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Check Out Our Civil Rights Act of 1964 Essay

The civil rights policy entails legislations and struggle to abolish racial discrimination against African Americans particularly those living in the Southern parts of America and other less advantaged groups in the country. This movement is at times referred to as the reconstruction era. It was a major breakthrough in 1964 when the policy was finally signed into law.

The issue of the Civil Rights Act of 1964 helps in appreciation of the struggle that the African Americans and other less advantaged groups had to go through to ensure that their civil rights were taken care of. The story behind this great achievement is quite an interesting one.  This policy has finally taken America through great changes in social, democratic and economic life.

Brief History

Civil Rights Act of 1964 came to birth during the reign of John F. Kennedy as the president of the United States of America. Kennedy was elected into the post in 1960. Formerly, Kennedy was not a big supporter of the issue of civil rights. In 1957, he opposed Eisenhower’s act (Wright).

As the new president, Kennedy was challenged by the facts that were undoubtedly indisputable. These facts were presented by an organization that was formed in 1960 to analyze Civil Rights issue in the U.S; that was the Civil Rights Commission. This commission discovered that African American Housing was considered unacceptable. They found out that African American life expectancy was less than compared to the whites by seven years. Another finding was that African American infant mortality rate was twice that of the white people. Moreover, it was very hard for African Americans to get mortgages from mortgage lenders. As a matter of fact, value of property was considered to go substantially down if a family of an African American moved in a neighborhood that was not a ghetto.

John F. Kennedy gave a very passionate speech and made these alarming facts known to the American public. On the background, the people of Eastern Europe were being subjected to bad treatment when Soviet government was in charge. Americans had constantly condemned the Russians over this matter of inhumane act against people of Eastern Europe, yet in their backyard issues of unfairness in terms of race and skin color have been taking place. The irony of the situation is that same issues of inequality that Americans condemned in Russia were clearly present in the United States.

At this time, Cuban missile crisis had taken much of Kennedy’s time and issues like Civil Rights were not a priority for the government. At some point this issue had been voted at the bottom of the important issues that the government was expected to attend to. Indeed there was a challenge for Kennedy in terms of  proceeding with the solution to the discrimination problem while this matter was so unpopular among politicians. Another problem was that Kennedy had won the election by a very small margin and therefore did not have a popular mandate to make any decision. Also there was the time of the Vietnam War issue though not officially assented. This consumed the government’s time (Wright).

Kennedy’s assassination was a shocker to the world. Lyndon Johnson, who was Kennedy’s vice president, was sworn in as president. Johnson had fought against full implementation of the Civil Rights Act in 1957, despite this fact he came to understanding that something needed to be done to improve the lives of the African Americans within the American society He used this occasion to push forward the Civil Rights Act of 1964. This cause was a part of Johnson’s vision for America.

The seeds of this Act were planted by Kennedy; Johnson strongly believed that he  had to ensure that this Act was pushed forward to celebrate Kennedy’s life Moreover, during this period the rise of strong activism from Martin Luther King and Malcolm X, as well as similar persons, who believed that the gain of Civil Rights needed to have a more militant approach.  During the 1950s this issue was given a passive approach. The ghettos of the Northern Cities were beginning to move towards militancy. The society had undergone transformation in a very short time. Johnson took notice of this and step into action to prevent any occurrence of unrest in the country.

 The passing of this bill was owed partially to the death of Kennedy. Apparently, no one could have attempted to block Kennedy’s bill at this time because the act would have gone against the mood of the public. Despite this fact, the bill had to actually survive the test of attempts to stop it in the congress. Johnson took to the fore front to fight for this bill. It would be inappropriate for anybody to fight against the wishes of the late president. Everyone was challenged on their patriotism. Johnson appealed to the public that was still traumatized by the murder of their president to gain their support. In order to win over the hard Southerners, he promised them that he would not allow the bill to accommodate anyone who would try to use it as an excuse to live an easy life irrespective of their color. By the beginning of 1964, the public opinion about Civil Rights had begun to change. 68% of the public now substantially supported the Civil Rights Act. The Act was signed by President Johnson in July 1964 (Wright).

Many people from the southern regions were dubious about the Act. It is probable that Johnson could reach the people of South because he originally was from the South. Ironically, the African Americans were at the fore front criticizing the act. They claimed that the act did not address everything they had been fighting for.  There were riots organized by African Americans in the northern region. Long after they formed a party called Mississippi Freedom Democratic Party,  they demanded for seats in the Democratic Party convention. Johnson was worried with the fact that African Americans failed to support this act.

Despite the protests, it is now believed that the 1964 Act was a very important ingredient to the American social and political advancement. This act is considered the greatest achievement made by Johnson during his term. Johnson always tried to justify the morality of his acts and condemned the immorality of any form of discrimination. His main wish and dream was to improve the American society and the Civil Rights Act was certainly the way forward.

The events that led to establishment of the Act date back to the earlier years when Europeans settled in North America. Black people were oppressed and enslaved by white people. Despite the revocation of slavery after the civil war, whites continued to be superior. At the beginning of the 20th century, African Americans were not allowed to associate with Whites in various institutions and accommodation areas. They were not to mix in public places like schools, hotels, restaurants, cars, beaches, recreational facilities, as well as many other places. Africans were considered lesser people and were constantly intimidated. In some public places, there were notices like, “Africans and dogs not allowed”. There were also cases of assault; workers for employment were selected on the basis of racial identity. Blacks were not offered same opportunities as the whites. Rights of citizenship like voting were not availed to the African Americans.

White and black liberal reformers strived to abolish these acts of oppression. In 1940, a renewed effort to fight for black rights was started. Philip Randolph threatened to organize a march of the blacks if President Roosevelt did not act to stop racial discrimination in the military forces and employment. Roosevelt agreed and formed a committee to look into employment practices.

Another contributing factor was the movement of blacks to the Northern and Western cities to work at the defense-related jobs. This movement increased in the 1950s and 1960s and highly boosted thevoting power of African Americans. The black soldiers who were serving abroad during the World War II witness less discrimination on racial ground. They therefore came back home determined to fight discrimination. After the war, civil rights supporters encouraged further signs of liberal reform. President Truman recognized that racial discrimination at home contradicted the claims of Americans to foster free world. In order to address the black votes, he ordered desegregation of the armed forces and called on the federal laws to improve civil rights.

Activists operated from the grassroots in an attempt to end school segregation. This was faced by challenges like the attempts to assassinate black leaders, as well as  other problems. One ruling that is considered a landmark in the American racial relations was the ruling of 1954. In 1954, grass root activists like Rosa Parks started a large scale bus boycott. Rosa was arrested for defying the rule that blacks had to move to the back when the whites did not get a seat at the front. Montgomery movement catalyzed the rise of rev Martin Luther King Jr. to lead the civil rights movement. Escalating violence against blacks in the south disheartened supporters of the racial justice during the year 1950, courts joined rights activists while adding the pressure to speed up the establishment of civil rights act.

The nature of the society in the United States also hastened the adoption of the civil rights act legislation. The minority groups began to be more vocal about and convincing in their demands. This made the Whites to begin to see the need to grant the way to civil rights law.

Historical pressure had a big influence on the government to enact the law. Dating from the slavery times, the rights of the blacks had been placed under the feet. It took a long time for activists to pump enough pressure on the authorities to see to the assent of the civil rights law (Wright).

Political factors influenced various groups of people in different ways. The way John F. Kennedy struggle to make this point sensible to distinct groups had a great impact on the way people responded to the call to support the civil rights act. Being a presidential aspirant, Kennedy had to carefully touch on some issues concerning the Civil Rights Act. In order to address the African American votes, Lyndon Johnson had to move on with the Kennedy legacy which was to ensure that what he started was finished (Wright)

The civil movement is an issue that was of gradual application from the 19th century. The activities of the civil rights leaders were heightened in 1945 -1950. The adoption attempts and rulings of 1957 to 1964 can be termed as the times the civil rights issue was widely spoken of in the public domain. When John F. Kennedy became the president in 1960, this issue took the center stage and by 1964, the new law was unveiled to the public. One thing led to another until the bill was finally assented to.

The Civil Rights Act became considerably effective after the time of implementation. All the statements that condemn the racial discrimination were put forward. The act did not come in effect immediately, for instance, there was a complaint from the African American community that the act did not fully address the crucial issues that affected them. The act had to undergo a number of amendments to accommodate all the needs of the citizens. Example is the 1991 amendment which tried to address, among others, employment discrimination cases. It is clear that the act had to go through gradual processes of adoption before it was finally suitable for every person. Some schools still have issues after the implementation, for instance in the south, , only 1% racial balance was achieved.

Main Statements of the Act

These are the main statements that constituted the civil rights act of 1964. They were fighting for equality in all aspects of the citizens’ life and needs.

Title 1: Voting rights; this intended to stop any unequal application of requirements of a voter to register as a viable voter. A literacy test, which was the main basis for sidelining blacks and the poor whites from the south, was also included in this section. This act required that the rules of voting and the procedure to be done equally and fairly to everyone irrespective of color or race.

Despite the fact of its positivity, the act did not address the following issues: economic retaliation, repression by police or physical violence wailed against voters who are not whites. While the act advocated for equal voter attention, it did not address the aspect of voter qualification besides citizenship (Wright).

