title: Mutual fund

text: In the United States, money market funds sold to retail investors and those investing in government securities may maintain a stable net asset value of $1 per share, when they comply with certain conditions. Money market funds sold to institutional investors that invest in non-government securities must compute a net asset value based on the value of the securities held in the funds.


title: Mutual fund

text: In the United States, at the end of 2019, assets in money market funds were $3.6 trillion, representing 14% of the industry.


title: Mutual fund

text: In the United States, at the end of 2019, assets in bond funds (of all types) were $5.7 trillion, representing 22% of the industry.


title: Mutual fund

text: Stock or equity funds invest in common stocks. Stock funds may focus on a particular area of the stock market, such as


title: Mutual fund

text: In the United States, at the end of 2019, assets in stock funds (of all types) were $15.0 trillion, representing 58% of the industry.


title: Mutual fund

text: Hybrid funds invest in both bonds and stocks or in convertible securities. Balanced funds, asset allocation funds, convertible bond funds, target date or target-risk funds, and lifecycle or lifestyle funds are all types of hybrid funds. The performance of hybrid funds can be explained by a combination of stock factors (e.g., Fama–French three-factor model), bond factors (e.g., excess returns of a Government bond index), option factors (e.g., implied stock-market volatility), and fund factors (e.g., the net supply of convertible bonds).


title: Mutual fund

text: Hybrid funds may be structured as fund of funds, meaning that they invest by buying shares in other mutual funds that invest in securities. Many funds of funds invest in affiliated funds (meaning mutual funds managed by the same fund sponsor), although some invest in unaffiliated funds (i.e., managed by other fund sponsors) or some combination of the two.


title: Mutual fund

text: In the United States, at the end of 2019, assets in hybrid funds were $1.6 trillion, representing 6% of the industry.


title: Mutual fund

text: Investors in a mutual fund pay the fund's expenses. Some of these expenses reduce the value of an investor's account; others are paid by the fund and reduce net asset value.


title: Mutual fund

text: The management fee is paid by the fund to the management company or sponsor that organizes the fund, provides the portfolio management or investment advisory services, and normally lends its brand to the fund. The fund manager may also provide other administrative services. The management fee often has breakpoints, which means that it declines as assets (in either the specific fund or in the fund family as a whole) increase. The fund's board reviews the management fee annually. Fund shareholders must vote on any proposed increase, but the fund manager or sponsor can agree to waive some or all of the management fees in order to lower the fund's expense ratio.


title: Mutual fund

text: Distribution charges pay for marketing, distribution of the fund's shares as well as services to investors. There are three types of distribution charges.


title: Mutual fund

text: A mutual fund pays expenses related to buying or selling the securities in its portfolio. These expenses may include brokerage commissions. These costs are normally positively correlated with turnover.


title: Mutual fund

text: Shareholders may be required to pay fees for certain transactions, such as buying or selling shares of the fund. A fund may charge a fee for maintaining an individual retirement account for an investor.


title: Mutual fund

text: Some funds charge redemption fees when an investor sells fund shares shortly after buying them (usually defined as within 30, 60, or 90 days of purchase). Redemption fees are computed as a percentage of the sale amount. Shareholder transaction fees are not part of the expense ratio.


title: Mutual fund

text: The expense ratio equals recurring fees and expenses charged to the fund during the year divided by average net assets. The management fee and fund services charges are ordinarily included in the expense ratio. Front-end and back-end loads, securities transaction fees, and shareholder transaction fees are normally excluded.


title: Mutual fund

text: To facilitate comparisons of expenses, regulators generally require that funds use the same formula to compute the expense ratio and publish the results.


title: Mutual fund

text: In the United States, a fund that calls itself "no-load" cannot charge a front-end load or back-end load under any circumstances and cannot charge a distribution and services fee greater than 0.25% of fund assets.


title: Mutual fund

text: Critics of the fund industry argue that fund expenses are too high. They believe that the market for mutual funds is not competitive and that there are many hidden fees so that it is difficult for investors to reduce the fees that they pay. They argue that the most effective way for investors to raise the returns they earn from mutual funds is to invest in funds with low expense ratios.


title: Mutual fund

text: Fund managers counter that fees are determined by a highly competitive market and, therefore, reflect the value that investors attribute to the service provided. They also note that fees are clearly disclosed.


title: Mutual fund

text: Mutual funds in the United States are required to report the average annual compounded rates of return for one-, five-and-ten year-periods using the following formula:


title: Mutual fund

text: "ERV" = ending redeemable value of a hypothetical $1,000 payment made at the beginning of the one-, five-, or ten-year periods at the end of those periods (or fractional portion).


title: Mutual fund

text: A fund's net asset value (NAV) equals the current market value of a fund's holdings minus the fund's liabilities (this figure may also be referred to as the fund's "net assets"). It is usually expressed as a per-share amount, computed by dividing net assets by the number of fund shares outstanding. Funds must compute their net asset value according to the rules set forth in their prospectuses. Most compute their NAV at the end of each business day.


title: Mutual fund

text: Valuing the securities held in a fund's portfolio is often the most difficult part of calculating net asset value. The fund's board typically oversees security valuation.


title: Mutual fund

text: A single mutual fund may give investors a choice of different combinations of front-end loads, back-end loads and distribution and services fee, by offering several different types of shares, known as share classes. All of them invest in the same portfolio of securities, but each has different expenses and, therefore, different net asset values and different performance results. Some of these share classes may be available only to certain types of investors.


title: Mutual fund

text: Typical share classes for funds sold through brokers or other intermediaries in the United States are:


title: Mutual fund

text: "Portfolio turnover" is a measure of the volume of a fund's securities trading. It is expressed as a percentage of the average market value of the portfolio's long-term securities. Turnover is the lesser of a fund's purchases or sales during a given year divided by average long-term securities market value for the same period. If the period is less than a year, turnover is generally annualized.


title: Trisomy X

text: Trisomy X, also known as triple X syndrome and characterized by the karyotype 47,XXX, is a chromosome disorder in which a female has an extra copy of the X chromosome. It is relatively common and occurs in 1 in 1,000 women but it is rarely diagnosed; fewer than 10% of those with the condition know they have it.


title: Trisomy X

text: Those who have symptoms can have learning disabilities, mild dysmorphic features such as hypertelorism (wide-spaced eyes) and clinodactyly (incurved little fingers), early menopause, and increased height. The average intelligence quotient (IQ) in trisomy X is 8590. As the symptoms of trisomy X are often not serious enough to prompt a karyotype test, many cases of trisomy X are diagnosed before birth via prenatal screening tests such as amniocentesis. Research on girls and women with the disorder finds that cases which were diagnosed postnatally, having been referred for testing because of obvious symptoms, are generally more severe than those diagnosed prenatally. Most women with trisomy X live normal lives, although their socioeconomic status is reduced compared to the general population.


title: Trisomy X

text: Trisomy X occurs via a process called nondisjunction, in which normal cell division is interrupted and produces gametes with too many or too few chromosomes. Nondisjunction is a random occurrence, and most girls and women with trisomy X have no family histories of chromosome aneuploidy. Advanced maternal age is mildly associated with trisomy X. Women with trisomy X can have children of their own, who in most cases do not have an increased risk of chromosome disorders; women with mosaic trisomy X, who have a mix of 46,XX (the typical female karyotype) and 47,XXX cells, may have an increased risk of chromosomally abnormal children.


title: Trisomy X

text: First reported in 1959 by the geneticist Patricia Jacobs, the early understanding of trisomy X was that of a debilitating disability observed in institutionalized women. Beginning in the 1960s, studies of people with sex chromosome aneuploidies from birth to adulthood found that they are often only mildly affected, fitting in with the general population, and that many never needed the attention of clinicians because of the condition.


title: Trisomy X

text: Trisomy X has variable effects, ranging from no symptoms at all to significant disability. Severity varies between people diagnosed prenatally (before birth) and postnatally (after birth), and postnatal cases are more severe on average. Symptoms associated with trisomy X include tall stature, mild developmental delay, subtle physical and skeletal anomalies, increased rates of mental health concerns, and earlier age of menopause.


title: Trisomy X

text: The physical and physiological impacts of trisomy X tend to be subtle. Tall stature is one of the major physical associations of trisomy X. Prior to age four, most girls with trisomy X are average height; growth picks up after this age, and is particularly rapid between the ages of four and eight. Of girls with trisomy X aged six to thirteen, 40% are above the 90th percentile in height. The average adult height in trisomy X has been estimated as and head circumference as 20th percentile. The added height in trisomy X is primarily in the limbs, with long legs and a shorter sitting height. Though head circumference is generally below the 50th percentile, microcephaly, a head circumference below the 5th percentile, is rare.


title: Trisomy X

text: Minor skeletal and craniofacial anomalies are associated with trisomy X. Subtle dysmorphisms seen in some females with trisomy X include hypertelorism (wide-spaced eyes), epicanthic folds (an additional fold of skin in the corners of the eyes), and upslanting palpebral fissures (the opening between the eyelids). These differences are usually minor and do not impact the daily lives of girls and women with the condition. Other skeletal anomalies associated with trisomy X include clinodactyly (incurved little fingers), radioulnar synostosis (the fusion of the long bones in the forearm), flat feet, and hyper-extensible joints. These findings are not unique to trisomy X, but rather are seen in sex chromosome aneuploidy disorders as a whole.


title: Trisomy X

text: Severe internal disease is rare in trisomy X. Genitourinary conditions are more common than in the general population, particularly kidney and ovary malformations. One study found that the autoimmune disorders lupus and Sjögren syndrome are more common in trisomy X than in the general population. Conditions such as sleep apnea, asthma, scoliosis, and hip dysplasia have also been linked to sex chromosome aneuploidies as a whole, including trisomy X. Although heart defects are common in pentasomy X, they are no more frequent in trisomy X than the general population.


title: Trisomy X

text: Puberty starts around the expected age and progresses as normal. Fertility is normal when not complicated by early menopause; a large population study found women with 47,XXX karyotypes to average 1.9 lifetime pregnancies, compared to 2.3 for women with "normal" 46,XX karyotypes, and to be no more likely to miscarry. Premature ovarian failure (POF), or early menopause, is a known complication of trisomy X. Premature ovarian failure is defined as menopause before the age of 40; in the general population, 1 in 100 women experience menopause before this age, 1 in 1,000 before age 30, and 1 in 10,000 before age 20. Amongst women with POF, 3% have trisomy X, compared to 1 in 1,000 in the general population. The average age of menopause for women with trisomy X is 45 years, compared to 50 years for women with 46,XX karyotypes. POF is more common in women with trisomy X who also have autoimmune disorders.


