title: Green card

text: An applicant in the United States can obtain two permits while the case is pending after a certain stage is passed in green card processing (filing of I-485).


title: Green card

text: U.S. permanent residents may sponsor for permanent residence in the United States the following relatives:


title: Green card

text: The Department of State's "Visa Bulletin," issued every month, gives the priority date for those petition beneficiaries currently entitled to apply for immigrant status through immigrant visas or adjustment of status. There is no annual quota for the spouses, unmarried children, and parents of U.S. citizens, so there is no waiting period for these applicants—just the required processing time. However, all other family-based categories have significant backlogs, even with a U.S. citizen petitioner.


title: Green card

text: Regardless of whether the family member being sponsored is located in the United States (and therefore likely to be applying for adjustment of status) or outside the United States (in which case the immigrant visa is the likely option), the process begins with the filing of an I-130 Petition for Alien Relative. The form and instructions can be found on the U.S. Citizenship and Immigration Services website. Required later in the process will be additional biographic data regarding the beneficiary (the person being sponsored) and a medical examination. Additional documents, such as police certificates, may be required depending on whether immigrant visa (consular processing) or adjustment of status is being utilized. All petitioners must supply the I-864 Affidavit of Support.


title: Green card

text: Moreover, applicants who are in the United States unlawfully may be eligible to receive a green card under a sole exception. For an undocumented immigrant to be granted permanent residency they must abide by the registry date and eligibility criteria. The registry provision date was first developed in 1929 with the intention to aid in the growing number of undocumented immigrants. Essentially, only immigrants who entered the United States before a certain date (registry date) qualify to receive a green card. Other parameters include continued stay since entering the country and good moral character. After being created in 1929, congress advanced the registry date a total of four times. First set to only grant residency to individuals who entered the country before or on June 3 1921, the date was then moved to July 1 1924, further to July 1 1940, once more to June 30 1948 and finally January 1 1972. The last advancement date comprised the Immigration Reform and Control Act (IRCA) along with other regularization provisions which included penalizing institutions that knowingly employed undocumented non-citizens. This was done through a set of congressional amendments that culminated in 1958 Act, where the requirement for non-citizens to be eligible only if they are not subject to deportation was removed. Since then the registry date has not been advanced despite the number of immigrants increasing by 10 million and a total of 385 individuals have been granted a green card since the last registry update in 1986. Currently the provision date only excludes non-citizens that are inadmissible to the United States on criminal or national-security grounds. The updated and current eligibility requirements for registry are as follows:


title: Green card

text: Green-card holders married to non-U.S. citizens are able to legally bring their spouses and minor children to join them in the US, but must wait for their priority date to become current. The foreign spouse of a green-card holder must wait for approval of an "immigrant visa" from the State Department before entering the United States. Due to numerical limitation on the number of these visas, the wait time for approval may be months or years. In the interim, the spouse cannot be legally present in the United States, unless they secure a visa by some other means. Green-card holders may opt to wait to become U.S. citizens, and only then sponsor their spouses and children, as the process is much faster for U.S. citizens. However, many green-card holders can choose to apply for the spouse or children and update their application after becoming a U.S. citizen.


title: Green card

text: U.S. green-card holders have experienced separation from their families, sometimes for years. A mechanism to unite families of green-card holders was created by the LIFE Act by the introduction of a "V visa", signed into law by President Clinton. The law expired on December 31, 2000, and V visas are no longer available. Several bills have been introduced in Congress to reinstate V visas, but so far none have been successful.


title: Green card

text: The most common challenges that USCIS faces in providing services in the green card process are: (1) the length of the application and approval process, and (2) the quotas of green cards granted. USCIS tries to shorten the time qualified applicants wait to receive permanent residence.


title: Green card

text: Under the current system, immediate family members (spouse, child, and dependent mother and father), have priority status for green cards and generally wait 6 months to a year to have their green card application approved. For non-immediate family members, the process may take up to 10 years. Paperwork is processed on a first-come, first-served basis, so new applications may go untouched for several months. To address the issue of slow processing times, USCIS has made a policy allowing applicants to submit the I-130 and I-485 forms at the same time. This has reduced the processing time. Another delay in the process comes when applications have mistakes. In these cases papers are sent back to the applicant, further delaying the process. Currently the largest cause of long wait times is not processing time, but rather immigrant visa quotas set by Congress.


title: Green card

text: Because of numerical quotas in many immigration categories, long wait times often prevent immigrants from receiving immigrant visas in a short time frame. The "Augusta Chronicle" in 2006 stated that an estimated two million people are on waiting lists in anticipation to become legal and permanent residents of the United States. Immigrants need visas to get off of these waiting lists, and Congress would need to change immigration law in order to accommodate them with legal status.