Title II: The act condemned discrimination based on race, color, religion or nationality in recreational facilities, motels, hotels and all other public amenities that were involved in public business.

Title III: This prohibits the municipal government from barring access to public utility on the basis of color, race, religion, or nationality.

Title IV: This act advocated for desegregation of public schools on the ground of race, color, religion or national origin. It therefore gave the authority to the U.S attorney General to file suits to ensure that this act is enforced.

Title V: Civil rights commission - this addressed the procedures that the commission was endowed with. It expanded the duties of the commission and extended its life through top 1968.

Title VI: Nondiscrimination in federal assisted programs- this authorized but avoided funds withdrawal from programs that engaged discrimination.

Title VII: Equality in criteria used to select applicants for employment- it condemned discrimination in business exceeding 25 people and created equal employment opportunities.

Title VIII: Registration and voting statistics- directed census bureau to conduct a registration and voter statistics but not to compel any one to give information they  are not comfortable with.

Title IX: Reviewing of cases- it made the remanding of civil rights cases reviewable in high federal courts and gave authority to the attorney General to act in some cases.

Title X: Community relations service, which created the service to aide communities in resolving cases that involved racial discrimination

Title XI: Miscellaneous. (Wright)

Setting it in Motion

Despite the need and pressure to set the civil rights act working, many challenges and controversies were experienced. Some wanted the rights to be implemented yet some opposed to it. At some point, it was considered an issue of least national importance. There was a great opposition from the south, but the president tried to ward them toward accepting this bill. He also advised the African leaders to control any negative demonstrations so as not to scare away potential supporters of the act. Kennedy likewise sought for support by holding meetings with various leaders and groups. He did this to ensure that there was support so that the congress would be under pressure to assent to the bill, yet at the same time he was jeopardizing the dwindling togetherness of politicians needed to see the bill through.

The fear of filibusters was another factor that contributed to the controversies and setbacks experienced by the act.  Both the Judiciary and Commerce committees were headed by conservative senators from the south, thus passing the bill would prove to be a challenge.

Another factor was the Republican Party. The house needed the republican majority to support the bill in order for it to pass, but apparently they would not find any good reason to support it. This called for a little compromise by the president though it surprised the civil right activists but there was no otherwise solution if the support was to be yielded.

 For the bill to be brought to consideration by the entire floor, it had to pass through the rules committee. The rules committee was at that time chaired by Howard W. Smith who had been an opponent of civil rights for a long time. He refused to grant the bill before the end of 1963. This led to delay in the whole process. In order to avoid the filibuster long speeches and hence delaying the process, it was proposed that two thirds of the senators present were to vote the cloture.

 Senate committee was bypassed to avoid any delay or pigeonholing of the bill but the senate committee was manned by conservatives. Most of the southern conservatives did not want to support the civil rights bill because they feared that they would be voted out by their constituents if they voted in the bill allowing Africans and Whites equal opportunities. The filibuster issue brought more damage to the Democratic Party than the Republican Party because only one Republican joined this controversial group (Wright).

After Implementation

The policy was assented to as a bill in the year 1964 by presidency of Lyndon Johnson. Until today, the policy is still in effect. There has been a great deal of transformations since this act was incepted.

Along the way, a number of amendments were added to the bill to fully accommodate everyone’s rights owing to the change of times and needs. The 1991 amendment was reaffirmation of the government’s commitment to affirmative action. In 2007, a supreme court ruled that the extent to which school districts could use race to avoid segregation was limited.

The bill of rights had positive effects on the American socio-economic state. Many improvements took place. African Americans have been appointed to big posts, there have been many success stories in business, education and government sector. In 1996, Gen. Collin Powell was the most preferred Republican presidential candidate but he declined to run for the seat. Currently, the White House occupants bear the blood of African origin (Wright, 9-33).

In conclusion, the civil rights activism in the United States went through great challenge. When we talk about equality today in terms of races, color and national origin, we have the reason to uphold and cherish them, given the paths it had to follow in order to eventually materialize. This act is still surviving and I strongly believe that no one will have the audacity to change it. There have arisen even more activism worldwide and human right is always in the forefront. America’s change to the positive and the dreams of activists who struggled to see equality descend were richly fulfilled.

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With soaring cities and majestic geography, Bolivia is a quiet world that still manifests the ancient.

Entering into La Paz is considered one of the greatest experiences South America has to offer. The mountaintop city is well hidden until you cross over the ridge and into the huge volcanic bowl where the city splays out before you. Outside La Paz, ancient relics give a glimpse of Bolivia’s mysterious past and the disappearance of a whole civilization. But the fascinating history and culture of Bolivia belies the simplicity of its modern life.

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Slip and Fall Injury Attorney Cypress, Texas

Proving Fault in Slip and Fall Mishaps in Cypress, TX

It is sometimes hard to show who is at fault for slip and fall accidents. Thousands of individuals each year are hurt, many seriously, from slipping and falling on a flooring, stairs, or other surface that has actually ended up being slick or harmful. Even ground that has actually ended up being unequal to an unsafe degree can lead to extreme injuries. However, often it may be challenging to prove that the owner of the residential or commercial property is accountable for a slip and fall mishap.
Could the Homeowner Have Avoided the Mishap?

If you or a loved one has been injured in a slip and fall accident, it might be appealing to look for justice in the form of a claim as soon as possible. But stop and ask this concern initially: If the property owner was more careful, could the mishap have been avoided?

For instance, even if a leaking roofing system leads to a slippery condition that you slip and fall on, the property owner might not be responsible for your injuries if there was a drainage grate in the floor designed to limit slippery conditions. In addition, property owners will not always be responsible for things that an affordable individual would have prevented, such as tripping over something that would generally be found in that area (like a leaf rake on a yard in the fall). Everyone has a duty to be aware of their surroundings and make efforts to avoid harmful conditions.

Property Owner’s Task to Keep Fairly Safe Issues for Cypress,Texas 77410

Nevertheless, this is not to say that property owners are never ever held responsible for the injuries of others that slipped and fell on their home. Although there is not a cut-and-dried guideline, property owners still should take affordable actions to guarantee that their property is devoid of harmful conditions that would cause a person to slip and fall. Nevertheless, this reasonableness is often stabilized against the care that the person that slipped and fell must have used. What follows are some guidelines that courts and insurer use when determining fault in slip and fall accidents.

Liability for Slip and Fall Mishaps

  • Either the homeowner or his staff member need to have understood of the hazardous condition since another, “reasonable” individual in his/her position would have learnt about the harmful condition and repaired it.
  • Either the property owner or his employee actually did know about the hazardous condition but did not fix or fix it.
  • Either the property owner or his worker triggered the hazardous condition (spill, broken floor covering, etc.).

Since lots of homeowner are, in general, pretty good about the maintenance on their premises, the first scenario is usually the one that is prosecuted in slip and fall mishaps. However, the first situation is also the most tricky to prove because of the words “must have understood.” After providing your evidence and arguments, it will depend on the judge or jury to choose whether the property owner must have understood about the slippery action that triggered you to fall.

  • For how long had the problem existed before your accident? Simply puts, if the leaking roofing over the stairwell had been leaking for the past three months, then it was less affordable for the owner to permit the leakage to continue than if the leak had actually simply started the night before and the proprietor was only awaiting the rain to stop in order to fix it.
  • What sort of daily cleansing activities does the property owner take part in? If the homeowner declares that he or she inspects the residential or commercial property daily, what kind of evidence can she or he show to support this claim?
  • If your slip and fall mishap included tripping over something that was left on the flooring that when had a genuine factor for existing, did the genuine reason still exist at the time of your accident? For example, tripping over a can of paint in a living room is most likely not reasonable if the last time the space had actually been painted was over 2 years earlier and the owner had no instant plans to repaint the space.

The meaning of Carelessness/Clumsiness in Cypress, TX 77410

  • Did you have a genuine reason for being on the property owner’s premises when the mishap taken place? Should the owner have anticipated you, or someone in a similar situation to you, being there?
  • Would individual of reasonable caution in the very same circumstance have seen and prevented the hazardous condition, or managed the condition in such a way that would have lessened the opportunities of slipping and falling (for instance, keeping the hand rails while decreasing icy stairs)?
  • Did the homeowner erect a barrier or give warning of the unsafe condition that caused your slip and fall mishap?
  • Were you participating in any activities that added to your slip and fall mishap? Examples include: playing around the edges of swimming pools, texting while walking, leaping or skipping, trying to ice skate while in your company shoes, and so on?

If you have actually been talking with the insurance provider about a possible settlement for your injuries, you will most likely be asked many concerns that are similar to these. Although you will not have to prove to the insurance company that you were extremely careful, you will probably have to reveal enough so that the insurance provider can conclude that you were not acting negligently.

Where Can I Get a Free Initial Case Review in Cypress, Texas?


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Some photos for Stuco Design and their work at the The T.R.E.E. Centre: a purpose built eco-building that provides an environment for learning about environmental issues through 4 key themes of Energy, Resources, Climate and Biodiversity.