title: Trisomy X

text: General cognitive functioning is reduced in trisomy X, with an average intelligence quotient of 8590. Performance IQ tends to be higher than verbal IQ. Though intellectual disability is rare, it is more prevalent than in the general population, occurring in about 510% of females with trisomy X compared to approximately 1% of the broader population. While the average is depressed, the effect of trisomy X varies substantially, and some women are highly intelligent.


title: Trisomy X

text: Infant milestones are normal to slightly delayed. A patient support organization reports crawling around the age of ten months and walking around sixteen to eighteen months, with first words acquired shortly after one year of age and fluent speech around age two. Speech therapy is needed in 40%90% of girls with trisomy X at some point in their lives, compared to around 38% of children in the general population. Expressive language skills tend to be more affected than receptive skills.


title: Trisomy X

text: Neuroimaging in trisomy X demonstrates decreased whole brain volumes, correlated with overall intellectual functioning. Amygdala volume may be smaller than expected after controlling for whole brain size. White matter abnormalities have been reported, although their significance is unknown. These findings are common to X-chromosome polysomy syndromes, and is seen in males with Klinefelter syndrome. Epilepsy or electroencephalogram abnormalities may be more common in those with trisomy X, particularly those who are also intellectually disabled. Epilepsy in sex chromosome aneuploidies as a whole is mild, amenable to treatment, and often attenuates or disappears with time. Tremor is reported in approximately a quarter of women with trisomy X and responds to the same treatments as in the general population.


title: Trisomy X

text: Autism spectrum disorders are more common in trisomy X, occurring in approximately 15% of girls with trisomy X compared to less than 1% of girls in the general population. Though much of the research is in children, research in adult women with trisomy X suggests higher rates of autistic symptomatology than the general population. Executive dysfunction, where people have difficulty regulating their actions and emotions, is more prevalent amongst those with trisomy X than the general population.


title: Trisomy X

text: The psychosocial adaptation of girls and women with trisomy X is dependent on environmental factors. Girls growing up in stable environments with healthy home lives tend to have relatively high adaptive and social functioning, while significant behavioural and psychological issues are predominantly seen in those from troubled social environments. Though girls with trisomy X usually have good relationships with peers, they trend towards immaturity; some behavioural issues in children with trisomy X are thought to be a consequence of the disconnect between apparent age, as understood via increased height, and cognitive and emotional maturity encouraging hard-to-reach expectations. Girls whose motor and language skills are more severely affected by trisomy X often experience low confidence and self-esteem. These traits vary in severity; though some women with trisomy X are significantly impaired, many are within the normal range of variance, and some are high-functioning and high-achieving.


title: Trisomy X

text: Some mental health issues are more frequent in women with trisomy X. Dysthymia and cyclothymia, milder forms of depression and bipolar disorder respectively, are more common than in the general population. Women with trisomy X average higher schizotypy, reporting higher levels of introversion, magical thinking, and impulsivity. Sex chromosome aneuploidies are associated with psychosis, and schizophrenic women are more likely to have trisomy X than the general female population. The prevalence of trisomy X in women with adult-onset schizophrenia is estimated to be around 1 in 400, compared to 1 in 1,000 in women as a whole; the prevalence in childhood onset schizophrenia is unclear, but may be as high as 1 in 40. Approximately one-fifth of women with trisomy X report clinically significant levels of anxiety. Women with trisomy X are often "late bloomers", experiencing high rates of psychological distress into early adulthood, but by their mid-thirties having stronger interpersonal bonds and healthy relationships. The study of mental health in trisomy X is complicated by the fact that girls and women who were diagnosed before birth seem to be more mildly affected than those diagnosed after. For instance, psychogenic stomach pains are reported in a disproportionate number of postnatally diagnosed patients, but fewer prenatally diagnosed ones.


title: Trisomy X

text: The most common karyotype in trisomy X is 47,XXX, where all cells have an additional copy of the X chromosome. Mosaicism, where both 47,XXX and other cell lines are present, occurs in approximately 10% of cases. Mosaic trisomy X has different outcomes to the non-mosaic condition. Common mosaic forms observed include 46,XX/47,XXX, 45,X0/47,XXX (with a Turner syndrome cell line), and 47,XXX/48,XXXX (with a tetrasomy X cell line). Complex mosaicism, with cell lines such as 45,X0/46,XX/47,XXX, can also be seen.


title: Trisomy X

text: The simplest form of mosaic trisomy X, with a 46,XX/47,XXX karyotype, is milder compared to full trisomy X. Cognitive development is more typical, with improved long-term life outcomes. Although generally milder, 46,XX/47,XXX mosaicism is associated with a higher risk of chromosome anomalies in offspring than full trisomy X. The increased risk of abnormal offspring in mosaicism has been hypothesized to be a consequence of oocyte abnormality in 46,XX/47,XXX women not seen in full 47,XXX. Some writers have recommended women with 46,XX/47,XXX karyotypes undergo screening for chromosomal disorders during pregnancy.


title: Trisomy X

text: Between 3% and 15% of females with Turner syndrome, defined by a karyotype with a single copy of the X chromosome, have a 47,XXX cell line. Mosaic karyotypes with both 45,X0 and 47,XXX cells are considered Turner syndrome rather than trisomy X, but the presence of 47,XXX cells influences the disorder. Non-mosaic Turner syndrome is characterized by primary amenorrhea and failure to begin or complete puberty, while 8090% of women with 45,X0/47,XXX mosaicism begin puberty naturally and approximately 6080% have spontaneous menses. Around two-thirds of 45,X0/47,XXX mosaics have clinically significant short stature, compared with virtually all women with non-mosaic Turner syndrome. Although women with trisomy X have lower IQs than the general population and women with Turner syndrome do not, intellectual disability does not appear to be more common in the mosaicism than for non-mosaic Turner's. Women with mosaic Turner syndrome tend to have similar dysmorphic features to those with non-mosaic Turner's syndrome, but less marked, and some have none of the traditional Turner's stigmata.


title: Trisomy X

text: Turner syndrome is characteristically associated with sterility, and only 2–7% of women with Turner's, including mosaic cases, are capable of pregnancy. In contrast, Turner's women with 47,XXX cell lines often complete puberty and are typically fertile. Women with the mosaicism experience premature ovarian failure; the average age of menopause in these women is around 30, with the onset of likely perimenopausal irregular menses occurring around age 20.


title: Trisomy X

text: Mosaicism with a tetrasomy X cell line generally appears more severe than typical trisomy X. Like trisomy X, tetrasomy X has a variable phenotype muddled by underdiagnosis. The tetrasomy is generally more severe than the trisomy; intellectual disability is characteristic, dysmorphic features more visible, and puberty often altered.


title: Trisomy X

text: Trisomy X, like other aneuploidy disorders, is caused by a process called nondisjunction. Nondisjunction occurs when homologous chromosomes or sister chromatids fail to separate properly during meiosis, the process that produces gametes (eggs or sperm), and result in gametes with too many or too few chromosomes. Nondisjunction can occur during gametogenesis, where the trisomy is present from conception, or zygote development, where it occurs after conception. When nondisjunction occurs after conception, the resulting karyotype is generally mosaic, with both 47,XXX and other cell lines.


title: Trisomy X

text: Most cases of trisomy X occur through maternal nondisjunction, with around 90% of cases traced to errors in oogenesis. The vast majority of cases of trisomy X occur randomly; they have nothing to do with the chromosomes of the parents and little chance of recurring in the family. Nondisjunction is related to advanced maternal age, and trisomy X specifically appears to have a small but significant maternal age effect. In a cohort of women with trisomy X born in the 1960s, the average maternal age was 33. The risk of women with full trisomy X having chromosomally abnormal children is low, likely below 1%. Recurrence may occur if the mother has mosaicism for trisomy X, particularly in ovarian cells, but this makes up a small fraction of cases.


title: Trisomy X

text: Chromosome aneuploidies such as trisomy X are diagnosed via karyotype, the process in which chromosomes are tested from blood, bone marrow, amniotic fluid, or placental cells. As trisomy X is generally mild or asymptomatic, most cases are never diagnosed. Around 10% of cases of trisomy X are diagnosed in the person's lifetime; many are ascertained coincidentally during prenatal testing via amniocentesis or chorionic villi sampling, which is routinely performed for advanced maternal age. Postnatal testing is typically prompted by tall stature, hypotonia, developmental disability or neurodivergence, mild dysmorphic features such as hypertelorism or clinodactyly, and premature ovarian failure.


title: Trisomy X

text: Tetrasomy X, characterized by four copies of the X chromosome, has some signs in common with more severe cases of trisomy X. Intellectual disability, generally mild, is more frequently seen in the tetrasomy than the trisomy. There is more of a tendency towards noticeable dysmorphic features such as hypertelorism, clinodactyly, and epicanthic folds. Unlike trisomy X, approximately half of women with tetrasomy X have no or incomplete pubertal development. Although in most cases tetrasomy X is significantly more severe than trisomy X, some cases of tetrasomy X are mild, and some cases of trisomy X severe. Like trisomy X, the full phenotypic range of tetrasomy X is unknown due to underdiagnosis. Pentasomy X, with five X chromosomes, may rarely be a differential diagnosis for trisomy X. The phenotype of pentasomy X is more severe than the trisomy or tetrasomy, with significant intellectual disability, heart defects, microcephaly, and short stature.


title: Trisomy X

text: Due to overlapping dysmorphic features, such as epicanthic folds and upslanting palpebral fissures, some cases of trisomy X may be ascertained due to suspicion of Down syndrome. When the primary symptom is tall stature, trisomy X may be considered alongside other conditions depending on the rest of the phenotype. Marfan syndrome may be considered due to the disproportion between limb and torso length observed in both syndromes, as well as both experiencing joint issues. Beckwith-Wiedemann syndrome, another disproportionate tall stature syndrome, can cause developmental disability similar to that seen in some cases of trisomy X.


title: Trisomy X

text: As karyotypic diagnosis is conclusive, differential diagnosis can be abandoned after karyotype in most cases of trisomy X. However, due to the relatively high prevalence of trisomy X, other congenital disorders may occur alongside a 47,XXX karyotype. Differential diagnosis remains indicated when the phenotype is particularly severe for what a 47,XXX karyotype alone explains, such as severe intellectual disability or significant malformation.


