisms also give rise to that organism's germline.


title: Mutation

text: Gene mutations include either the replacement of one of the nucleotides with the nucleotide by the other nucleotide or may be by the addition or the deletion of the nucleotide. This would be explained as the sudden change or the alteration in nucleotide sequence of the DNA molecule, which would affect one pair of nucleotide or the bigger art of the gene on chromosome. These gene mutations can be further classified as:


title: Mutation

text: 1.      Point mutations: This results when there is difference in only one base pair of nucleotide which can also be called as base pair substitution and this is also one of the common type among the gene mutations. Point mutations can be again divided into three types of mutations namely Silent mutations, Nonsense mutations, Missense mutations.


title: Mutation

text: This occurs when there is a change in codon for one amino acid molecule is swapped or is into the other codon of the same amino acid molecule and is also referred as “synonymous mutations”


title: Mutation

text: This occurs when the codon of one amino acid is interchanged with the codon of another amino acid and can also be referred as non-synonymous mutations.


title: Mutation

text: This kind of mutation results when there is addition or deletion of DNA base molecules changes the reading frame of the gene. This mutations would be insertions or deletions.


title: Mutation

text: This type of mutation occurs when there is a difference in the number of DNA bases by eliminating a piece of DNA.


title: Mutation

text: This type of mutations occur when there is replacement of one base pair by the other base pair. This mutations are further classified as Transition mutation and transversion mutation,


title: Mutation

text: a)      Transition mutation:  This occurs when the base of one chemical is replaced by the other base of the same chemical molecule (4). It mainly happens when there is the transposing of the purine molecules i.e., A is transposed by G or by the transposing of pyrimidine molecules i.e., C by T in the DNA molecule.


title: Mutation

text: b)      Tranvsersion Mutation: This occurs when there is an opposite replacement of a category base chemical by another base of the other category . This is mainly due to the incorrect replacement of the DNA bases i.e., when a pyrimidine is replaced with purine molecule.


title: Mutation

text: A change in the genetic structure that is not inherited from a parent, and also not passed to offspring, is called a somatic mutation"." Somatic mutations are not inherited by an organism's offspring because they do not affect the germline. However, they are passed down to all the progeny of a mutated cell within the same organism during mitosis. A major section of an organism therefore might carry the same mutation. These types of mutations are usually prompted by environmental causes, such as ultraviolet radiation or any exposure to certain harmful chemicals, and can cause diseases including cancer.""


title: Mutation

text: With plants, some somatic mutations can be propagated without the need for seed production, for example, by grafting and stem cuttings. These type of mutation have led to new types of fruits, such as the "Delicious" apple and the "Washington" navel orange.


title: Mutation

text: Human and mouse somatic cells have a mutation rate more than ten times higher than the germline mutation rate for both species; mice have a higher rate of both somatic and germline mutations per cell division than humans. The disparity in mutation rate between the germline and somatic tissues likely reflects the greater importance of genome maintenance in the germline than in the soma.


title: Mutation

text: In order to categorize a mutation as such, the "normal" sequence must be obtained from the DNA of a "normal" or "healthy" organism (as opposed to a "mutant" or "sick" one), it should be identified and reported; ideally, it should be made publicly available for a straightforward nucleotide-by-nucleotide comparison, and agreed upon by the scientific community or by a group of expert geneticists and biologists, who have the responsibility of establishing the "standard" or so-called "consensus" sequence. This step requires a tremendous scientific effort. Once the consensus sequence is known, the mutations in a genome can be pinpointed, described, and classified. The committee of the Human Genome Variation Society (HGVS) has developed the standard human sequence variant nomenclature, which should be used by researchers and DNA diagnostic centers to generate unambiguous mutation descriptions. In principle, this nomenclature can also be used to describe mutations in other organisms. The nomenclature specifies the type of mutation and base or amino acid changes.


title: Mutation

text: Mutation rates vary substantially across species, and the evolutionary forces that generally determine mutation are the subject of ongoing investigation.


title: Mutation

text: In humans, the mutation rate is about 50-90 "de novo" mutations per genome per generation, that is, each human accumulates about 50-90 novel mutations that were not present in his or her parents. This number has been established by sequencing thousands of human trios, that is, two parents and at least one child.


title: Mutation

text: The genomes of RNA viruses are based on RNA rather than DNA. The RNA viral genome can be double-stranded (as in DNA) or single-stranded. In some of these viruses (such as the single-stranded human immunodeficiency virus), replication occurs quickly, and there are no mechanisms to check the genome for accuracy. This error-prone process often results in mutations.


title: Mutation

text: There is a widespread assumption that mutations are (entirely) "random" with respect to their consequences (in terms of probability). This was shown to be wrong as mutation frequency can vary across regions of the genome, with such DNA repair- and mutation-biases being associated with various factors. For instance, biologically important regions were found to be protected from mutations and mutations beneficial to the studied plant were found to be more likely – i.e. mutation is "non-random in a way that benefits the plant".


title: Mutation

text: Changes in DNA caused by mutation in a coding region of DNA can cause errors in protein sequence that may result in partially or completely non-functional proteins. Each cell, in order to function correctly, depends on thousands of proteins to function in the right places at the right times. When a mutation alters a protein that plays a critical role in the body, a medical condition can result. One study on the comparison of genes between different species of "Drosophila" suggests that if a mutation does change a protein, the mutation will most likely be harmful, with an estimated 70 percent of amino acid polymorphisms having damaging effects, and the remainder being either neutral or weakly beneficial. Some mutations alter a gene's DNA base sequence but do not change the protein made by the gene. Studies have shown that only 7% of point mutations in noncoding DNA of yeast are deleterious and 12% in coding DNA are deleterious. The rest of the mutations are either neutral or slightly beneficial.


title: Mutation

text: If a mutation is present in a germ cell, it can give rise to offspring that carries the mutation in all of its cells. This is the case in hereditary diseases. In particular, if there is a mutation in a DNA repair gene within a germ cell, humans carrying such germline mutations may have an increased risk of cancer. A list of 34 such germline mutations is given in the article DNA repair-deficiency disorder. An example of one is albinism, a mutation that occurs in the OCA1 or OCA2 gene. Individuals with this disorder are more prone to many types of cancers, other disorders and have impaired vision.


title: Mutation

text: DNA damage can cause an error when the DNA is replicated, and this error of replication can cause a gene mutation that, in turn, could cause a genetic disorder. DNA damages are repaired by the DNA repair system of the cell. Each cell has a number of pathways through which enzymes recognize and repair damages in DNA. Because DNA can be damaged in many ways, the process of DNA repair is an important way in which the body protects itself from disease. Once DNA damage has given rise to a mutation, the mutation cannot be repaired.


title: Mutation

text: On the other hand, a mutation may occur in a somatic cell of an organism. Such mutations will be present in all descendants of this cell within the same organism. The accumulation of certain mutations over generations of somatic cells is part of cause of malignant transformation, from normal cell to cancer cell.


title: Mutation

text: Cells with heterozygous loss-of-function mutations (one good copy of gene and one mutated copy) may function normally with the unmutated copy until the good copy has been spontaneously somatically mutated. This kind of mutation happens often in living organisms, but it is difficult to measure the rate. Measuring this rate is important in predicting the rate at which people may develop cancer.


title: Mutation

text: Point mutations may arise from spontaneous mutations that occur during DNA replication. The rate of mutation may be increased by mutagens. Mutagens can be physical, such as radiation from UV rays, X-rays or extreme heat, or chemical (molecules that misplace base pairs or disrupt the helical shape of DNA). Mutagens associated with cancers are often studied to learn about cancer and its prevention.


title: Mutation

text: Prions are proteins and do not contain genetic material. However, prion replication has been shown to be subject to mutation and natural selection just like other forms of replication. The human gene PRNP codes for the major prion protein, PrP, and is subject to mutations that can give rise to disease-causing prions.