title: Green card

text: The number of green cards that can be granted to family-based applicants depends on what preference category they fall under. An unlimited number of immediate relatives can receive green cards because there is no quota for that category. Family members who fall under the other various preference categories have fixed quotas; however, the number of visas issued from each category may vary because unused visas from one category may roll over into another category.


title: Green card

text: Many immigrants opt for this route, which typically requires an employer to "sponsor" (i.e., to petition before USCIS) the immigrant (known as the "alien beneficiary") through a presumed future job (in some special categories, the applicant may apply on their behalf without a sponsor). The three-step process outlined above is described here in more detail for employment-based immigration applications. After the process is complete, the alien is expected to take the certified job offered by the employer to substantiate their immigrant status, since the application ultimately rests on the alien's employment with that company in that particular position.


title: Green card

text: Each year, around 50,000 immigrant visas are made available through the Diversity Visa (DV) program, also known as the Green Card Lottery to people who were born in countries with low rates of immigration to the United States (fewer than 50,000 immigrants in the past five years). Applicants can only qualify by country of chargeability, not by citizenship. Anyone who is selected under this lottery will be given the opportunity to apply for permanent residence. They can also file for their spouse and any unmarried children under the age of 21.


title: Green card

text: If permanent residence is granted, the winner (and their family, if applicable) receives an immigrant visa in their passport(s) that has to be "activated" within six months of issuance at any port of entry to the United States. If already in the U.S. adjustment of status may be pursued. The new immigrant receives a stamp on the visa as proof of lawful admittance to the United States, and the individual is now authorized to live and work permanently in the United States. Finally, the actual "green card" typically arrives by mail within a few months.


title: Green card

text: There is a growing number of fraudulent green card lottery scams, in which false agents take money from applicants by promising to submit application forms for them. Most agents are not working for the distribution service. Some claim that they can increase the chance of winning the lottery, when in fact, they may delay or not submit the application. Likewise, some claim to provide to winners free airline tickets or other benefits, such as submissions in future years or cash funds. There is no way to guarantee their claims, and there are numerous nefarious reasons for them not to fulfill their promises. Applicants are advised to use only official U.S. government websites, in which the URL ends in .gov.


title: Green card

text: Other fraud perpetrators will e-mail potential victims posing as State Department or other government officials with requests to wire or transfer money online as part of a "processing fee." These fraudulent e-mails are designed to steal money from unsuspecting victims. The senders often use illegitimate e-mail addresses and logos designed to make them look more like official government correspondence. One easy way to tell that an email address is fraudulent is that it does not end with ".gov". One particularly common fraud email asks potential victims to wire money via Western Union to an individual (the name varies) at the following address in the United Kingdom: 24 Grosvenor Square, London. These emails come from a variety of email addresses designed to impersonate the U.S. State Department. The USCIS blog has published information on this email scam and how to report fraudulent emails to the authorities. The U.S. government has issued warnings about this type of fraud or similar business practices.


title: Green card

text: The "registry" is a provision of the INA which allows an alien who has previously entered the United States illegally to obtain legal permanent residence simply on the basis of having de facto resided in the country over a very long time. To avail themself of the benefit of this provision, the alien has to prove that they have continuously resided since before the stipulated "registry date". The concept of "registry" was first added to the INA in 1929, with the registry date set to June 3, 1921. Since then, the registry date has been adjusted several times, being set to July 1, 1924; June 28, 1940; and June 30, 1948. The most recent adjustment to the registry date came with the Immigration Reform and Control Act of 1986, when it was set to January 1, 1972. A number of bills have been introduced in Congress since then to further alter the registry date, but they have not been passed.


title: Green card

text: On October 2, 2020, the USCIS declared the inadmissibility based on belonging or affiliation to Communist parties or any, unspecified, "totalitarian party". Membership or affiliation with such parties, whether US or foreign, would be incompatible with the oath of allegiance to the naturalization of the United States of America, which includes a commitment to "support and defend the Constitution and laws of the United States". Exceptions to the inadmissibility rule include circumstances where membership is: "Involuntary; Solely when under 16 years of age; By operation of law; or For purposes of obtaining employment, food rations, or other essentials of living and where necessary for such purposes." The ban would affect current members of Chinese Communist Party and Communist Youth League of China, for example.


title: Green card

text: Lawful permanent residents, also known as green card holders, have certain rights and responsibilities as highlighted by the United States Citizenship and Immigration Services and other federal agencies.


title: Green card

text: LPRs can secure many types of jobs just like U.S. citizens can. LPRs can register property under their names and live anywhere within the United States. They can similarly operate any type of business in the United States.


