title: Jeff Merkley

text: In June 2019 Merkley and 14 other senators introduced the Affordable Medications Act, legislation intended to promote transparency by mandating that pharmaceutical companies disclose the amount of money going toward research and development in addition to both marketing and executives' salaries. The bill also abolished the restriction preventing the federal Medicare program from using its buying power to negotiate lower drug prices for beneficiaries and hinder drug company monopoly practices used to keep prices high and disable less expensive generics entering the market.


title: Jeff Merkley

text: In August 2019 Merkley was one of 19 senators to sign a letter to United States Secretary of the Treasury Steve Mnuchin and United States Secretary of Health and Human Services Alex Azar requesting data from the Trump administration in order to help states and Congress understand the potential consequences of the Texas v. United States Affordable Care Act lawsuit, writing that an overhaul of the present health care system would form "an enormous hole in the pocketbooks of the people we serve as well as wreck state budgets".


title: Jeff Merkley

text: As a member of the United States Senate Committee on Banking, Housing, and Urban Affairs, Merkley has contributed legislation toward fixing the subprime mortgage crisis. The Dodd–Frank Wall Street Reform and Consumer Protection Act contained an amendment by Merkley and Senator Amy Klobuchar protecting consumers from deceptive mortgage lending practices. The amendment prohibits mortgage lenders from receiving hidden payments when they sell high-cost loans and prohibits brokers from receiving higher pay for selling riskier or higher-fee loans. It also bolsters underwriting standards.


title: Jeff Merkley

text: To speed the recovery of the housing market, Merkley supports aggressive efforts to create refinancing alternatives to costly and time-consuming foreclosures, including allowing federal bankruptcy judges to modify existing mortgages so they can keep their home under new terms. In July 2012 Merkley proposed a broad new refinancing plan for homeowners who owe more than their houses are worth and therefore cannot refinance. Under his plan, any homeowner who is current on their mortgage could refinance into a 4% mortgage for 15 years or a 5% mortgage for 30 years.


title: Jeff Merkley

text: In April 2019 Merkley was one of 41 senators to sign a bipartisan letter to the housing subcommittee praising the United States Department of Housing and Urban Development's Section 4 Capacity Building program as authorizing "HUD to partner with national nonprofit community development organizations to provide education, training, and financial support to local community development corporations (CDCs) across the country" and expressing disappointment that Trump's budget "has slated this program for elimination after decades of successful economic and community development." The senators wrote that they hoped the subcommittee would support continued funding for Section 4 in Fiscal Year 2020.


title: Jeff Merkley

text: In October 2017 Merkley was one of 19 senators to sign a letter to Administrator of the Environmental Protection Agency Scott Pruitt questioning Pruitt's decision to repeal the Clean Power Plan, asserting that the repeal's proposal used "mathematical sleights of hand to over-state the costs of industry compliance with the 2015 Rule and understate the benefits that will be lost if the 2017 repeal is finalized" and would fail to "satisfy the requirements of the law, nor will it slow the increase in frequency and intensity of extreme weather events, the inexorable rise in sea levels, or the other dire effects of global warming that our planet is already experiencing."


title: Jeff Merkley

text: In September 2018 Merkley was one of eight senators to sponsor the Climate Risk Disclosure Act, a bill described by cosponsor Elizabeth Warren as using "market forces to speed up the transition from fossil fuels to cleaner energy—reducing the odds of an environmental and financial disaster without spending a dime of taxpayer money."


title: Jeff Merkley

text: In November 2018 Merkley was one of 25 Democratic senators to cosponsor a resolution specifying key findings of the Intergovernmental Panel On Climate Change report and National Climate Assessment. The resolution affirmed the senators' acceptance of the findings and support for bold action to address climate change.


title: Jeff Merkley

text: In March 2019 Merkley was one of 11 senators to sponsor the Climate Security Act of 2019, legislation forming a new group within the State Department that would develop strategies to integrate climate science and data into national security operations and restore the post of special envoy for the Arctic, which Trump eliminated in 2017. The envoy would advise the president and the administration on the potential effects of climate on national security and be responsible for facilitating all interagency communication between federal science and security agencies.


title: Jeff Merkley

text: Merkley has consistently supported policies that promote American energy independence and investment in alternative energy sources. In 2010 he and Senators Tom Carper, Tom Udall, and Michael Bennet introduced the Oil Independence for a Stronger America Act, which set a goal to achieve complete independence from overseas oil by 2030. The same senators put forward a similar piece of legislation again in 2011. Merkley supports increasing national fuel economy standards, and advocates for a 6 to 7 percent annual improvement for vehicles over current mileage standards. He has also been a strong supporter of electric vehicles. In 2011 Merkley and Senator Lamar Alexander introduced the Promoting Electric Vehicles Act, a bill designed to provide short-term incentives for the rapid development and production of electric vehicles.


title: Jeff Merkley

text: In March 2019, Merkley was an original cosponsor of a bipartisan bill intended to mandate that the Environmental Protection Agency declare per- and polyfluoroalkyl substances hazardous substances that can be addressed with cleanup funds via the EPA Superfund law and require that polluters undertake or pay for remediation within a year of the bill's enaction.


title: Jeff Merkley

text: Merkley supports increased transparency in campaign financing and limits on independent political spending by corporations. Merkley has been critical of both the 2010 Supreme Court case Citizens United v. Federal Election Commission, and of the court's decision in 2012 not to revisit this case. Merkley called the 2012 decision "disturbing and damaging." In response to the Supreme Court decision, in July 2012 Merkley and six other senators sponsored the Disclose Act. Among other provisions, the legislation would require public disclosure of political donors that give $10,000 or more.


title: Jeff Merkley

text: Merkley has been a leader in trying to reform the rules of the Senate, including those about the filibuster. On January 5, 2011, he and Senators Tom Udall and Tom Harkin introduced a resolution intended to increase debate and accountability in the Senate. The resolution proposed to eliminate the filibuster on motions to proceed, eliminate secret holds, guarantee consideration of amendments for both majority and minority, require a "talking filibuster" in which senators opposed to holding a straight up-or-down vote must continuously debate on the Senate floor, and expedite the nominations process. Upon introducing the resolution, Merkley stated: "The Senate is broken. We are failing to fulfill our legislative responsibilities." On January 27 his "talking filibuster" proposal received 46 Senate votes.


title: Jeff Merkley

text: To protest the nomination of Neil Gorsuch to the U.S. Supreme Court, in April 2017 Merkley staged an all-night protest on the Senate floor. He ended his filibuster speech after 15 hours. "This is a stolen seat," he said in a statement, referring to Senate Republicans' successful attempt to block Obama's appointment of Merrick Garland. "This is the first time in American history that one party has blockaded a nominee for almost a year in order to deliver a seat to a president of their own party."


title: Jeff Merkley

text: During the Postal Reform Act debate in the Senate in April 2012, Merkley led the effort to pass an amendment that would impose a one-year moratorium on the closure of most rural post offices. After that, the bill would prohibit the closure of post offices more than 10 miles from another post office and impose conditions limiting the closure of others. Twenty rural post offices in Oregon face closure because of the postal service's financial problems.


title: Jeff Merkley

text: Merkley supports same-sex marriage and introduced the Employment Non-Discrimination Act (ENDA) in the Senate during the 111th United States Congress as S. 1584. BlueOregon, a progressive Oregon blog, commented on Merkley's suitability to be lead sponsor of ENDA, noting that as Speaker of the Oregon House of Representatives he had successfully guided Oregon's state version of ENDA, the Oregon Equality Act, to become law.


title: Jeff Merkley

text: In 2010 Merkley cosponsored legislation to repeal Don't Ask Don't Tell (DADT) and allow gay Americans to serve openly in the military. In March 2011 Merkley cosponsored the Respect for Marriage Act (RFMA) to repeal the Defense of Marriage Act (DOMA), legislation that bars the federal government from recognizing same-sex marriages. With 11 other RFMA cosponsors, including fellow Oregon Senator Ron Wyden, Merkley released a video as part of the It Gets Better Project, the anti-bullying initiative aimed at inspiring at-risk LGBT youth.


title: Jeff Merkley

text: In May 2014, days before the FCC was scheduled to rewrite its net neutrality rules, Merkley was one of 11 senators to sign a letter to FCC Chairman Tom Wheeler charging that Wheeler's proposal would destroy net neutrality and urging the FCC to "consider reclassifying Internet providers to make them more like traditional phone companies, over which the agency has clear authority to regulate more broadly."


title: Jeff Merkley

text: In October 2018 Merkley was one of 20 senators to sign a letter to Secretary of State Mike Pompeo urging him to reverse the rolling back of a policy that granted visas to same-sex partners of LGBTQ diplomats who had unions that were not recognized by their home countries, writing that too many places around the world have seen LGBTQ individuals "subjected to discrimination and unspeakable violence, and receive little or no protection from the law or local authorities" and that refusing to let LGBTQ diplomats bring their partners to the US would be equivalent to upholding "the discriminatory policies of many countries around the world."


title: Jeff Merkley

text: In December 2018 Merkley voted for the First Step Act, legislation aimed at reducing recidivism rates among federal prisoners by expanding job training and other programs in addition to forming an expansion of early-release programs and modifications on sentencing laws such as mandatory minimum sentences for nonviolent drug offenders, "to more equitably punish drug offenders."


title: Jeff Merkley

text: In June 2019 Merkley was one of 18 senators to sign a letter to Pompeo requesting an explanation of a State Department decision not to issue a statement that year commemorating Pride Month or issue the annual cable outlining activities for embassies commemorating Pride Month. They also asked why the LGBTI special envoy position had remained vacant and asserted that "preventing the official flying of rainbow flags and limiting public messages celebrating Pride Month signals to the international community that the United States is abandoning the advancement of LGBTI rights as a foreign policy priority."


title: Jeff Merkley

text: In March 2019 Merkley was one of 38 senators to sign a letter to United States Secretary of Agriculture Sonny Perdue warning that dairy farmers "have continued to face market instability and are struggling to survive the fourth year of sustained low prices" and urging his department to "strongly encourage these farmers to consider the Dairy Margin Coverage program."


title: Jeff Merkley

text: In June 2019 Merkley and 18 other Democratic senators sent a letter to USDA Inspector General (IG) Phyllis K. Fong requesting that the IG investigate USDA instances of retaliation and political decision-making and asserting that not to conduct an investigation would mean these "actions could be perceived as a part of this administration’s broader pattern of not only discounting the value of federal employees, but suppressing, undermining, discounting, and wholesale ignoring scientific data produced by their own qualified scientists."