title: Trisomy X

text: The prognosis of trisomy X is broadly good, with adult independence most often achieved, if delayed. Most adults achieve normal life outcomes, pursuing education, employment, or homemaking. Childhood and adolescence, particularly in compulsory education, tends to be more difficult for those with trisomy X than adult life. Parents report their daughters' struggling both academically and socially at school, particularly during secondary education, while adults report better adaptation after leaving education and entering the workforce. Of the women in the cohort studies followed to early adulthood, 7 of 37 dropped out of high school, while three attended university. Compared to age-matched women in the general population, women with trisomy X are 68% as likely to live with a partner, 64% as likely to have children, 36% as likely to hold higher education qualifications, and almost twice as likely to be retired from the workforce.


title: Trisomy X

text: Physical health is generally good and many women with trisomy X live into old age. Little data exists on aging in trisomy X. Data from the Danish Cytogenetic Central Register, which covers 13% of women with trisomy X in Denmark, suggests a life expectancy of 71 for women with full trisomy X and 78 for mosaics, compared to 84 for controls. The limited sample, composed only of women with trisomy X who have come to medical attention, has led to speculation this number is an underestimate.


title: Trisomy X

text: Women with trisomy X who were diagnosed prenatally have better outcomes as a group than those diagnosed postnatally, and 46,XX/47,XXX mosaics better than those with full trisomy X. Some of the improved outcome in prenatal diagnosis appears to be a function of higher socioeconomic status amongst parents.


title: Trisomy X

text: Trisomy X is a relatively common genetic disorder, occurring in around 1 in 1,000 female births. Despite this prevalence, only around 10% of cases are diagnosed during their lifetime. Large cytogenetic studies in Denmark find a diagnosed prevalence of 6 in 100,000 females, around 7% of the actual number of girls and women with trisomy X expected to exist in the general population. Diagnosis in the United Kingdom is particularly low, with an estimated 2% of cases medically recognized. Amongst the 244,000 women in the UK Biobank research sample, 110 were found to have 47,XXX karyotypes, corresponding to approximately half the number expected in the population. The fact this number is still reduced compared to the broader population is thought to be an effect of UK Biobank participants being less likely to be of low IQ and low socioeconomic status than the general population, both of which are more frequent in trisomy X.


title: Trisomy X

text: Trisomy X only occurs in females, as the Y chromosome is in most cases necessary for male sexual development. In addition to its high base rate, trisomy X is more common in some clinical subpopulations. The karyotype occurs in an estimated 3% of women with early menopause, 1 in 350 with Sjögren syndrome, and 1 in 400 with systemic lupus erythematosus.


title: Trisomy X

text: The first known case of trisomy X, in a woman who experienced premature ovarian failure at the age of 19, was diagnosed in 1959 by a team led by Patricia Jacobs. The late 1950s and early 1960s were a period of frequent ascertainment of previously unknown sex chromosome aneuploidies, with the 47,XXX karyotype discovered alongside 45,X0 and 47,XXY the same year. Early studies on sex chromosome aneuploidy screened patients residing in institutions, depicting the karyotypes as incapacitating; even at the time, this research was criticized for giving an inaccurate portrait of sex chromosome aneuploidy. Early reports of women with trisomy X have since been criticized for a dehumanizing ableist perspective, showing nude photographs of institutionalized women described as "mental deficiency patients".


title: Trisomy X

text: In response to the biased early studies, a newborn screening program for sex chromosome aneuploidy disorders was implemented in the 1960s. Almost 200,000 neonates were screened in Aarhus, Toronto, New Haven, Denver, Edinburgh, and Winnipeg; those found to have sex chromosome aneuploidies were followed up for 20 years for most of the cohorts, and longer for the Edinburgh and Denver cohorts. The children with trisomy X and Klinefelter's had their karyotypes disclosed to their parents, but due to the then-present perception that XYY syndrome was associated with violent criminality, those diagnoses were hidden from the family.


title: Trisomy X

text: These studies dispelled the idea that sex chromosome aneuploidies were "tantamount to a life of serious handicaps" and revealed their high prevalence in the population. They provided extensive information on the outcomes of trisomy X and other sex chromosome aneuploidies, forming much of the medical literature on the topic to this day. However, the small sample sizes of the long-term follow-ups in particular stymies extrapolation; by 1999, only 16 women in Edinburgh were still being followed. In 2007, Nicole Tartaglia founded the eXtraordinarY Kids Clinic in Denver to study children with sex chromosome aneuploidies; around one-fifth of patients at the clinic had trisomy X . In 2020, she introduced the eXtraordinarY Babies Study, a planned cohort study on people prenatally diagnosed with sex chromosome aneuploidies.


title: Trisomy X

text: The first description of trisomy X used the term 'superfemale' to describe the karyotype by analogy to "Drosophila" flies, a term that was immediately disputed. Curt Stern proposed the use of 'metafemale', which Jacobs criticized as both medically inaccurate and an "illegitimate product of a Graeco-Roman alliance". Bernard Lennon, opposing the use of 'superfemale' as misleading and possessed of an inappropriate "emotional element", suggested 'XXX syndrome'. For some years, the disorder was predominantly known as 'triple X syndrome' or 'triple X', though the latter is now discouraged.


title: Trisomy X

text: Awareness and diagnosis of sex chromosome aneuploidies is increasing. In the late 2010s, several state governments across the United States declared May to be National X & Y Chromosome Variation Awareness Month.


title: Trisomy X

text: Descriptions of trisomy X overwhelmingly consider the karyotype from a medical perspective, rather than a sociological or educational one. One topic in the sociological discussion of trisomy X and other sex chromosome aneuploidies is disability-selective abortion. Fetuses with sex chromosome aneuploidies are more likely to be aborted, though fetuses with trisomy X are less likely than for such conditions as a whole. A literature review of 19 studies found that nearly one-third of pregnancies with a child with trisomy X were aborted; it also found that parents who were counselled by a genetic counseller with expertise in sex chromosome aneuploidies, rather than an obstetrician or gynecologist, were less likely to abort. Abortion rates in sex chromosome aneuploidies have decreased over time with improved counselling.


title: Trisomy X

text: Trisomy X has been observed in other species that use the XY sex-determination system. Six cases of trisomy X have been recorded in dogs, for which the karyotype is 79,XXX compared to 78,XX for an euploid female dog. Unlike in humans, trisomy X in dogs is strongly linked to infertility, either primary anestrus or infertility with an otherwise normal estrous cycle. Canine trisomy X is thought to be underascertained, as most pet dogs are desexed and so underlying infertility will not be discovered. Three of the six known cases of canine trisomy X demonstrated behavioural issues such as fearfulness, inciting speculation about a link between the karyotype and psychological concerns as seen in humans with the condition. An additional dog with normal fertility and no reported behavioural issues was found to have a mosaic 78,XX/79,XXX karyotype. The canine X chromosome has a particularly large pseudoautosomal region, and dogs accordingly have a lower rate of monosomy X than observed in other species; however, a large pseudoautosomal region is not considered a contraindication for trisomy X, and canine trisomy X may have a comparable prevalence to the human form.


title: Trisomy X

text: Trisomy X is also observed in cattle, where it corresponds to a 61,XXX karyotype. A survey of 71 heifers who failed to become pregnant after two breeding seasons found two cases of trisomy X. As of 2021 a total of eight heifers with Trisomy X have been identified, seven of them were infertile. The condition also affect the river buffalo where the three known cases were sterile.


title: Frankfurt Airport

text: Frankfurt Airport (; , also known as "Rhein-Main-Flughafen") is a major international airport located in Frankfurt, the fifth-largest city of Germany and one of the world's leading financial centres. It is operated by Fraport and serves as the main hub for Lufthansa, including Lufthansa CityLine and Lufthansa Cargo as well as Condor and AeroLogic. The airport covers an area of of land and features two passenger terminals with capacity for approximately 65 million passengers per year; four runways; and extensive logistics and maintenance facilities.


title: Frankfurt Airport

text: Frankfurt Airport is the busiest airport by passenger traffic in Germany as well as the 4th busiest in Europe after London–Heathrow, Paris–Charles de Gaulle and Amsterdam Airport Schiphol. The airport is also the 13th busiest worldwide by total number of passengers in 2016, with 60.786 million passengers using the airport in 2016. In 2017, Frankfurt Airport handled 64.5 million passengers and nearly 70 million in 2018. It also had a freight throughput of 2.076 million metric tonnes in 2015 and is the busiest airport in Europe by cargo traffic. As of summer 2017, Frankfurt Airport serves more than 300 destinations in 5 continents, making it the airport with the most direct routes in the world.


title: Frankfurt Airport

text: The southern side of the airport ground was home to the Rhein-Main Air Base, which was a major air base for the United States from 1947 until 2005, when the air base was closed and the property was acquired by Fraport (now occupied by Terminal 3). The airport celebrated its 80th anniversary in July 2016.


title: Frankfurt Airport

text: Frankfurt Airport lies southwest of central Frankfurt, near the Autobahn intersection Frankfurter Kreuz, where two of the most heavily used motorways in Europe (A3 and A5) meet. The airport grounds, which form a city district of Frankfurt named Frankfurt-Flughafen, are surrounded by the Frankfurt City Forest. The southern portion of the airport grounds extend partially into the cities of Rüsselsheim am Main and Mörfelden-Walldorf, and a western portion of the grounds lie within the city of Kelsterbach.


title: Frankfurt Airport

text: The airport is centrally located in the Frankfurt/Rhine-Main region, Germany's third-largest metropolitan region, which itself has a central location in the densely populated region of the west-central European megalopolis. Thereby, along with a strong rail and motorway connection, the airport serves as a major transport node for the greater region, less than two hours by ground to Cologne, the Ruhr Area, and Stuttgart.


title: Frankfurt Airport

text: The base opened as a German commercial airport in 1936, with the northern part of the base used as a field for fixed-wing aircraft and the extreme southern part near Zeppelinheim serving as a base for rigid airships. That section of Rhein-Main later became the base for the Graf Zeppelin, its sister ship LZ-130, and, until 6 May 1937, for the ill-fated Hindenburg.


title: Frankfurt Airport

text: The airships were dismantled and their huge hangars demolished on 6 May 1940 during conversion of the base to military use. Luftwaffe engineers subsequently extended the single runway, and erected hangars and other facilities for German military aircraft. During World War II, the Luftwaffe used the field sporadically as a fighter base and as an experimental station for jet aircraft.


title: Frankfurt Airport

text: On 16 November 1909, the world's first airline was founded in Frankfurt am Main: The "Deutsche Luftschiffahrts-Aktiengesellschaft" (DELAG). DELAG then built the first airport in Frankfurt, called "Airship Base at Rebstock", which was located in Bockenheim in the western part of the city and was primarily used for airships in the beginning. It opened in 1912 and was extended after World War I, but in 1924, an expert's report already questioned the possibility of further expansions at this location.