title: Green card

text: LPRs are also subject to similar obligations as U.S. citizens. For example, male LPRs between the ages of 18 and 25 are subject to registering in the Selective Service System. Like U.S. citizens, LPRs must pay taxes on their worldwide income (this includes filing annual U.S. income tax returns). LPRs are not permitted to vote in federal elections and they cannot be elected to federal office. They may vote in certain local elections, and hold local and state offices (subject to state/city law and Constitutionality).


title: Green card

text: As part of immigration reform under the Immigration Reform and Control Act of 1986 (IRCA), as well as further reform enacted in the Illegal Immigration Reform and Immigrant Responsibility Act of 1996 (IIRIRA), eligible persons who properly apply for permanent residency based on either a recent marriage to a U.S. citizen or as an investor are granted such privilege only on a conditional basis, for two years. An exception to this rule is the case of a U.S. citizen legally sponsoring a spouse in which the marriage at the time of the adjustment of status (I-485) is more than two years old. In this case, the conditional status is waived and a 10-year "permanent resident card" is issued after the USCIS approves the case. A permanent resident under the conditional clause may receive an I-551 stamp as well as a permanent resident card. The expiration date of the conditional period is two years from the approval date. The immigrant visa category is CR (conditional resident).


title: Green card

text: When this two-year conditional period is over, the permanent residence automatically expires and the applicant is subject to deportation and removal unless, up to 90 days before the conditional residence expires, the applicant files form I-751 "Petition to Remove Conditions on Residence" (if conditional permanent residence was obtained through marriage) or form I-829 "Petition by Entrepreneur to Remove Conditions" (if conditional permanent residence was obtained through investment) with USCIS to have the conditions removed. Once the application is received, permanent residence is extended in 1-year intervals until the request to remove conditions is approved or denied. For conditional permanent residence obtained through marriage, both spouses must sign the form I-751; if the spouses are divorced, it is possible to get a waiver of the other spouse's signing requirement, if it can be proved that the marriage was bona fide.


title: Green card

text: The USCIS requires that the application for the removal of conditions provide both general and specific supporting evidence that the basis on which the applicant obtained conditional permanent residence was not fraudulent. For an application based on marriage, birth certificates of children, joint financial statements, and letters from employers, friends and relatives are some types of evidence that may be accepted. That is to ensure that the marriage was in good faith and not a fraudulent marriage of convenience with a sole intention of obtaining a green card. A follow-up interview with an immigration officer is sometimes required but may be waived if the submitted evidence is sufficient. Both the spouses must usually attend the interview.


title: Green card

text: The applicant receives an I-551 stamp in their foreign passport upon approval of their case. The applicant is then free from the conditional requirement once the application is approved. The applicant's new permanent resident card arrives via mail to their house several weeks to several months later and replaces the old two-year conditional residence card. The new card must be renewed after 10 years, but permanent resident status is now granted for an indefinite term if residence conditions are satisfied at all times. The USCIS may request to renew the card earlier because of security enhancements of the card or as a part of a revalidation campaign to exclude counterfeit green cards from circulation.


title: Green card

text: The two-year conditional residence period counts toward satisfying a residency requirement for U.S. naturalization, and other purposes. Application for the removal of conditions must be adjudicated before a separate naturalization application could be reviewed by the USCIS on its own merits.


title: Green card

text: Conditional permanent residents have all of the equal "rights, privileges, responsibilities and duties which apply to all other lawful permanent residents." The only difference is the requirement to satisfy the conditions (such as showing marriage status or satisfying entrepreneur requirements) before the two-year period ends.


title: Green card

text: A green-card holder may abandon permanent residence by filing form I-407, with the green card, at a U.S. Embassy.


title: Green card

text: Under certain conditions, permanent residence status can be lost involuntarily. This includes committing a criminal act that makes a person removable from the United States. A person might also be found to have abandoned their status if they move to another country to live there permanently, stay outside the US for more than 365 days (without getting a re-entry permit before leaving), or fail to file an income tax return on their worldwide income. Permanent resident status can also be lost if it is found that the application or grounds for obtaining permanent residence was fraudulent. The failure to renew the permanent resident card does not result in the loss of status, except in the case of conditional permanent residents as noted above. Nevertheless, it is still a good idea to renew the green card on time because it also acts as a work permit and travel permit (advance parole), but if the green card is renewed late, there is no penalty or extra fee to pay.


title: Green card

text: A person who loses permanent residence status is immediately removable from the United States and must leave the country as soon as possible or face deportation and removal. In some cases the person may be banned from entering the country for three or seven years, or even permanently.


title: Green card

text: foreign workers who have owned a green card in eight of the last 15 years and choose to relinquish it will be subject to the expatriation tax, which taxes unrealized gains above $600,000, anywhere in the world. However this will only apply to those people who have a federal tax liability greater than $139,000 a year or have a worth of more than $2 million or have failed to certify to the IRS that they have been in compliance with U.S. federal tax obligations for the past five years.