title: Mutation

text: Although mutations that cause changes in protein sequences can be harmful to an organism, on occasions the effect may be positive in a given environment. In this case, the mutation may enable the mutant organism to withstand particular environmental stresses better than wild-type organisms, or reproduce more quickly. In these cases a mutation will tend to become more common in a population through natural selection. Examples include the following:


title: Mutation

text: HIV resistance: a specific 32 base pair deletion in human CCR5 (CCR5-Δ32) confers HIV resistance to homozygotes and delays AIDS onset in heterozygotes. One possible explanation of the etiology of the relatively high frequency of CCR5-Δ32 in the European population is that it conferred resistance to the bubonic plague in mid-14th century Europe. People with this mutation were more likely to survive infection; thus its frequency in the population increased. This theory could explain why this mutation is not found in Southern Africa, which remained untouched by bubonic plague. A newer theory suggests that the selective pressure on the CCR5 Delta 32 mutation was caused by smallpox instead of the bubonic plague.


title: Mutation

text: Malaria resistance: An example of a harmful mutation is sickle-cell disease, a blood disorder in which the body produces an abnormal type of the oxygen-carrying substance hemoglobin in the red blood cells. One-third of all indigenous inhabitants of Sub-Saharan Africa carry the allele, because, in areas where malaria is common, there is a survival value in carrying only a single sickle-cell allele (sickle cell trait). Those with only one of the two alleles of the sickle-cell disease are more resistant to malaria, since the infestation of the malaria "Plasmodium" is halted by the sickling of the cells that it infests.


title: Mutation

text: Antibiotic resistance: Practically all bacteria develop antibiotic resistance when exposed to antibiotics. In fact, bacterial populations already have such mutations that get selected under antibiotic selection. Obviously, such mutations are only beneficial for the bacteria but not for those infected.


title: Mutation

text: Lactase persistence. A mutation allowed humans to express the enzyme lactase after they are naturally weaned from breast milk, allowing adults to digest lactose, which is likely one of the most beneficial mutations in recent human evolution.


title: Mutation

text: Compensated pathogenic deviations refer to amino acid residues in a protein sequence that are pathogenic in one species but are wild type residues in the functionally equivalent protein in another species. Although the amino acid residue is pathogenic in the first species, it is not so in the second species because its pathogenicity is compensated by one or more amino acid substitutions in the second species. The compensatory mutation can occur in the same protein or in another protein with which it interacts.


title: Mutation

text: It is critical to understand the effects of compensatory mutations in the context of fixed deleterious mutations due to the population fitness decreasing because of fixation. Effective population size refers to a population that is reproducing. An increase in this population size has been correlated with a decreased rate of genetic diversity. The position of a population relative to the critical effect population size is essential to determine the effect deleterious alleles will have on fitness. If the population is below the critical effective size fitness will decrease drastically, however if the population is above the critical effect size, fitness can increase regardless of deleterious mutations due to compensatory alleles.


title: Mutation

text: As the function of a RNA molecule is dependent on its structure, the structure of RNA molecules is evolutionarily conserved. Therefore, any mutation that alters the stable structure of RNA molecules must be compensated by other compensatory mutations. In the context of RNA, the sequence of the RNA can be considered as ' genotype' and the structure of the RNA can be considered as its 'phenotype'. Since RNAs have relatively simpler composition than proteins, the structure of RNA molecules can be computationally predicted with high degree of accuracy. Because of this convenience, compensatory mutations have been studied in computational simulations using RNA folding algorithms.


title: Mutation

text: Compensatory mutations can be explained by the genetic phenomenon epistasis whereby the phenotypic effect of one mutation is dependent upon mutation(s) at other loci. While epistasis was originally conceived in the context of interaction between different genes, intragenic epistasis has also been studied recently. Existence of compensated pathogenic deviations can be explained by 'sign epistasis', in which the effects of a deleterious mutation can be compensated by the presence of a epistatic mutation in another loci. For a given protein, a deleterious mutation (D) and a compensatory mutation (C) can be considered, where C can be in the same protein as D or in a different interacting protein depending on the context. The fitness effect of C itself could be neutral or somewhat deleterious such that it can still exist in the population, and the effect of D is deleterious to the extent that it cannot exist in the population. However, when C and D co-occur together, the combined fitness effect becomes neutral or positive. Thus, compensatory mutations can bring novelty to proteins by forging new pathways of protein evolution : it allows individuals to travel from one fitness peak to another through the valleys of lower fitness.


title: Mutation

text: DePristo et al. 2005 outlined two models to explain the dynamics of compensatory pathogenic deviations (CPD). In the first hypothesis P is a pathogenic amino acid mutation that and C is a neutral compensatory mutation. Under these conditions, if the pathogenic mutation arises after a compensatory mutation, then P can become fixed in the population. The second model of CPDs states that P and C are both deleterious mutations resulting in fitness valleys when mutations occur simultaneously. Using publicly available, Ferrer-Costa et al. 2007 obtained compensatory mutations and human pathogenic mutation datasets that were characterized to determine what causes CPDs. Results indicate that the structural constraints and the location in protein structure determine whether compensated mutations will occur.


title: Mutation

text: Lunzer et al. tested the outcome of swapping divergent amino acids between two orthologous proteins of isopropymalate dehydrogenase (IMDH). They substituted 168 amino acids in "Escherichia coli" IMDH that are wild type residues in IMDH "Pseudomonas aeruginosa". They found that over one third of these substitutions compromised IMDH enzymatic activity in the "Escherichia coli" genetic background. This demonstrated that identical amino acid states can result in different phenotypic states depending on the genetic background. Corrigan et al. 2011 demonstrated how staphylococcus aureus was able to grow normally without the presence of lipoteichoic acid due to compensatory mutations. Whole genome sequencing results revealed that when Cyclic-di-AMP phosphodiesterase (GdpP) was disrupted in this bacterium, it compensated for the disappearance of the cell wall polymer, resulting in normal cell growth.


title: Mutation

text: Research has shown that bacteria can gain drug resistance through compensatory mutations that do not impede or having little effect on fitness. Previous research from Gagneux et al. 2006 has found that laboratory grown M. tuberculosis strains with rifampicin resistance have reduced fitness, however drug resistant clinical strains of this pathogenic bacteria do not have reduced fitness. Comas et al. 2012 used whole genome comparisons between clinical strains and lab derived mutants to determine the role and contribution of compensatory mutations in drug resistance to rifampicin. Genome analysis reveal rifampicin resistant strains have a mutation in rpoA and rpoC. A similar study investigated the bacterial fitness associated with compensatory mutations in rifampin resistant Escherichia coli. Results obtained from this study demonstrate that drug resistance is linked to bacterial fitness as higher fitness costs are linked to greater transcription errors.


title: Mutation

text: Gong et al. collected obtained genotype data of influenza nucleoprotein from different timelines and temporally ordered them according to their time of origin. Then they isolated 39 amino acid substitutions that occurred in different timelines and substituted them in a genetic background that approximated the ancestral genotype. They found that 3 of the 39 substitutions significantly reduced the fitness of the ancestral background. Compensatory mutations are new mutations that arise and have a positive or neutral impact on a populations fitness. Previous research has shown that populations have can compensate detrimental mutations. Burch and Chao tested Fisher's geometric model of adaptive evolution by testing whether bacteriophage φ6 evolves by small steps. Their results showed that bacteriophage φ6 fitness declined rapidly and recovered in small steps . Viral nucleoproteins have been shown to avoid cytotoxic T lymphocytes (CTLs) through arginine-to glycine substitutions. This substitution mutations impacts the fitness of viral nucleoproteins, however compensatory co-mutations impede fitness declines and aid the virus to avoid recognition from CTLs. Mutations can have three different effects; mutations can have deleterious effects, some increase fitness through compensatory mutations, and lastly mutations can be counterbalancing resulting in compensatory neutral mutations.


title: Mutation

text: Mutationism is one of several alternatives to Darwinian evolution that have existed both before and after the publication of Charles Darwin's 1859 book, "On the Origin of Species". In the theory, mutation was the source of novelty, creating new forms and new species, potentially instantaneously, in a sudden jump. This was envisaged as driving evolution, which was limited by the supply of mutations.