title: Frankfurt Airport

text: With the foundation of Deutsche Luft Hansa in 1926, a rapid boom of civilian air travel started, and soon the airship base became too small to handle the demand. Plans for a new and larger airport located in the Frankfurt City Forest south-west of Schwanheim were approved in 1930 but were not realized due to the Great Depression. After the "Machtergreifung" in 1933, the government revived the plans and started the construction of the new airport.


title: Frankfurt Airport

text: A two-storey station building with a six-storey tower originated in 1935 on the northern part of the airport, as well as other operating and outbuildings for maintenance and storage of aircraft. The approximately 100 hectares runway received a grass cover.


title: Frankfurt Airport

text: The official opening of the new " Flug- und Luftschiffhafen Rhein-Main" took place on 8 July 1936. The first plane that landed was a Ju 52/3m. Six days later, on 14 July 1936, LZ 127 "Graf Zeppelin "landed at the airport. In 1936, 800 tons of cargo and 58,000 passengers were transported, and in 1937 these figures increased to 70,000 passengers and 966 tons of cargo. In the coming years, the new airport was the home base for the two largest German airships, LZ 127 "Graf Zeppelin "and LZ 129 "Hindenburg". In 1938, Frankfurt was a central distribution point for the transport of airmail to North America.


title: Frankfurt Airport

text: On 6 May 1937, the "Hindenburg, "flying from Frankfurt to New York, exploded shortly before it was scheduled to dock at Lakehurst. 36 people died. The accident marked the end of scheduled airship traffic and the end of the airship era.


title: Frankfurt Airport

text: After the beginning of World War II in 1939, all foreign airlines left the airport, and control of air traffic was transferred to the Luftwaffe. On 9 May 1940, the first bombers took off to attack France. From August to November 1944, a concentration camp was established in Walldorf, close to the airport site, where Jewish female prisoners were forced to work for the airport. The Allies of World War II destroyed the runway system with airstrikes in 1944, and the Wehrmacht blew up buildings and fuel depots in 1945, shortly before the US Army took control of the airport on 25 March 1945. After the German Instrument of Surrender, the war in Europe ended and the US Army started to build a new temporary runway at Frankfurt Airport. The southern part of the airport ground was occupied to build the Rhein-Main Air Base as an Air Force Base for the United States Air Forces in Europe.


title: Frankfurt Airport

text: In 1948, the Soviet Union blocked the Western Allies' rail and road access to the sectors of West Berlin under Allied control. Their aim was to force the western powers to allow the Soviet zone to start supplying Berlin with food and fuel, thereby giving the Soviets practical control over the entire city. In response, the Western Allies organised the Berlin Airlift to carry supplies via air to the people in West Berlin. The airports in Frankfurt, Hamburg and Hannover were the primary bases for Allied aircraft. The heavy use of these so-called "Raisin Bombers" caused damage to the runway in Frankfurt and forced the US Army to build a second parallel runway. The airlift ended in September 1949 after the Soviet Union ended their blockade.


title: Frankfurt Airport

text: In 1951, restrictions for German air travellers were lifted and civil air traffic started to grow again. In 1952, Frankfurt Airport handled more than 400,000 passengers; a year later it was more than half a million. About 100 to 120 aeroplanes took off from and landed in Frankfurt daily. In 1955, Lufthansa resumed flights to and from Frankfurt and in the same year the Federal Republic of Germany gained its air sovereignty back from the Allies. In 1957, the northern runway was extended, first to and then to , to make it compatible with jet aircraft.


title: Frankfurt Airport

text: The airport did not emerge as a major international airline hub until 1958 when a new passenger terminal called "Empfangsanlage Ost" (Terminal East, literally "Arrival Facility East") opened in the north-east corner of the airport site. Only four years later it was clear that the terminal was already too small for the demand. In 1961, Frankfurt already had 2.2 million passengers and 81,000 take-offs and landings, making it the second busiest airport in Europe behind Heathrow Airport, London.


title: Frankfurt Airport

text: In 1962, it was decided to build an even larger terminal with a capacity of 30 million passengers per year. Work on this terminal began in 1965. The southern runway was extended to in 1964. In 1970, a new hangar was inaugurated; this accommodated six jet aircraft and was the world's largest hangar at the time.


title: Frankfurt Airport

text: The new terminal, called "Terminal Mitte" (Central Terminal, today known as Terminal 1) is divided into three concourses (A, B and C) with 56 gates and an electric baggage handling system. Everything opened to the public on 14 March 1972. It was assumed that the terminal capacity would be sufficient for the next 30 years. Along with the new terminal a railway station (Frankfurt Airport station) was opened, the first airport railway station in the Federal Republic of Germany. A few days later the old "Empfangsanlage Ost" was closed.


title: Frankfurt Airport

text: Planning for a third runway (called "Startbahn 18 West") began in 1973. This project spawned massive protests by residents and environmentalists. The main points of conflict were increasing noise and pollution and the cutting down of protected trees in the Frankfurt City Forest. While the protests and related lawsuits were unsuccessful in preventing construction, the "Startbahn West" protests were one of the major crystallisation points for the German environmental movement of the 1980s. The protests even continued after the runway had been opened in 1984 and in 1987 two police officers were killed by a gunman. This incident ended the "Startbahn West" protests for good. Because of its orientation in the north–south direction, in contrast to the other east–west runways, the use of the third runway is limited. The Startbahn West can only be used for takeoffs to the south to avoid interference with air traffic on the other runways. Owing to this restriction the runway must be partially or fully closed when northward winds are too strong.


title: Frankfurt Airport

text: In 1990, work on a new terminal ("Terminal 2") began because it was anticipated that "Terminal Mitte" would reach its capacity limit sooner than expected. The new terminal, divided into concourses D and E, was built to the east of the existing terminal where once the "Empfangsanlage Ost" had been. With its opening in 1994, Frankfurt Airport increased its terminal capacity to 54 million passengers per year. Along with the terminal opening, a people mover system called "Sky Line" was established to provide a fast connection between "Terminal 2" and "Terminal Mitte" (now renamed "Terminal 1").


title: Frankfurt Airport

text: In 1999 a second railway station, primarily for InterCityExpress long-distance trains (called Frankfurt Airport long-distance station), opened near Terminal 1 as part of the new Cologne–Frankfurt high-speed rail line. At the same time local and regional rail services were based at the existing underground station, now renamed Frankfurt Airport regional station.


title: Frankfurt Airport

text: On 30 December 2005, the Rhein-Main Air Base in the southern part of the airport ground was closed and the US Air Force moved to Ramstein Air Base. The property was handed back to Fraport which allows the airport to use it to build a new passenger terminal. The property of the housing area for the soldiers, called "Gateway Gardens", which was located north-east of the airport site, was given back to the city of Frankfurt in the same year and will be developed as a business district in the following years.


title: Frankfurt Airport

text: From 2005 to 2007, a large Airbus A380 maintenance facility was built at Frankfurt Airport because Lufthansa wanted to station their future A380 aircraft fleet there. Both terminals also underwent major renovations in order to handle the A380, including the installation of a third boarding bridge at several gates. Lufthansa's first Airbus A380 went into operation in June 2010 and was named "Frankfurt am Main".


title: Frankfurt Airport

text: In 2011, a large office building called "The Squaire" (a blend of "square" and "air") opened at Frankfurt Airport. It was built on top of the Airport long-distance station and is considered the largest office building in Germany with floor area. Main tenants are KPMG and two Hilton Hotels.


title: Frankfurt Airport

text: Since 2012, the people mover "The Squaire Metro" connects the Squaire with the nine-storey parking structure. On a length of about 300 metres the so-called MiniMetro system with its two cabins can carry up to 1,300 passengers per hour. The constructor of the system was the Italian manufacturer Leitner.


title: Frankfurt Airport

text: Plans to build a fourth runway at Frankfurt Airport were underway in 1997, but owing to violent conflicts with the concept Fraport let residents' groups and environmentalists participate in the process to find a mutually acceptable solution. In 2000, a task force presented their conclusion which generally approved a new runway, but of shorter length (only 2.8 kilometres compared to the other three 4-kilometre-long runways), which would serve as a landing-only runway for smaller aircraft. Additional requirements included improved noise protection arrangements and a strict ban on night flights between 11 pm and 5 am across the whole airport. In 2001, Fraport applied for approval to build the new runway, with three possible options. The conclusion was that a runway north-west of the airport site would have the least impact on local residents and the surrounding environment. The plans were approved by the Hessian government in December 2007, but the requested ban on night flights was lifted because it was argued that an international airport like Frankfurt would need night flights, especially for worldwide freight transport. Construction of the new long "Runway Northwest" in the Kelsterbach Forest began in early 2009.


title: Frankfurt Airport

text: In 2012, the website "Airport Watch" reports weekly protests have been occurring at the airport since the opening of a fourth runway a year previously.


title: Frankfurt Airport

text: The new runway officially went into operation on 20 October 2011, with an aircraft carrying Chancellor Angela Merkel, performing the first landing on 21 October. The centre line separation from the existing north runway is about . This allows simultaneous instrument landing system (ILS) operations on these two runways, which has not been possible on the other parallel runways, which do not meet the minimum separation for ILS operations. This allowed the airport to increase its capacity from 83 to 126 aircraft movements per hour.


title: Frankfurt Airport

text: On 11 October 2011, the Hessian Administration Court ruled that night flights between 11pm and 5am (the so-called "Mediationsnacht") are no longer allowed at Frankfurt Airport after the inauguration of the new runway, and therefore overrode the approval from the Hessian government from 2007 which allowed 17 scheduled flights per night. On 4 April 2012, the German Administrative Court confirmed the decision of the Hessian Administration Court, banning night flights between 11pm and 5am.


title: Frankfurt Airport

text: To handle the predicted passenger amount of about 90 million in 2020, a new terminal section adjacent to Terminal 1 for an additional six million passengers opened on 10 October 2012. It is called "Flugsteig A-Plus" and exclusively used by Lufthansa mainly for their long-haul flights. Flugsteig A-Plus features eight parking positions that are able to handle four Airbus A380s or seven Boeing 747-8/747-400 at once.


title: Frankfurt Airport

text: In November 2016, Ryanair announced the opening of a new base at Frankfurt Airport with four routes to Spain and Portugal. This move by Ryanair was heavily blasted, especially by Lufthansa, as Ryanair was granted high discounts and incentives regarding the airport's fees. On 28 February 2017, Ryanair announced its winter programme for Frankfurt which will see a further 20 new routes being added.