title: Green card

text: If the green card is not relinquished, then the holder is subject to double taxation when living or working outside of the United States, whether or not within their home nation, although double taxation may be mitigated by foreign tax credits.


title: Green card

text: While most of the information on the card is self-evident, the computer- and human-readable signature at the bottom is not. The format follows the machine-readable travel document TD1 format:


title: Green card

text: A full list of category codes (i.e. IR1, E21, etc.) can be found in the "Federal Register" or Foreign Affairs Manual.


title: Green card

text: Since May 11, 2010, new green cards contain an RFID chip and can be electronically accessed at a distance. They are shipped with a protective sleeve intended to protect the card from remote access, but it is reported to be inadequate.


title: Green card

text: The following countries and territories generally allow U.S. permanent residents to enter the country without a visa for purposes of tourism.


title: Green card

text: "This article in most part is based on law of the United States, including statutory and published case law."


title: Kia Sorento

text: The Kia Sorento () is a mid-size crossover SUV (formerly a body-on-frame SUV until 2009) produced since 2002 by South Korean manufacturer Kia.


title: Kia Sorento

text: Debuted in February 2002, the first generation Sorento was a traditional truck-based body-on-frame SUV. All American Sorentos also came with dual front airbags and dual side-curtain airbags in the front and rear. An optional four-wheel drive system with low range received praise for adding to the vehicle's off-road ability.


title: Kia Sorento

text: It had two transmission options, a 5-speed manual or 4- and 5-speed automatic (pre-2005 models have a 4-speed automatic, whilst 2005 Sorentos came with a 5-speed tip-tronic style automatic). First generation Sorentos are equipped with a Hyundai-manufactured 3.5-liter 24-valve DOHC V6 engine producing at 5500 rpm, and of torque at 3,000 rpm.


title: Kia Sorento

text: Common features of the first generation Sorento were 4-wheel disc brakes (standard on all models), optional anti-lock braking system (ABS), and a 21.1-gallon (79.9 litres) fuel tank.


title: Kia Sorento

text: There were two trim levels available for the Sorento: either the base LX or the up-level EX. Both models included an AM/FM stereo with a single-disc CD player and an eight-speaker audio system, dual front airbags and front and rear side-impact SRS airbags (side-impact front and rear SRS airbags for North American-market models ONLY), cloth seating surfaces, a power-adjustable front driver's seat, air conditioning, power door locks and windows, tinted windows, aluminum-alloy wheels, keyless entry, wood interior trim accents, a split-folding second-row rear bench seat, and monotone exterior paint as standard equipment. Features such as satellite radio (on later models), leather-trimmed seating surfaces, heated front seats, a ten-speaker premium audio system, cassette and CD players, an in-dash CD changer, power front bucket seats, seventeen-inch (17") aluminum-alloy wheels, a power sunroof, two-tone exterior paint, and a security system were available regardless of trim level choice.


title: Kia Sorento

text: The 2007 Sorento received upgrades, such as the transition from the 3.5-liter Sigma to the 3.3-liter with and , and the 3.8-liter Lambda, with and and increased tow capacity from to . Projector beam headlamps were added, along with new tail lamps. The 5-speed manual transmission was no longer available; the 5-speed Sportmatic tip-tronic automatic transmission was made standard for all vehicles. Most of the EX trim had full-time AWD and 4x4 Low modes; The LX had a part-time system with 2WD High (rear wheel drive), 4WD High (not for dry pavement) and 4WD Low modes. The 2007 Kia Sorento earned a five-star crash safety rating, the highest rating possible, for all seating positions in frontal and side impact crash tests conducted by the National Highway Traffic Safety Administration (NHTSA). The tail lights and front end were upgraded, but the two-box design stayed.


title: Kia Sorento

text: The 2003 Sorento received Poor to Average ratings from the Insurance Institute for Highway Safety (IIHS). The 2007 facelifted version had improved safety ratings for moderate overlap front crashes and head restraints & seats, but retained its Poor side impact rating.


title: Kia Sorento

text: A redesigned Sorento (codename XM) was launched in South Korea in April 2009. The second generation was Kia's first model to be manufactured in the United States, in Kia's new US$1 billion West Point, Georgia, factory (which also builds the sister vehicle to the Sorento, the Hyundai Santa Fe). The second generation used Kia's corporate Tiger Nose grille, and was the first Kia vehicle to offer Kia UVO. The vice president of marketing for Kia Motors America said that Kia initially considered changing the name due to the radical change in the Sorento's body style.


title: Kia Sorento

text: The second-generation Sorento introduced Kia's new design language, and introduced new features and technology that would later become available on other Kia models.