title: Jeff Merkley

text: In July 2019 Merkley was one of eight senators to introduce the Agricultural Trucking Relief Act, a bill that would alter the definition of an agricultural commodity to include both horticultural and aquacultural products and promote a larger consistency in regulation in both federal and state agencies as part of an attempt to ease regulatory burdens on trucking and the agri-community. Merkley said the bill "is a necessary step forward in clarifying trucking rules, to make sure businesses in every sector of Oregon’s agriculture industry have the same ability to deliver their products while they’re still fresh."


title: Jeff Merkley

text: In 2019 Merkley and 34 other senators introduced the Child Care for Working Families Act, a bill that created 770,000 new child care jobs and ensured that families making less than 75% of the state median income did not pay for child care, with higher-earning families having to pay "their fair share for care on a sliding scale, regardless of the number of children they have." The legislation also supported universal access to high-quality preschool programs for all 3- and 4-year-olds and changed child care workforce compensation and training to aid both teachers and caregivers.


title: Jeff Merkley

text: In July 2015 Merkley was one of eight senators to sign a letter to U.S. Chamber of Commerce President Tom Donahue requesting the chamber stop lobbying against anti-smoking regulations on the grounds that "its international clout to fight so ardently against regulations of dangerous tobacco products is contrary to United States foreign policy and global health goals."


title: Jeff Merkley

text: In December 2016 Merkley was one of 17 senators to sign a letter to Trump asking him to fulfill a campaign pledge to bring down the cost of prescription drugs, stating their willingness "to advance measures to achieve this goal", and calling on Trump "to partner with Republicans and Democrats alike to take meaningful steps to address the high cost of prescription drugs through bold administrative and legislative actions."


title: Jeff Merkley

text: In December 2018 Merkley was one of 21 senators to sign a letter to Commissioner of Food and Drugs Scott Gottlieb stating their approval of the actions of the Food and Drugs Administration to hinder youth access to e-cigarettes and urging the FDA "to take additional, stronger steps to prevent and reduce e-cigarette use among youth."


title: Jeff Merkley

text: In January 2019 Merkley and 39 other senators introduced the Background Check Expansion Act, a bill that would require background checks for the sale or transfer of all firearms including all unlicensed sellers. Exceptions to the bill's background check requirement included transfers between members of law enforcement, loaning firearms for either hunting or sporting events on a temporary basis, giving firearms to members of one's immediate family, transferring them as part of an inheritance, or giving a firearm to another person temporarily for immediate self-defense.


title: Jeff Merkley

text: In February 2019 Merkley was one of 38 senators to sign a letter to Senate Judiciary Committee Chairman Lindsey Graham calling on him to hold a hearing on universal background checks and noting Graham's statement to the press that he "intended to have the Committee work on ‘red flag’ legislation and potentially also background checks, both actions" the senators supported.


title: Jeff Merkley

text: In July 2019 Merkley and 15 other Senate Democrats introduced the Protecting Sensitive Locations Act, which mandated that ICE agents get approval from a supervisor before engaging in enforcement actions at sensitive locations except in special circumstances and that agents receive annual training in addition to being required to annually report enforcement actions in those locations.


title: Jeff Merkley

text: In March 2018 Merkley spearheaded a letter signed by nine other senators lambasting a proposal from FCC Chairman Ajit Pai that would curb the scope of benefits from the Lifeline program during a period when roughly 6.5 million people in poor communities relied on Lifeline for access to high-speed internet, arguing that it was Pai's "obligation to the American public, as the Chairman of the Federal Communications Commission, to improve the Lifeline program and ensure that more Americans can afford access, and have means of access, to broadband and phone service." The senators also advocated insuring "Lifeline reaches more Americans in need of access to communication services."


title: Jeff Merkley

text: Merkley has competed in and finished Ironman Triathlons. He has said his workouts help him manage the stress of his job.


title: Jeff Merkley

text: Merkley's first cousin's great-granddaughter, Rebecka Ann Carnes, was killed alongside eight others in the 2015 Umpqua Community College shooting.


title: Pleiotropy

text: Pleiotropy (from Greek , 'more', and , 'way') occurs when one gene influences two or more seemingly unrelated phenotypic traits. Such a gene that exhibits multiple phenotypic expression is called a pleiotropic gene. Mutation in a pleiotropic gene may have an effect on several traits simultaneously, due to the gene coding for a product used by a myriad of cells or different targets that have the same signaling function.


title: Pleiotropy

text: Pleiotropy can arise from several distinct but potentially overlapping mechanisms, such as gene pleiotropy, developmental pleiotropy, and selectional pleiotropy. Gene pleiotropy occurs when a gene product interacts with multiple other proteins or catalyzes multiple reactions. Developmental pleiotropy occurs when mutations have multiple effects on the resulting phenotype. Selectional pleiotropy occurs when the resulting phenotype has many effects on fitness (depending on factors such as age and gender).


title: Pleiotropy

text: An example of pleiotropy is phenylketonuria, an inherited disorder that affects the level of phenylalanine, an amino acid that can be obtained from food, in the human body. Phenylketonuria causes this amino acid to increase in amount in the body, which can be very dangerous. The disease is caused by a defect in a single gene on chromosome 12 that codes for enzyme phenylalanine hydroxylase, that affects multiple systems, such as the nervous and integumentary system.


title: Pleiotropy

text: Pleiotropic gene action can limit the rate of multivariate evolution when natural selection, sexual selection or artificial selection on one trait favors one allele, while selection on other traits favors a different allele. Some gene evolution is harmful to an organism. Genetic correlations and responses to selection most often exemplify pleiotropy.


title: Pleiotropy

text: Pleiotropic traits had been previously recognized in the scientific community but had not been experimented on until Gregor Mendel's 1866 pea plant experiment. Mendel recognized that certain pea plant traits (seed coat color, flower color, and axial spots) seemed to be inherited together; however, their correlation to a single gene has never been proven. The term "pleiotropie" was first coined by Ludwig Plate in his Festschrift, which was published in 1910. He originally defined pleiotropy as occurring when "several characteristics are dependent upon ... [inheritance]; these characteristics will then always appear together and may thus appear correlated". This definition is still used today.


title: Pleiotropy

text: After Plate's definition, Hans Gruneberg was the first to study the mechanisms of pleiotropy. In 1938 Gruneberg published an article dividing pleiotropy into two distinct types: "genuine" and "spurious" pleiotropy. "Genuine" pleiotropy is when two distinct primary products arise from one locus. "Spurious" pleiotropy, on the other hand, is either when one primary product is utilized in different ways or when one primary product initiates a cascade of events with different phenotypic consequences. Gruneberg came to these distinctions after experimenting on rats with skeletal mutations. He recognized that "spurious" pleiotropy was present in the mutation, while "genuine" pleiotropy was not, thus partially invalidating his own original theory. Through subsequent research, it has been established that Gruneberg's definition of "spurious" pleiotropy is what we now identify simply as "pleiotropy".


title: Pleiotropy

text: In 1941 American geneticists George Beadle and Edward Tatum further invalidated Gruneberg's definition of "genuine" pleiotropy, advocating instead for the "one gene-one enzyme" hypothesis that was originally introduced by French biologist Lucien Cuénot in 1903. This hypothesis shifted future research regarding pleiotropy towards how a single gene can produce various phenotypes.


title: Pleiotropy

text: In the mid-1950s Richard Goldschmidt and Ernst Hadorn, through separate individual research, reinforced the faultiness of "genuine" pleiotropy. A few years later, Hadorn partitioned pleiotropy into a "mosaic" model (which states that one locus directly affects two phenotypic traits) and a "relational" model (which is analogous to "spurious" pleiotropy). These terms are no longer in use but have contributed to the current understanding of pleiotropy.


title: Pleiotropy

text: By accepting the one gene-one enzyme hypothesis, scientists instead focused on how uncoupled phenotypic traits can be affected by genetic recombination and mutations, applying it to populations and evolution. This view of pleiotropy, "universal pleiotropy", defined as locus mutations being capable of affecting essentially all traits, was first implied by Ronald Fisher's Geometric Model in 1930. This mathematical model illustrates how evolutionary fitness depends on the independence of phenotypic variation from random changes (that is, mutations). It theorizes that an increasing phenotypic independence corresponds to a decrease in the likelihood that a given mutation will result in an increase in fitness. Expanding on Fisher's work, Sewall Wright provided more evidence in his 1968 book "Evolution and the Genetics of Populations: Genetic and Biometric Foundations" by using molecular genetics to support the idea of "universal pleiotropy". The concepts of these various studies on evolution have seeded numerous other research projects relating to individual fitness.


title: Pleiotropy

text: In 1957 evolutionary biologist George C. Williams theorized that antagonistic effects will be exhibited during an organism's life cycle if it is closely linked and pleiotropic. Natural selection favors genes that are more beneficial prior to reproduction than after (leading to an increase in reproductive success). Knowing this, Williams argued that if only close linkage was present, then beneficial traits will occur both before and after reproduction due to natural selection. This, however, is not observed in nature, and thus antagonistic pleiotropy contributes to the slow deterioration with age (senescence).


title: Pleiotropy

text: Pleiotropy describes the genetic effect of a single gene on multiple phenotypic traits. The underlying mechanism is genes that code for a product that is either used by various cells or has a cascade-like signaling function that affects various targets.


title: Pleiotropy

text: Most genetic traits are polygenic in nature: controlled by many genetic variants, each of small effect. These genetic variants can reside in protein coding or non-coding regions of the genome. In this context pleiotropy refers to the influence that a specific genetic variant, e.g., a single nucleotide polymorphism or SNP, has on two or more distinct traits.


title: Pleiotropy

text: Genome-wide association studies (GWAS) and machine learning analysis of large genomic datasets have led to the construction of SNP based polygenic predictors for human traits such as height, bone density, and many disease risks. Similar predictors exist for plant and animal species and are used in agricultural breeding.


title: Pleiotropy

text: One measure of pleiotropy is the fraction of genetic variance that is common between two distinct complex human traits: e.g., height vs bone density, breast cancer vs heart attack risk, or diabetes vs hypothyroidism risk. This has been calculated for hundreds of pairs of traits, with results shown in the Table. In most cases examined the genomic regions controlling each trait are largely disjoint, with only modest overlap.


title: Pleiotropy

text: One basic model of pleiotropy's origin describes a single gene locus to the expression of a certain trait. The locus affects the expressed trait only through changing the expression of other loci. Over time, that locus would affect two traits by interacting with a second locus. Directional selection for both traits during the same time period would increase the positive correlation between the traits, while selection on only one trait would decrease the positive correlation between the two traits. Eventually, traits that underwent directional selection simultaneously were linked by a single gene, resulting in pleiotropy.