title: Frankfurt Airport

text: Albanian citizen, Arid Uka, a 21 year old at the time, targeted a United States Air Force bus parked outside the terminal building that was supposed to transport fifteen U.S. airmen to Ramstein Air Base. He reportedly walked up to a waiting airman, asked him for a cigarette, and wanted to know whether the airmen were bound for Afghanistan. When the airman said yes, according to German prosecutor Rainer Griesbaum, Uka waited for the airman to turn away and then shot him in the back of the head, killing him. Shouting "Allahu Akbar!" the attacker then entered the bus, shooting and killing the driver, and continued to fire three shots at two other airmen, wounding them. When he pointed his pistol at the head of another airman and pulled the trigger, the weapon jammed. Uka fled, but was pursued by the civilian airport employee Lamar Joseph Conner and Staff Sergeant Trevor Donald Brewer and shortly afterwards overpowered by two German police officers. He was subsequently arrested. Conner and Brewer later received the Order of Merit of the Federal Republic of Germany in a ceremony on 16 January 2012. Federal Interior Minister Hans-Peter Friedrich presented the decoration, citing their "exemplary courage and action which helped the Federal Police arrest the suspect". Uka was sentenced to Life and will be deported.


title: Frankfurt Airport

text: Portions of the airport were closed in early 2020 due to the COVID-19 pandemic. The Northwest Runway and Runway 18 West were closed on March 23 and re-purposed for parking unused aircraft. Terminal 2 was also closed, and all passenger operations were concentrated in Terminal 1. The Northwest Runway re-opened in July to handle summer tourist demand, while Runway 18 West remained closed. With almost no passenger traffic in the spring months, Frankfurt's total passenger volume in 2020 fell to 18.8 million, the lowest figure recorded since 1984.


title: Frankfurt Airport

text: Frankfurt Airport has two large main passenger terminals (1 and 2) and a much smaller dedicated First Class Terminal which is operated and exclusively used by Lufthansa. As is the case at London–Heathrow, Tokyo–Narita, Toronto–Pearson and Chicago–O'Hare's future Global Terminal, terminal operations are grouped for airlines and airline alliances rather than into domestic and international routes.


title: Frankfurt Airport

text: Terminal 1 is the older and larger one of the two passenger terminals. The landside is 420 metres long. It has been enlarged several times and is divided into concourses "A", "B", "C" and "Z" and has a capacity of approximately 50 million passengers per year. Terminal 1 is functionally divided into three levels, the departures level on the upper floor with check-in counters, the arrivals level with baggage claim areas on the ground floor and, underneath, a distribution floor with access to the regional station and underground and multilevel parking. Departures and arrivals levels each have separate street approaches. A bus station is located at arrivals level. Terminal 1 has a total of 103 gates, which include 54 gates equipped with jetways (25 in Concourse A, 18 in Concourse B, 11 in Concourse C). Concourse "Z" sits on top of Concourse "A" sharing the same jet bridges between both concourses. Flights to non-Schengen destinations depart from the "Z" gates and Schengen flights depart from the "A" gates.


title: Frankfurt Airport

text: Pier A was extended by 500 metres in 2000, and a link between Terminal 1 and Terminal 2, as well as the Hall C extension opened in 2008.


title: Frankfurt Airport

text: On 10 October 2012, an 800-metre-long westward expansion of Terminal 1 called "Pier A-Plus" went into operation. It provides more stands for wide-body aircraft like the Airbus A380.


title: Frankfurt Airport

text: Terminal 1 is primarily used by Lufthansa, its associated companies (Brussels Airlines, Eurowings, Swiss International Air Lines and Austrian Airlines) and its Star Alliance partners (e.g. Aegean Airlines, Air Canada, Air China, Air India, All Nippon Airways, Asiana Airlines, Croatia Airlines, Egyptair, Ethiopian Airlines, LOT Polish Airlines, Scandinavian Airlines, Singapore Airlines, South African Airways, TAP Air Portugal, Thai Airways International, Turkish Airlines and United Airlines).


title: Frankfurt Airport

text: Some airlines that are not part of the Lufthansa Group or Star Alliance also use Terminal 1. They include Air Malta, Bulgaria Air, Iran Air, Oman Air and Tunisair among others.


title: Frankfurt Airport

text: Terminal 2, which has a capacity of 15 million passengers a year, was opened in 1994 and is divided into concourses "D" and "E". A continuous concourse between Terminal 1C and 2D provides direct, but non-public access between the two terminals. It has eight gates with jetways and 34 apron stands, a total of 42 gates and is able to handle wide-body aircraft such as the Airbus A380.


title: Frankfurt Airport

text: Terminal 2 is primarily used by airlines of the oneworld (e.g. American Airlines, British Airways, Cathay Pacific, Finnair, Iberia, Japan Airlines, Qatar Airways, Royal Air Maroc, Royal Jordanian and S7 Airlines (suspended)) and SkyTeam alliances (e.g. Aeroflot (currently suspended), Air France, China Airlines, China Eastern Airlines, Czech Airlines, Delta Air Lines, KLM, Korean Air, Saudia, TAROM and Vietnam Airlines; SkyTeam member Middle East Airlines operates out of Terminal 1, in concourses B and C).


title: Frankfurt Airport

text: Terminal 2 is also used by airlines that do not belong to any of the three major airline alliances, including Air Moldova, Air Serbia, China Southern Airlines, Emirates, Kuwait Airways, LATAM Airlines, and Somon Air, among others.


title: Frankfurt Airport

text: Fraport announced in late 2022 that Terminal 2 will be closed for refurbishment in 2026 until at least 2029. All tennants are to be relocated into the then fully completed Terminal 3.


title: Frankfurt Airport

text: Passengers and visitors can change terminals with the people mover system SkyLine which has three stops in Terminal 1 (at gates AZ, B and C) as well as one in Terminal 2 for all gates. Some stops can only be used by passengers in or outside the Schengen zone which is achieved by separated cars and station entrances. The travel time between the terminals is 2 minutes with trains arriving every 2–3 minutes during the day. Each train has two cars, one airside (outside the Schengen area) and one landside (within the Schengen area). Most stations have a platform on each side of the train, so landside passengers can only step out onto the landside platform, and airside passengers can only step out onto the airside platform. Additionally there is regular bus service between the terminals.


title: Frankfurt Airport

text: Frankfurt Airport has four runways of which three are arranged parallel in east–west direction and one in north–south direction. In 2010 three runways (Runways North, South and West) handled 464,432 aircraft movements, which equated to 83 movements per hour. With the start of operation of the Northwest Runway in October 2011 the airport was predicted to be able to handle 126 movements per hour. It is predicted that aircraft movements will increase up to 700,000 in the year 2020. By using the fourth runway, Frankfurt Airport is able for the first time to handle simultaneous parallel landings, because the distance between the north and the north-west runways is . Simultaneous parallel landings were not possible with the north and south runway pairing, because the separation distance did not meet the safety standards.


title: Frankfurt Airport

text: During normal operation the two outer parallel runways (07L/25R and 07R/25L) are used for landings and the central parallel runway (07C/25C) and the Runway West (18) for take-offs. The three parallel runways have two markings because they can be operated in two directions while the Runway West can only be used in one direction.


title: Frankfurt Airport

text: In 2009, the German government decided to create third terminals for both Frankfurt Airport and Munich Airport in order to handle expected passenger flows of 90 million in Frankfurt by 2020 and 50 million in Munich by 2017. The new terminal is scheduled to be built by Fraport, south of the existing terminals on the grounds of the former Rhein-Main Air Base. The new "Terminal 3" is to accommodate up to 25 million passengers and will feature 75 new aircraft positions when completely constructed. An extension of the "SkyLine" people mover system is planned to connect the new terminal to Terminals 1 and 2 and the airport train stations.


title: Frankfurt Airport

text: In August 2014, the city of Frankfurt granted building permission for the first phase of Terminal 3. The groundbreaking for the new terminal took place on 5 October 2015. Its first phase, consisting of the main building and two of the planned four piers (concourses 3H and 3J), is planned to open by 2026 and will be able to handle 15 million additional passengers per year. Total costs are estimated at 3 billion euros.


title: Frankfurt Airport

text: In 2017, Frankfurt Airport first indicated that the second-phase construction of the easternmost pier (concourse 3G) could be moved forward so that low-cost carriers can use this pier from 2021. After approval by municipal authorities in 2018, the piers will be constructed and used according to the following timetable:


title: Frankfurt Airport

text: Due to the COVID-19 pandemic, Fraport postponed the opening of the new terminal to 2026 in March 2021.


title: Frankfurt Airport

text: Check-in area, concourses 3H and 3J (central piers): Construction by 2023 including transport systems for visitors, passengers and luggage to the other terminals


title: Frankfurt Airport

text: Concourse 3K (westernmost pier): Possible third-phase expansion depending on development of passenger numbers


title: Frankfurt Airport

text: A new passenger transport system is planned for the connection of the new terminal 3 and the existing terminals 1 and 2. It will use a track which is separate from the existing SkyLine people mover but will allow for interchanges between them. It is scheduled to have four stops in the final stage near the airport's two railway stations, at Terminals 1C and 2DE as well as the new Terminal 3.


title: Frankfurt Airport

text: Lufthansa and their Star Alliance partners account for the majority of all traffic at Frankfurt Airport. The following airlines offer year-round and seasonal scheduled and charter flights at Frankfurt Airport:


title: Frankfurt Airport

text: Frankfurt Airport is the second-largest multimodal transport airport in Europe and has several logistics facilities. These facilities are grouped at two areas at the airport ground: In the north (CargoCity Nord) and in the south (CargoCity Süd). In 2010 it was the second-busiest airport by cargo traffic in Europe after Paris–Charles de Gaulle Airport, handling 2,231,348 metric tonnes of loaded and unloaded freight. CargoCity is the name of the two large main areas featuring most of the airport's freight handling facilities:


title: Frankfurt Airport

text: The airport ground and the surrounding area of Frankfurt Airport offer a large variety of on-airport businesses as well as airport-related businesses, including office space, hotels, shopping areas, conference rooms and car parks. The development of an airport city has significantly accelerated in recent years.


title: Frankfurt Airport

text: The Frankfurt Airport Centre 1 (FAC 1) near Terminal 1 offers office and conference facilities, the newer FAC 2 is located within Terminal 2 and offers office space for airlines.


title: Frankfurt Airport

text: The Airport City Mall is located on the landside of Terminal 1, departure hall B. It offers national and international retailers and label stores, a supermarket and several restaurants.