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Configuration file

Understanding BEASTling is, mostly, a matter of understanding the configuration file format. Config files have the following form:

param1a = value1a
param2a = value2a
param3a = value3a
param4a = value4a
param5a = value5a
param1b = value1b
param2b = value2b
param3b = value3b
param1c = value1c
param2c = value2c
param3c = value3c
param4c = value4c

i.e. they are divided into sections, which are indicated by names enclosed in square brackets (in the above, the section names are section1, section2, etc.), and each section consists of some number of parameters and assigned values. Each line of each section corresponds to assigning one value to one parameter, the the parameter name on the left of the equals sign and the value on the right.

BEASTling configuration files can range from very simple (the only section which is compulsory is one or more model sections) to relatively complicated - although in all cases they are vastly simpler than any BEAST XML file. If you provide minimal configuration information, “sensible defaults” will be used for all settings.

It is your responsibility to know what the defaults are and to make sure that they truly are sensible for your application.

The recognised config file sections are as follows:

admin section

The admin section may contain the following parameters:

  • basename: this is any user-friendly string which will be used in e.g. filenames. If the basename is, say, “IE_cognates”, then the BEAST XML file which BEASTling produces will be named IE_cognates.xml, and when the BEAST analysis is run, the trees will be logged in IE_trees.nex, etc. If unspecified, it will default to “beastling”.
  • glottolog_release: the number of a Glottolog release (>=2.7), from which to obtain the language classification.
  • screenlog: this must be set to “True” or “False” and controls whether or not BEAST should output basic MCMC data like ESS to the screen while running. Default is True.
  • log_probabilities: “True” or “False”. Controls whether or not the prior, likelihood and posterior should be logged to a file called basename.log. This is generally a good idea, so that you can check e.g. ESSes for these things in Tracer, so the default is True.
  • log_params: “True” or “False”. Controls whether or not all model parameters are also included in basename.log. Default is False.
  • log_trees: “True” or “False”. Controls whether or not sampled trees should be logged to basename.nex. Default is True.
  • log_all: “True” or “False”. Setting this true is simply a shorthand for setting log_probabilities and log_params and log_trees to all be true. Default is False.
  • log_every: an integer specifying how many MCMC samples should elapse between consecutive entries in the log file. If not specified, BEASTling will set this based on the chainlength such that the log file will be 10,000 entries long. This is a good compromise between getting lots of information about the posterior and conserving disk space.

MCMC section

The MCMC section may contain the following parameters:

  • chainlength: number of iterations to run the MCMC chain for. Default is 10,000,000.
  • path_sampling: “True” or “False”. If True, BEAST will use path sampling to estimate the marginal likelihood of data under the provided models, rather than sampling from the posterior. Default is False.
  • sample_from_prior: “True” or “False”. If True, BEAST will ignore all supplied data and the tree, all clock rates and any model parameters will all be sampled from their prior distributions. Default is False.

In path sampling analyses, i.e. if and only if path_sampling = True is set, then the following parameters will also be used. They will be ignored if MCMC is used to sample directly from the posterior or prior.

  • alpha: A floating point value used as a parameter for the Beta distribution from which the exponents at each step of a patch sampling analysis are sampled. Default is 0.3, this should not be changed unless you know what you are doing.
  • do_not_run: “True” or “False”. If True, BEAST will generate scripts or batch files for running the different steps of the analysis, but not actually run them. This lets you manually run the different steps on different computers in parallel. It’s then up to you to calculate the marginal likelihood using BEAST’s PathSampleAnalyser program. See the official BEAST path sampling documentation for more details.
  • log_burnin: A floating point value giving the proportion of chainlength which will be discarded as burnin for each step of a path sampling analysis, for the purpose of computing the marginal likelihood estimate.
  • preburnin: A floating point value giving the proportion of chainlength which will be discarded as burnin for the first step only of a path sampling analysis.
  • steps: number of steps to use in a path sampling analysis.

languages section

The languages section may contain the following parameters:

  • exclusions: One of:
    • A comma-separated list of language names or codes to exclude from the analysis, spelled exactly as they are in the data file(s).
    • The path to a file which contains one language per line.

This can be used by itself to remove a few problematic languages from a data file, or in conjunction with families or macroareas to better control which languages are included, e.g. you may set macroareas = Africa, but use excludes to remove some outliers like Austronesian languages on Madagascar or Indo-European languages in South Africa.

  • families: One of:
    • A comma-separated list of language families to include in the analysis, spelled exactly as they are in Glottolog. E.g. Indo-European, Uralic, Dravidian.
    • The path to a file which contains one language family per line.

If no value is assigned to this parameter, all languages present in the data file will be included (unless languages (see below) is used. families and languages cannot both be used in a single configuration.

  • languages: One of:
    • A comma-separated list of language names or codes to include in the analysis, spelled exactly as they are in the data file(s).

If no value is assigned to this parameter, all languages present in the data file will be included (unless families (see above) is used. languages and families cannot both be used in a single configuration.

  • macroareas: One of:
    • A comma-separated list of Glottolog macroareas to include in the analysis
    • The path to a file which contains one macroarea per line.

Valid macroareas are: Africa, Australia, Eurasia, North America, Papunesia, South America. This can be used in conjunction with languages or families, in which case a language must meet both criteria to be included. E.g. if you set families = Afro-Asiatic and macroareas = Africa, you will get only the Afro-Asiatic languages located in Africa, and those located in Eurasia will be excluded.

  • monophyly (or monophyletic): “True” or “False”. Controls whether or not to impose the family structure in Glottolog as monophyly constraints in the BEAST analysis. Default is False. If True, very fine-grained control over exactly how much constraint is opposed can be gained by using additional options, documented below.
  • monophyly_levels: An integer specifying how many levels of the Glottolog classification to impost as a monophyly constraints. By default, levels are added in a top-down fashion (but see monophyly_direction below). E.g. if monophyly_levels = 3 is specified, then Indo-European languages will be constrained to be monophyletic (one level), and so will Armenian, Celtic and Germanic, among others (two levels), and so will be Gothic and Northwest Germanic, among others (three levels), but North Germanic and West Germanic, or any descendant groups, will not be. This allows one to enforce the high level structure of Glottolog, while leaving the “fine details” of relationships among leaves to be inferred from data. If no value is specified, the entire Glottolog classification will be imposed.
  • monophyly_direction: One of top_down (the default) or bottom_up. Determines the effect of monophyly_levels. If monophyly_direction = top_down, constraints will be added from the roots of Glottolog trees downward (e.g. Indo-European, Germanic, North Germanic,…). If bottom_up, constraints will be added from the leaves upward (e.g. Macro-Swedish, East Scandinavian, North Germanic,…).
  • monophyly_newick: If you disagree with Glottolog’s classification of the languages in your dataset (or would simply like to refine them by resolving some polytomies), you can use this option to do so. The value should either be a filename containing a tree in Newick format, or a valid Newick tree string (unless your analysis has very few languages, using an external file is probably preferable to keep your BEASTling config short and neat). The provided tree should not be a fully resolved binary tree, but should use polytomies to represent your beliefs about relatedness of languages. If you believe that a grou of languages are related, but know nothing about the internal structure of the clade, they should all descend from a single parent node. The languages in the provided tree may be a superset of the languages in your analysis - the monophyly tree will be pruned appropriately.
    • monophyly_start_depth: An integer specifying an initial number of levels of the Glottolog classification to skip over when implying constraints (default 0). E.g., with top down constraints, setting monophyly_start_depth=2 will skip over Indo-European and Germanic, so that if monophyly_levles=3, the imposed levels will be, e.g. Western Germanic, Franconian and High Franconian. With bottom up constraints, this controls skipping initial levels above the leaves.
  • monophyly_end_depth: An integer specifying a level in the Glottolog classification below which constraints will not be imposed. If monophyly_end_depth is specified, then monophyly_direction and monophyly_levels are ignored. The imposed constraints will be those between monophyly_start_depth and monophyly_end_depth, interpreted in a top down fashion. This is a “low level” approach to controling monophyly, and in general the “configurational sugar” of using monophyly_direction, monophyly_start and monophyly_levels should be preferred.
  • overlap: One of union or intersection. Controls how to deal with language sets mismatches between input data.
    • If set to union (the default), languages missing in one data set will be added with missing datapoints (“?”) for all features.
    • If set to intersection, only languages present in all data sets will be used.
  • sample_branch_lengths: If True, the branch lengths of the starting tree. If False, the starting branch lengths will be kept fixed. Use this in conjunction with starting_tree when you have a tree you trust and want to fit model parameters to it. Default is True.
  • sample_topology: If true, the topology of the starting tree (i.e. the details of which leaves are connected to which and how) will be sampled during the analysis to fit the data. If false, the topology will be kept fixed. Use this in conjunction with starting_tree when you have a tree you trust and want to fit model parameters to it. Default is True.
  • starting_tree: Used to provide a starting tree. Can be a Newick format tree or the name of a file which contains a Newick format tree. If not specified, a random starting tree (compatible with monophyly constraints, if active) will be used. The languages in the provided tree may be a superset of the languages in your analysis - the starting tree will be pruned appropriately. Note that BEASTling currently does not check that your starting tree is compatible with your monophyly constraints, if any, so it’s up to you to do this (if you don’t, the starting prior probability will be zero and BEAST will not run).
  • subsample_size: An integer, specifying a number of languages to subsample down to if more languages than this are present in the data and compatible with other options (families, macroareas, etc.). Useful if your dataset(s) contain many languages resulting in slow analyses or memory issues, and you want to experiment on a small subset of your data before doing a slower full run on a more powerful machine. Exactly the same subsample will be returned on each run of BEASTling as long as the value of subsample_size and the full set of languages remains the same, so you can still, e.g. do meaning model comparions.