title: Kia Sorento

text: The four-cylinder model returned to the lineup for North American models after being absent between 2007 and 2010. The engine was transverse, and the suspension all-independent. The change in body construction as well as the loss of a low-ratio transfer case made the Sorento 475 pounds less than the old one model for model, to gain in performance and economy.


title: Kia Sorento

text: The second generation Sorento was originally available in four models – the Base, LX, EX and top-of-the-line SX models. The SX is only available with the 3.5-liter V6. The Base and LX both come standard with the 2.4-liter straight-4 and EX has the GDI version of the same engine which is rated 191 hp. The V6 is available as an upgrade for both the LX and EX. The SX Limited model became available in 2012.


title: Kia Sorento

text: The Sorento received a mid-cycle refresh for the 2014 model year, unveiled in 2012 at the Los Angeles International Auto Show, and went on sale in first quarter of 2013. Major changes included a revised instrument panel, front and rear end with new tail lights modeled after the Optima, as well as several other mechanical and interior changes.


title: Kia Sorento

text: For 2015, the six-speed manual transmission option, previously only available on the Base and LX models, was discontinued, leaving the six-speed automatic transmission as the only transmission option for the Sorento.


title: Kia Sorento

text: The 2011 Sorento received a "Top Safety Pick" rating from the Insurance Institute for Highway Safety (IIHS).


title: Kia Sorento

text: The 2011 Sorento was awarded the maximum five-star safety rating from the crash safety experts, European New Car Assessment Programme (Euro NCAP) and Australasian New Car Assessment Program (ANCAP). The XM Sorento awarded 'Top Safety Pick' from Insurance Institute for Highway Safety (IIHS) in the United States.


title: Kia Sorento

text: The second generation Sorento was awarded New Zealand Autocar magazine SUV of the Year, "great looker, does absolutely everything as it should. Engine is world class". The Kia Sorento EX V6 model earned an “Excellent” overall score by American magazine Consumer Reports’ July 2010 issue.


title: Kia Sorento

text: As part of 2014 Sorento market launch in the US, a campaign titled "It has an answer for everything" was unveiled during Super Bowl XLVII. "Space Babies" (directed by Jake Scott) commercial was premiered in the fourth quarter, featuring the existence of a faraway planet known as "Babylandia" and follows infant boys, girls, dogs, pandas and more on their journey to Earth to join their new families. After taking it all in, the curious child begins to offer an alternative theory passed on by a friend but his quick-thinking father calls upon UVO's voice-activated jukebox feature to hurriedly change the subject and survive another day in the adventures of parenthood. "Tight Space" (directed by Peter Darley Miller and Colin Jeffery) showed two of the CUV's available features – power-folding mirrors and power liftgate – help a determined father make the slimmest parking garage space manageable while his skeptical wife and children look on.


title: Kia Sorento

text: Kia Motors revealed the third generation Sorento in South Korea on August 28, 2014. The vehicle later made its European debut at the 2014 Paris Motor Show. The third generation Sorento shares a platform with the third-generation Kia Carnival, and is available in either 5-seater or 7-seater, depending on configuration. It is 95mm longer than the previous generation, but lower for better handling. Kia claims a rigidity strengthening of 14% on its high tensile steel and the Sorento scored good evaluation in small overlap crash test by IIHS. In the US, the Sorento continues to be produced at the West Point, Georgia assembly plant.


title: Kia Sorento

text: Available engines are a 3.3-liter "Lambda II" V6, the existing 2.4-liter GDi I4 that make the same output as the outgoing engine, and the new 2.0-liter turbo I4. A 2.2-liter CRDi diesel engine with variable geometry turbocharger (VGT) is also available.


title: Kia Sorento

text: The third generation Sorento comes equipped with a six-speed manual transmission or six-speed automatic transmission. Drivetrains are front-wheel drive or all-wheel drive.


title: Kia Sorento

text: In the United States, the 2016 Kia Sorento is offered in five models, and four models within the United Kingdom. KX-1 base model, KX-2, KX-3 and KX-4 with the GT-Line from late 2018 onwards replacing the KX-4.


title: Kia Sorento

text: In Pakistan, Kia Pakistan unveiled its car at a Power Play event held at the Karachi factory on 14 February 2021. The event was held at Kia Motor Corporation's production plant, where various personalities from the automotive sector were invited. The car offered in Pakistan is the third generation of Sorento. The SUV is offered in three tiers with two power train options, a 2.4-liter front-wheel drive and all-wheel drive model, and a 3.5-liter front-wheel drive model.