title: Frankfurt Airport

text: The Squaire is an office building with a total floor area of . It is directly connected to Terminal 1 through a connecting corridor for pedestrians. The accounting firm KPMG, Lufthansa and two Hilton Hotels ("Hilton Garden Inn Frankfurt Airport" with 334 rooms and Hilton Frankfurt Airport with 249 rooms) occupy space in The Squaire.


title: Frankfurt Airport

text: The Main Airport Centre, named after the Main river, is an office building with ten floors and about of office space. It is located at the edge of the Frankfurt City Forest near Terminal 2.


title: Frankfurt Airport

text: Sheraton Hotels and Resorts offers 1,008 guest rooms adjacent to Terminal 1 and a conference centre for up to 200 delegates.


title: Frankfurt Airport

text: Gateway Gardens is a former housing area for the US Air Force personnel based at the Rhein-Main Air Base, close to Terminal 2. Like the air base, the housing area was closed in 2005. Since then the area is being developed into a business location for airport-related companies. Lufthansa moved its airline catering subsidiary LSG Sky Chefs to Gateway Gardens, Condor and SunExpress are headquartered here. DB Schenker, the logistics company of Deutsche Bahn, have built a high-rise building.


title: Frankfurt Airport

text: In December 2019, local trains were re-routed to run via Gateway Gardens station. The new stop for S-Bahn trains is located between Frankfurt Airport Regional Station and Frankfurt-Stadion station. The journey time will increase by 4 minutes but Deutsche Bahn have stated that they will use new trains (ET423) which will be faster and have more capacity.


title: Frankfurt Airport

text: Frankfurt Airport can easily be accessed by car, taxi, train or bus as it features an extensive transport network. There are two railway stations at the airport: one for suburban/regional trains and one for long-distance trains.


title: Frankfurt Airport

text: Frankfurt Airport regional station ("Frankfurt Flughafen Regionalbahnhof") at Terminal 1, concourse B, provides access to the S-Bahn commuter rail lines "S8" and "S9". Each of these lines have trains departing every 15 minutes during daytime to Hanau Central Station eastwards via Frankfurt Central Station and Offenbach East Station or Wiesbaden Central Station westwards via Rüsselsheim or Mainz Central Station (line S8) or Mainz-Kastel Station (line S9).


title: Frankfurt Airport

text: Regional Express (RE) trains to Saarbrücken, Koblenz or Würzburg call at this station. These trains provide less frequent but additional connections between Frankfurt Airport and the Central Station.


title: Frankfurt Airport

text: Frankfurt Airport long-distance station ("Frankfurt Flughafen Fernbahnhof") was opened in 1999. The station is squeezed in between the motorway A 3 and the four-lane "Bundesstraße" B43, linked to Terminal 1 by a connecting corridor for pedestrians that bridges the Autobahn. It is the end point of the newly built Cologne–Frankfurt high-speed rail line, which links southern Germany to the Rhine-Ruhr metropolitan area, the Netherlands and Belgium via Cologne at speeds up to . About 10 trains per hour depart in all directions.


title: Frankfurt Airport

text: Deutsche Bahn operates the AIRail Service in conjunction with Lufthansa, American Airlines and Emirates. The service operates to the central stations of Bonn, Cologne, Düsseldorf, Freiburg, Karlsruhe, Leipzig, Hamburg, Hannover, Mannheim, Munich, Nuremberg, Stuttgart and to Kassel-Wilhelmshöhe.


title: Frankfurt Airport

text: Frankfurt Airport is located in the Frankfurt City Forest and directly connected to an Autobahn intersection called Frankfurter Kreuz where the A3 and A5 meet. It takes a 10–15 minutes by car or taxi to get to Frankfurt Central Station or the centre of the city.


title: Frankfurt Airport

text: Passengers driving their own cars can park in multilevel parking garages (mostly underground) along the terminals. A long term holiday parking lot is located south of the runways and connected by shuttle bus to the terminals.


title: Frankfurt Airport

text: Terminal 1 and Terminal 2 can be reached by bicycle because one of the roads that run north of the airport passing the terminals can legally be used by bicycle. The airport authority has confirmed that the newly built terminal 3 will also be reachable by bicycle.


title: Frankfurt Airport

text: Various transport companies provide bus services to the airport from the surrounding areas as well as by coach to long-distance destinations.


title: Frankfurt Airport

text: Previously All Nippon Airways operated a bus service to Düsseldorf exclusively for ANA customers; that way Düsseldorf passengers would be transported to Frankfurt Airport to board their ANA flights. In 2014 ANA established a separate flight from Tokyo to Düsseldorf, causing the bus services to end.


title: Frankfurt Airport

text: In 2006, 29.5% of the 12,299,192 passengers whose air travel originated in Frankfurt came by private car, 27.9% came by rail, 20.4% by taxi, 11.1% parked their car at the airport for the duration of their trip, 5.3% came by bus, and 4.6% arrived with a rental car.


title: Frankfurt Airport

text: Frankfurt Airport is featured in the Discovery Channel series "X-Ray Mega Airport" (also known as "Inside Frankfurt Airport").


title: Frankfurt Airport

text: Jinder Mahal pinned R-Truth at the Frankfurt Airport for the 24/7 Championship. This title change was shown on WWE.com and WWE's official social media accounts.


title: The Other Woman (2014 film)

text: The Other Woman is a 2014 American romantic comedy film directed by Nick Cassavetes, written by Melissa Stack, and starring Cameron Diaz, Leslie Mann, Kate Upton, Nikolaj Coster-Waldau, Nicki Minaj, Taylor Kinney, and Don Johnson. The film follows three womenCarly (Diaz), Kate (Mann), and Amber (Upton)who are all romantically involved with the same man (Coster-Waldau). After finding out about each other, the trio take their revenge on him.


title: The Other Woman (2014 film)

text: Development of "The Other Woman" began in January 2012, when 20th Century Fox hired Stack to write the script, based on the original idea from 1996 comedy "The First Wives Club". Casting was done between November 2012 and June 2013. Filming began on April 29, 2013, in locations including Manhattan, Long Island, the Hamptons, Dockers Waterside Restaurant on Dune Road in Quogue, and the Bahamas, and it concluded on August 27 that year. Aaron Zigman composed the score and LBI Productions produced the film. The film was released on April 25, 2014, in the United States, and distributed worldwide by 20th Century Fox. The film received mostly negative reviews from critics, but was a box office success, grossing $196.7 million worldwide.


title: The Other Woman (2014 film)

text: Carly Whitten (Cameron Diaz), a New York attorney, is dating handsome and charismatic businessman Mark King (Nikolaj Coster-Waldau), with whom she has been having sex for two months. Carly plans to introduce Mark to her father Frank (Don Johnson) over dinner, only for Mark to cancel on them and go out of town because of a "flood" at his Connecticut home. Encouraged by Frank, Carly dresses up in a sexy plumber's outfit and heads to Mark's house to seduce him. However, she is horrified to be met at the door by Mark's wife Kate (Leslie Mann), whom she had assumed to be Mark's housekeeper. Thrown for a loop by this revelation, Carly accidentally breaks one of Kate's garden urns, and flees in embarrassment and shock.


title: The Other Woman (2014 film)

text: The next day, Kate shows up at Carly's law firm, having found her contact details in Mark's phone book. Carly admits to a panicked Kate that Mark has been cheating on her, but assures her she had no idea Mark was married. Initially annoyed by her constant presence at her apartment or work, Carly begins to warm up to Kate after a wild sleepover and a boozy heart-to-heart. Kate discovers that Mark is seeing yet another woman, who she thinks is Carly secretly continuing her previous relationship with Mark. Confronting Carly about this, they argue before realizing that Mark is seeing a third woman as both Carly and Kate have been refusing sex with him.


title: The Other Woman (2014 film)

text: Carly and Kate follow Mark to the Hamptons, where they stay at the house of Kate's brother Phil (Taylor Kinney), who is immediately attracted to Carly. The duo spies on Mark and find him with his mistress Amber (Kate Upton), a beautiful swimsuit supermodel, on the beach. When Mark leaves for the gym, they inform Amber that Mark has been cheating on all of them.


title: The Other Woman (2014 film)

text: All three women decide to get revenge on him together. Kate spikes his smoothies with estrogen pills to swell his nipples, has their dog licking his toothbrush before soaking it in their toilet, and adds hair-removal cream to his shampoo. Carly spikes his water with a laxative to give him heavy diarrhea. Amber uses an ugly drag queen sexual partner against him.


title: The Other Woman (2014 film)

text: While carrying out the various pranks, they discover Mark has been embezzling money from various startup companies his workplace helps to develop. Meanwhile, Carly begins to connect romantically and feel a bond with Phil. The women's camaraderie begins to fall apart when Kate finds herself still in love with Mark after caving in and having sex with him. Carly exposes Mark's fraud before texting him, upsetting Kate and Amber.


title: The Other Woman (2014 film)

text: Later, Mark goes to the Bahamas on a supposed business trip and Kate decides to follow and expose him. When she arrives she is surprised to find Carly and Amber waiting for her. They explain that Mark has set up Kate as the owner of the companies he defrauded, which, if his fraud is discovered, would result in Kate going to prison rather than him. She also finds out he has been seeing yet another woman, someone he has met on this trip. This, and the possibility of her facing prison, motivates her to take action, with the help of Carly's legal expertise. Amber confides to Carly that she is seeing someone else too.


title: The Other Woman (2014 film)

text: When Mark returns from the trip, he visits Carly at her office. He is locked in a conference room by her assistant and friend Lydia (Nicki Minaj) and is stunned to see his wife, his girlfriend, and his summer fling sitting there all together. They proceed to confront him with his infidelities and embezzlement. With Carly as her attorney, Kate presents divorce papers and a list of their assets. She reveals how she, named CEO by Mark, has returned all of his embezzled money to the companies from which he stole it, saving them both from jail time as well as bankrupting Mark, much to his shock and hysterical outrage. Mark's former business partner Nick (David Thornton) then arrives and acknowledges Kate's work while firing him. Everyone watches in amusement as a furious Mark accidentally smashes into an empty room's glass paneling, drastically hurting his nose and ripping his coat, as he begins to look destitute. He exits to find his car being towed for being near the red zone before receiving a departing punch in the face from Frank as payback. Some time later, Carly, Kate, and Amber happily toast to their friendship, promising to never sleep with the same guy ever again.