Note that the current subsampling implementation chooses languages uniformly at random from the full set, so the distribution over families, macroareas, etc. will usually be approximately equal to the corresponding distribution for the full set, but this is not guaranteed and there is a chance that e.g. some families represented in the full set will be missing from the subsample. More principled subsampling approaches may be available in future releases.

calibration section

If you wish to estimate divergence times as part of your analysis, it is essentially to provide some amount of calibration data, i.e. estimates of the times when some known divergences are believed to have occurred (based on e.g. archaeological or historical evidence). One calibration is the minimum required, but you can add as many as you like. More is generally better, although large numbers of calibrations can cause problems too. To include calibrations, you should add a calibration section to your config file. This section should contain one parameter for each distinct calibration point that you wish to use.

The name of each parameter should be some identifier for a group of languages (e.g. a Glottolog family name like “Indo-European”, but there are other options. See below for more on ways to specify languages, including originate calibrations and tip dates). The value for each calibration can be a string in one of several supported formats, representing your prior beliefs about the time the calibration event diverged. The two simplest formats are to specify a range of ages, or a single upper or lower bounding age.

Ranges can be specified as follows:

Austronesian = 4750 - 5800

This says that you strongly believe the disintegration of proto-Austronesian happened between 4750 and 5800 units of time in the past. This example calibration has been given in years, but the units are actually arbitrary and you could just as well provide dates in millenia BP:

Austronesian = 4.75 - 5.8

Or centuries BP, fortnights BP, etc. The units only matter when it comes time to interpret parameters like tree heights, clock rates or mutation rates, but using centuries or millenia BP is a good practice.

When given this kind of calibration (i.e. a range of dates), BEASTling will set a Normal distribution prior on the age of the family indicated. The mean of the distribution will be equal to the midpoint of the provided range (5275 for the first case above). The standard deviation will be set such that 95% of the probability mass will lie within the range provided. In other words, the range you provide is treated as a 95% credibility interval.

Bounds can be specified as follows:

Austronesian = > 4750

Austronesian = < 5800

With this kind of calibration, BEASTling will set a uniform distribution prior on the age of the family indicated. The upper or lower bound will be set to the provided age, and the other bound will be set to zero or infinity as appropriate.

If you require more control over your priors, you can explicitly provide the type of distribution (either normal, lognormal or uniform) and the parameters, as well as specify an offset, as follows:

Austronesian = normal(5275, 535.71)           # First param is mean, second is standard deviation
Austronesian = lognormal(8.57, 0.05)          # First param is mean (in log space), second is standard deviation
Austronesian = rognormal(5275, 0.05)          # First param is mean (in real space), second is standard deviation
Iranian = 2600 + rlognormal(400, 0.8)         # As per above but with an offset

Finally, it is possible to specify an age range and ask for a lognormal distribution to be fitted to it, as follows:

Austronesian = lognormal(4750 - 5800)

With this kind of calibration, BEASTling will set a lognormal distribution prior on the age of the family indicated. The mean of the distribution will be set so that the median of the lognormal distribution equals the midpoint of the range provided. The standard deviation will be set to the mean of two values: one with the property that the provided lower bound is at the 5th percentile of the lognormal distribution, and one with the property that the provided upper bound is at the 95th percentile. The provided interval does not quite end up being a 95% credible interval, but it is roughly so. Explicitly set the lognormal parameters as shown above if you need more control over the matching than this.

Providing a Glottolog-recognised family name like “Austronesian” is one way to identify a group of languages to calibrate, but there are others. If your data uses ISO codes or Glottocodes to identify languages, then you can use Glottocodes for calibration points, e.g.:

aust1307 = 4750 - 5800

A comma-separated list of family names or Glottocodes will be interpreted as the common ancestor of those families (and this will introduce a constraint that those families are monophyletic):

Finnic, Saami = 2000 - 3000

If you wish to calibrate on a group of languages which do not comprise a Glottolog node, you can simply use a comma-separated list of languages (named however they are in your datafiles):

esto1258, liv1244, sout2679 = 1 - 1.5

Whichever of the above methods you use, you can enclosed the identifier in originate( ) to place the calibration not on the MRCA of the languages/families specificed, but on the originate, i.e. the top of the branch leading to the MRCA.

originate(Indo-European) = > 8000

Originate calibrations can be used even with single languages:

originate(jpn) = > 5

Finally, if your data includes an extinct language which is a leaf node (e.g. data for Tocharian, but not for proto-Germanic which isn’t a leaf) and you have some idea of how long ago the language died out, you can place a calibration on that “tip date” by listing just the single language:

xto = 1000 - 1500

If a date range is provided as above, in the resulting analysis BEAST will sample and log the tip date for that language. However, tip calibrations are also the one time when you can provide a point calibration as opposed to a range:

xto = 1375

In which case the tip date will be set to precisely the provided value and no sampling will occur.

model sections

A BEASTling config file must include at least one model section, but it can contain several. Model sections are different from almost all other sections in that you must give each one a name. A [model] section is invalid, but [model mymodel] will work. Suppose you want to perform an analysis using both cognate data and structural data, and you want to use different model settings for the different kinds of data (say different substitution models). You could have a [model cognate] section and a [model structure] section. You can have as many models as you like, as long as each one gets a unique name.

Each model section must contain the following parameters, i.e. they are mandatory and BEASTling will refuse to work if you ommit them:

  • model: should specify the name of the substitution model type you want to use. Available models are:
    • “covarion” (Binary covarion model)
    • “bsvs” (Bayesian Stochastic Variable Selection)
    • “mk” (Lewis Mk model)

    For more information on the available models, see Substitution models.

  • data: should be one of:
    • A path to a file containing your language data in a compatible .csv format
    • The string “stdin” if you wish for data to be read from stdin rather than a file.

    Note that if data is a relative path, this will be interpreted relative to the current working directory when beastling is run, not relative to the location of the configuration file.

    Regardless of whether data is read from a file or from stdin, it must be in one of the two compatible .csv formats. These are described in Data formats. Note that BEASTling can also be made to read data from stdin by using the --stdin command line argument.

Additionally, each model section may contain the following parameters, i.e. they are optional. Note that these are only the options supported by all (or most) substitution models. Most substitution models also have their own specific options. Check your model’s documentation at the Substitution models page to see these.

  • ascertained: “True” or “False”. Controls whether or not to perform ascertainment correction for the absence of non-constant features in the data. This will have no effect on the sampled tree topology but will influence estimates of branch lengths and the age the tree and clades. By default, this will be set to true if you provided any calibrations (because in this case you most likely care about estimated ages) and to false if you have not (on the assumption that in this case you are more interested in topology). Use this parameter to make your intention explicit. Note that if you have set remove_constant_features = False in a binary covarion analysis (see below) and your analysis does indeed contain constant features, you cannot set this parameter to “True”. See Ascertainment correction for more explanation of ascertainment correction in BEASTling.
  • binarised or binarized: “True” or “False”. This option is only relevant if the binary covarion model is being used (see Binary Covarion). If your data set only contains features with two possible values, in some situations BEASTling needs to know whether this represents “true” binary data (e.g. presense or absence of some syntactic trait) or whether your data is a “binarisation” of some multistate data (such as cognate class assignments). Set this to False for true binary data and True for binarised cognate data.
  • clock: Assigns the clock to use for this model. See clock sections below for details.
  • features: Is used to select a subset of the features in the given data file. Should be one of:
    • A comma-separated list of feature names (as they are given in the data CSV’s header line)
    • A path to a file which contains one feature name per line
  • feature_rates: If you want to include rate variation in your model, but rather than estimating rates you would like to supply your own (e.g. using the results of some other analysis), you can use this parameter to provide the path to a CSV file where each line provides the rate for a single feature. Lines should consist of a feature identifier, followed by a comma, followed by a floating point rate. Note that you do not have to also set rate_variation = True. In fact, if you do so, your provided rates will be used as starting values for rate estimation, rather than remaining fixed. If you are using rate_variation, rather than feature identifiers you should put the identifiers for your rate categories before the colons.
  • file_format: Can be used to explicitly set which of the two supported .csv file formats the data for this model is supplied in, to be used if BEASTling is mistakenly trying to parse one format as the other (which should be very rare). Should be one of:
    • “beastling”
    • “cldf”
  • frequencies: Used to control the equilibrium distribution of the substitution model. All models support settings of “uniform” (for a uniform distribution), “empirical” (to use the relative frequencies of different states in the dataset) or “estimate” (to estimate the the equilibrium distribution via sampling during MCMC). Some models may support additional options (e.g. “approximate” for Lewis Mk). If not specified, all models will default to “empirical”, which is a more realistic setting than “uniform” for large datasets, while being less computationally intensive than “estimate”.
  • language_column: Can be used to indicate the column name in the .csv file header which corresponds to the unique language identifier. If the column name is one of “iso”, “iso_code”, “glotto”, “glotto_code”, “language”, “language_id”, “lang” or “lang_id”, BEASTling will recognise it automatically. This parameter is only needed if you have a pre-existing data file which uses a different column name which you don’t want to change (perhaps because it would break compatibility with another tool).
  • pruned: “True” or “False”. Make use of “pruned trees”. This can improve performance in data sets with a lot of missing data. Default is False.
  • rate_partition: Name of a file specifying a partition of all features into disjoint categories which should share the same substitution rate. Each line should contain an identifying label for the category, a colon, and then a comma-separated list of feature names. Every feature should belong to exactly one category in the partition. If rate_vartion is set to True, these rates will be estimated. Alternatively, you can use feature_rates to provide fixed rates (or initial values for estimation).
  • rate_variation: “True” or “False”. Estimate a separate substitution rate for each feature (or feature category if using rate_partition). Substitution rates are constrainted to have a mean of 1.0 and have a a Gamma prior.
  • reconstruct: A list of features for which ancestral state reconstruction (ASR) should be performed, i.e. for which BEAST will estimate the unobserved feature values at internal nodes of the tree. Can be specified in the same fashion as features, i.e. a comma-separated list or the name of a file with one feature per line. Specifying an asterisk (*) will reconstruct all features in the data set. If ASR is used, an additional logfile of trees will be produced by BEAST, distinguished from the regular tree log via the addition of the _reconstruct suffix.
  • remove_constant_features: “True” or “False”. This option is only relevant if the binary covarion model is being used (see Binary Covarion). Your setting will be ignored if you are using the Lewis Mk or BSVS models, as these models cannot sensible accommodate constant features. By default, this is set to “True”, which means that if your data set contains any features which have the same value for all of the languages in your analysis (which is not necessarily all of the languages in your data file, if you are using the “families” parameter in your “languages” section!), BEASTling will automatically remove that feature from the analysis (since it cannot possibly provide any phylogenetic information). If you want to keep these constant features in, you must explicitly set this parameter to False. You may want to do this if you have rate variation enabled to help estimate the distribution of rates across features, but if your data set contains many constant features you should be careful about interpreting the results.
  • minimum_data: Indicates the minimum percentage of languages that a feature should have data present for to be included in an analysis. E.g, if set to 50, any feature in the dataset which has more question marks than actual values for the selected languages will be excluded.