title: Pleiotropy

text: Other more complex models compensate for some of the basic model's oversights, such as multiple traits or assumptions about how the loci affect the traits. They also propose the idea that pleiotropy increases the phenotypic variation of both traits since a single mutation on a gene would have twice the effect.


title: Pleiotropy

text: Pleiotropy can have an effect on the evolutionary rate of genes and allele frequencies. Traditionally, models of pleiotropy have predicted that evolutionary rate of genes is related negatively with pleiotropyas the number of traits of an organism increases, the evolutionary rates of genes in the organism's population decrease. However, this relationship has not been clearly found in empirical studies.


title: Pleiotropy

text: In mating, for many animals the signals and receptors of sexual communication may have evolved simultaneously as the expression of a single gene, instead of the result of selection on two independent genes, one that affects the signaling trait and one that affects the receptor trait. In such a case, pleiotropy would facilitate mating and survival. However, pleiotropy can act negatively as well. A study on seed beetles found that intralocus sexual conflict arises when selection for certain alleles of a gene that are beneficial for one sex causes expression of potentially harmful traits by the same gene in the other sex, especially if the gene is located on an autosomal chromosome.


title: Pleiotropy

text: Pleiotropic genes act as an arbitrating force in speciation. William R. Rice and Ellen E. Hostert (1993) conclude that the observed prezygotic isolation in their studies is a product of pleiotropy's balancing role in indirect selection. By imitating the traits of all-infertile hybridized species, they noticed that the fertilization of eggs was prevented in all eight of their separate studies, a likely effect of pleiotropic genes on speciation. Likewise, pleiotropic gene's stabilizing selection allows for the allele frequency to be altered.


title: Pleiotropy

text: Studies on fungal evolutionary genomics have shown pleiotropic traits that simultaneously affect adaptation and reproductive isolation, converting adaptations directly to speciation. A particularly telling case of this effect is host specificity in pathogenic ascomycetes and specifically, in "venturia", the fungus responsible for apple scab. These parasitic fungi each adapts to a host, and are only able to mate within a shared host after obtaining resources. Since a single toxin gene or virulence allele can grant the ability to colonize the host, adaptation and reproductive isolation are instantly facilitated, and in turn, pleiotropically causes adaptive speciation. The studies on fungal evolutionary genomics will further elucidate the earliest stages of divergence as a result of gene flow, and provide insight into pleiotropically induced adaptive divergence in other eukaryotes.


title: Pleiotropy

text: Sometimes, a pleiotropic gene may be both harmful and beneficial to an organism, which is referred to as "antagonistic pleiotropy". This may occur when the trait is beneficial for the organism's early life, but not its late life. Such "trade-offs" are possible since natural selection affects traits expressed earlier in life, when most organisms are most fertile, more than traits expressed later in life.


title: Pleiotropy

text: This idea is central to the antagonistic pleiotropy hypothesis, which was first developed by G.C. Williams in 1957. Williams suggested that some genes responsible for increased fitness in the younger, fertile organism contribute to decreased fitness later in life, which may give an evolutionary explanation for senescence. An example is the p53 gene, which suppresses cancer but also suppresses stem cells, which replenish worn-out tissue.


title: Pleiotropy

text: Unfortunately, the process of antagonistic pleiotropy may result in an altered evolutionary path with delayed adaptation, in addition to effectively cutting the overall benefit of any alleles by roughly half. However, antagonistic pleiotropy also lends greater evolutionary "staying power" to genes controlling beneficial traits, since an organism with a mutation to those genes would have a decreased chance of successfully reproducing, as multiple traits would be affected, potentially for the worse.


title: Pleiotropy

text: Sickle cell anemia is a classic example of the mixed benefit given by the staying power of pleiotropic genes, as the mutation to Hb-S provides the fitness benefit of malaria resistance to heterozygotes, while homozygotes have significantly lowered life expectancy. Since both of these states are linked to the same mutated gene, large populations today are susceptible to sickle cell despite it being a fitness-impairing genetic disorder.


title: Pleiotropy

text: Albinism is the mutation of the TYR gene, also termed tyrosinase. This mutation causes the most common form of albinism. The mutation alters the production of melanin, thereby affecting melanin-related and other dependent traits throughout the organism. Melanin is a substance made by the body that is used to absorb light and provides coloration to the skin. Indications of albinism are the absence of color in an organism's eyes, hair, and skin, due to the lack of melanin. Some forms of albinism are also known to have symptoms that manifest themselves through rapid-eye movement, light sensitivity, and strabismus.


title: Pleiotropy

text: Pleiotropy in genes has been linked between certain psychiatric disorders as well. Deletion in the 22q11.2 region of chromosome 22 has been associated with schizophrenia and autism. Schizophrenia and autism are linked to the same gene deletion but manifest very differently from each other. The resulting phenotype depends on the stage of life at which the individual develops the disorder. Childhood manifestation of the gene deletion is typically associated with autism, while adolescent and later expression of the gene deletion often manifests in schizophrenia or other psychotic disorders. Though the disorders are linked by genetics, there is no increased risk found for adult schizophrenia in patients who experienced autism in childhood.


title: Pleiotropy

text: A 2013 study also genetically linked five psychiatric disorders, including schizophrenia and autism. The link was a single nucleotide polymorphism of two genes involved in calcium channel signaling with neurons. One of these genes, CACNA1C, has been found to influence cognition. It has been associated with autism, as well as linked in studies to schizophrenia and bipolar disorder. These particular studies show clustering of these diseases within patients themselves or families. The estimated heritability of schizophrenia is 70% to 90%, therefore the pleiotropy of genes is crucial since it causes an increased risk for certain psychotic disorders and can aid psychiatric diagnosis.


title: Pleiotropy

text: A common example of pleiotropy is the human disease phenylketonuria (PKU). This disease causes mental retardation and reduced hair and skin pigmentation, and can be caused by any of a large number of mutations in the single gene on chromosome 12 that codes for the enzyme phenylalanine hydroxylase, which converts the amino acid phenylalanine to tyrosine. Depending on the mutation involved, this conversion is reduced or ceases entirely. Unconverted phenylalanine builds up in the bloodstream and can lead to levels that are toxic to the developing nervous system of newborn and infant children. The most dangerous form of this is called classic PKU, which is common in infants. The baby seems normal at first but actually incurs permanent intellectual disability. This can cause symptoms such as mental retardation, abnormal gait and posture, and delayed growth. Because tyrosine is used by the body to make melanin (a component of the pigment found in the hair and skin), failure to convert normal levels of phenylalanine to tyrosine can lead to fair hair and skin.


title: Pleiotropy

text: The frequency of this disease varies greatly. Specifically, in the United States, PKU is found at a rate of nearly 1 in 10,000 births. Due to newborn screening, doctors are able to detect PKU in a baby sooner. This allows them to start treatment early, preventing the baby from suffering from the severe effects of PKU. PKU is caused by a mutation in the PAH gene, whose role is to instruct the body on how to make phenylalanine hydroxylase. Phenylalanine hydroxylase is what converts the phenylalanine, taken in through diet, into other things that the body can use. The mutation often decreases the effectiveness or rate at which the hydroxylase breaks down the phenylalanine. This is what causes the phenylalanine to build up in the body. The way to treat PKU is to manage one's diet. Phenylalanine is ingested through food, so a diet should decrease types of foods that have high amounts of phenylalanine. Foods with high levels of protein must be avoided. These include breast milk, eggs, chicken, beef, pork, fish, nuts, and other foods. A special PKU formula can be obtained in order for the body to have protein.


title: Pleiotropy

text: Sickle cell anemia is a genetic disease that causes deformed red blood cells with a rigid, crescent shape instead of the normal flexible, round shape. It is caused by a change in one nucleotide, a point mutation in the HBB gene. The HBB gene encodes information to make the beta-globin subunit of hemoglobin, which is the protein red blood cells use to carry oxygen throughout the body. Sickle cell anemia occurs when the HBB gene mutation causes both beta-globin subunits of hemoglobin to change into hemoglobinS (HbS).


title: Pleiotropy

text: Sickle cell anemia is a pleiotropic disease because the expression of a single mutated HBB gene produces numerous consequences throughout the body. The mutated hemoglobin forms polymers and clumps together causing the deoxygenated sickle red blood cells to assume the disfigured sickle shape. As a result, the cells are inflexible and cannot easily flow through blood vessels, increasing the risk of blood clots and possibly depriving vital organs of oxygen. Some complications associated with sickle cell anemia include pain, damaged organs, strokes, high blood pressure, and loss of vision. Sickle red blood cells also have a shortened lifespan and die prematurely.


title: Pleiotropy

text: Marfan syndrome (MFS) is an autosomal dominant disorder which affects 1 in 5–10,000 people. MFS arises from a mutation in the FBN1 gene, which encodes for the glycoprotein fibrillin-1, a major constituent of extracellular microfibrils which form connective tissues. Over 1,000 different mutations in FBN1 have been found to result in abnormal function of fibrillin, which consequently relates to connective tissues elongating progressively and weakening. Because these fibers are found in tissues throughout the body, mutations in this gene can have a widespread effect on certain systems, including the skeletal, cardiovascular, and nervous system, as well as the eyes and lungs.


title: Pleiotropy

text: Without medical intervention, prognosis of Marfan syndrome can range from moderate to life-threatening, with 90% of known causes of death in diagnosed patients relating to cardiovascular complications and congestive cardiac failure. Other characteristics of MFS include an increased arm span and decreased upper to lower body ratio.


title: Pleiotropy

text: A gene recently discovered in laboratory house mice, termed "mini-muscle", causes, when mutated, a 50% reduction in hindlimb muscle mass as its primary effect (the phenotypic effect by which it was originally identified). In addition to smaller hindlimb muscle mass, the mutant mice exhibit lower heart rates during physical activity, and a higher endurance. Mini Muscle Mice also exhibit larger kidneys and livers. All of these morphological deviations influence the behavior and metabolism of the mouse. For example, mice with the Mini Muscle mutation were observed to have a higher per-gram aerobic capacity. The mini-muscle allele shows a mendelian recessive behavior. The mutation is a single nucleotide polymorphism (SNP) in an intron of the myosin heavy polypeptide4 gene.


title: Pleiotropy

text: DNA repair pathways that repair damage to cellular DNA use many different proteins. These proteins often have other functions in addition to DNA repair. In humans, defects in some of these multifunctional proteins can cause widely differing clinical phenotypes. As an example, mutations in the XPB gene that encodes the largest subunit of the basal Transcription factor II H have several pleiotropic effects. XPB mutations are known to be deficient in nucleotide excision repair of DNA and in the quite separate process of gene transcription. In humans, "XPB" mutations can give rise to the cancer-prone disorder xeroderma pigmentosum or the noncancer-prone multisystem disorder trichothiodystrophy. Another example in humans is the "ERCC6" gene, which encodes a protein that mediates DNA repair, transcription, and other cellular processes throughout the body. Mutations in "ERCC6" are associated with disorders of the eye (retinal dystrophy), heart (cardiac arrhythmias), and immune system (lymphocyte immunodeficiency).