title: The Other Woman (2014 film)

text: In the postscript, Carly and Phil move in together and Carly gets pregnant with Phil's child. Kate takes over Mark's job with Nick and becomes CEO of several successful companies, making big profits under her honest leadership. It is revealed Frank was the guy Amber had started seeing and the two are traveling the world together.


title: The Other Woman (2014 film)

text: On January 16, 2012, it was announced that 2007 Black Listed screenwriter Melissa Stack was hired by 20th Century Fox to write an untitled female revenge comedy, which Julie Yorn would produce through LBI Productions. The film's script was described as the original idea from the 1996 film "The First Wives Club", but with younger leads. The film's title was revealed to be "The Other Woman" on November 13. In January of the following year, Nick Cassavetes signed on to direct the film.


title: The Other Woman (2014 film)

text: In November 2012, Cameron Diaz was in talks for the lead role. Diaz's representative also revealed that actress Kristen Wiig was under consideration for the wife role. In March 2013, Leslie Mann and Nikolaj Coster-Waldau were in talks to join the film, and Diaz was confirmed for her role. The following month, Kate Upton, Taylor Kinney, and Nicki Minaj, in her feature film debut, joined the film. Don Johnson was cast in June as Diaz's character's father.


title: The Other Woman (2014 film)

text: In March 2013, the shooting was set to begin late-spring or early summer 2013 in New York City. Later it was told that the production would begin in May 2013. Principal photography began on April 29, 2013, and filming was completed by August 27, 2013. Much of the filming took place in parts of New York, including Long Island, The Hamptons, and Westhampton Beach. From July 18 to 23, filming took place in New Providence, where Nassau, The Bahamas, was used as the filming location. The Atlantis Paradise Island was also used as the shooting location. Isola Trattoria and Crudo Bar at Mondrian Hotel in SoHo, Manhattan, was used for the scene in which the women meet for a celebration toast at the end of the film.


title: The Other Woman (2014 film)

text: "The Other Woman"s music was composed by Aaron Zigman, who was reportedly set to score the film on May 31, 2013. The film featured songs from various artists including Etta James, Ester Dean, Morcheeba, Cyndi Lauper, Britt Nicole, Patty Griffin, Lorde, Keyshia Cole and Iggy Azalea.


title: The Other Woman (2014 film)

text: On March 31, 2014, the film had a world premiere in Amsterdam; the next day, on April 1, it had a UK premiere at the Curzon Mayfair Cinema in London. The film later had a US premiere on April 21 in Westwood, California.


title: The Other Woman (2014 film)

text: On March 25, 2014, Fox appealed the R-rating, which Motion Picture Association of America gave the film for sexual references. The studio wanted a PG-13 rating. On April 9, the MPAA's rating appeals board took back the R and gave the film a PG-13; the sources confirmed that there were no changes made to get the film PG-13. "The Other Woman" was released on April 25 in the United States.


title: The Other Woman (2014 film)

text: "The Other Woman" opened at number 1 in North America on April 25, 2014, in 3,205 theaters debuting atop the weekend box office with earnings of $24.7 million across the three days. The film grossed $83.9 million in the United States and Canada and $112.8 million in other territories for a total worldwide gross of $196.7 million, against a production budget of $40 million.


title: The Other Woman (2014 film)

text: "The Other Woman" was released on DVD and Blu-ray on July 29, 2014. The Blu-ray edition features a gag reel, giggle fits, a gallery and deleted scenes. In the United States, the film has grossed $9,592,336 from DVD sales and $4,163,463 from Blu-ray sales, making a total of $13,755,799.


title: The Other Woman (2014 film)

text: , "The Other Woman" holds a 25% approval rating on Rotten Tomatoes, based on 164 reviews with an average rating of 4.24/10. The site's critical consensus reads, ""The Other Woman" definitely boasts a talented pedigree, but all that skill is never fully brought to bear on a story that settles for cheap laughs instead of reaching its empowering potential." On Metacritic, the film has a score of 39 out of 100 based on reviews from 35 critics, indicating "generally unfavorable reviews". Audiences polled by CinemaScore gave the film an average grade of "B+" on an A+ to F scale.


title: The Other Woman (2014 film)

text: Justin Chang of "Variety" said, "Beneath the wobbly pratfalls and the scatological setpieces, there's no denying the film's mean-spirited kick, or its more-than-passing interest in what makes its women tick." "The Hollywood Reporter's" critic Todd McCarthy said: "It would have helped if director Nick Cassavetes had something resembling a sure hand at comedy." Ignatiy Vishnevetsky of "The A.V. Club" gave the film grade C−, saying "All of a sudden, a spotted Great Dane squats in the middle of a Manhattan apartment and out plop several gleaming, glistening CGI turds. It's one of those cases where a Hollywood movie inadvertently summarizes itself in a single shot." Michael Phillips of "Chicago Tribune" gave the film two and a half stars out of four, saying "Line to line, it's fresher than any number of guy-centric "Hangover"-spawned affairs, despite director Cassavetes' lack of flair for slapstick." "The Boston Globe's" Ty Burr gave the film one out of four stars and said, "It's 'The First Wives Club' rewritten for younger, less demanding audiences, or a '9 to 5' with absolutely nothing at stake." Stephanie Zacharek of "The Village Voice" said, "The Other Woman doesn't give these actresses much to do except look ridiculous, if not sneaky and conniving."


title: The Other Woman (2014 film)

text: Michael Sragow of "Orange County Register" gave the film grade C, saying that the film is "a coarse, rickety comedy." Richard Corliss wrote for "Time" magazine that "All three women are less watchable and amusing than Nicki Minaj as Carly's legal assistant Lydia." Film critic Stephen Holden of "The New York Times" said that the film is "so dumb, lazy, clumsily assembled and unoriginal, it could crush any actor forced to execute its leaden slapstick gags and mouth its crude, humorless dialogue." James Berardinelli of "ReelViews" wondered, "Has it come to this for director Nick Cassavetes?", comparing his career negatively to that of his father, John Cassavetes. Berardinelli elaborated, "what a comedown to find him in charge of such an unfocused, unfunny, scatologically-obsessed 'comedy.'" Christy Lemire of "RogerEbert.Com" gave the film two out of four stars and said, "While "The Other Woman" raises some thoughtful questions about independence, identity and the importance of sisterhood, ultimately it would rather poop on them and then throw them through a window in hopes of the getting the big laugh." Wesley Morris of "Grantland" said, "No one knows which takes are funny and which aren't. More than once, all three women, especially poor Upton, are caught looking like they don't know what they're doing."


title: The Other Woman (2014 film)

text: Bilge Ebiri of the magazine "New York" said, "You can't shake the feeling that in a just world, all these women – even Kate Upton – would have better material than this." Connie Ogle of "The Miami Herald" gave the film three out of four stars and called the film a "goofy, ridiculous, with more gross-out humor than is strictly necessary but still funny. It falls into the category of Girlfriend Films – as in, go with your girlfriends and leave your date/partner/spouse at home with the PlayStation or the NBA playoffs." Colin Covert of "Star Tribune" gave the film three out of four stars, saying "It's an escapist women's empowerment comedy like many others, but elevated by the simple virtue of being, for most of its length, very, very funny." Ann Hornaday of "The Washington Post" gave the film one and a half stars out of four, saying "A movie as generic and forgettable as the sofa-size art on its characters' walls." Linda Holmes wrote for "NPR", calling the film "a conceptually odious, stupid-to-the-bone enterprise ..." Betsy Sharkey of the "Los Angeles Times" advised guys to "Step away from the vehicle, because "The Other Woman" is out of control and intent on running down a certain kind of male."


title: Basal ganglia

text: The basal ganglia (BG), or basal nuclei, are a group of subcortical nuclei, of varied origin, in the brains of vertebrates. In humans, and some primates, there are some differences, mainly in the division of the globus pallidus into an external and internal region, and in the division of the striatum. The basal ganglia are situated at the base of the forebrain and top of the midbrain. Basal ganglia are strongly interconnected with the cerebral cortex, thalamus, and brainstem, as well as several other brain areas. The basal ganglia are associated with a variety of functions, including control of voluntary motor movements, procedural learning, habit learning, conditional learning, eye movements, cognition, and emotion.


title: Basal ganglia

text: The main components of the basal ganglia – as defined functionally – are the striatum, consisting of both the dorsal striatum (caudate nucleus and putamen) and the ventral striatum (nucleus accumbens and olfactory tubercle), the globus pallidus, the ventral pallidum, the substantia nigra, and the subthalamic nucleus. Each of these components has a complex internal anatomical and neurochemical organization. The largest component, the striatum (dorsal and ventral), receives input from many brain areas beyond the basal ganglia, but only sends output to other components of the basal ganglia. The globus pallidus receives input from the striatum, and sends inhibitory output to a number of motor-related areas. The substantia nigra is the source of the striatal input of the neurotransmitter dopamine, which plays an important role in basal ganglia function. The subthalamic nucleus receives input mainly from the striatum and cerebral cortex and projects to the globus pallidus.


title: Basal ganglia

text: Popular theories implicate the basal ganglia primarily in action selection – in helping to decide which of several possible behaviors to execute at any given time. In more specific terms, the basal ganglia's primary function is likely to control and regulate activities of the motor and premotor cortical areas so that voluntary movements can be performed smoothly. Experimental studies show that the basal ganglia exert an inhibitory influence on a number of motor systems, and that a release of this inhibition permits a motor system to become active. The "behavior switching" that takes place within the basal ganglia is influenced by signals from many parts of the brain, including the prefrontal cortex, which plays a key role in executive functions. It has also been hypothesized that the basal ganglia are not only responsible for motor action selection, but also for the selection of more cognitive actions. Computational models of action selection in the basal ganglia incorporate this.


title: Basal ganglia

text: The basal ganglia are of major importance for normal brain function and behaviour. Their dysfunction results in a wide range of neurological conditions including disorders of behaviour control and movement, as well as cognitive deficits that are similar to those that result from damage to the prefrontal cortex. Those of behaviour include Tourette syndrome, obsessive–compulsive disorder, and addiction. Movement disorders include, most notably Parkinson's disease, which involves degeneration of the dopamine-producing cells in the substantia nigra; Huntington's disease, which primarily involves damage to the striatum; dystonia; and more rarely hemiballismus. The basal ganglia have a limbic sector whose components are assigned distinct names: the nucleus accumbens, ventral pallidum, and ventral tegmental area (VTA). There is considerable evidence that this limbic part plays a central role in reward learning as well as cognition and frontal lobe functioning, via the mesolimbic pathway from the VTA to the nucleus accumbens that uses the neurotransmitter dopamine, and the mesocortical pathway. A number of highly addictive drugs, including cocaine, amphetamine, and nicotine, are thought to work by increasing the efficacy of this dopamine signal. There is also evidence implicating overactivity of the VTA dopaminergic projection in schizophrenia.