title: Mutation

text: Before Darwin, biologists commonly believed in saltationism, the possibility of large evolutionary jumps, including immediate speciation. For example, in 1822 Étienne Geoffroy Saint-Hilaire argued that species could be formed by sudden transformations, or what would later be called macromutation. Darwin opposed saltation, insisting on gradualism in evolution as in geology. In 1864, Albert von Kölliker revived Geoffroy's theory. In 1901 the geneticist Hugo de Vries gave the name "mutation" to seemingly new forms that suddenly arose in his experiments on the evening primrose "Oenothera lamarckiana", and in the first decade of the 20th century, mutationism, or as de Vries named it "mutationstheorie", became a rival to Darwinism supported for a while by geneticists including William Bateson, Thomas Hunt Morgan, and Reginald Punnett.


title: Mutation

text: Understanding of mutationism is clouded by the mid-20th century portrayal of the early mutationists by supporters of the modern synthesis as opponents of Darwinian evolution and rivals of the biometrics school who argued that selection operated on continuous variation. In this portrayal, mutationism was defeated by a synthesis of genetics and natural selection that supposedly started later, around 1918, with work by the mathematician Ronald Fisher. However, the alignment of Mendelian genetics and natural selection began as early as 1902 with a paper by Udny Yule, and built up with theoretical and experimental work in Europe and America. Despite the controversy, the early mutationists had by 1918 already accepted natural selection and explained continuous variation as the result of multiple genes acting on the same characteristic, such as height.


title: Mutation

text: Mutationism, along with other alternatives to Darwinism like Lamarckism and orthogenesis, was discarded by most biologists as they came to see that Mendelian genetics and natural selection could readily work together; mutation took its place as a source of the genetic variation essential for natural selection to work on. However, mutationism did not entirely vanish. In 1940, Richard Goldschmidt again argued for single-step speciation by macromutation, describing the organisms thus produced as "hopeful monsters", earning widespread ridicule. In 1987, Masatoshi Nei argued controversially that evolution was often mutation-limited. Modern biologists such as Douglas J. Futuyma conclude that essentially all claims of evolution driven by large mutations can be explained by Darwinian evolution.


title: Eosinophil

text: Eosinophils, sometimes called eosinophiles or, less commonly, acidophils, are a variety of white blood cells (WBCs) and one of the immune system components responsible for combating multicellular parasites and certain infections in vertebrates. Along with mast cells and basophils, they also control mechanisms associated with allergy and asthma. They are granulocytes that develop during hematopoiesis in the bone marrow before migrating into blood, after which they are terminally differentiated and do not multiply. They form about 2 to 3% of WBCs.


title: Eosinophil

text: These cells are eosinophilic or "acid-loving" due to their large acidophilic cytoplasmic granules, which show their affinity for acids by their affinity to coal tar dyes: Normally transparent, it is this affinity that causes them to appear brick-red after staining with eosin, a red dye, using the Romanowsky method. The staining is concentrated in small granules within the cellular cytoplasm, which contain many chemical mediators, such as eosinophil peroxidase, ribonuclease (RNase), deoxyribonucleases (DNase), lipase, plasminogen, and major basic protein. These mediators are released by a process called degranulation following activation of the eosinophil, and are toxic to both parasite and host tissues.


title: Eosinophil

text: In normal individuals, eosinophils make up about 1–3% of white blood cells, and are about 12–17 micrometres in size with bilobed nuclei. While they are released into the bloodstream as neutrophils, eosinophils reside in tissue. They are found in the medulla and the junction between the cortex and medulla of the thymus, and, in the lower gastrointestinal tract, ovaries, uterus, spleen, and lymph nodes, but not in the lungs, skin, esophagus, or some other internal organs under normal conditions. The presence of eosinophils in these latter organs is associated with disease. For instance, patients with eosinophilic asthma have high levels of eosinophils that lead to inflammation and tissue damage, making it more difficult for patients to breathe. Eosinophils persist in the circulation for 8–12 hours, and can survive in tissue for an additional 8–12 days in the absence of stimulation. Pioneering work in the 1980s elucidated that eosinophils were unique granulocytes, having the capacity to survive for extended periods of time after their maturation as demonstrated by ex-vivo culture experiments.


title: Eosinophil

text: TH2 and ILC2 cells both express the transcription factor GATA-3, which promotes the production of TH2 cytokines, including the interleukins (ILs). IL-5 controls the development of eosinophils in the bone marrow, as they differentiate from myeloid precursor cells. Their lineage fate is determined by transcription factors, including GATA and C/EBP. Eosinophils produce and store many secondary granule proteins prior to their exit from the bone marrow. After maturation, eosinophils circulate in blood and migrate to inflammatory sites in tissues, or to sites of helminth infection in response to chemokines like CCL11 (eotaxin-1), CCL24 (eotaxin-2), CCL5 (RANTES), 5-hydroxyicosatetraenoic acid and 5-oxo-eicosatetraenoic acid, and certain leukotrienes like leukotriene B4 (LTB4) and MCP1/4. Interleukin-13, another TH2 cytokine, primes eosinophilic exit from the bone marrow by lining vessel walls with adhesion molecules such as VCAM-1 and ICAM-1.


title: Eosinophil

text: When eosinophils are activated, they undergo cytolysis, where the breaking of the cell releases eosinophilic granules found in extracellular DNA traps. High concentrations of these DNA traps are known to cause cellular damage, as the granules they contain are responsible for the ligand-induced secretion of eosinophilic toxins which cause structural damage. There is evidence to suggest that eosinophil granule protein expression is regulated by the non-coding RNA EGOT.


title: Eosinophil

text: There are also eosinophils that play a role in fighting viral infections, which is evident from the abundance of RNases they contain within their granules, and in fibrin removal during inflammation. Eosinophils, along with basophils and mast cells, are important mediators of allergic responses and asthma pathogenesis and are associated with disease severity. They also fight helminth (worm) colonization and may be slightly elevated in the presence of certain parasites. Eosinophils are also involved in many other biological processes, including postpubertal mammary gland development, oestrus cycling, allograft rejection and neoplasia. They have also been implicated in antigen presentation to T cells.


title: Eosinophil

text: Eosinophils are responsible for tissue damage and inflammation in many diseases, including asthma. High levels of interleukin-5 has been observed to up regulate the expression of adhesion molecules, which then facilitate the adhesion of eosinophils to endothelial cells, thereby causing inflammation and tissue damage.


title: Eosinophil

text: An accumulation of eosinophils in the nasal mucosa is considered a major diagnostic criterion for allergic rhinitis (nasal allergies).


title: Eosinophil

text: Following activation by an immune stimulus, eosinophils degranulate to release an array of cytotoxic granule cationic proteins that are capable of inducing tissue damage and dysfunction. These include:


title: Eosinophil

text: Major basic protein, eosinophil peroxidase, and eosinophil cationic protein are toxic to many tissues. Eosinophil cationic protein and eosinophil-derived neurotoxin are ribonucleases with antiviral activity. Major basic protein induces mast cell and basophil degranulation, and is implicated in peripheral nerve remodelling. Eosinophil cationic protein creates toxic pores in the membranes of target cells, allowing potential entry of other cytotoxic molecules to the cell, can inhibit proliferation of T cells, suppress antibody production by B cells, induce degranulation by mast cells, and stimulate fibroblast cells to secrete mucus and glycosaminoglycan. Eosinophil peroxidase forms reactive oxygen species and reactive nitrogen intermediates that promote oxidative stress in the target, causing cell death by apoptosis and necrosis.


title: Eosinophil

text: An increase in eosinophils, i.e., the presence of more than 500 eosinophils/microlitre of blood is called an eosinophilia, and is typically seen in people with a parasitic infestation of the intestines; autoimmune and collagen vascular disease (such as rheumatoid arthritis) and Systemic lupus erythematosus; malignant diseases such as eosinophilic leukemia, clonal hypereosinophilia, and Hodgkin lymphoma; lymphocyte-variant hypereosinophilia; extensive skin diseases (such as exfoliative dermatitis); Addison's disease and other causes of low corticosteroid production (corticosteroids suppress blood eosinophil levels); reflux esophagitis (in which eosinophils will be found in the squamous epithelium of the esophagus) and eosinophilic esophagitis; and with the use of certain drugs such as penicillin. But, perhaps the most common cause for eosinophilia is an allergic condition such as asthma. In 1989, contaminated L-tryptophan supplements caused a deadly form of eosinophilia known as eosinophilia-myalgia syndrome, which was reminiscent of the toxic oil syndrome in Spain in 1981.