title: Pleiotropy

text: Chickens exhibit various traits affected by pleiotropic genes. Some chickens exhibit frizzle feather trait, where their feathers all curl outward and upward rather than lying flat against the body. Frizzle feather was found to stem from a deletion in the genomic region coding for α-Keratin. This gene seems to pleiotropically lead to other abnormalities like increased metabolism, higher food consumption, accelerated heart rate, and delayed sexual maturity.


title: Pleiotropy

text: Domesticated chickens underwent a rapid selection process that led to unrelated phenotypes having high correlations, suggesting pleiotropic, or at least close linkage, effects between comb mass and physiological structures related to reproductive abilities. Both males and females with larger combs have higher bone density and strength, which allows females to deposit more calcium into eggshells. This linkage is further evidenced by the fact that two of the genes, HAO1 and BMP2, affecting medullary bone (the part of the bone that transfers calcium into developing eggshells) are located at the same locus as the gene affecting comb mass. HAO1 and BMP2 also display pleiotropic effects with commonly desired domestic chicken behavior; those chickens who express higher levels of these two genes in bone tissue produce more eggs and display less egg incubation behavior.


title: Pure function

text: Thus a pure function is a computational analogue of a mathematical function. Some authors, particularly from the imperative language community, use the term "pure" for all functions that just have the above property 2 (discussed below).


title: Pure function

text: I/O is inherently impure: input operations undermine referential transparency, and output operations create side effects. Nevertheless, there is a sense in which function can perform input or output and still be pure, if the sequence of operations on the relevant I/O devices is modeled explicitly as both an argument and a result, and I/O operations are taken to fail when the input sequence does not describe the operations actually taken since the program began execution.


title: Pure function

text: The second point ensures that the only sequence usable as an argument must change with each I/O action; the first allows different calls to an I/O-performing function to return different results on account of the sequence arguments having changed.


title: Pure function

text: Functions that have just the above property 2 allow for compiler optimization techniques such as common subexpression elimination and loop optimization similar to arithmetic operators. A C++ example is the codice_1 method, returning the size of a string, which depends on the memory contents where the string points to, therefore lacking the above property 1. Nevertheless, in a single-threaded environment, the following C++ code


title: Pure function

text: Since pure functions have identical return values for identical arguments, they are well suited to unit testing.


title: Glowworm

text: Glowworm or glow-worm is the common name for various groups of insect larvae and adult larviform females that glow through bioluminescence. They include the European common glow-worm and other members of the Lampyridae, but bioluminescence also occurs in the families Elateridae, Phengodidae and Rhagophthalmidae among beetles; as well as members of the genera Arachnocampa, Keroplatus and Orfelia among keroplatid fungus gnats.


title: Glowworm

text: Four families of beetles are bioluminescent. The wingless larviform females and larvae of these bioluminescent species are usually known as "glowworms". Winged males may or may not also exhibit bioluminescence. Their light may be emitted as flashes or as a constant glow, and usually range in colour from green, yellow, to orange. The families are closely related, and are all members of the beetle superfamily, Elateroidea. Phylogenetic analyses have indicated that bioluminescence may have a single evolutionary origin among the families Lampyridae, Phengodidae, and Rhagophthalmidae; but is likely to have arisen independently among Elateridae.


title: Glowworm

text: Three genera of fungus gnats are bioluminescent, and known as "glowworms" in their larval stage. They produce a blue-green light. The larvae spin sticky webs to catch food. They are found in caves, overhangs, rock cavities, and other sheltered, wet areas. They are usually classified under the family Keroplatidae, but this is not universally accepted and some authors place them under Mycetophilidae instead. Despite the similarities in function and appearance, the bioluminescent systems of the three genera are not homologous and are believed to have evolved separately.


title: Mycoplasma pneumoniae

text: Mycoplasma pneumoniae is a very small bacterium in the class Mollicutes. It is a human pathogen that causes the disease mycoplasma pneumonia, a form of atypical bacterial pneumonia related to cold agglutinin disease. "M. pneumoniae" is characterized by the absence of a peptidoglycan cell wall and resulting resistance to many antibacterial agents. The persistence of "M. pneumoniae" infections even after treatment is associated with its ability to mimic host cell surface composition.


title: Mycoplasma pneumoniae

text: In 1898, Nocard and Roux isolated an agent assumed to be the cause of cattle pneumonia and named it "microbe de la peripneumonie" Microorganisms from other sources, having properties similar to the pleuropneumonia organism (PPO) of cattle, soon came to be known as pleuropneumonia-like organisms (PPLO), but their true nature remained unknown. Many PPLO were later proven to be the cause of pneumonias and arthritis in several lower animals.


title: Mycoplasma pneumoniae

text: In 1944, Monroe Eaton had used embryonated chicken eggs to cultivate an agent thought to be the cause of human primary atypical pneumonia (PAP), commonly known as "walking pneumonia." This unknown organism became known as the "Eaton agent". At that time, Eaton's use of embryonated eggs, then used for cultivating viruses, supported the idea that the Eaton agent was a virus. Yet it was known that PAP was amenable to treatment with broad-spectrum antibiotics, making a viral etiology suspect.


title: Mycoplasma pneumoniae

text: Robert Chanock, a researcher from the NIH who was studying the Eaton agent as a virus, visited the Wistar Institute in Philadelphia in 1961 to obtain a cell culture of a normal human cell strain developed by Leonard Hayflick. This cell strain was known to be exquisitely sensitive to isolate and grow human viruses. Chanock told Hayflick of his research on the Eaton agent, and his belief that its viral nature was questionable. Although Hayflick knew little about the current research on this agent, his doctoral dissertation had been done on animal diseases caused by PPLO. Hayflick knew that many lower animals suffered from pneumonias caused by PPLOs (later to be termed "mycoplasmas"). Hayflick reasoned that the Eaton agent might be a mycoplasma, and not a virus.


title: Mycoplasma pneumoniae

text: Chanock had never heard of mycoplasmas, and at Hayflick’s request sent him egg yolk containing the Eaton agent.


title: Mycoplasma pneumoniae

text: Using a novel agar and fluid medium formulation he had devised, Hayflick isolated a unique mycoplasma from the egg yolk. This was soon proven by Chanock and Hayflick to be the causative agent of PAP. When this discovery became known to Dr. Emmy Klieneberger-Nobel of the Lister Institute in London, the world’s leading authority on these organisms, she suggested that the organism be named "Mycoplasma hayflickiae". Hayflick demurred in favor of "Mycoplasma pneumoniae".


title: Mycoplasma pneumoniae

text: This smallest free-living microorganism was the first to be isolated and proven to be the cause of a human disease. For his discovery, Hayflick was presented with the Presidential Award by the International Organization of Mycoplasmology. The inverted microscope under which Hayflick discovered "Mycoplasma pneumoniae" is kept by the Smithsonian Institution.


title: Mycoplasma pneumoniae

text: The term mycoplasma ( meaning fungus, and , meaning formed) is derived from the fungal-like growth of some mycoplasma species. The mycoplasmas were classified as Mollicutes (“mollis”, meaning soft and “cutis”, meaning skin) in 1960 due to their small size and genome, lack of cell wall, low G+C content and unusual nutritional needs. "M. pneumoniae" has also been designated as an arginine nonfermenting species. Mycoplasmas are further classified by the sequence composition of 16s rRNA. All mycoplasmas of the "pneumoniae" group possess similar 16s rRNA variations unique to the group, of which "M. pneumoniae" has a 6.3% variation in the conserved regions, that suggest mycoplasmas formed by degenerative evolution from the gram-positive eubacterial group that includes "bacilli", "streptococci", and "lactobacilli". "M. pneumoniae" is a member of the family Mycoplasmataceae and order Mycoplasmatales.


title: Mycoplasma pneumoniae

text: Mycoplasmas, which are among the smallest self-replicating organisms, are parasitic species that lack a cell wall and periplasmic space, have reduced genomes, and limited metabolic activity. "Mycoplasma pneumoniae" cells have an elongated shape that is approximately 0.1–0.2 µm (100-200 nm) in width and 1-2 µm (1000-2000 nm) in length. The extremely small cell size means they are incapable of being examined by light microscopy; a stereomicroscope is required for viewing the morphology of "M. pneumoniae" colonies, which are usually less than 100 µm in length. The inability to synthesize a peptidoglycan cell wall is due to the absence of genes encoding its formation and results in an increased importance in maintenance of osmotic stability to avoid desiccation. The lack of a cell wall also calls for increased support of the cell membrane(reinforced with sterols), which includes a rigid cytoskeleton composed of an intricate protein network and, potentially, an extracellular capsule to facilitate adherence to the host cell. "M. pneumoniae" are the only bacterial cells that possess cholesterol in their cell membrane (obtained from the host) and possess more genes that encode for membrane lipoprotein variations than other mycoplasmas, which are thought to be associated with its parasitic lifestyle. "M. pneumoniae" cells also possess an attachment organelle, which is used in the gliding motility of the organism by an unknown mechanism.


title: Mycoplasma pneumoniae

text: Sequencing of the "M. pneumoniae" genome in 1996 revealed it is 816,394 bp in size. The genome contains 687 genes that encode for proteins, of which about 56.6% code for essential metabolic enzymes; notably those involved in glycolysis and organic acid fermentation. "M. pneumoniae" is consequently very susceptible to loss of enzymatic function by gene mutations, as the only buffering systems against functional loss by point mutations are for maintenance of the pentose phosphate pathway and nucleotide metabolism. Loss of function in other pathways is suggested to be compensated by host cell metabolism. In addition to the potential for loss of pathway function, the reduced genome of "M. pneumoniae" outright lacks a number of pathways, including the TCA cycle, respiratory electron transport chain, and biosynthesis pathways for amino acids, fatty acids, cholesterol and purines and pyrimidines. These limitations make "M. pneumoniae" dependent upon import systems to acquire essential building blocks from their host or the environment that cannot be obtained through glycolytic pathways. Along with energy costly protein and RNA production, a large portion of energy metabolism is exerted to maintain proton gradients (up to 80%) due to the high surface area to volume ratio of "M. pneumoniae" cells. Only 12 – 29% of energy metabolism is directed at cell growth, which is unusually low for bacterial cells, and is thought to be an adaptation of its parasitic lifestyle.


title: Mycoplasma pneumoniae

text: Unlike other bacteria, "M. pneumoniae" uses the codon UGA to code for tryptophan rather than using it as a stop codon.