clock sections

clock sections are quite similar to model sections, in that they must be given names, e.g. [clock myclock]. A BEASTling config file may include any number of clock sections, including zero, but it makes no practical sense to define more clock sections than you have model sections. clock sections are used to define clock models, which determine how tree branch lengths are transformed into a measure of evolutionary time. Each model in your analysis has an associated clock model. You can share one clock across all your models, or give each model its own clock, or assign clocks in any other way you like.

If no clock section is defined, all models will be associated with a default clock (of type “strict”). Alternatively:

  • You may define your own [clock default] section. Because the name is default, this clock will be associated with all model sections, unless those sections have a different clock specifically assigned.
  • You may explicitly assign a clock to a model by setting the model section’s clock option equal to the name of a clock section.
  • If a model section and a clock section have the same name, then they are automatically associated with each other (unless the model section explicitly assigns a different clock.

  • type: should specify the type of clock model type you want to use. Available models are:
    • “strict” (Strict clock)
    • “relaxed” (Uncorrelated relaxed clock)
    • “random” (Random local clock)

For more information on the available models, see Clock models.

geography section

Adding a geography section to your BEASTling config file will include a phylogeographic component in your analysis. Only a single geography section can exist in a configuration file, and unlike clock and model sections, geography sections do not need to be named (i.e. do not use [geography mygeo] or similar).

A geography section does not require any parameters. Spherical phylogeography is the only phylogeographic model currently supported. This model requires latitude and longitude coordinates for each language in the analysis. If your languages are labelled using Glottocodes or ISO codes, location information will automatically be sourced from Glottolog. If you are not using Glottocodes or ISO codes, or you would like to use locations other than those provided by Glottolog, you can provide your own location data in CSV format using using the data parameter (see below). Languages in your analysis for which location data is missing will have their locations sampled as part of the MCMC run (if BEASTling is run in --verbose mode, you will be notified of these languages).

Your geography section may optionally contain any of the following parameters.

  • clock: should specify the name of a clock model (just like the clock parameter in a [model] section) which will be used for the phylogeographic diffusion model. If this is not provided, the phylogeographic model will use the analysis’ default clock, which will be shared with any language models in the analysis. In general, this is not desirable, so unless you are running a geography-only analysis, you should specify a separate geographic clock.
  • data: by default, phylogeographic analyses will use latitude and longitude data from Glottolog to provide the locations for languages, assuming languages are labelled with ISO codes or Glottocodes. If your languages are not labelled this way (or Glottolog is missing location data for your languages, or you disagree with Glottolog’s location and would like to override it with your own), you will need to provide your own loaction data using this parameter. The value should be a filename, or a comma-separated list of filenames. The files should be CSV or TSV files with at least three columns. One should provide language identifiers which match your data, and the header should be one of the same names that are allowed for data files (i.e. iso, iso_code, glotto, glottocode, language, language_id, lang or lang_id). The other two should provide latitude and longitude values and should be labelled latitude or lat and longitude or lon respectively. Latitude and longitude values should be decimal values using positive or negative sign to indicate North/South and East/West (i.e. do not use “60N” or similar formats), or question marks if they are unknown (languages with unknown location will be dropped from the analysis). If multiple filenames are provided, later (i.e. rightmost) files will override earlier (i.e. leftmost) files if they contain locations for the same languages. In this way you can list multiple sources of location data from least to most reliable and each language will receive the most reliable location.
  • sampling_points: by default, phylogeographic analyses integrate over the locations of all internal nodes in the trees. You can ask BEAST to sample the locations for some interior points using this parameter. Perhaps you are actually interested in inferring the location of some well-defined point in your tree (e.g. in a phylogeographic analysis of Indo-European you may be interested in the location of proto-Germanic or proto-Balto-Slavic). Even if you are not interested in these locations, specifying some sampling points (say 5) may actually speed the analysis up somewhat, as changes to the tree topology do not require likelihood calculations to propagate all the way up the tree. Your sampling points may be specified using Glottocodes or names from Glottolog (e.g. “Germanic”).

geo_priors section

In the same way that a [calibration] section is used to add temporal calibrations to an analysis, a [geo_priors] section can be used to add spatial calibrations to an analysis. This only makes sense for analyses which include a phylogeographic component, and if your configuration file contains a [geo_priors] section but not a [geography] section, BEASTling will complain loudly.

The name of each parameter should be a comma-separated list of family names or Glottocodes, exactly as per temporal calibrations. The value should be a path to a KML file specifying a polygon which represents the region you believe the MRCA of the listed family/families should be confined to. Note that, unlike data files, the contents of the KML file will not end up included in the BEAST XML. This means the XML and KML file(s) will need to be distributed together for the analysis to be reproducable.


Struggling to upload an image - Getting 504 timeout every time

I am struggling to add an image to a task.
I am able to get users and projects, scan them, build a task for the right user and project, get the successful result and ID for that task and then I can’t upload my image.

I am trying hard to follow the instructions in the API creating a multipart/form Post request to:

When I point my request at my own cgi script sitting on an independent server I get 200’s back and a png on the server that I have uploaded. When I point my request at asana I get timeouts. The differences I can see between the two servers is my cgi perl script and the fact that my server is running apache and asana is not. I am not sure if there is something finickey I am missing in my request and was hoping someone might shed some light on what I am missing.

Here is the wireshark capture of my request (http of course not https in this case) hitting my own server:

From what I can tell the request is well formed. NOTE: in this case I have an extra field that I think is extraneous (The task field) the docs make reference to the taskid field. That seemed redundant due to the presence of the id in the url but I have tried with and without that field just to make sure.

Hi there @IGuy,

We’ve heard from a couple of our channels that there may be something awry with our attachment API endpoint. Since it uses a slightly different mechanism than our in-product attachments, it’s possible we may have a regression, or over time the API mechanism may have gotten a little crufty.

I’ve pinged the team that this is likely a bug and we’ll take a look. Sorry for the hassle, but my hunch is, you’re not doing anything wrong and we have some investigation to do on our end. Thanks!


What’s Parachute Mobile?

Parachute Mobile is a unique combination of two great hobbies; ham radio and skydiving. About four times a year the team gets together to conduct “Missions” where licensed hams jump out of a plane at 13,500 feet. They deploy their parachutes right away (HAHO: High Altitude High Opening) and make as many contacts (QSOs) has possible. The Drop Zone is located in Byron, California at the Byron Airport. Contacts have been made from as far away as Eureka and Fresno. One-of-a-kind QSL cards are issued for each mission. It takes a lot of work to conduct a Parachute Mobile Mission due to the payload that goes with each jumper. First off, we provide APRS biotelemetry during the jump. This means you can fallow the jumper on APRS.FI. Not only can you track altitude and distance traveled, but the heart rate and oxygen percentage of the jumper. We also stream live video from the jumper’s point of view. To make this all happen a trained ground crew prepares each jumper up with all the equipment before the jump. Safely is paramount, so a safety check is completed before each jump as well.