title: Basal ganglia

text: In terms of development, the human central nervous system is often classified based on the original three primitive vesicles from which it develops: These primary vesicles form in the normal development of the neural tube of the embryo and initially include the prosencephalon, mesencephalon, and rhombencephalon, in rostral to caudal (from head to tail) orientation. Later in development of the nervous system each section itself turns into smaller components. During development, the cells that migrate tangentially to form the basal ganglia are directed by the lateral and medial ganglionic eminences. The following table demonstrates this developmental classification and traces it to the anatomic structures found in the basal ganglia. The structures relevant to the basal ganglia are shown in bold.


title: Basal ganglia

text: The basal ganglia form a fundamental component of the cerebrum. In contrast to the cortical layer that lines the surface of the forebrain, the basal ganglia are a collection of distinct masses of gray matter lying deep in the brain not far from the junction of the thalamus. They lie to the side of and surround the thalamus. Like most parts of the brain, the basal ganglia consist of left and right sides that are virtual mirror images of each other.


title: Basal ganglia

text: In terms of anatomy, the basal ganglia are divided into four distinct structures, depending on how superior or rostral they are (in other words depending on how close to the top of the head they are): Two of them, the striatum and the pallidum, are relatively large; the other two, the substantia nigra and the subthalamic nucleus, are smaller. In the illustration to the right, two coronal sections of the human brain show the location of the basal ganglia components. Of note, and not seen in this section, the subthalamic nucleus and substantia nigra lie farther back (posteriorly) in the brain than the striatum and pallidum.


title: Basal ganglia

text: The striatum is a subcortical structure generally divided into the dorsal striatum and ventral striatum, although a medial lateral classification has been suggested to be more relevant behaviorally and is being more widely used.


title: Basal ganglia

text: The striatum is composed mostly of medium spiny neurons. These GABAergic neurons project to the external (lateral) globus pallidus and internal (medial) globus pallidus as well as the substantia nigra pars reticulata. The projections into the globus pallidus and substantia nigra are primarily dopaminergic, although enkephalin, dynorphin and substance P are expressed. The striatum also contains interneurons that are classified into nitrergic neurons (due to use of nitric oxide as a neurotransmitter), tonically active (i.e. constantly releasing neurotransmitter unless inhibited) cholinergic interneurons, parvalbumin-expressing neurons and calretinin-expressing neurons. The dorsal striatum receives significant glutamatergic inputs from the cortex, as well as dopaminergic inputs from the substantia nigra pars compacta. The dorsal striatum is generally considered to be involved in sensorimotor activities. The ventral striatum receives glutamatergic inputs from the limbic areas as well as dopaminergic inputs from the VTA, via the mesolimbic pathway. The ventral striatum is believed to play a role in reward and other limbic functions. The dorsal striatum is divided into the caudate and putamen by the internal capsule while the ventral striatum is composed of the nucleus accumbens and olfactory tubercle. The caudate has three primary regions of connectivity, with the head of the caudate demonstrating connectivity to the prefrontal cortex, cingulate cortex and amygdala. The body and tail show differentiation between the dorsolateral rim and ventral caudate, projecting to the sensorimotor and limbic regions of the striatum respectively. Striatopallidal fibres connect the striatum to the pallidus.


title: Basal ganglia

text: The "pallidum" consists of a large structure called the globus pallidus ("pale globe") together with a smaller ventral extension called the ventral pallidum. The globus pallidus appears as a single neural mass, but can be divided into two functionally distinct parts, called the internal (or medial) and external (lateral) segments, abbreviated GPi and GPe. Both segments contain primarily GABAergic neurons, which therefore have inhibitory effects on their targets. The two segments participate in distinct neural circuits. The GPe receives input mainly from the striatum, and projects to the subthalamic nucleus. The GPi receives signals from the striatum via the "direct" and "indirect" pathways. Pallidal neurons operate using a disinhibition principle. These neurons fire at steady high rates in the absence of input, and signals from the striatum cause them to pause or reduce their rate of firing. Because pallidal neurons themselves have inhibitory effects on their targets, the net effect of striatal input to the pallidum is a reduction of the tonic inhibition exerted by pallidal cells on their targets (disinhibition) with an increased rate of firing in the targets.


title: Basal ganglia

text: The substantia nigra is a midbrain gray matter portion of the basal ganglia that has two parts – the pars compacta (SNc) and the pars reticulata (SNr). SNr often works in unison with GPi, and the SNr-GPi complex inhibits the thalamus. Substantia nigra pars compacta (SNc) however, produces the neurotransmitter dopamine, which is very significant in maintaining balance in the striatal pathway. The circuit portion below explains the role and circuit connections of each of the components of the basal ganglia.


title: Basal ganglia

text: The subthalamic nucleus is a diencephalic gray matter portion of the basal ganglia, and the only portion of the ganglia that produces an excitatory neurotransmitter, glutamate. The role of the subthalamic nucleus is to stimulate the SNr-GPi complex and it is part of the indirect pathway. The subthalamic nucleus receives inhibitory input from the external part of the globus pallidus and sends excitatory input to the GPi.


title: Basal ganglia

text: Multiple models of basal ganglia circuits and function have been proposed, however there have been questions raised about the strict divisions of the direct and indirect pathways, their possible overlap and regulation. The circuitry model has evolved since the first proposed model in the 1990s by DeLong in the parallel "processing model", in which the cortex and substantia nigra pars compacta project into the dorsal striatum giving rise to an inhibitory indirect and excitatory direct pathway.


title: Basal ganglia

text: Generally, the basal ganglia circuitry is divided into five pathways: one limbic, two associative (prefrontal), one oculomotor, and one motor pathway. (The motor and oculomotor pathways are sometimes grouped into one motor pathway.) The five general pathways are organized as follows:


title: Basal ganglia

text: The direct pathway, originating in the dorsal striatum inhibits the GPi and SNr, resulting in a net disinhibition or excitation of the thalamus. This pathway consists of medium spiny neurons (MSNs) that express dopamine receptor D1, muscarinic acetylcholine receptor M4, and adenosine receptor A1. The direct pathway has been proposed to facilitate motor actions, timing of motor actions, gating of working memory, and motor responses to specific stimuli.


title: Basal ganglia

text: The (long) indirect pathway originates in the dorsal striatum and inhibits the GPe, resulting in disinhibition of the GPi which is then free to inhibit the thalamus. This pathway consists of MSNs that express dopamine receptor D2, muscarinic acetylcholine receptor M1, and adenosine receptor A2a. This pathway has been proposed to result in global motor inhibition(inhibition of all motor activity), and termination of responses. Another shorter indirect pathway has been proposed, which involves cortical excitation of the subthalamic nucleus resulting in direct excitation of the GPe, and inhibition of the thalamus. This pathway is proposed to result in inhibition of specific motor programs based on associative learning.


title: Basal ganglia

text: A combination of these indirect pathways resulting in a hyperdirect pathway that results in inhibition of basal ganglia inputs besides one specific focus has been proposed as part of the "center surround theory". This hyperdirect pathway is proposed to inhibit premature responses, or globally inhibit the basal ganglia to allow for more specific top down control by the cortex.


title: Basal ganglia

text: The interactions of these pathways are currently under debate. Some say that all pathways directly antagonize each other in a "push pull" fashion, while others support the "center surround theory", in which one focused input into the cortex is protected by inhibition of competing inputs by the rest of the indirect pathways.


title: Basal ganglia

text: The basal ganglia contains many afferent glutamatergic inputs, with predominantly GABAergic efferent fibers, modulatory cholinergic pathways, significant dopamine in the pathways originating in the ventral tegmental area and substantia nigra, as well as various neuropeptides. Neuropeptides found in the basal ganglia include substance P, neurokinin A, cholecystokinin, neurotensin, neurokinin B, neuropeptide Y, somatostatin, dynorphin, enkephaline. Other neuromodulators found in the basal ganglia include nitric oxide, carbon monoxide, and phenylethylamine.


title: Basal ganglia

text: The functional connectivity, measured by regional co-activation during functional neuroimaging studies, is broadly consistent with the parallel processing models of basal ganglia function. The putamen was generally coactivated with motor areas such as the supplementary motor area, caudal anterior cingulate cortex and primary motor cortex, while the caudate and rostral putamen were more frequently coactivated with the rostral ACC and DLPFC. The ventral striatum was significantly associated with the amygdala and hippocampus, which although was not included in the first formulations of basal ganglia models, has been an addition to more recent models.


title: Basal ganglia

text: One intensively studied function of the basal ganglia is its role in controlling eye movements. Eye movement is influenced by an extensive network of brain regions that converges on a midbrain area called the superior colliculus (SC). The SC is a layered structure whose layers form two-dimensional retinotopic maps of visual space. A "bump" of neural activity in the deep layers of the SC drives an eye movement directed toward the corresponding point in space.


title: Basal ganglia

text: The SC receives a strong inhibitory projection from the basal ganglia, originating in the substantia nigra pars reticulata (SNr). Neurons in the SNr usually fire continuously at high rates, but at the onset of an eye movement they "pause", thereby releasing the SC from inhibition. Eye movements of all types are associated with "pausing" in the SNr; however, individual SNr neurons may be more strongly associated with some types of movements than others. Neurons in some parts of the caudate nucleus also show activity related to eye movements. Since the great majority of caudate cells fire at very low rates, this activity almost always shows up as an increase in firing rate. Thus, eye movements begin with activation in the caudate nucleus, which inhibits the SNr via the direct GABAergic projections, which in turn disinhibits the SC.


title: Basal ganglia

text: Extracellular dopamine in the basal ganglia has been linked to motivational states in rodents, with high levels being linked to satiated state, medium levels with seeking, and low with aversion. The limbic basal ganglia circuits are influenced heavily by extracellular dopamine. Increased dopamine results in inhibition of the Ventral pallidum, entopeduncular nucleus, and substantia nigra pars reticulata, resulting in disinhibition of the thalamus. This model of direct D1, and indirect D2 pathways explain why selective agonists of each receptor are not rewarding, as activity at both pathways is required for disinhibition. The disinhibition of the thalamus leads to activation of the prefrontal cortex and ventral striatum, selective for increased D1 activity leading to reward. There is also evidence from non-human primate and human electrophysiology studies that other basal ganglia structures including the globus pallidus internus and subthalamic nucleus are involved in reward processing.