title: Mycoplasma pneumoniae

text: "Mycoplasma pneumoniae" has a reduced metabolome in comparison to other bacterial species.  This means that the pathogen has much fewer metabolic reactions in comparison to other bacterial species such as "B.subtilis" and "Escherichia coli".


title: Mycoplasma pneumoniae

text: Since "Mycoplasma pneuomiae" has a reduced genome, it has a smaller number of overall paths and metabolic enzymes, which contributes to its more linear metabolome. A linear metabolome causes "Mycoplasma pneumoniae" to be less adaptable to external factors.  Additionally, since "Mycoplasma pneumoniae" is a reduced genome, the majority of its metabolic enzymes are essential. This is in contrast to another model organism, "Escherichia coli", in which only 15% of its metabolic enzymes are essential. In summary, the linear topology of "Mycoplasma pneumonaie's" metabolome leads to reduced efficiency in its metabolic reactions, but still maintains similar levels of metabolite concentrations, cellular energetics, adaptability, and global gene expression.


title: Mycoplasma pneumoniae

text: The table above depicts the mean path length for the metabolomes of "M. pneumonaie", "E. coli", "L. lactis", and "B. subtilis". This number describes, essentially, the mean number of reactions that occur in the metabolome. "Mycoplasma pneuomonaie", on average, has a high number of reactions per path within its metabolome in comparison to other model bacterial species.


title: Mycoplasma pneumoniae

text: One effect of "Mycoplasma pneumoniae"’s unique metabolome is its longer duplication time. It takes the pathogen significantly more time to duplicate on average compared to other model organism bacteria. This may be due to the fact that "Mycoplasma pneumoniae’s" metabolome is less efficient than that of "Escherichia coli".


title: Mycoplasma pneumoniae

text: The metabolome of "Mycoplasma pneumoniae" can also be informative in analyzing its pathogenesis. Extensive study of the metabolic network of this organism has led to the identification of biomarkers that can potentially reveal the presence of the extensive complications the bacteria can cause. Metabolomics is increasingly being used as a useful tool for the verification of biomarkers of infectious pathogens.


title: Mycoplasma pneumoniae

text: "Mycoplasma pneumoniae" grows exclusively by parasitizing mammals. Reproduction, therefore, is dependent upon attachment to a host cell. According to Waite and Talkington, specialized reproduction occurs by “binary fission, temporally linked with duplication of its attachment organelle, which migrates to the opposite pole of the cell during replication and before nucleoid separation”. Mutations that affect the formation of the attachment organelle not only hinder motility and cell division, but also reduce the ability of "M. pneumoniae" cells to adhere to the host cell.


title: Mycoplasma pneumoniae

text: "Mycoplasma pneumoniae" parasitizes the respiratory tract epithelium of humans. Adherence to the respiratory epithelial cells is thought to occur via the attachment organelle, followed by evasion of host immune system by intracellular localization and adjustment of the cell membrane composition to mimic the host cell membrane.


title: Mycoplasma pneumoniae

text: Adherence of "M. pneumoniae" to a host cell (usually a respiratory tract cell, but occasionally an erythrocyte or urogenital lining cell) is the initiating event for pneumonic disease and related symptoms. The specialized attachment organelle is a polar, electron dense and elongated cell extension that facilitates motility and adherence to host cells. It is composed of a central filament surrounded by an intracytoplasmic space, along with a number of adhesins and structural and accessory proteins localized at the tip of the organelle.


title: Mycoplasma pneumoniae

text: A variety of proteins are known to contribute to the formation and functionality of the attachment organelle, including the accessory proteins HMW1–HMW5, P30, P56, and P90 that confer structure and adhesin support, and P1, P30 and P116 which are involved directly in attachment. This network of proteins participates not only in the initiation of attachment organelle formation and adhesion but also in motility.


title: Mycoplasma pneumoniae

text: The P1 adhesin (trypsin-sensitive protein) is a 120 kDa protein highly clustered on the surface of the attachment organelle tip in virulent mycoplasmas. Both the presence of P1 and its concentration on the cell surface are required for the attachment of "M. pneumoniae" to the host cell. "M. pneumoniae" cells treated with monoclonal antibodies specific to the immunogenic C-terminus of the P1 adhesin have been shown to be inhibited in their ability to attach to the host cell surface by approximately 75%, suggesting P1 is a major component in adherence. These antibodies also decreased the ability of the cell to glide quickly, which may contribute to decreased adherence to the host by hindering their capacity to locate a host cell. Furthermore, mutations in P1 or degradation by trypsin treatment yield avirulent "M. pneumoniae" cells. Loss of proteins in the cytoskeleton involved in the localization of P1 in the tip structure, such as HMW1–HMW3, also cause avirulence due to the lack of adhesin clustering. Another protein considered to play an important role in adherence is P30, as "M. pneumoniae" cells with mutations in this protein or that have had antibodies raised against P30 are incapable of adhering to host cells. P30 is not involved in the localization of P1 in the tip structure since P1 is trafficked to the attachment organelle in P30 mutants, but rather it may function as a receptor-binding accessory adhesin. P30 mutants also display distinct morphological features such as multiple lobes and a rounded shape as opposed to elongated, which suggests P30 may interact with the cytoskeleton during formation of the attachment organelle.


title: Mycoplasma pneumoniae

text: A number of eukaryotic cell surface components have been implicated in the adherence of "M. pneumoniae" cells to the respiratory tract epithelium. Among them are sialoglycoconjugates, sulfated glycolipids, glycoproteins, fibronectin, and neuraminic acid receptors. Lectins on the surface of the bacterial cells are capable of binding oligosaccharide chains on glycolipids and glycoproteins to facilitate attachment, in addition to the proteins TU and pyruvate dehydrogenase E1 β, which bind to fibronectin.


title: Mycoplasma pneumoniae

text: "Mycoplasma pneumoniae" is known to evade host immune system detection, resist antibiotic treatment, and cross mucosal barriers, which may be due to its ability to fuse with host cells and survive intracellularly. In addition to the close physical proximity of "M. pneumoniae" and host cells, the lack of cell wall and peculiar cell membrane components, like cholesterol, may facilitate fusion (1). Internal localization may produce chronic or latent infections as "M. pneumoniae" is capable of persisting, synthesizing DNA, and replicating within the host cell even after treatment with antibiotics. The exact mechanism of intracellular localization is unknown, however the potential for cytoplasmic sequestration within the host explains the difficulty in completely eliminating "M. pneumoniae" infections in afflicted individuals.


title: Mycoplasma pneumoniae

text: In addition to evasion of host immune system by intracellular localization, "M. pneumoniae" can change the composition of its cell membrane to mimic the host cell membrane and avoid detection by immune system cells. "M. pneumoniae" cells possess a number of protein and glycolipid antigens that elicit immune responses, but variation of these surface antigens would allow the infection to persist long enough for "M. pneumoniae" cells to fuse with host cells and escape detection. The similarity between the compositions of "M. pneumoniae" and human cell membranes can also result in autoimmune responses in several organs and tissues.


title: Mycoplasma pneumoniae

text: The main cytotoxic effect of "M. pneumoniae" is local disruption of tissue and cell structure along the respiratory tract epithelium due to its close proximity to host cells. Attachment of the bacteria to host cells can result in loss of cilia, a reduction in metabolism, biosynthesis, and import of macromolecules, and, eventually, infected cells may be shed from the epithelial lining. M. pneumoniae produces a unique virulence factor known as Community Acquired Respiratory Distress Syndrome (CARDS) toxin. The CARDS toxin most likely aids in the colonization and pathogenic pathways of M. pneumoniae, leading to inflammation and airway dysfunction. In addition, the formation of hydrogen peroxide is a key virulence factor in "M. pneumoniae" infections. Attachment of "M. pneumoniae" to erythrocytes permits diffusion of hydrogen peroxide from the bacteria to the host cell without detoxification by catalase or peroxidase, which can injure the host cell by reducing glutathione, damaging lipid membranes and causing protein denaturation. Local damage may also be a result of lactoferrin acquisition and subsequent hydroxyl radical, superoxide anion and peroxide formation. The cytotoxic effects of "M. pneumoniae" infections translate into common symptoms like coughing and lung irritation that may persist for months after infection has subsided. Local inflammation and hyperresponsiveness by infection induced cytokine production has been associated with chronic conditions such as bronchial asthma and has also been linked to progression of symptoms in individuals with cystic fibrosis and COPD.


title: Mycoplasma pneumoniae

text: The incidence of disease does not appear to be related to season or geography; however, infection tends to occur more frequently during the summer and fall months when other respiratory pathogens are less prevalent. Reinfection and epidemic cycling is thought to be a result of P1 adhesin subtype variation. Approximately 40% of community-acquired pneumonia is due to "M. pneumoniae" infections, with children and elderly individuals being most susceptible, however no personal risk factors for acquiring "M. pneumoniae" induced pneumonia have been determined. Transmission of "M. pneumoniae" can only occur through close contact and exchange of aerosols by coughing due to the increased susceptibility of the cell wall-lacking organism to desiccation. Outbreaks of "M. pneumoniae" infections tend to occur within groups of people in close and prolonged proximity, including schools, institutions, military bases, and households.


title: Mycoplasma pneumoniae

text: "M. pneumoniae" is known to cause a host of symptoms such as primary atypical pneumonia, tracheobronchitis, and upper respiratory tract disease. Primary atypical pneumonia is one of the most severe types of manifestation, with tracheobronchitis being the most common symptom and another 15% of cases, usually adults, remain asymptomatic. Symptomatic infections tend to develop over a period of several days and manifestation of pneumonia can be confused with a number of other bacterial pathogens and conditions that cause pneumonia. Tracheobronchitis is most common in children due to a reduced immune system capacity, and up to 18% of infected children require hospitalization. Common mild symptoms include sore throat, wheezing and coughing, fever, headache, rhinitis, myalgia and feelings of unease, in which symptom intensity and duration can be limited by early treatment with antibiotics. Rarely, "M. pneumoniae" pneumonia results in death due to lesions and ulceration of the epithelial lining, pulmonary edema, and bronchiolitis obliterans. Extrapulmonary symptoms such as autoimmune responses, central nervous system complications, and dermatological disorders have been associated with "M. pneumoniae" infections in up to 25% of cases.