title: Eosinophil

text: Eosinophils play an important role in asthma as the number of accumulated eosinophils corresponds to the severity of asthmatic reaction. Eosinophilia in mice models are shown to be associated with high interleukin-5 levels. Furthermore, mucosal bronchial biopsies conducted on patients with diseases such as asthma have been found to have higher levels of interleukin-5 leading to higher levels of eosinophils. The infiltration of eosinophils at these high concentrations causes an inflammatory reaction. This ultimately leads to airway remodelling and difficulty of breathing.


title: Eosinophil

text: Eosinophils can also cause tissue damage in the lungs of asthmatic patients. High concentrations of eosinophil major basic protein and eosinophil-derived neurotoxin that approach cytotoxic levels are observed at degranulation sites in the lungs as well as in the asthmatic sputum.


title: Eosinophil

text: Monoclonal antibodies such as dupilumab and lebrikizumab target IL-13 and its receptor, which reduces eosinophilic inflammation in patients with asthma due to lowering the number of adhesion molecules present for eosinophils to bind to, thereby decreasing inflammation. Mepolizumab and benralizumab are other treatment options that target the alpha subunit of the IL-5 receptor, thereby inhibiting its function and reducing the number of developing eosinophils as well as the number of eosinophils leading to inflammation through antibody-dependent cell-mediated cytotoxicity and eosinophilic apoptosis.


title: Eosinophil

text: Within the fat (adipose) tissue of CCR2 deficient mice, there is an increased number of eosinophils, greater alternative macrophage activation, and a propensity towards type 2 cytokine expression. Furthermore, this effect was exaggerated when the mice became obese from a high fat diet.


title: Eosinophil

text: Mouse models of eosinophilia from mice infected with T. canis showed an increase in IL-5 mRNA in mice spleen. Mouse models of asthma from OVA show a higher TH2 response. When mice are administered IL-12 to induce the TH1 response, the TH2 response becomes suppressed, showing that mice without TH2 cytokines are significantly less likely to express asthma symptoms.


title: Salami

text: Salami ( ) is a cured sausage consisting of fermented and air-dried meat, typically pork. Historically, salami was popular among Southern, Eastern, and Central European peasants because it can be stored at room temperature for up to 45 days once cut, supplementing a potentially meager or inconsistent supply of fresh meat. Countries and regions across Europe make their own traditional varieties of salami.


title: Salami

text: The word 'salami' in English comes from the plural form of the Italian (). It is a singular or plural word in English for cured meats of a European (particularly Italian) style. In Romanian, Bulgarian, and Turkish, the word is "salam"; in Hungarian, it is "szalámi"; in Czech it is "salám"; in Slovak, it is "saláma" while Polish, French, German, Greek and Dutch have the same word as English. The name may be derived from the Latin word "salumen".


title: Salami

text: The word originates from the word "sale" ("salt") with a termination ("-ame") that in Italian indicates a collective noun. Thus, it originally referred to all kinds of salted meats. The Italian tradition of cured meats includes several styles, and the word "salame" soon specifically meant only the most popular kind—a salted and spiced meat, ground and extruded into an elongated, thin casing (usually cleaned animal intestine), then left to undergo natural fermentation and drying for days, months, or even years.


title: Salami

text: Fermentation—allowing beneficial or benign organisms to grow in food to prevent destructive or toxic ones from growing, with respect to meat, has been around for thousands of years. This is evident in the presence of various types of sausages found globally. Also, environmental conditions dictate what food processes are used, as seen in the Mediterranean and southern Europe, where "meat products are dried to lower water activity (Aw) values, taking advantage of the long, dry and sunny days, while in northern Europe, fermented sausages require smoking for further preservation."


title: Salami

text: In Europe, the main countries that produce salami are France, Germany, Hungary, Italy, and Spain, which make several hundred million kilograms per year.


title: Salami

text: Worldwide, the many different versions of sausage each have their own cultural and flavor profiles. Additionally, each sausage has its own type of seasonings and amount of salt, making each flavor and texture unique. This wide array of fermented sausages, especially in terms of salami, shows its ubiquitous but exclusive nature. For example, due to immigration to North America, European settlers brought many traditions, including fermented meats such as pepperoni. Similar types of sausages are found in the Middle East, where various meats such as beef, lamb, and mutton are used; or in China, where "lap cheong" (translated literally as "waxed intestines") are usually pork.


title: Salami

text: Likewise, in Central Europe, Hungarian salami is quite popular. Hungarian salami is "intensively smoked, and then its surface is inoculated with mold starters or spontaneous mold growth."


title: Salami

text: A traditional "salami", with its typical marbled appearance, is made from beef or pork (sometimes specifically veal). Beef is usual in halal and kosher salami, which never include pork for religious reasons. Makers also use other meats, including venison and poultry (mostly turkey). Goose salami is traditional in parts of Northern Italy. Salami has also been made from horse meat. In the Provence region of France, donkey meat is used for salami, as well, the product being sold in street markets.


title: Salami

text: The maker usually ferments the raw meat mixture for a day, then stuffs it into either an edible natural or inedible cellulose casing, and hangs it up to cure. Some recipes apply heat to about 40 °C (104 °F) to accelerate fermentation and drying. Higher temperatures (about 60 °C (140 °F)) stop the fermentation when the salami reaches the desired pH, but the product is not fully cooked (75 °C (167 °F) or higher). Makers often treat the casings with an edible mold ("Penicillium") culture. The mold imparts flavor, helps the drying process, and helps prevent spoilage during curing.


title: Salami

text: Though completely uncooked, salami is not raw, but cured. "Salame cotto" (cotto salami)—typical of the Piedmont region in Italy—is cooked or smoked before or after curing to impart a specific flavor, but not for any benefit of cooking. Before cooking, a "cotto salame" is considered raw and not ready to eat.


title: Salami

text: Three major stages are involved in the production of salami: preparation of raw materials, fermentation, and ripening and drying. Minor differences in the formulation of the meat or production techniques give rise to the various kinds of salami across different countries.


title: Salami

text: Before fermentation, raw meat (usually pork or beef depending on the type of salami that is produced) is ground (usually coarsely) and mixed with other ingredients such as salt, sugar, spices, pepper and yeast, and, if the particular salami variety requires it, lactic acid bacterial starter culture.


title: Salami

text: This mixture is then inserted into casings of the desired size. To achieve the flavor and texture that salami possesses, fermentation, which can also be referred to as a slow acidification process promoting a series of chemical reactions in the meat, has to take place. Direct acidification of meat was found to be inappropriate for salami production, since it causes protein denaturation and an uneven coagulation, thereby causing an undesirable texture in the salami.


title: Salami

text: For a more modern controlled fermentation, makers hang the salami in warm, humid conditions for 1–3 days to encourage the fermenting bacteria to grow, then hang it in a cool, humid environment to slowly dry. In a traditional process, the maker skips the fermentation step and immediately hangs the salami in a cool, humid curing environment. Added sugars (usually dextrose) provide a food source for the curing bacteria.


title: Salami

text: The bacteria produce lactic acid as a waste product, which lowers the pH and coagulates the proteins, reducing the meat's water-holding capacity. The bacteria-produced acid makes the meat an inhospitable environment for pathogenic bacteria and imparts a tangy flavor that distinguishes salami from machine-dried pork. Salami flavor relies as much on how these bacteria are cultivated as it does on the quality and variety of the other ingredients. Originally, makers introduced wine into the mix, favouring the growth of other beneficial bacteria. Now, they use starter cultures.


title: Salami

text: The climate of the curing environment, casing size, and style determine the drying and curing process. According to the particular variety of salami, different fermentation methods involving different acids have been explored to create various colours and flavors. Starter cultures such as lactic acid bacteria (LAB) and coagulase-negative cocci (CNC) like specific strains of "Staphylococcus xylosus" or "Micrococcus" are most commonly used in salami production. More species of LAB and CNC were discovered during recent decades and they were found to have different fermentation temperatures with variable rates of acidification. Despite the fact that these bacteria can help maintain a longer shelf life for meat products and even retard the growth of pathogens, there are a few studies that argue some starter cultures may be related to the production of enterotoxins or biogenic amines that can be harmful to the human body. Therefore, starter cultures have to be carefully selected by producers and properly used in fermentation.