title: Kia Sorento

text: The Kia Sorento received updates for 2018 or 2019 depending on market location, these included a new front grille, bumper covers and exterior lighting with similar design cues derived from the 2019 Kia Forte and the 2018 Kia Cadenza for the 2019 model year. The L, LX, EX and SX trim levels received refreshed projector beam headlamps with LED positioning lights. The SXL trim received new LED headlamps with LED daytime running lights, LED amber turn signal and positioning lights, and LED tail lamps.


title: Kia Sorento

text: Other changes include new exterior colors, new wheels, third row seating now standard on all trim levels with all engine types, driver attention warning system added to all trim levels, and a 2.4-liter engine replaced the 2.0-liter engine on lower trim levels. The 2019 Kia Sorento features a 3.3-liter V6 engine on higher trim levels. The trim levels are available with all-wheel drive, except for the base L trim, which is only available with front-wheel drive.


title: Kia Sorento

text: The 2017 Sorento received a "Top Safety Pick" rating from the Insurance Institute for Highway Safety (IIHS).


title: Kia Sorento

text: In November 2014, Kia Motors collaborated with 20th Century Fox to create a Wolverine-themed Sorento to promote the home media release of "". The custom Sorento made its debut at the 2015 Australian Open, with a series of videos featuring Rafael Nadal teaming up with the X-Men to save the tennis event from the Sentinels.


title: Kia Sorento

text: In January 2015, Kia Motors released their Sorento Super Bowl XLIX commercial featuring Pierce Brosnan.


title: Kia Sorento

text: The fourth generation Sorento was officially unveiled through a series of images on February 17, 2020. The unveiling of the production version had originally been planned for the later-cancelled Geneva Motor Show.


title: Kia Sorento

text: The updated Sorento sports a larger design with an extended wheelbase ( longer) while the vehicle's overall length is extended by . There are two engine options: a hybrid (a 1.6-liter turbocharged four-cylinder and single electric motor, amounting to and of torque) and a traditional gasoline-only engine (a 2.5-liter turbocharged four-cylinder, matched with an 8-speed dual-clutch automatic transmission, output at and . A plug-in hybrid variation and additional gasoline engine options are also being planned, along with a multi-collision brake system and a remote smartphone surround view monitor.


title: Kia Sorento

text: On September 22, 2020, the fourth-generation Kia Sorento made its debut in North America. It is offered in several different trim levels: LX, S, EX, SX, SX Prestige, and SX Prestige X-Line. LX and S models is powered by a naturally-aspirated 2.5-liter 4-cylinder Smartstream gasoline engine producing , while EX, SX, SX Prestige, and SX Prestige X-Line models uses a 2.5-liter turbocharged Smartstream 4-cylinder gasoline engine producing . All North American Sorento uses an 8-speed automatic transmission, though models equipped with the 2.5-liter turbo engine uses an 8-speed dual-clutch transmission. Sorento hybrid models will be available after the initial launch in late 2020. The V6 engine is no longer offered. In 2021, Kia announced the introduction of the Sorento PHEV which gets 261 hp from its 1.6 litre turbo four-cylinder mated to an electric motor. Claimed EV range is 51 km (32 miles) and has a combined range of 740 km (460 miles). Prices are to be announced later.


title: Kia Sorento

text: Kia continued to build the North American-market Sorento at its assembly plant in West Point, Georgia, United States. All models include front-wheel-drive, except for the SX Prestige X-Line model and the hybrid models, which include standard all-wheel-drive. All North American-market 2021 Sorento feature three rows of seating, with higher trim levels featuring second-row captain's chairs in place of the standard second-row rear split bench seat.


title: Kia Sorento

text: In January 2021, the Sorento 1.6 T-GDi Hybrid 2 was named Large SUV of the Year by "What Car?" magazine. "What Car?" awarded the Sorento five stars out of five in its review of the car.


title: Kia Sorento

text: In June 2022, the Sorento won Auto Trader UK's New Car Award for Best 7 Seater. "Auto Trader" awarded the Sorento four and a half stars out of five in its review of the car.


title: Apoptosis

text: Apoptosis (from ) is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, DNA fragmentation, and mRNA decay. The average adult human loses between 50 and 70 billion cells each day due to apoptosis. For an average human child between eight and fourteen years old, approximately twenty to thirty billion cells die per day.


title: Apoptosis

text: In contrast to necrosis, which is a form of traumatic cell death that results from acute cellular injury, apoptosis is a highly regulated and controlled process that confers advantages during an organism's life cycle. For example, the separation of fingers and toes in a developing human embryo occurs because cells between the digits undergo apoptosis. Unlike necrosis, apoptosis produces cell fragments called apoptotic bodies that phagocytes are able to engulf and remove before the contents of the cell can spill out onto surrounding cells and cause damage to them.