title: Mycoplasma pneumoniae

text: Diagnosis of "Mycoplasma pneumoniae" infections is complicated by the delayed onset of symptoms and the similarity of symptoms to other pulmonary conditions. Often, "M. pneumoniae" infections are diagnosed as other conditions and, occasionally, non-pathogenic mycoplasmas present in the respiratory tract are mistaken for "M. pneumoniae". Historically, diagnosis of "M. pneumoniae" infections was made based on the presence of cold agglutinins and the ability of the infected material to reduce tetrazolium. Causative diagnosis is dependent upon laboratory testing, however these methods are more practical in epidemiological studies than in patient diagnosis. Culture tests are rarely used as diagnostic tools; rather immunoblotting, immunofluorescent staining, hemadsorption tests, tetrazolium reduction, metabolic inhibition tests, serological assays, and polymerase chain reaction (PCR) are used for diagnosis and characterization of bacterial pneumonic infections. PCR is the most rapid and effective way to determine the presence of "M. pneumoniae", however the procedure does not indicate the activity or viability of the cells present. Enzyme immunoassay (EIA) serological assays are the most common method of "M. pneumoniae" detection used in patient diagnosis due to the low cost and relatively short testing time. One drawback of serology is that viable organisms are required, which may overstate the severity of infection. Neither of these methods, along with others, has been available to medical professionals in a rapid, efficient and inexpensive enough form to be used in routine diagnosis, leading to decreased ability of physicians to diagnose "M. pneumoniae" infections.


title: Mycoplasma pneumoniae

text: The majority of antibiotics used to treat "M. pneumoniae" infections are targeted at bacterial rRNA in ribosomal complexes, including macrolides, tetracycline, ketolides, and fluoroquinolone, many of which can be administered orally. Macrolides are capable of reducing hyperresponsiveness and protecting the epithelial lining from oxidative and structural damage, however they are capable only of inhibiting bacteria (bacteriostatic) and are not able to cause bacterial cell death. The most common macrolides used in the treatment of infected children in Japan are erythromycin and clarithromycin, which inhibit bacterial protein synthesis by binding 23S rRNA. Administration of antibiotics has been proven to reduce the longevity and intensity of "M. pneumoniae" infections in comparison to cases left untreated. Additionally, some high-dose steroid therapies have shown to reverse neurological effects in children with complicated infections.


title: Mycoplasma pneumoniae

text: The difficulty in eradicating "Mycoplasma pneumoniae" infections is due to the ability of the bacterium to persist within an individual, as well as the lack of cell wall in "M. pneumoniae", which renders multiple antibiotics directed at the bacterial cell wall ineffective in treating infections. "M. pneumoniae" therefore displays resistance to antimicrobials such as β-lactams, glycopeptides, sulfonamides, trimethoprim, polymixins, nalidixic acid, and rifampin. Antimicrobial drug resistance rates for "Mycoplasma pneumoniae" were determined in clinical specimens and isolates obtained during 2011–2012 in Ontario, Canada. Of 91 "M. pneumoniae" drug-resistant specimens, 11 (12.1%) carried nucleotide mutations associated with macrolide resistance in the 23S rRNA gene. None of the "M. pneumoniae" specimens were resistant to fluoroquinolones or tetracyclines.


title: Mycoplasma pneumoniae

text: Doxycycline can be used for treating "Mycoplasma pneumonia", which usually presents with persistent, incessant cough that lasts for several weeks and shows interstitial pulmonary infiltrates on a chest x-ray.


title: Mycoplasma pneumoniae

text: Vaccine design for "M. pneumoniae" has been focused primarily on prevention of host cell attachment, which would prevent initiation of cytotoxicity and subsequent symptoms. To date, vaccines targeted at the P1 adhesin have shown no reduction in the onset of infection, and some vaccine trials resulted in worsened symptoms due to immune system sensitization. Recent experiments in mouse models have linked this phenomenon to immune system sensitization by the lipid moieties of "M. pneumoniae" lipoproteins. Introduction of peptides that block adhesion receptors on the surface of the host cell may also be able to prevent attachment of "M. pneumoniae".


title: Mycoplasma pneumoniae

text: Transmission of "Mycoplasma pneumoniae" infections is difficult to limit because of the several day period of infection before symptoms appear. The lack of proper diagnostic tools and effective treatment for the bacterium also contribute to the outbreak of infection. Using network theory, Meyers "et al." analyzed the transmission of "M. pneumoniae" infections and developed control strategies based on the created model. They determined that cohorting patients is less effective due to the long incubation period, and so the best method of prevention is to limit caregiver-patient interactions and reduce the movement of caregivers to multiple wards.


title: Sardaar Gabbar Singh

text: Sardaar Gabbar Singh is a 2016 Indian Telugu-language action comedy film directed by K. S. Ravindra, based on an original story and screenplay by Pawan Kalyan. A sequel to "Gabbar Singh" (2012), it stars Pawan Kalyan reprising his role from the previous film alongside Kajal Aggarwal and Sharad Kelkar (his Telugu debut). In the film, brave policeman Gabbar Singh (Kalyan) rescues the residents of Rathanpur when they are forced to face the wrath of Bhairav Singh (Kelkar), who unceremoniously usurps their land.


title: Sardaar Gabbar Singh

text: Initially titled "Gabbar Singh 2", the film began production on 21 February 2014 in Hyderabad with Sampath Nandi as the film. He later walked out of the film and was then replaced by Ravindra. Principal photography began in May 2015 at Maharashtra. The film was renamed "Sardaar Gabbar Singh" in mid-2015. Filming took place extensively in Hyderabad, Secunderabad, Gujarat and Kerala before concluding in March 2016. Devi Sri Prasad composed the film's music, while Arthur A. Wilson and Gautham Raju served as the cinematographer and editor, respectively.


title: Sardaar Gabbar Singh

text: "Sardaar Gabbar Singh" was released worldwide on 8 April 2016, along with a Hindi dubbed version, on a screen count of 2,600 thus becoming the second biggest Telugu release after "" (2015). It received overwhelmingly negative reviews from critics, but still became a commercial success grossing over ₹140 crore on a budget of ₹75 crore.


title: Sardaar Gabbar Singh

text: A kingdom called Ratanpur is taken ruthlessly by a crime lord Bhairav Singh. The princess of the kingdom is named Arshi Devi, and the whole kingdom is afraid of Bhairav Singh. Then a maverick cop Sardaar Gabbar Singh came along and put an end to all of the worryings.


title: Sardaar Gabbar Singh

text: In October 2012, Pawan Kalyan agreed to act in a film produced by Sharrath Marar, the former CEO of MAA TV, after completing work on Trivikram Srinivas' "Attarintiki Daredi" (2013). Before the theatrical release of "Dabangg 2" (2012), producer Bandla Ganesh registered the title "Gabbar Singh in Hyderabad" at the Andhra Pradesh Film Chamber which fuelled speculations that this would be the remake of "Dabangg 2" and the sequel of "Gabbar Singh" (2012), which itself was the official Telugu remake of "Dabangg" featuring Kalyan, Shruti Haasan and Abhimanyu Singh reprising the respective roles played by Salman Khan, Sonakshi Sinha and Sonu Sood in the original. Devi Sri Prasad and Jayanan Vincent were retained as the film's music director and cinematographer from the prequel's technical crew. Sampath Nandi was chosen to direct the film and Marar was announced to execute the film's production. At the same time, the film was reported to have a fresh storyline.


title: Sardaar Gabbar Singh

text: Besides producing the film, Kalyan himself wrote the story and made it clear to his team that "Gabbar Singh" sequel would be based on an original script and would not be a remake of "Dabangg 2". Considering the response generated by "Attarintiki Daredi" and the subsequent change in his on-screen image, Kalyan put the pre-production activities on hold and made changes to the script. Some elements of family drama were added, and the aggression and expressions of the lead character were toned down. Kalyan also opted to complete his work on Kishore Kumar Pardasany's "Gopala Gopala" (2015) first and Nandi meanwhile planned to produce the film "Galipatam" (2014) on a low budget.


title: Sardaar Gabbar Singh

text: The film's official launch ceremony took place on 21 February 2014 at Hyderabad and was tentatively titled "Gabbar Singh 2". L. Satyanand supervised the film's script and was assisted by Sridhar Seepana and Kishore Gopu. Harish Pai was chosen as the film's creative head and Gautham Raju was signed to edit the film. Due to delay in finalising the female lead, Kalyan was reportedly upset and joined the sets of "Gopala Gopala" and start works related to his political outfit Jana Sena Party. The crew of the film were instructed to regroup when Kalyan summons them. Nandi walked out of the film in November 2014 and refused to reveal the reasons, saying that he is not authorised to speak about the same. Vincent suggested K. S. Ravindra to Kalyan who was impressed with his narrative skills and finalised him as the new director. Sai Madhav Burra was chosen to write the film's dialogues.


title: Sardaar Gabbar Singh

text: The film was renamed to "Sardaar" in late July 2015 in order to avoid paying royalty to the title "Gabbar Singh" to a Mumbai-based studio that held the rights of the title. Kalyan chose this title since the character of Gabbar Singh played by Amjad Khan was referred to by his henchmen as Sardaar in "Sholay" (1975). Eros International announced on 15 August 2015 to IANS that it would co-produce the film in association with Pawan Kalyan Creative Works and Northstar Entertainment Pvt. Ltd. and the film's title was renamed to "Sardaar Gabbar Singh". Arthur A. Wilson replaced Vincent as the film's cinematographer due to clash of opinions between the latter and Ravindra.


title: Sardaar Gabbar Singh

text: Kalyan sported a long hair and thick beard for a few important sequences in the film and a clean shaven look for the rest of the film. The makers considered to sign a new actress after considering Samantha Ruth Prabhu, Pranitha Subhash and Anushka Sharma for the same. Shruti Haasan and Asin were approached to play the female lead in the film. Navneet Kaur Dhillon was reported to be signed as the female lead in late May 2014. Akshara Haasan was approached for the same later who declined the offer gently saying that it would raise expectations on her next films and so responsibilities. Deepika Padukone, Sonakshi Sinha, Parineeti Chopra and Katrina Kaif were approached for the female lead role who turned down the offer citing unavailability of bulk dates and Anisha Ambrose, who made a cameo appearance in "Gopala Gopala", was chosen by Kalyan as the female lead.


title: Sardaar Gabbar Singh

text: Ambrose was trained in the nuances of acting, perfecting dancing and several other aspects in the workshop sessions conducted by Ravindra in April 2015 before joining the film's sets. During the shoot of the first schedule, the makers saw Sharad Kelkar performance in a soap opera and approached him to play the antagonist. Kelkar's inclusion in the cast was confirmed in June 2015. Charandeep, known for his work in the films "Jilla" (2014) and "Pataas" (2015), was signed as one of the antagonists in the film. Kajal Aggarwal, who initially declined to be a part of the film two years ago due to scheduling conflicts, was approached again in August 2015 for the female lead role. She met the film's unit and gave her consent, marking her first collaboration with Kalyan.