Mission 14 will be a special event in conjunction with Radiofest in Monterey, California March 23, 2013. Check back soon to get updates.

Spectacular pictures of Mission 13 will be posted soon.

Team Coordinator


Award Year

Award Type

First Prize

Dissertation Advisor

Morley Gunderson

Legislation is typically passed to accomplish some goal that benefits the majority of society. Sometimes, however, legislation leads to unanticipated and undesirable outcomes. This dissertation examines the ‘side-effects’ of three different Canadian labour laws. Chapter one examines the impact of voting laws on certification success in British Columbia from 1978 to 1998. During that time period, a voting system was introduced in 1984, and was then repealed in 1993. Chapter two examines the impact of welfare cheques on the likelihood of injection drug users leaving the hospital against medical advice (“AMA”), thereby interrupting treatment. The effect of such behavior on subsequent readmission and the probability of an overdose are also estimated. The final chapter utilizes a natural experiment to evaluate the long-run impact of unemployment insurance. The similar UI systems in Maine and New Brunswick in the 1940s and early 1950s were compared over time taking into account the increased generosity of the Canadian system after 1960. Using the five decennial censuses from 1940–1991, the comparison between these two jurisdictions over time is exploited to estimate the effects of UI program parameters on labor market outcomes.

Link to dissertation full text


Squid skin could be the solution to camouflage material

Credit: Adam Glanzman/Northeastern University

The chromatophore organs, which appear as hundreds of multi-colored freckles on the surface of a cephalopod's body, contribute to fast changes in skin color. In a paper published last week in Advanced Optical Materials, Deravi's group describes its work in isolating the pigment granules within these organs to better understand their role in color change. The researchers discovered these granules have remarkable optical qualities and used them to make thin films and fibers that could be incorporated into textiles, flexible displays, and future color-changing devices. Deravi's lab collaborated with the U.S. Army Natick Soldier Research, Development, and Engineering Center for the study.

By removing individual pigment particles from the squid, Deravi was able to explore the breadth of their capabilities as static materials. One particle is only 500 nanometers in size, which is 150 times smaller than the diameter of a human hair. Deravi's team layered and reorganized the particles and found they could produce an expansive color pallet.

"We're showing these pigments are a powerful tool that can produce ultra-thin films that are really rich in colors," Deravi said.

"From a scientific and technical engineering perspective, understanding how light scattering affects color is very important, and this is an exciting new development in the field of optics in biology," said Richard Osgood, a collaborator from the U.S. Army Natick Soldier Research, Development, and Engineering Center. "This is an unusual harnessing of optics and physics knowledge in scattering to understand biological systems."

The researchers made spools of fibers from the squids' pigment particles and are now exploring uses for the material. The fibers are so visually interesting that it's not difficult to imagine weaving them into fabric for clothing or other art forms. But perhaps the most exciting possible application is wearable, flexible screens and textiles that are capable of adaptive coloration. Osgood said the research could allow the Army to create new capabilities for soldiers.

"For more than a decade, scientists and engineers have been trying to replicate this process and build these devices that can color match, color change, and camouflage just like the cephalopods, but many of them come nowhere near the speed or dynamic range of color that the animals can display," Deravi said. "Cephalopods have evolved to incorporate these specific pigment granules for a reason, and we're starting to piece together what that reason is."

Media Contact

John O'Neill
[email protected]

Original Source


Identification of Inhibitors of Human and Plasmodium Falciparum Orotate Phosphoribosyltransferase and Orotidine 5'-Monophosphate Decarboxylase, and a Novel Hybrid Screening Technique

Author: Michael Roach

Roach, Michael, 2015 Identification of Inhibitors of Human and Plasmodium Falciparum Orotate Phosphoribosyltransferase and Orotidine 5'-Monophosphate Decarboxylase, and a Novel Hybrid Screening Technique, Flinders University, School of Biological Sciences

The enzymes of the de novo pyrimidine biosynthetic pathway are ideal drug targets for the treatment of malarial infections as, unlike the human host, the parasite is solely reliant on this pathway for survival. Furthermore, this pathway is associated with, and therefore, a drug target for a variety of diseases including cancer, autoimmune disorders and viral infections. Hence, this study focussed on the use of bioinformatics approaches to identify potential lead compounds against human and Plasmodium enzymes from this pathway.

The Plasmodium falciparum de novo biosynthesis enzymes orotate phosphoribosyltransferase (OPRTase) and orotidine 5’-monophosphate decarboxylase (ODCase) were recombinantly expressed and purified. The expression and purification of P. falciparum OPRTase (PfOPRTase) was optimised in this study to an extent which enabled biochemical assay and x-ray crystallography experiments to be performed on the enzyme. Constructs were made for the recombinant expression of the bifunctional human homologue Uridine Monophosphate Synthase (HsUMPS) as well as its individual OPRTase (HsOPRTase) and ODCase (HsODCase) domains. These were successfully expressed and purified.

A 3-D homology model for the structure of PfOPRTase was generated. The PfOPRTase homology model and crystal structures for P. falciparum ODCase (PfODCase), HsOPRTase and HsODCase were screened virtually by docking against approximately 1 million drug-like compounds. The hits were analysed and 19 novel, diverse compounds were selected for inhibition assays.

Recombinant HsOPRTase, HsODCase, PfOPRTase and PfODCase were used in biochemical inhibition assays to characterise the 19 compounds that were identified by virtual screening for inhibition. For PfOPRTase and HsOPRTase, nine compounds showed inhibition against one or both enzymes and five were specific for one of the homologues. These inhibitors would be suitable for further development with hit to lead (H2L) drug discovery experiments.

Eight very promising inhibitors for PfODCase and HsODCase were identified which led to some small scale ‘hit expansion’ H2L experiments, and further biochemical evaluation. Seven compounds successfully underwent further inhibition kinetic characterisation. One inhibitor had good potency (Ki/αKi~ 50 µM) and six inhibitors were specific for one of the homologues. Four of the inhibitors (including the most potent inhibitor) satisfy the criteria for drug-likeness and bioavailability.

An alternative substrate for HsODCase was discovered and characterised. The discovery of this alternative substrate and the unexpected modes of inhibition of the identified ODCase inhibitors allowed for new insights into the structure and catalytic mechanism of this enzyme. Interconnectivity between the ODCase dimer active sites is likely.

Finally, a novel method was developed for performing virtual screening on an enzyme target. This novel method is a ‘hybrid’ of structure- and ligand-based methods. The method requires knowledge of only a single known binder and a crystal structure. It is estimated to be approximately 60-fold faster than a typical structure-based approach. It outperformed a typical structure based approach with 25 % better mean bias towards actives, 45 % better mean enrichment at 1 %, whilst maintaining similar hit diversity. It performed similarly compared to a ligand-based approach for bias towards actives and enrichment at 1 % (but with far greater consistency) and 30 % better hit diversity.

Keywords: in silico screening, virtual screening, hybrid screening, drug discovery, OPRTase, ODCase, UMPS, orotate phosphoribosyltransferase, orotidine 5'-monophosphate decarboxylase, uridine monophosphate synthase, plasmodium falciparum

Subject: Biological Sciences thesis

Thesis type: Doctor of Philosophy
Completed: 2015
School: School of Biological Sciences
Supervisor: R. Ian Menz


Tải bản đầy đủ - 0 (trang)
1 The Vacuum State, and the Double Role of the Hamiltonian (Cont'd)

Tải bản đầy đủ - 0trang

The Discretized Hamiltonian Formalism in PQ Theory

We can state this differently: solutions of the equations of motion are stationary

if they are in thermal equilibrium (possibly with one or more chemical potentials

added). In a thermal equilibrium, we have the Boltzmann distribution:

Wi = Ce−βEi +

μ j Rj i

where β = 1/kT is the inverse of the temperature T , with Boltzmann constant k,

and i labels the states; μj are chemical potentials, and Rj i the corresponding conserved quantities.

If the energies Ei were not properly bounded from below, the lowest energies

would cause this expression to diverge, particularly at low temperatures.

What is needed is a lower bound of the energies Ei so as to ensure stability of our

world. Furthermore, having a ground state is very important to construct systematic

approximations to solutions of the time-independent Schrödinger equation, using

extremum principles. This is not just a technical problem, it would raise doubt on

the mere existence of correct solutions to Schrödinger’s equation, if no procedure

could be described that allows one to construct such solutions systematically.

In our world we do have a Hamiltonian function, equal to the total energy, that

is locally conserved and bounded from below. Note that “locally conserved” means

that a locally defined tensor Tμν (x, t) exists that obeys a local conservation law,

∂μ Tμν = 0, and this feature is connected in important ways not only to the theory of

special relativity, but also to general relativity.

Thus, the first role played by the Hamiltonian is that it brings law and order in

the universe, by being (1) conserved in time, (2) bounded from below, and (3) local

(that is, it is the sum of completely localized contributions).

Deriving an equation of motion that permits the existence of such a function, is

not easy, but was made possible by the Hamiltonian procedure, first worked out for

continuum theories (see Sect. 5.6.2 in Part I).