title: Salami

text: After fermentation, the sausage must be dried. This changes the casings from water-permeable to reasonably airtight. A white covering of either mold or flour helps prevent photo-oxidation of the meat and rancidity in the fat.


title: Salami

text: Ripening and drying happens after fermentation. This stage causes the main physical and microbial changes through the large amount of water loss. About half of the water is evaporated and further water loss has to be prevented by packaging. Nonuniform drying processes could cause the formation of a hard shell on the surface of salami. This is similar to other food products such as fruits that undergo dehydration to decrease the risk of diseases or spoilage-causing microbial growth. In modern manufacturing temperature and relative humidity are strictly controlled according to the size of the salami.


title: Salami

text: Nitrates or nitrites may be added to provide additional color and inhibit growth of harmful bacteria from the genus "Clostridium". Salt, acidity, nitrate/nitrite levels, and dryness of the fully cured salami combine to make the uncooked meat safe to consume. High quality, fresh ingredients are important to helping prevent deadly microorganisms and toxins from developing.


title: Salami

text: The quality of salami is dependent on the quality of the raw materials and the level of technology used in its production. The aroma and taste of salami are developed by enzymatic and non-enzymatic reactions. The characteristic fermented meat flavour is believed to be developed by a combination of endogenous enzymatic activities and the lactic acid produced by the starter culture. Lactic acid bacteria develop the tangy flavor of salami through the fermentation of carbohydrates and produces an appealing red color to the meat after fermentation, while coagulase-negative cocci can catabolize amino acids and fatty acids to produce volatile compounds. The flavour itself consists of odour properties, which comes from volatile substances, and taste and tactile properties, which comes from non-volatile substances that are a result of enhancers and synergists.


title: Salami

text: When smoke is applied to salami, it also affects the taste, smell, appearance, and texture. Some of these changes are due to the formation of phenolic compounds, which slow fat oxidation. The pyrolysis of cellulose and hemicelluloses in the salami casing produces carbonyls, which develop the colour of the meat.


title: Salami

text: More than 400 volatile compounds have been identified in different types of dry-fermented sausages. For example, the organic compounds identified in Hungarian salami produced the dominant flavours of smokiness, sweetness, pungency, sourness, and cloves; secondary flavours included cooked meat, cheese, popcorn, cooked potato, mushroom, seasoning, phenols, roasting, sulfur, and sweatiness. Some minor flavours included malt, garlic, fruit, pine, grass, citrus, honey, caramel, and vanilla. The overall smoky note is the result of numerous phenols. Whether these odorants are formed in the salami or simply transferred from the raw materials during manufacturing is unknown; systematic studies have yet to compare the odorants present in the raw materials to those in the final product.


title: Salami

text: Salami will remain stable for long periods of time, as it has a low water activity and contains preservatives, colourings, flavourings, antioxidants and acidifying cultures. Semi-ripened salami will maintain its flavour for a long time under retail display conditions, but it will eventually deteriorate due to the development of incipient rancidity. The shelf life of salami is mainly determined by sensory deterioration, which is the result of various oxidation phenomena; pathogenic or spoilage bacteria do not readily proliferate in dry-cured sausage. The main cause of flavour deterioration in dry-cured sausage is rancidity, though the possible formation of other off-flavours, such as mouldy, acid, putrid or pungent traits, may contribute to the decreased quality.


title: Salami

text: The use of coriander essential oil in salami has been shown to increase the higher synthetic antioxidant effect of butylated hydroxytoluene, which delays lipid oxidation and the rancid aroma and taste that come with it. Additionally, salami with coriander essential oil shows improvements in the sensory attributes of taste, odor, texture, brightness, and red colour intensity.


title: Salami

text: Many Old World salami are named after their region or country of origin—such as Arles, Genoa, Hungarian, and Milano salami. Many are flavored with garlic. Some types—including some varieties from Spain ("salchichón"), Hungary (pick salami), and Italy (such as Neapolitan varieties that led to American pepperoni) include paprika or chili powder. Varieties also differ by coarseness or fineness of the chopped meat and size and style of the casing.


title: Salami

text: Naples-type salami is also a popular Southern Italian dry fermented sausage made of coarsely minced pork meat. In Northeast Italy, traditional dry fermented salami sausages made of fresh pork display unique organoleptic sensory profiles characterized by accented acidity, slight sourness, and elastic semi hard consistency. Other popular dry salamis in Italy are mainly made from a combination of pork and small bits of beef, seasoned with garlic; pepperoni is also made of pork and beef, and is usually smoked; and chorizo is highly spiced and smoked.


title: Salami

text: Hungarian-type salami is a specialty in salami production, because it is first slightly smoked and mold-ripened afterward. "Szegedi téliszalámi", a Hungarian winter salami, is made of raw pork, bacon, salt, spices, sugars, and sodium nitrite. The Mangalitsa pork breed, with horse large intestine used as its casing to preserve and serve it. This type acquires a grey mold cover on it and has a firm texture and excellent keeping quality after a 30% weight loss reached in 3 to 4 months.


title: Salami

text: Dry fermented sausage ('salami aeros') is an important product of the Greek meat industry with an annual production of about 10,000 tons. Its manufacture varies depending on the skill and experience of the meat manufacturer rather than a process solely based on scientific and technological means of production. This type of traditional sausage, which undergoes spontaneous fermentation, is of superior quality compared to those inoculated with starters and made in industrial scale. The quality of this type of traditional salami is often more expensive due to its high quality.


title: Salami

text: In Germany, Westphalian salami is made with fast technology from pork meat, pepper, garlic, and sometimes mustard seeds, and is smoked, firm, sliceable product with a distinct fermentation/sour flavor. The sausages are stuffed into large-diameter casings and ripened by lowering the temperature from 24 °C to 12–14 °C until a water loss of 25% is obtained.


title: Salami

text: In the Netherlands, the most popular Dutch products are finely chopped salami, "Cervelat", "Snijworst" (with high fat content and rind added), "Boerenmetworst" (which is coarsely chopped), and chorizo (which is less spicy than the Spanish product). In Russia, typical products are Moscow-type and Russian-type salamis made from pork and beef meat. A particular feature of Moscow-type salami is the large size of fat particles (7–8 mm) that give the sausage a rough cover.


title: Salami

text: There are many aspects of salami that can be considered both negative and positive to human health. Salami has been found to be a possible allergen to some people due to the use of penicillium species mold starter during the drying and curing portion of processing to add flavor and stop growth of undesirable molds. These molds occur predominantly in the skin of salami.


title: Salami

text: Fermented pork back fat that is used to make salami has very high saturated fatty acid and cholesterol content, which are popularly believed to increase the risk of heart disease and pancreatitis. However, it has been shown that it is possible to replace the pork back fat in salami with extra virgin olive oil, thereby changing the fatty acid profile of the salami. Olive oil contains far more monounsaturated and polyunsaturated fatty acids, so this substitution purportedly creates a healthier product. Salami is considered slightly acidic due to lactic acid that is present. Salami where extra virgin olive oil was substituted for the pork back fat has been shown to have a lower pH of around 5.00 compared to its original levels of around 6.35 to 6.55, making the salami more acidic. These lower pH levels are healthier for humans as higher populations of lactic acid bacteria inhibit the spread of spoilage microorganisms.


title: Salami

text: In 1994, there was an outbreak of "" with 17 cases all occurring from the consumption of pre-sliced salami that was processed by one company. A research investigation of the factory where the salami was processed found that all processing techniques and production methods complied with all regulations, and there was no evidence of contamination after processing.


title: Salami

text: Preservation of any meat products is important. Some fungi can create undesirable color and flavor in the contaminated meat and produce toxins. Some fungi that are not harmful to humans, such as those that are formed on the surface of dried salami, are an indication of maturation after ripening. Thus, producers have to eliminate fungi that have potential risks to human health. As natural preservatives are becoming more desirable food additives than artificial preservatives in food industries, some studies about salami have been focusing on the use of essential oils such as oregano and clove oil as preservatives that can be applied to salami production due to their anti-fungal activities. Several types of oils including rosemary, clove, oregano and sage oils were found to have different levels of inhibition effect to various types of fungi that could possibly grow on salami. Since several of these oils contain volatile compounds whose amount can affect the flavor of the food, researchers often perform a sensory test to find the amount of the oil that can best serve as an anti-fungal preservative but have the least effect on the flavor or appearance of the salami.