title: Apoptosis

text: Because apoptosis cannot stop once it has begun, it is a highly regulated process. Apoptosis can be initiated through one of two pathways. In the "intrinsic pathway" the cell kills itself because it senses cell stress, while in the "extrinsic pathway" the cell kills itself because of signals from other cells. Weak external signals may also activate the intrinsic pathway of apoptosis. Both pathways induce cell death by activating caspases, which are proteases, or enzymes that degrade proteins. The two pathways both activate initiator caspases, which then activate executioner caspases, which then kill the cell by degrading proteins indiscriminately.


title: Apoptosis

text: In addition to its importance as a biological phenomenon, defective apoptotic processes have been implicated in a wide variety of diseases. Excessive apoptosis causes atrophy, whereas an insufficient amount results in uncontrolled cell proliferation, such as cancer. Some factors like Fas receptors and caspases promote apoptosis, while some members of the Bcl-2 family of proteins inhibit apoptosis.


title: Apoptosis

text: German scientist Carl Vogt was first to describe the principle of apoptosis in 1842. In 1885, anatomist Walther Flemming delivered a more precise description of the process of programmed cell death. However, it was not until 1965 that the topic was resurrected. While studying tissues using electron microscopy, John Kerr at the University of Queensland was able to distinguish apoptosis from traumatic cell death. Following the publication of a paper describing the phenomenon, Kerr was invited to join Alastair Currie, as well as Andrew Wyllie, who was Currie's graduate student, at University of Aberdeen. In 1972, the trio published a seminal article in the "British Journal of Cancer". Kerr had initially used the term programmed cell necrosis, but in the article, the process of natural cell death was called "apoptosis". Kerr, Wyllie and Currie credited James Cormack, a professor of Greek language at University of Aberdeen, with suggesting the term apoptosis. Kerr received the Paul Ehrlich and Ludwig Darmstaedter Prize on March 14, 2000, for his description of apoptosis. He shared the prize with Boston biologist H. Robert Horvitz.


title: Apoptosis

text: For many years, neither "apoptosis" nor "programmed cell death" was a highly cited term. Two discoveries brought cell death from obscurity to a major field of research: identification of the first component of the cell death control and effector mechanisms, and linkage of abnormalities in cell death to human disease, in particular cancer. This occurred in 1988 when it was shown that BCL2, the gene responsible for follicular lymphoma, encoded a protein that inhibited cell death.


title: Apoptosis

text: The 2002 Nobel Prize in Medicine was awarded to Sydney Brenner, H. Robert Horvitz and John Sulston for their work identifying genes that control apoptosis. The genes were identified by studies in the nematode "C. elegans" and homologues of these genes function in humans to regulate apoptosis.


title: Apoptosis

text: In Greek, apoptosis translates to the "falling off" of leaves from a tree. Cormack, professor of Greek language, reintroduced the term for medical use as it had a medical meaning for the Greeks over two thousand years before. Hippocrates used the term to mean "the falling off of the bones". Galen extended its meaning to "the dropping of the scabs". Cormack was no doubt aware of this usage when he suggested the name. Debate continues over the correct pronunciation, with opinion divided between a pronunciation with the second "p" silent ( ) and the second "p" pronounced (). In English, the "p" of the Greek "-pt-" consonant cluster is typically silent at the beginning of a word (e.g. pterodactyl, Ptolemy), but articulated when used in combining forms preceded by a vowel, as in helicopter or the orders of insects: diptera, lepidoptera, etc.


title: Apoptosis

text: We are most grateful to Professor James Cormack of the Department of Greek, University of Aberdeen, for suggesting this term. The word "apoptosis" () is used in Greek to describe the "dropping off" or "falling off" of petals from flowers, or leaves from trees. To show the derivation clearly, we propose that the stress should be on the penultimate syllable, the second half of the word being pronounced like "ptosis" (with the "p" silent), which comes from the same root "to fall", and is already used to describe the drooping of the upper eyelid.


title: Apoptosis

text: The initiation of apoptosis is tightly regulated by activation mechanisms, because once apoptosis has begun, it inevitably leads to the death of the cell. The two best-understood activation mechanisms are the intrinsic pathway (also called the mitochondrial pathway) and the extrinsic pathway. The "intrinsic pathway" is activated by intracellular signals generated when cells are stressed and depends on the release of proteins from the intermembrane space of mitochondria. The "extrinsic pathway" is activated by extracellular ligands binding to cell-surface death receptors, which leads to the formation of the death-inducing signaling complex (DISC).


title: Apoptosis

text: A cell initiates intracellular apoptotic signaling in response to a stress, which may bring about cell suicide. The binding of nuclear receptors by glucocorticoids, heat, radiation, nutrient deprivation, viral infection, hypoxia, increased intracellular concentration of free fatty acids and increased intracellular calcium concentration, for example, by damage to the membrane, can all trigger the release of intracellular apoptotic signals by a damaged cell. A number of cellular components, such as poly ADP ribose polymerase, may also help regulate apoptosis. Single cell fluctuations have been observed in experimental studies of stress induced apoptosis.