Hamilton’s equations are the most natural ones that guarantee this mechanism to

work: first make a judicious choice of kinetic variables xi and pi , then start with

any function H ({xi , pj }) that is bounded and local as desired, and subsequently

write down the equations for dxi /dt and dpj /dt that guarantee that dH /dt = 0.

The principle is then carried over to quantum mechanics in the standard way.

Thus, in standard physics, we have a function or operator called Hamiltonian that

represents the conserved energy on the one hand, and it generates the equations of

motion on the other.

And now, we argue that, being such a fundamental notion, the Hamiltonian principle should also exist for discrete systems.

any conspicuous reason for not converting into a more “probable” state. Therefore, the argument

presented here must be handled with care.

The Hamilton Problem for Discrete Deterministic Systems

19.2 The Hamilton Problem for Discrete Deterministic Systems

Consider now a discrete, deterministic system. Inevitably, time will also be discrete.

Time steps must be controlled by a deterministic evolution operator, which implies

that there must be a smallest time unit, call it δt. When we write the evolution

operator U (δt) as U (δt) = e−iE δt then E quant is defined modulo 2π/δt, which

means that we can always choose E quant to lie in the segment

0 ≤ E quant < 2π/δt,

Instead, in the real world, energy is an additively conserved quantity without any

periodicity. In the PQ formalism, we have seen what the best way is to cure such a

situation, and it is natural to try the same trick for time and energy: we must add a

conserved, discrete, integer quantum to the Hamiltonian operator: E class = 2πN/δt,

so that we have an absolutely conserved energy,

E = E quant + E class .

E class

In the classical theory, we can only use

to ensure that our system is stable, as

described in the previous section.

In principle, it may seem to be easy to formulate a deterministic classical system

where such a quantity E class can be defined, but, as we will see, there will be some

obstacles of a practical nature. Note that, if Eq. (19.3) is used to define the total

energy, and if E class reaches to infinity, then time can be redefined to be a continuous

variable, since now we can substitute any value t in the evolution operator U (t) =

e−iEt .

One difficulty can be spotted right away: usually, we shall demand that energy

be an extensive quantity, that is, for two widely separated systems we expect

E tot = E1 + E2 + E int ,

where E int can be expected to be small, or even negligible. But then, if both E1 and

E2 are split into a classical part and a quantum part, then either the quantum part of

E tot will exceed its bounds (19.2), or E class will not be extensive, that is, it will not

even approximately be the sum of the classical parts of E1 and E2 .

An other way of phrasing the problem is that one might wish to write the total

energy E tot as

E tot =

Ei →

dd x H(x),

lattice sites i

tot over

where Ei or H(x) is the energy density. It may be possible to spread Eclass

as a sum over lattice sites, but

the lattice, and it may be possible to rewrite E

then it remains hard to see that the total quantum part stays confined to the interval

[0, 2π/δt) while it is treated as an extensive variable at the same time. Can the

excesses be stowed in E int ?

This question will be investigated further in our treatment of the technical details

of the cellular automaton, Chap. 22.

The Discretized Hamiltonian Formalism in PQ Theory

19.3 Conserved Classical Energy in PQ Theory

If there is a conserved classical energy E class (P , Q), then the set of P , Q values

with the same total energy E forms closed surfaces ΣE . All we need to demand for

a theory in (P , Q) space is that the finite-time evolution operator U (δt) generates

motion along these surfaces [116]. That does not sound hard, but in practice, to

generate evolution laws with this property is not so easy. This is because we often

also demand that our evolution operator U (δt) be time-reversible: there must exist

an inverse, U −1 (δt).

In classical mechanics of continuous systems, the problem of characterizing

some evolution law that keeps the energy conserved was solved: let the continuous

degrees of freedom be some classical real numbers {qi (t), pi (t)}, and take energy

E to be some function

E = H (p, q) = T (p) + V (q) + p · A(q),

although more general functions that are bounded from below are also admitted. The

last term, describing typically magnetic forces, often occurs in practical examples,

but may be omitted for simplicity to follow the general argument.

Then take as our evolution law:

∂H (p, q)

= q˙i =

p˙ i = −

∂H (p, q)

One then derives

dH (p, q)

= H˙ =

q˙i +

p˙ i = p˙ i q˙i − q˙i p˙ i = 0.

This looks so easy in the continuous case that it may seem surprising that this

principle is hard to generalize to the discrete systems. Yet formally it should be easy

to derive some energy-conserving evolution law:

Take a lattice of integers Pi and Qi , and some bounded, integer energy function H (P , Q). Consider some number E for the total energy. Consider all

points of the surface ΣE on our lattice defined by H (P , Q) = E. The number

of points on such a surface could be infinite, but let us take the case that it is finite. Then simply consider a path Pi (t), Qi (t) on ΣE , where t enumerates the

integers. The path must eventually close onto itself. This way we get a closed

path on ΣE . If there are points on our surface that are not yet on the closed

path that we just constructed, then we repeat the procedure starting with one

of those points. Repeat until ΣE is completely covered by closed paths. These

closed paths then define our evolution law.

At first sight, however, generalizing the standard Hamiltonian procedure now seems

to fail. Whereas the standard Hamiltonian formalism (19.8) for the continuous case

involves just infinitesimal time steps and infinitesimal changes in coordinates and

momenta, we now need finite time steps and finite changes. One could think of

making finite-size corrections in the lattice equations, but that will not automatically

Conserved Classical Energy in PQ Theory

work, since odds are that, after some given time step, integer-valued points in the

surface ΣE may be difficult to find. Now with a little more patience, a systematic

approach can be formulated, but we postpone it to Sect. 19.4.

19.3.1 Multi-dimensional Harmonic Oscillator

A superior procedure will be discussed in the next subsections, but first let us consider the simpler case of the multi-dimensional harmonic oscillator of Sect. 17.2,

Sect. 17.2.2: take two symmetric integer-valued tensors Tij = Tj i , and Vij = Vj i .

The evolution law alternates between integer and half-odd integer values of the time

variable t. See Eqs. (17.77) and (17.78):

Qi (t + 1) = Qi (t) + Tij Pj t +

Pi t +

= Pi t −

− Vij Qj (t).

According to Eqs. (17.84), (17.85), (17.88) and (17.89), the conserved classical

Hamiltonian is

H = 12 Tij Pi t +

= 12 Tij Pi t +

Pj t −

Pj t +

+ 12 Vij Qi (t)Qj (t)

+ 12 Vij Qi (t)Qj (t + 1)

= 12 P + T P + + 12 P + T V Q + 12 QV Q

P + + 12 QV T P + + 12 V Q + Q

= P+

− 18 T V T P + +

− 18 V T V Q

Q + 12 P T V Q + 12 T P + ,

where in the last three expressions, Q = Q(t) and P + = P (t + 12 ). Equations (19.11) follow from the evolution equations (19.9) and (19.10) provided that

T and V are symmetric.

One reads off that this Hamiltonian is time-independent. It is bounded from below if not only V and T but also either V − 14 V T V or T − 14 T V T are bounded

from below (usually, one implies the other).

Unfortunately, this requirement is very stringent; the only solution where this

energy is properly bounded is a linear or periodic chain of coupled oscillators, as in

our one-dimensional model of massless bosons. On top of that, this formalism only

allows for strictly harmonic forces, which means that, unlike the continuum case,

no non-linear interactions can be accommodated for. A much larger class of models

will be exhibited in the next section.

Returning first to our model of massless bosons in 1 + 1 dimensions, Sect. 17, we

note that the classical evolution operator was defined over time steps δt = 1, and this

means that, knowing the evolution operator specifies the Hamiltonian eigenvalue up

to multiples of 2π . This is exactly the range of a single creation or annihilation

operator a L,R and a L,R† . But these operators can act many times, and therefore the

total energy should be allowed to stretch much further. This is where we need the

The Discretized Hamiltonian Formalism in PQ Theory

exactly conserved discrete energy function (19.11). The fractional part of H , which

we could call E quant , follows uniquely from the evolution operator U (δt). Then we

can add multiples of 2π times the energy (19.11) at will. This is how the entire

range of energy values of our 2 dimensional boson model results from our mapping.

It cannot be a coincidence that the angular energy function E quant together with the

conserved integer valued energy function E class taken together exactly represent the

spectrum of real energy values for the quantum theory. This is how our mappings

19.4 More General, Integer-Valued Hamiltonian Models

with Interactions

According to the previous section, we recuperate quantum models with a continuous

time variable from a discrete classical system if not only the evolution operator over

a time step δt is time-reversible, but in addition a conserved discrete energy beable

E class exists, taking values 2πN/δt where N is integer. Again, let us take δt = 1. If

the eigenvalues of U op (δt) are called e−iE , with 0 ≤ E quant < 2π then we can

define the complete Hamiltonian H to be

H = E quant + E class = 2π(ν + N ),

where 0 ≤ ν < 1 (or alternatively, −1/2 < ν ≤ 1/2) and N is integer. The quantity

conjugated to that is a continuous time variable. If we furthermore demand that

E class is bounded from below then Eq. (19.12) defines a genuine quantum system

with a conserved Hamiltonian that is bounded from below.