title: History of Ireland

text: The first evidence of human presence in Ireland dates to around 33,000 years ago, with further findings dating the presence of homo sapiens to around 10,500 to 7,000 BC. The receding of the ice after the Younger Dryas cold phase of the Quaternary around 9700 BC, heralds the beginning of Prehistoric Ireland, which includes the archaeological periods known as the Mesolithic, the Neolithic from about 4000 BC and the Copper Age beginning around 2500 BC with the arrival of the Beaker Culture. The Irish Bronze Age proper begins around 2000 BC and ends with the arrival of the Iron Age of the Celtic Hallstatt culture, beginning about 600 BC. The subsequent La Tène culture brought new styles and practices by 300 BC.


title: History of Ireland

text: Greek and Roman writers give some information about Ireland during the Classical period (see "protohistoric" period), by which time the island may be termed "Gaelic Ireland". By the late 4th century AD Christianity had begun to gradually subsume or replace the earlier Celtic polytheism. By the end of the 6th century it had introduced writing along with a predominantly monastic Celtic Christian church, profoundly altering Irish society. Viking raids and settlement from the late 8th century AD resulted in extensive cultural interchange, as well as innovation in military and transport technology. Many of Ireland's towns were founded at this time as Viking trading posts and coinage made its first appearance. Viking penetration was limited and concentrated along coasts and rivers, and ceased to be a major threat to Gaelic culture after the Battle of Clontarf in 1014. The Norman invasion in 1169 resulted again in a partial conquest of the island and marked the beginning of more than 800 years of English political and military involvement in Ireland. Initially successful, Norman gains were rolled back over succeeding centuries as a Gaelic resurgence reestablished Gaelic cultural preeminence over most of the country, apart from the walled towns and the area around Dublin known as The Pale.


title: History of Ireland

text: Reduced to the control of small pockets, the English Crown did not make another attempt to conquer the island until after the end of the Wars of the Roses (1488). This released resources and manpower for overseas expansion, beginning in the early 16th century. However, the nature of Ireland's decentralised political organisation into small territories (known as túatha), martial traditions, difficult terrain and climate and lack of urban infrastructure, meant that attempts to assert Crown authority were slow and expensive. Attempts to impose the new Protestant faith were also successfully resisted by both the Gaelic and Norman-Irish. The new policy fomented the rebellion of the Hiberno-Norman Earl of Kildare Silken Thomas in 1534, keen to defend his traditional autonomy and Catholicism, and marked the beginning of the prolonged Tudor conquest of Ireland lasting from 1534 to 1603. Henry VIII proclaimed himself King of Ireland in 1541 to facilitate the project. Ireland became a potential battleground in the wars between Catholic Counter-Reformation and Protestant Reformation Europe.


title: History of Ireland

text: England's attempts to either conquer or assimilate both the Hiberno-Norman lordships and the Gaelic territories into the Kingdom of Ireland provided the impetus for ongoing warfare, notable examples being the 1st Desmond Rebellion, the 2nd Desmond Rebellion and the Nine Years War. This period was marked by the Crown policies of, at first, surrender and regrant, and later, plantation, involving the arrival of thousands of English and Scottish Protestant settlers, and the displacement of both the Hiberno-Normans (or Old English as they were known by then) and the native Catholic landholders. With English colonies going back to the 1550s, Ireland was arguably the first English and then British territory colonised by a group known as the West Country Men. Gaelic Ireland was finally defeated at the battle of Kinsale in 1601 which marked the collapse of the Gaelic system and the beginning of Ireland's history as fully part of the English and later British Empire.


title: History of Ireland

text: During the 17th century, this division between a Protestant landholding minority and a dispossessed Catholic majority was intensified and conflict between them was to become a recurrent theme in Irish history. Domination of Ireland by the Protestant Ascendancy was reinforced after two periods of religious war, the Irish Confederate Wars in 1641-52 and the Williamite war in 1689–91. Political power thereafter rested almost exclusively in the hands of a minority Protestant Ascendancy, while Catholics and members of dissenting Protestant denominations suffered severe political and economic privations under the Penal Laws.


title: History of Ireland

text: On 1 January 1801, in the wake of the republican United Irishmen Rebellion, the Irish Parliament was abolished and Ireland became part of a new United Kingdom of Great Britain and Ireland formed by the Acts of Union 1800. Catholics were not granted full rights until Catholic Emancipation in 1829, achieved by Daniel O’Connell. The catastrophe of the Great Famine struck Ireland in 1845 resulting in over a million deaths from starvation and disease and a million refugees fleeing the country, mainly to America. Irish attempts to break away continued with Parnell's Irish Parliamentary Party which strove from the 1880s to attain Home Rule through the parliamentary constitutional movement, eventually winning the Home Rule Act 1914, although this Act was suspended at the outbreak of World War I. In 1916, the Easter Rising succeeded in turning public opinion against the British establishment after the execution of the leaders by British authorities. It also eclipsed the home rule movement. In 1922, after the Irish War of Independence most of Ireland seceded from the United Kingdom to become the independent Irish Free State but under the Anglo-Irish Treaty the six northeastern counties, known as Northern Ireland, remained within the United Kingdom, creating the partition of Ireland. The treaty was opposed by many; their opposition led to the outbreak of the Irish Civil War, in which Irish Free State, or "pro-treaty", forces proved victorious.


title: History of Ireland

text: The history of Northern Ireland has since been dominated by the division of society along sectarian faultlines and conflict between (mainly Catholic) Irish nationalists and (mainly Protestant) British unionists. These divisions erupted into the Troubles in the late 1960s, after civil rights marches were met with opposition by authorities. The violence escalated after the deployment of the British Army to maintain authority led to clashes with nationalist communities. The violence continued for twenty-eight years until an uneasy, but largely successful peace was finally achieved with the Good Friday Agreement in 1998.


title: History of Ireland

text: What is known of pre-Christian Ireland comes from references in Roman writings, Irish poetry, myth, and archaeology. While some possible Paleolithic tools have been found, none of the finds is convincing of Paleolithic settlement in Ireland. However a bear bone found in Alice and Gwendoline Cave, County Clare, in 1903 may push back dates for the earliest human settlement of Ireland to 10,500 BC. The bone shows clear signs of cut marks with stone tools and has been radiocarbon dated to 12,500 years ago.


title: History of Ireland

text: It is possible that humans crossed a land bridge during the warm period, referred to as the Bølling-Allerød warming, that lasted between 14,700 and 12,700 years ago towards the end of the last ice age, and allowed the reinhabitation of northern Europe. A sudden return to freezing conditions known as the Younger Dryas cold phase, which lasted from 10,900 BC to 9700 BC, may have depopulated Ireland. During the Younger Dryas, sea levels continued to rise and no ice-free land bridge between Great Britain and Ireland ever returned.


title: History of Ireland

text: The earliest confirmed inhabitants of Ireland were Mesolithic hunter-gatherers, who arrived sometime around 7900 BC. While some authors take the view that a land bridge connecting Ireland to Great Britain still existed at that time, more recent studies indicate that Ireland was separated from Britain by c. 14,000 BC when the climate was still cold and local ice caps persisted in parts of the country. The people remained hunter-gatherers until about 4000 BC. It is argued this is when the first signs of agriculture started to show, leading to the establishment of a Neolithic culture, characterised by the appearance of pottery, polished stone tools, rectangular wooden houses, megalithic tombs, and domesticated sheep and cattle. Some of these tombs, as at Knowth and Dowth, are huge stone monuments and many of them, such as the Passage Tombs of Newgrange, are astronomically aligned. Four main types of Irish Megalithic Tombs have been identified: dolmens, court cairns, passage tombs and wedge-shaped gallery graves. In Leinster and Munster, individual adult males were buried in small stone structures, called cists, under earthen mounds and were accompanied by distinctive decorated pottery. This culture apparently prospered, and the island became more densely populated. Near the end of the Neolithic new types of monuments developed, such as circular embanked enclosures and timber, stone and post and pit circles.