title: Sardaar Gabbar Singh

text: Kabir Duhan Singh confirmed his inclusion in the film's cast after completing a schedule and said that he would be seen as the one who handles all the activities of Kelkar in the film. During the scripting stage, there was a shorter role for a second, parallel female lead which was developed by the creative team on par with the first female lead after the shooting began. A source from the film's unit called it a "very energetic and active character". Trisha Krishnan was approached for the same in mid April 2015. Raai Laxmi inclusion in the film's cast was confirmed on 2 September 2015. She was reported to play a crucial role in the film and to be appeared in a special song along with Kalyan. Speaking about her role, Laxmi said that her role is a crucial one and shall stay till the end of the film, adding that it "starts off as something in the beginning, it transitions into something else altogether as the movie unfolds".


title: Sardaar Gabbar Singh

text: Sanjjanaa was signed to play the role of a Gujarati princess in the film who subserviently follows her husband. She called it an important character with a "traditional and royal persona", adding that it is not "one of those blink-and-miss roles" and will be seen right from the start to the end. The film's unit revealed that her wardrobe consists largely of nine-yard sarees and heavy jewellery. In mid March 2016, Kajal revealed that she would be seen as a princess, who was from another era dressed in exquisite Indian attires which is a very contemporary character unlike Indu from "Magadheera" (2009).


title: Sardaar Gabbar Singh

text: Anand Sai and Rajesh and Archa Mehta were signed as the film's art director and costume designer respectively. Bhaskar Raju was signed as the film's production controller. The film's shoot began on 29 May 2015 at Malshej Ghat in Maharashtra. Some important sequences of the first schedule were shot in a special village set and Kalyan was expected to join the sets from the first week of June. The film's unit took a break after completing the first schedule since Kalyan was busy with his political commitments. A fight sequence featuring Kalyan and others were shot at the Aluminium factory located in Gachibowli in late July 2015. The second schedule was wrapped up on 5 August 2015, and filming continued at Ameerpet in mid August 2015.


title: Sardaar Gabbar Singh

text: The third schedule commenced on 8 September 2015 at Ramoji Film City, Hyderabad where key scenes were shot. Kalyan joined the film's sets on the next day and the schedule lasted till the end of September 2015. Filming of the item number commenced on 30 September 2015 in a set erected by Brahma Kadali at Ramanaidu Studios in Nanakramguda. Laxmi however chose not to call it an item number and termed it an "inspirational song that will everyone will love and remember for a long time". The song's shoot was wrapped up on 8 October 2015. Kalyan and the film's unit left for Gujarat in late October 2015 for location scouting. They returned to Hyderabad shortly and the next schedule commenced from 1 November 2015.


title: Sardaar Gabbar Singh

text: Few scenes on Kalyan, Ali, Brahmaji and others were filmed near the Le Palais Royal and Crown Villa Gardens in Secunderabad. A 25-day long schedule began from 15 November 2015 at Gujarat. Ali and Brahmaji joined the film's shoot shortly. Kajal joined the film's sets at Vadodara on 27 November 2015 and few scenes featuring her and Kalyan were filmed. She completed her part in the schedule on 4 December 2015. Kabir Singh Duhan joined the film's sets on the next day and scenes featuring him and Kalyan were filmed. After Kalyan completed his portions and left for Hyderabad, Marar said that scenes on the remaining cast would be filmed at Rajkot in Gujarat.


title: Sardaar Gabbar Singh

text: The final schedule, starting on 4 January 2016 at Hyderabad, was announced to last for a month and on its completion, the film's post-production activities were planned to be commenced. A village set worth 20 million was erected in Hyderabad for the same in the place where "Gabbar Singh" was filmed. A schedule of 20 days was planned and all the principal cast participated in the shoot. The set featured an elaborate railway track, a market, and a group of houses and the cost escalated to 45 million. Upon its completion, the next schedule commenced in Kerala in February 2016 and few portions were filmed at the Athirappilly Falls. Upon its completion, the film's shoot continued in Hyderabad and by mid-February 2016, 90% of the film's talkie part was wrapped up.


title: Sardaar Gabbar Singh

text: After filming a marriage sequence on Kalyan and Kajal, a horse fair sequence, which forms a part of the climax, was filmed at Ramoji Film City in late February 2016. 100 horses, horsemen, many junior artists and a crew supporting three units worked simultaneously. 1000 members formed the teams and 40 artists from the film were present along with the horses, ten vintage cars, and many luxury cars. The pre-climax sequences were filmed in early March 2016 and a set was erected for the same. An elaborate sequence paying homage to Chiranjeevi was performed by Kalyan who was trained by a choreographer to ensure perfection. The filming of the climax sequences was resumed shortly. A duet on Kalyan and Kajal was filmed at Switzerland from 24 March 2016, upon whose completion, the principal photography was wrapped up.


title: Sardaar Gabbar Singh

text: The film's soundtrack is composed by Devi Sri Prasad, who also scored music for its predecessor "Gabbar Singh" (2012). The soundtrack album features six tracks, with lyrics written by Ananta Sriram, Ramajogayya Sastry and Prasad himself. He remixed a popular song "Naa Koka Baagunda" from the Chiranjeevi-starrer "Kondaveeti Raja" (1986) for this film. Although being rumoured that the soundtrack will be released at a launch event held in Amaravati (the new capital city of Andhra Pradesh), the soundtrack was released on 20 March 2016, at H.I.C.C. Novotel in Hyderabad. Pawan Kalyan's elder brother, Chiranjeevi attended as chief guest. The album was released by Eros Music, the same day on streaming platforms.


title: Sardaar Gabbar Singh

text: The album received mixed reviews from critics. "123Telugu" gave a positive review stating that the film has "a well packaged album from DSP". "Behindwoods" gave 2.5 out of 5 and stated "an average album from DSP". "Indiaglitz" gave 2.75 out of 5 and stated "A complete album for the masses and classes alike". "Moviecrow" gave 2.75 out of 5 stating "DSP's Sardaar Gabbar Singh has nothing extraordinary to offer and the tunes are largely tepid and run of the mill one". "Bollywood Life" gave 2.5 out of 5 stating "The album of Sardaar Gabbar Singh is decent but was bit of a let down".


title: Sardaar Gabbar Singh

text: On the occasion of Pawan Kalyan's birthday (2 September 2015), the makers unveiled the first look poster and teaser through social media. On 14 January 2016, coincidinge with Sankranthi, the producer Sharath Marar unveiled three posters and a teaser though social media and YouTube. The second teaser crossed one million views upon its release through YouTube. Another teaser of the film was launched on 14 March 2016, through Telugu and Hindi, was well received by audiences. The trailer of Sardaar Gabbar Singh, was released on 20 March 2016, which coincided the audio launch function held in Hyderabad.


title: Sardaar Gabbar Singh

text: "Sardaar Gabbar Singh" was released on 8 April 2016, coinciding with Ugadi. However, in order to avoid clash with Allu Arjun's "Sarrainodu" and Mahesh Babu's "Brahmotsavam", the makers postponed the release to 11 May 2016, the date where its predecessor "Gabbar Singh" (2012) was released. In January 2016, the makers rescheduled the release date to 8 April 2016. On 14 March 2016, Eros International which acquired the theatrical rights, also planned to release a Hindi dubbed version on the same day of its Telugu original's release date. Kalyan said in a statement that this film has a universal story and film making cannot be confined to a certain area or demographics and our film attempts a unique connect with India, especially the Hindi belt.


title: Sardaar Gabbar Singh

text: "Sardaar Gabbar Singh" was released in more than 2600 screens worldwide, with 1800 theatres across India, and 800 theatres overseas, thus becoming the second biggest release from Telugu cinema, after "" (2015). The advance bookings of the film kickstarted on 4 April 2016 before release, which had 100% of tickets being sold in the opening day, and 85% of the tickets in the opening weekend. The film had a biggest release in USA, with 100 theatres across 14 states, and was premiered on 7 April 2016, before the Indian release. Also the film is releasing globally in 42 countries marking the first Telugu film to release in that many countries.


title: Sardaar Gabbar Singh

text: Eros International acquired the worldwide theatrical, digital, Hindi dubbing and music rights, apart from co-producing the film. The distribution rights of Nizam region were acquired by Dilip Tandon of Indra Films for 21 crore. The Ceded rights were sold to Narasimha Prasad Films for 10.5 crore; Vizag theatrical rights were sold to Kanthi Krishna Films for 7.2 crore. Godavari East and West thearical rights were sold to Anusri Films for 5.4 crore and Shanumka Films for 4.4 crore respectively. Guntur theatrical rights were sold for SV Cinemas for 5.5 crore. Krishna theatrical rights were sold to Tollywood Creations to an amount of 4.3 crore, while Nellore rights of the film were sold to SLNS Pictures for 2.7 crore. Karnataka theatrical rights were sold to Mars Pictures for 8.5 crore. Bhadrakali Pictures acquired the Tamil Nadu theatrical rights for 1.2 crore and The Hindi dubbing and North India release rights were secured by Eros for 6 crore. Overseas theatrical rights were sold to iDream Media for 10.5 crore; thus the film earned 87.2 crore from theatrical rights alone.


title: Sardaar Gabbar Singh

text: The television rights of the film were secured by Star India for 21 crore, along with its Hindi dubbed version. The film had a premiere on Star Maa on 17 July 2016, where it registered a TRP rating of 15.24, close to "" and "Srimanthudu" (which had scored TRP ratings of 21.84 and 21.24 respectively).


title: Sardaar Gabbar Singh

text: "Sardaar Gabbar Singh" registered a opening of 35 crore from the domestic box office (Andhra Pradesh and Telangana), with a share of 26 crore for its distributors. The film became the biggest opener for a Kalyan-starrer, surpassing "Attarintiki Daredi" (2013), which earlier earned 26.75 crore at the box office.


title: Sardaar Gabbar Singh

text: Further, Sardaar Gabbar Singh, surpassed "Srimanthudu" (2015), to become the second highest opener, after "" (2015). However, the mixed word-of-mouth, have affected the collections, where it saw a dip in the box office in the second day. The film managed to collect 57 crore in the second weekend. As of 10 days, the film grossed approximately ₹140 crore against a budget of ₹75 at the worldwide box office by the end of its lifetime. With a total share of 80 crore to its distributors.


title: Sardaar Gabbar Singh

text: The film premiered in 300 screens in North America on 7 April, where it collected $615,853 (4.10 crore) at the U.S. box office. As of 10 days, the film has earned $1,058,000 (7.04 crore).