As stated earlier, it appears to be difficult to construct explicit, non-trivial examples of such models. If we try to continue along the line of harmonic oscillators,

perhaps with some non-harmonic forces added, it seems that the standard Hamiltonian formalism fails when the time steps are finite, and if we find a Hamiltonian that

is conserved, it is usually not bounded from below. Such models then are unstable;

they will not lead to a quantum description of a model that is stable.

In this section, we shall show how to cure this situation, in principle. We concentrate on the construction of a Hamiltonian principle that keeps a classical energy

function E class exactly conserved in time.

In the multidimensional models, we had adopted the principle that we in turn

update all variables Qi , then all Pi . That has to be done differently. To obtain better

models, let us phrase our assignment as follows:

Formulate a discrete, classical time evolution law for some model with the following properties:

i The time evolution operation must be a law that is reversible in time.3 Only then

will we have an operator U (δt) that is unitary and as such can be re-written as

the exponent of −i times a Hermitian Hamiltonian.

3 When

information loss is allowed, as in Sect. 7 of Part I, we shall have to relax this condition.

More General, Integer-Valued Hamiltonian Models with Interactions

ii There must exist a discrete function E class depending on the dynamical variables

of the theory, that is exactly conserved in time.

iii This quantity E class must be bounded from below.

When these first three requirements are met we will be able to map this system on a

quantum mechanical model that may be physically acceptable. But we want more:

iv Our model should be sufficiently generic, that is, we wish that it features interactions.

v Ideally, it should be possible to identify variables such as our Pi and Qi so that

we can compare our model with systems that are known in physics, where we

have the familiar Hamiltonian canonical variables p and q.

vi We would like to have some form of locality; as in the continuum system, our

Hamiltonian should be described as the integral (or sum) of a local Hamiltonian

density, H(x), and there should exist a small parameter ε > 0 such that at fixed

time t, H(x) only depends on variables located at x with |x − x| < ε.

The last condition turns our system in some discretized version of a field theory

(P and Q are then fields depending on a space coordinate x and of course on time t).

One might think that it would be hopeless to fulfill all these requirements. Yet there

exist beautiful solutions which we now construct. Let us show how our reasoning

Since we desire an integer-valued energy function that looks like the Hamiltonian

of a continuum theory, we start with a Hamiltonian that we like, being a continuous

function Hcont (q, p) and take its integer part, when also p and q are integer. More

precisely (with the appropriate factors 2π , as in Eqs. (16.6) and (18.22) in previous

chapters): take Pi and Qi integer and write4

E class (Q, P ) = 2πH class (Q, P ),

H class (Q, P ) = int

2π Hcont (Q, 2π P )

where ‘int’ stands for the integer part, and

Qi = int(qi ),

Pi = int(pi /2π),

for all i.

This gives us a discrete, classical ‘Hamiltonian function’ of the integer degrees

of freedom Pi and Qi . The index i may take a finite or an infinite number of values

(i is finite if we discuss a finite number of particles, infinite if we consider some

version of a field theory).

Soon, we shall discover that not all classical models are suitable for our construction: first of all: the oscillatory solutions must oscillate sufficiently slowly to

stay visible in our discrete time variable, but, as we shall see, our restrictions will

be somewhat more severe than this.

4 Later, in order to maintain some form of locality, we will prefer to take our ‘classical’ Hamiltonian

to be the sum of many integer parts, as in Eq. (19.27), rather than the floor of the sum of local parts,

as in Eq. (19.13).

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IPCC explores the ethics and economics of fighting climate change

The real-world implications of those ethical questions of responsibility will play out over the next several months of U.N. climate treaty talks, making ethics -- along with a chapter on the costs of mitigating emissions -- among the report's most controversial topics, sources said.

The United States and several other countries have sent members of their climate negotiating teams to Berlin, where governments this week are wrangling line-by-line over the final wording of a 29-page document that highlights thousands of pages of findings.

"Governments are just so wary about the implications of the IPCC for the negotiations. Anything that is touching on burden-sharing ... I think will be just impossible to get into the summary for policymakers," said one person close to the discussions.

Indeed, an early version of the summary obtained by ClimateWire plays it safe, noting merely that international cooperation on climate change "involves ethical considerations, including equitable effort-sharing." Countries, it notes, have contributed in different ways to the accumulation of greenhouse gases in the atmosphere and differ in their abilities to mitigate emissions.

"Evidence suggests that perceived fairness can influence the level of cooperation among individuals, and that finding may suggest that processes and outcomes seen as fair will lead to more international cooperation as well," the summary says.

Authors involved in the ethics chapters, who agreed only to talk generally about efforts to examine and synthesize the research until the IPCC report is formally released Sunday, said the charged questions of what constitutes dangerous man-made interference of the climate system and what countries should bear the burden of mitigation are ones the IPCC has taken on in the past.

A value judgement of 'what is dangerous'

But unlike other areas the United Nations' climate science body has taken on, like sea-level rise or glacier melt, these are questions that can't be measured or modeled with scientific accuracy. Rather, much of the research that has been done on the ethics of burden sharing rests on a set of principles that are essentially a matter of moral opinion about how, ideally, the world should work.

"We are trying to look at the social, economic and ethical conceptions of [things like] what is 'dangerous'? It's a matter of natural sciences ... but it also is making a value judgment about what we as humans consider dangerous," said Kevin Urama, executive director of the Africa Technology Policy Studies Network in Kenya and a co-lead coordinating author of the ethics chapter.

"The ethics deals a lot with justice, fairness, distributional weights. Basically, it sets a pace for better understanding for policymakers," Urama said.

"Really, what we're dealing with climate change or historic responsibility is 'What do we think is the ethical way to view someone who did something harmful, but before anyone realized it was harmful?'" said Charles Kolstad, a Stanford Institute for Economic Policy Research economist and co-lead coordinating author of the chapter.

Some of those questions are in fact answered in common law, Kolstad noted. Still, though, he said that while the IPCC lays out ethical theories that policymakers can use, the authors don't make conclusions.

"Some people thought if we put an ethics chapter in there, that would answer the question definitively. That was wishful thinking," Kolstad said. "We indicate that you can't find a definitive answer to this question of burden sharing by looking at the research. It has to be negotiated."

Mitigation increases; consumption drops?

That's a given. Wealthy countries like the United States already have been making a play to just avoid the entire question of a nation's "fair share" of emissions cuts by having countries volunteer to do what they can and impose a type of peer review process in which other countries or actors can assess the others' efforts. China and other developing nations, meanwhile, have called on countries to justify their pledges by describing how they take equity into account.

"The questions around equity can't be avoided if we want to have an ambitious agreement," said David Waskow, director of the World Resources Institute's International Climate Initiative. "If you completely avoid those questions, you're stuck with a pretty global requirement that doesn't in fact figure out how the actions can be taken at the end of the day."

In another part of the report that is also drawing some concern, the IPCC summary estimates with high confidence that ratcheting down emissions to keep the carbon dioxide concentration in the atmosphere below 480 parts per million by the end of the century will result in global consumption losses of 1 to 4 percent in 2030. That will jump to 2 to 12 percent in 2100 compared to what would happen without mitigation, the report notes without attaching a dollar figure to the estimate.

"These costs do not consider the benefits of mitigation, including the reduction in climate impacts," the summary notes.

Meanwhile, the IPCC also veers away from scientific research and into legal, economic and political science scholarship in the first-ever chapter on international cooperation.

It remains to be seen whether the summary for policymakers' judgment on the 1997 Kyoto Protocol will remain in the final version. They cited, with medium confidence, that the first binding step toward implementing U.N. climate goals "has not been as successful as intended."

Twitter: @LFFriedman | Email:


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Negativity will follow us but we can decide how we want to face it

The way we view the world largely depends on our thoughts, actions and attitude. When we are sensitive to our surroundings, we will notice sympathy and hope around. When we have anger and hatred in us, we will only see negativity all around.

It is true that there are many negative things happening around sadly we only get to hear about them through newspaper, internet and mobiles. But there are many positive things too happening in the world but we do not get to hear them because they do not have readership and TRP.

There will be negative things in life always but we can decide how we want to look at them. Certain things that we hear, see and read will cause a deep sense of frustration, aversion and unfathomable anger. But we need to remain peaceful and make sure that such things do not happen in our area.

We will be regularly challenged by pessimists and by depressing incidents. By now, we are well aware that negativity does not help us in anyway. It only pushes us down. It only suffocates us. So choose positive thoughts, send out positive energy, celebrate hope and celebrate life.

Freedom from past is necessary to lead a positive life. We need to practice forgiveness. Drop regrets, hatred and revenge. Letting go is the best option for a pleasant present and wonderful future.

Switch off the television, internet and all forms of news media. Smell the flowers, walk with the dog, enjoy silence or take a long walk. Our true nature and true wisdom will be revealed in these long walks and moments of silence.

Sometimes unknowingly, we might have developed certain behavior patterns that are attracting lot of negative energy. We need to identify them. There will be some disconnections. We need to check them. We need to check our goals and how far we have reached and are we taking the right path to reach the goal.

Practice gratitude. Pray, work hard and find intelligent solutions to problems. Focus on your goals. Develop courage to drop all that is harming us from leading a beautiful life.

Develop patience, drop anger and ego, stop hating and start loving and keep smiling.
Abhilash Rajendran


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