title: History of Ireland

text: The Céide Fields is an archaeological site on the north County Mayo coast in the west of Ireland, about


title: History of Ireland

text: 7 kilometres northwest of Ballycastle, and the site is the most extensive Neolithic site in Ireland and contains the oldest known field systems in the world. Using various dating methods, it was discovered that the creation and development of the Céide Fields goes back some five and a half thousand years (~3500 BC).


title: History of Ireland

text: The short-lived Irish Copper Age and subsequent Bronze Age, which came to Ireland around 2000 BC, saw the production of elaborate gold and bronze ornaments, weapons and tools. There was a movement away from the construction of communal megalithic tombs to the burial of the dead in small stone cists or simple pits, which could be situated in cemeteries or in circular earth or stone-built burial mounds known respectively as barrows and cairns. As the period progressed, inhumation burial gave way to cremation and by the Middle Bronze Age, remains were often placed beneath large burial urns. During the late Bronze Age, there was an increase in stored weapons, which has been taken as evidence for greater warfare. Fleshed Bog Bodies also appear at this time, continuing into the Iron Age.


title: History of Ireland

text: The Iron Age in Ireland began about 600 BC. The period between the start of the Iron Age and the historic period (AD 431) saw the gradual infiltration of small groups of Celtic-speaking people into Ireland, with items of the continental Celtic La Tene style being found in at least the northern part of the island by about 300 BC. The result of a gradual blending of Celtic and indigenous cultures would result in the emergence of Gaelic culture by the fifth century. It is also during the fifth century that the main over-kingdoms of In Tuisceart, Airgialla, Ulaid, Mide, Laigin, Mumhain, Cóiced Ol nEchmacht began to emerge (see Kingdoms of ancient Ireland). Within these kingdoms, a rich culture flourished. The society of these kingdoms was dominated by an upper class consisting of aristocratic warriors and learned people, which possibly included Druids.


title: History of Ireland

text: Linguists realised from the 17th century onwards that the language spoken by these people, the Goidelic languages, was a branch of the Celtic languages. This is usually explained as a result of invasions by Celts from the continent. However, other research has postulated that the culture developed gradually and continuously and that the introduction of Celtic language and elements of Celtic culture may have been a result of cultural exchange with Celtic groups in southwest continental Europe from the Neolithic to the Bronze Age.


title: History of Ireland

text: The hypothesis that the native Late Bronze Age inhabitants gradually absorbed Celtic influences has since been supported by some recent genetic research.


title: History of Ireland

text: In 60 AD, it is said that the Romans invaded Anglesey in Wales causing concerns across the Irish Sea, but there is a small controversy on if they even set foot into Ireland. The closest Rome got to conquering Ireland was in 80 AD, when, according to Turtle Bunbury from the Irish Times, “Túathal Techtmar, the son of a deposed high king, who is said to have invaded Ireland from afar in order to regain his kingdom at about this time”.


title: History of Ireland

text: The Romans referred to Ireland as Hibernia around AD 100. Ptolemy, in AD 100, recorded Ireland's geography and tribes. Ireland was never a part of the Roman Empire, but Roman influence was often projected well beyond its borders. Tacitus writes that an exiled Irish prince was with Agricola in Roman Britain and would return to seize power in Ireland. Juvenal tells us that Roman "arms had been taken beyond the shores of Ireland". In recent years, some experts have hypothesized that Roman-sponsored Gaelic forces (or perhaps even Roman regulars) mounted some kind of invasion around AD 100, but the exact relationship between Rome and the dynasties and peoples of Hibernia remains unclear.


title: History of Ireland

text: Irish confederations (the Scoti) attacked and some settled in Britain during the Great Conspiracy of 367. In particular, the Dál Riata settled in western Scotland and the Western Isles.


title: History of Ireland

text: The middle centuries of the first millennium AD marked great changes in Ireland. Politically, what appears to have been a prehistoric emphasis on tribal affiliation had been replaced by the 8th century by patrilineal dynasties ruling the island's kingdoms. Many formerly powerful kingdoms and peoples disappeared. Irish pirates struck all over the coast of western Britain in the same way that the Vikings would later attack Ireland. Some of these founded entirely new kingdoms in Pictland and, to a lesser degree, in parts of Cornwall, Wales, and Cumbria. The Attacotti of south Leinster may even have served in the Roman military in the mid-to-late 300s.


title: History of Ireland

text: Perhaps it was some of the latter returning home as rich mercenaries, merchants, or slaves stolen from Britain or Gaul, that first brought the Christian faith to Ireland. Some early sources claim that there were missionaries active in southern Ireland long before St. Patrick. Whatever the route, and there were probably many, this new faith was to have the most profound effect on the Irish.


title: History of Ireland

text: Tradition maintains that in A.D. 432, St. Patrick arrived on the island and, in the years that followed, worked to convert the Irish to Christianity. St Patrick's "Confession", in Latin, written by him is the earliest Irish historical document. It gives some information about the Saint. On the other hand, according to Prosper of Aquitaine, a contemporary chronicler, Palladius was sent to Ireland by the Pope in 431 as ""first Bishop to the Irish believing in Christ"", which demonstrates that there were already Christians living in Ireland. Palladius seems to have worked purely as Bishop to Irish Christians in the Leinster and Meath kingdoms, while Patrick – who may have arrived as late as 461 – worked first and foremost as a missionary to the pagan Irish, in the more remote kingdoms in Ulster and Connacht.


title: History of Ireland

text: Patrick is traditionally credited with preserving and codifying Irish laws and changing only those that conflicted with Christian practices. He is credited with introducing the Roman alphabet, which enabled Irish monks to preserve parts of the extensive oral literature. The historicity of these claims remains the subject of debate and there is no direct evidence linking Patrick with any of these accomplishments. The myth of Patrick, as scholars refer to it, was developed in the centuries after his death.


title: History of Ireland

text: Irish scholars excelled in the study of Latin learning and Christian theology in the monasteries that flourished shortly thereafter. Missionaries from Ireland to England and Continental Europe spread the news of the flowering of learning, and scholars from other nations came to Irish monasteries. The excellence and isolation of these monasteries helped preserve Latin learning during the Early Middle Ages. The period of Insular art, mainly in the fields of illuminated manuscripts, metalworking, and sculpture flourished and produced such treasures as the Book of Kells, the Ardagh Chalice, and the many carved stone crosses that dot the island. Insular style was to be a crucial ingredient in the formation of the Romanesque and Gothic styles throughout Western Europe. Sites dating to this period include clochans, ringforts and promontory forts.


title: History of Ireland

text: The plagues of the 660s and the 680s had a traumatic effect on Irish society. The golden age of the saints was over, together with the generation of kings who could fire a saga-writer's imagination. The literary tradition looks back to the reign of the sons of Aed Slaine (Diarmait and Blathmac, who died in 665) as to the end of an era. Antiquaries, brehons, genealogists and hagiographers, felt the need to collect ancient traditions before they were totally forgotten. Many were in fact swallowed by oblivion; when we examine the writing of Tirechan we encounter obscure references to tribes that are quite unknown to the later genealogical tradition. The laws describe a ... society that was obsolescent, and the meaning and use of the word "moccu" dies out with archaic Old Irish at the beginning of the new century.


title: History of Ireland

text: The first English involvement in Ireland took place in this period. Tullylease, Rath Melsigi and Maigh Eo na Saxain were founded by 670 for English students who wished to study or live in Ireland. In summer 684, an English expeditionary force sent by Northumbrian King Ecgfrith raided Brega.


title: History of Ireland

text: The first recorded Viking raid in Irish history occurred in 795 AD when Vikings from Norway looted the island. Early Viking raids were generally fast-paced and small in scale. These early raids interrupted the golden age of Christian Irish culture and marked the beginning of two centuries of intermittent warfare, with waves of Viking raiders plundering monasteries and towns throughout Ireland. Most of those early raiders came from western Norway.