title: Sardaar Gabbar Singh

text: Writing for "The Times of India", Pranita Jonnalagada gave the film 2.5 out of 5 and stated, "This film surely is about a lot of guts (such lazy direction, anyone?), guns (even in songs!) and love (Pawan Kalyan has adorably dedicated this film to his fans)." A critic from "Sify" gave 2.75 out of 5 and stated "Pawan's show and Kajal are saving grace but narration is a letdown. Despite a good interval bang, post interval it drags on without much redeeming factors." Sreedhar Pillai of "Firstpost" summarised "Sardaar Gabbar Singh is strictly targeted at Pawan Kalyan’s huge fan base. It is all sound and fury, with no story and goes on and on." Karthik Keramalu of News18 gave the film 2.5 out of 5 satting that "The film's story loses its focus mid-way." Nandini Ramanath of "Scroll", stated "Kalyan, who has written the movie, doesn’t only want to please his fans. He appears to be campaign mode (In real life, Kalyan is also a politician and is the founder of the Jana Sena Party). Scenes in "Sardaar Gabbar Singh" stink of electioneering and dialogues are of pure sloganeering. At 163 minutes then, "Sardaar Gabbar Singh" is one of the longest propaganda videos out there." "Indiaglitz" gave the film 3 out of 5 stating, "Pawan's one-man show.  For those of you looking for him to do non-heroic comedy in khaki, this film has much stuff on platter."


title: Sardaar Gabbar Singh

text: A critic from "The Indian Express", criticised the screenplay stating that "Sardaar Gabbar Singh is so lazily written that it is literally a struggle to sit through the film." Haricharan Pudipeddi of Hindustan Times gave a rating of 2 out of 5 stating "Even though Pawan Kalyan the actor shines in Sardaar Gabbar Singh, the writer fails miserably, and there’s so much he needs to learn from this debacle." Suresh Kavirayani of "Deccan Chronicle" gave the film 2.5 out of 5 stating "The film leaves one with the feeling that something was missing, perhaps the magic of Pawan Kalyan." Sangeetha Devi Dundoo of "The Hindu" stated "The film lacks a taut screenplay that can string together crowd-pleasing moments." "Bollywood Life" gave the film 2 out of 5 stating "Sardaar Gabbar Singh is definitely not worth the hype it has been receiving." "Behindwoods" gave the film a rating of 2.25 out of 5 stating, "Pawan Kalyan show all the way! But that's just not enough." "Daily News and Analysis" gave the film 2.5 out of 5 stating "It may be Pawan Kalyan’s take on the classic "Sholay," but this movie is only for Pawan Kalyan fans."


title: Inishmore

text: Inishmore ( , or ) is the largest of the Aran Islands in Galway Bay, off the west coast of Ireland. With an area of and a population of 762 (as of 2016), it is the second-largest island off the Irish coast (after Achill) and most populous of the Aran Islands.


title: Inishmore

text: The island is in the Irish-speaking Gaeltacht and has a strong Irish culture. Much of the island is karst landscape and it has a wealth of ancient and medieval sites including Dún Aonghasa, described as "the most magnificent barbaric monument in Europe" by George Petrie.


title: Inishmore

text: Before the 20th century, the island was usually called "Árainn" or "Árainn Mhór", which is thought to mean "kidney-shaped" or "ridge". It was anglicized as 'Aran', 'Aran More' or 'Great Aran'. This has caused some confusion with Arranmore, County Donegal, which has the same Irish name. The name 'Inishmore' was "apparently concocted by the Ordnance Survey for its map of 1839" as an anglicization of "Inis Mór" ("big island"), as there is no evidence of its use before then.


title: Inishmore

text: Because the island is in the Gaeltacht, "Árainn" is the only legal placename in Irish or English as declared in the Official Languages Act 2003.


title: Inishmore

text: The island is an extension of the Burren. The terrain of the island is composed of limestone pavements with crisscrossing cracks known as "grikes", leaving isolated rocks called "clints".


title: Inishmore

text: The limestones date from the Visean period (Lower Carboniferous), formed as sediments in a tropical sea approximately 350 million years ago, and compressed into horizontal strata with fossil corals, crinoids, sea urchins and ammonites. Glaciation following the Namurian phase facilitated greater denudation.


title: Inishmore

text: The result is that Inis Mór and the other islands are among the finer examples of Glacio-Karst landscape in the world. The effects of the last glacial period (the Midlandian) are most in evidence, with the island overrun by ice during this glaciation. The impact of earlier Karstification (solutional erosion) has been eliminated by the last glacial period. So any Karstification now seen dates from approximately 10,000 years ago and the island Karst is thus recent.


title: Inishmore

text: Solutional processes have widened and deepened the grikes of the limestone pavement. Pre-existing lines of weakness in the rock (vertical joints) contribute to the formation of extensive fissures separated by clints (flat pavement like slabs). The rock karstification facilitates the formation of subterranean drainage.


title: Inishmore

text: The island supports arctic, Mediterranean and alpine plants side by side, due to the unusual environment. Like the Burren, the Aran islands are known for their unusual assemblage of plants and animals.


title: Inishmore

text: The grikes (crevices) provide moist shelter, thus supporting a wide range of plants including dwarf shrubs. Where the surface of the pavement is shattered into gravel, many of the hardier Arctic or alpine plants can be found.


title: Inishmore

text: But when the limestone pavement is covered by a thin layer of soil, patches of grass are seen, interspersed with plants like the gentian and orchids.


title: Inishmore

text: Insects present include the butterfly the pearl-bordered fritillary ("Boloria euphrosyne"), brown hairstreak ("Thecla betulae"), marsh fritillary ("Euphydryas aurinia") and wood white ("Leptidea sinapis"); the moths, the burren green ("Calamia tridens"), Irish annulet ("Gnophos dumetata") and transparent burnet ("Zygaena purpuralis"); and the hoverfly "Doros profuges".


title: Inishmore

text: Inis Mór today is a major tourist destination, with bed and breakfast accommodation scattered across the island. Private minibuses, horse-drawn carriages and bicycles are the main methods of getting about for the numerous tourists who visit the island in the summer months.


title: Inishmore

text: There is a small museum illustrating the history of Dún Aonghasa and its possible functions, while the Aran Sweater Market is a focal point for visitors who can trace the culture and history associated with the Aran sweater through the on-site museum. Nearby are a Neolithic tomb and a small heritage park at Dún Eochla, featuring examples of a traditional thatched cottage and poteen distillery.


title: Inishmore

text: The "Tempull Breccain" (Church of Brecan), commonly called the Seven Churches of Aran, is a complex of churches and other buildings dedicated to the 5th-century Saint Brecan, once a popular destination for pilgrims. In the centre of the island, at its highest point is the Inishmore Lighthouse, it was decommissioned in 1857 and replaced by the lights at Eeragh and Inisheer.


title: Inishmore

text: The island plays host to Ted Fest each year. Established in 2004, it is a celebration of the sitcom "Father Ted". Festival goers dress as their favourite characters, watch their favourite episodes and take part in various "Ted" related events and competitions.


title: Inishmore

text: Diving is possible. A particularly popular location for this is Poll na bPéist (hole of worms/sea monsters), located at the southern coast of the island, which is a large naturally formed rectangular pool communicating via underground channels with the sea. Since 2012, Inis Mór has hosted an event as part of the Red Bull Cliff Diving World Series.


title: Inishmore

text: The island is serviced by Aran Ferries ferry from Rossaveal and Doolin. These are passenger-only ferries; cars and heavy goods are transported on unscheduled services.


title: Inishmore

text: Aer Arann Islands runs daily scheduled flights from Inis Mór Aerodrome to Connemara Airport using Britten Norman Islander aircraft.


title: Inishmore

text: The island features heavily in Martin McDonagh's play "The Lieutenant of Inishmore". McDonagh would also use Inishmore as a filming location for his film "The Banshees of Inisherin".


title: Inishmore

text: Inis Mór was used as a recording location for the 1997 film "The Matchmaker" and the 2010 film "Leap Year".


title: Inishmore

text: The island appeared on the premiere episode of "The Amazing Race 12" with teams needing to find Teampall Bheanáin after they arrived.


title: Inishmore

text: The music video for Dermot Kennedy's "For Island Fires and Family" (video released 10 January 2019) was filmed entirely on Inis Mór.


title: Inishmore

text: The table below reports data on Inis Mór's population taken from "Discover the Islands of Ireland" (Alex Ritsema, Collins Press, 1999) and the census of Ireland.


title: Cheaper by the Dozen

text: Cheaper by the Dozen is a semi-autobiographical novel written by Frank Bunker Gilbreth Jr. and Ernestine Gilbreth Carey, published in 1948. The novel recounts the authors' childhood lives growing up in a household of 12 children. The bestselling book was later adapted into a feature film by Twentieth Century Fox in 1950 and followed up by the sequel, "Belles on Their Toes" (1950), which was adapted as a 1952 film.


title: Cheaper by the Dozen

text: The book tells the story of time and motion study and efficiency experts Frank Bunker Gilbreth and Lillian Moller Gilbreth, and their children as they reside in Montclair, New Jersey, for many years. Lillian Gilbreth was described in the 1940s as "a genius in the art of living".


title: Cheaper by the Dozen

text: The best-selling biographical novel was composed by two of the children, who wrote about their childhoods. Gilbreth's home doubled as a sort of real-world laboratory that tested her and her husband Frank's ideas about education and efficiency. The book is more of a series of stories, many of which are humorous, with little overarching narrative.


title: Cheaper by the Dozen

text: The title comes from one of Frank Sr.'s favorite jokes: it often happened that when he and his family were out driving and stopped at a red light, a pedestrian would ask, "Hey, Mister! How come you got so many kids?" Gilbreth would pretend to ponder the question carefully, and then, just as the light turned green, would say, "Well, they come cheaper by the dozen, you know", and drive off.


title: Cheaper by the Dozen

text: At several points in the book, a total number of children is spoken of as being 12. In real life, although the Gilbreths had 12 children who survived infanthood, only up to 11 were living at the time of the stories. In fact, when Mary died of diphtheria at age five, seven of her siblings were not yet born, so there never were 12 children alive at the same time. The only chapter that mentions Mary by name is the one that tells the stories of the children's births; otherwise, she is not mentioned and her absence is not explained. It was not until the sequel, "Belles on Their Toes", was published in 1950 that Mary's death is mentioned in a footnote. In the rest of the book, only the 11 children who lived to adulthood are mentioned by name. From oldest to youngest, they are Anne, Ernestine (Ern), Martha (Mart), Frank Jr., Bill, Lillian (Lill), Fred, Dan, John (Jack), Bob, and Jane.


title: Cheaper by the Dozen

text: The stories in the book are organized topically. They skip around in time, and the details of the timing are not always made clear. For example, Bill is mentioned as having been six-years-old at the time of the story in which he honks the car horn while his father is under the hood trying to fix the engine. This would have been around 1919, before the three youngest children were born, though this detail is not mentioned.