title: History of Ireland

text: The Vikings were expert sailors, who travelled in longships, and by the early 840s, had begun to establish settlements along the Irish coasts and to spend the winter months there. The longships were technologically advanced, allowing them to travel faster through the narrow rivers. Vikings founded settlements in several places; most famously in Dublin. Most of the settlements were near the water, allowing the Vikings to trade using their longships. Written accounts from this time (early to mid 840s) show that the Vikings were moving further inland to attack (often using rivers) and then retreating to their coastal headquarters.


title: History of Ireland

text: In 852, the Vikings landed in Dublin Bay and established a fortress. Dublin became the centre for the trade of many goods, especially slaves. Bringing back new ideas and motivations, they began settling more permanently. In the tenth century, an earthen bank was constructed around the city with a second larger bank built outside that in the eleventh century. On the interior of the town, an extensive series of defences have been excavated at Fishamble Street, Dublin. The site featured nine waterfronts, including two possible flood banks and two positive defensive embankments during the Viking Age. The early embankments were non-defensive, being only one metre high, and it is uncertain how much of the site they encircled. After several generations a group of mixed Irish and Norse ethnic background arose, the "Gall-Gaels", '("Gall" being the Old Irish word for foreign).


title: History of Ireland

text: The second wave of Vikings made stations at winter bases called longphorts to serve as control centres to exert a more localized force on the island through raiding. The third wave in 917 established towns as not only control centres, but also as centres of trade to enter into Irish economy and greater Western Europe. Returning to Dublin, they set up a market town. Over the next century, a great period of economic growth would spread across the pastoral country. The Vikings introduced the concept of international trade to the Irish, as well as popularizing a silver-based economy with local trade and the first minting of coins in 997.


title: History of Ireland

text: In 902 Máel Finnia mac Flannacain of Brega and Cerball mac Muirecáin of Leinster joined forces against Dublin, and "The heathens were driven from Ireland, i.e. from the fortress of Áth Cliath [Dublin]". They were allowed by the Saxons to settle in Wirral, England, but would however later return to retake Dublin.


title: History of Ireland

text: The Vikings never achieved total domination of Ireland, often fighting for and against various Irish kings. The great High King of Ireland, Brian Boru, defeated the Vikings at the Battle of Clontarf in 1014 which began the decline of Viking power in Ireland but the towns which Vikings had founded continued to flourish, and trade became an important part of the Irish economy.


title: History of Ireland

text: Brian Boru, by more or less unifying Ireland, changed the High Kingship in the way that the High King would now have more power and control over the country and could manage the country's affairs. This led to prosperity for Ireland over the next few years. The Irish economy grew as international trade became more common. The towns founded by the Vikings continued to grow and thrive as centres of Irish trade and finance. They remain so to this day.


title: History of Ireland

text: Despite the breaking of Norse power in Ireland, the Norse still maintained control of the Kingdom of Dublin. Although the King of Leinster levied tribute from the Norse, they rarely directly intervened in the affairs of the city-state, as it brought trade to the area. This changed, however, when Diarmuit mac Maél na mBó, King of Leinster, captured Dublin in 1052. This gave the Irish greater access to the Kingdom of the Isles. Diarmuit was able to become High King of Ireland, and after his death, the O'Brien dynasty, who ruled Ireland since the days of Brian Boru, reclaimed the High Kingship and Irish influence in the Irish Sea area would increase dramatically over the next few decades, notably under High King Muircherteach Ua Briain, who was noted for his interest in foreign affairs.


title: History of Ireland

text: Perhaps it was Muircherteach's increasing power in the Isles that led Magnus Barefoot, King of Norway, to lead campaigns against the Irish in 1098 and again in 1102 to bring Norse areas back under Norwegian control, while also raiding the various British kingdoms. Although direct conflict with the Kingdom of Norway seemed imminent, the two Kings formed an alliance by the marriage of Muircherteach's daughter to Magnus' son. The two would campaign together in Ulster, until Magnus was killed in an ambush by the Ulaid in August 1103, under mysterious circumstances (it is possible Muircherteach ordered his killing). Muircherteach was also politically involved in the Kingdoms of Scotland and England, as well as Wales.


title: History of Ireland

text: One of the most prosperous reigns of any High King was the reign of Toirdelbach Ua Conchobhair, who had overthrown Muircherteach and partitioned Munster in 1118. As King of Connacht and then King of Ireland, Ireland underwent a period of modernization and elevation on the European stage. Under his rule, the first castles in Ireland were built bringing improved defence and brought a new aspect to Irish warfare. He also built a naval base and castle at Dún Gaillimhe. A settlement grew around this castle which would grow to be the city of Galway today. He was a superb military commander and this allowed him to keep control of Ireland, with the help of the castles he built and his fleet based at Dún Gaillimhe. He also had commercial and political links with the rulers of France, Spain and England, increasing Ireland's international presence which brought more trade to the island. His reign lasted more than 50 years.


title: History of Ireland

text: One of Tairrdelbach's sons, Ruadhrí, would later go on to be High King himself. He was arguably the first High King without opposition, however, he would later abdicate following the Norman invasion of Ireland.


title: History of Ireland

text: By the 12th century, Ireland was divided politically into a shifting hierarchy of petty kingdoms and over-kingdoms. Power was exercised by the heads of a few regional dynasties vying against each other for supremacy over the whole island. One of these men, King Diarmait Mac Murchada of Leinster was forcibly exiled by the new High King, Ruaidri mac Tairrdelbach Ua Conchobair of the Western kingdom of Connacht. Fleeing to Aquitaine, Diarmait obtained permission from Henry II to recruit Norman knights to regain his kingdom. The first Norman knights landed in Ireland in 1167, followed by the main forces of Normans, Welsh and Flemings. Several counties were restored to the control of Diarmait, who named his son-in-law, the Norman Richard de Clare, known as Strongbow, heir to his kingdom. This troubled King Henry, who feared the establishment of a rival Norman state in Ireland. Accordingly, he resolved to establish his authority. In 1177, Prince John Lackland was made Lord of Ireland by his father Henry II of England at the Council of Oxford.


title: History of Ireland

text: With the authority of the papal bull Laudabiliter from Adrian IV, Henry landed with a large fleet at Waterford in 1171, becoming the first King of England to set foot on Irish soil. Henry awarded his Irish territories to his younger son John with the title "Dominus Hiberniae" ("Lord of Ireland"). When John unexpectedly succeeded his brother as King John of England, the "Lordship of Ireland" fell directly under the English Crown.


title: History of Ireland

text: The Normans initially controlled the entire east coast, from Waterford to eastern Ulster, and penetrated a considerable distance inland as well. The counties were ruled by many smaller kings. The first Lord of Ireland was King John, who visited Ireland in 1185 and 1210 and helped consolidate the Norman-controlled areas while ensuring that the many Irish kings swore fealty to him.


title: History of Ireland

text: Throughout the thirteenth century, the policy of the English Kings was to weaken the power of the Norman Lords in Ireland. For example, King John encouraged Hugh de Lacy to destabilise and then overthrow the Lord of Ulster, before naming him as the first Earl of Ulster. The Hiberno-Norman community suffered from a series of invasions that ceased the spread of their settlement and power. Politics and events in Gaelic Ireland served to draw the settlers deeper into the orbit of the Irish.


title: History of Ireland

text: Furthermore, unlike the Anglo-Normans, the Gaelic kings did not keep detailed estate inventories and accounts. Coupled with the absence of archaeological evidence to the contrary, this has tempted many scholars of medieval western Ireland to agree with the twelfth-century historian Giraldus Cambrensis who argued that the Gaelic kings did not build castles.


title: History of Ireland

text: By 1261 the weakening of the Normans had become manifest when Fineen MacCarthy defeated a Norman army at the Battle of Callann. The war continued between the different lords and earls for about 100 years, causing much destruction, especially around Dublin. In this chaotic situation, local Irish lords won back large amounts of land that their families had lost since the conquest and held them after the war was over.


title: History of Ireland

text: The Black Death arrived in Ireland in 1348. Because most of the English and Norman inhabitants of Ireland lived in towns and villages, the plague hit them far harder than it did the native Irish, who lived in more dispersed rural settlements. After it had passed, Gaelic Irish language and customs came to dominate the country again. The English-controlled territory shrank to a fortified area around Dublin (the Pale), whose rulers had little real authority outside (beyond the Pale).