title: Apoptosis

text: Before the actual process of cell death is precipitated by enzymes, apoptotic signals must cause regulatory proteins to initiate the apoptosis pathway. This step allows those signals to cause cell death, or the process to be stopped, should the cell no longer need to die. Several proteins are involved, but two main methods of regulation have been identified: the targeting of mitochondria functionality, or directly transducing the signal via adaptor proteins to the apoptotic mechanisms. An extrinsic pathway for initiation identified in several toxin studies is an increase in calcium concentration within a cell caused by drug activity, which also can cause apoptosis via a calcium binding protease calpain.


title: Apoptosis

text: The intrinsic pathway is also known as the mitochondrial pathway. Mitochondria are essential to multicellular life. Without them, a cell ceases to respire aerobically and quickly dies. This fact forms the basis for some apoptotic pathways. Apoptotic proteins that target mitochondria affect them in different ways. They may cause mitochondrial swelling through the formation of membrane pores, or they may increase the permeability of the mitochondrial membrane and cause apoptotic effectors to leak out. They are very closely related to intrinsic pathway, and tumors arise more frequently through intrinsic pathway than the extrinsic pathway because of sensitivity. There is also a growing body of evidence indicating that nitric oxide is able to induce apoptosis by helping to dissipate the membrane potential of mitochondria and therefore make it more permeable. Nitric oxide has been implicated in initiating and inhibiting apoptosis through its possible action as a signal molecule of subsequent pathways that activate apoptosis.


title: Apoptosis

text: During apoptosis, cytochrome "c" is released from mitochondria through the actions of the proteins Bax and Bak. The mechanism of this release is enigmatic, but appears to stem from a multitude of Bax/Bak homo- and hetero-dimers of Bax/Bak inserted into the outer membrane. Once cytochrome "c" is released it binds with Apoptotic protease activating factor – 1 ("Apaf-1") and ATP, which then bind to "pro-caspase-9" to create a protein complex known as an apoptosome. The apoptosome cleaves the pro-caspase to its active form of caspase-9, which in turn cleaves and activates pro-caspase into the effector "caspase-3".


title: Apoptosis

text: Mitochondria also release proteins known as SMACs (second mitochondria-derived activator of caspases) into the cell's cytosol following the increase in permeability of the mitochondria membranes. SMAC binds to "proteins that inhibit apoptosis" (IAPs) thereby deactivating them, and preventing the IAPs from arresting the process and therefore allowing apoptosis to proceed. IAP also normally suppresses the activity of a group of cysteine proteases called caspases, which carry out the degradation of the cell. Therefore, the actual degradation enzymes can be seen to be indirectly regulated by mitochondrial permeability.


title: Apoptosis

text: Two theories of the direct initiation of apoptotic mechanisms in mammals have been suggested: the "TNF-induced" (tumor necrosis factor) model and the "Fas-Fas ligand-mediated" model, both involving receptors of the "TNF receptor" (TNFR) family coupled to extrinsic signals.


title: Apoptosis

text: TNF-alpha is a cytokine produced mainly by activated macrophages, and is the major extrinsic mediator of apoptosis. Most cells in the human body have two receptors for TNF-alpha: TNFR1 and TNFR2. The binding of TNF-alpha to TNFR1 has been shown to initiate the pathway that leads to caspase activation via the intermediate membrane proteins TNF receptor-associated death domain (TRADD) and Fas-associated death domain protein (FADD). cIAP1/2 can inhibit TNF-α signaling by binding to TRAF2. FLIP inhibits the activation of caspase-8. Binding of this receptor can also indirectly lead to the activation of transcription factors involved in cell survival and inflammatory responses. However, signalling through TNFR1 might also induce apoptosis in a caspase-independent manner. The link between TNF-alpha and apoptosis shows why an abnormal production of TNF-alpha plays a fundamental role in several human diseases, especially in autoimmune diseases. The TNF-alpha receptor superfamily also includes death receptors (DRs), such as DR4 and DR5. These receptors bind to the proteinTRAIL and mediate apoptosis. Apoptosis is known to be one of the primary mechanisms of targeted cancer therapy. Luminescent iridium complex-peptide hybrids (IPHs) have recently been designed, which mimic TRAIL and bind to death receptors on cancer cells, thereby inducing their apoptosis.


title: Apoptosis

text: The fas receptor (First apoptosis signal) – (also known as "Apo-1" or "CD95") is a transmembrane protein of the TNF family which binds the Fas ligand (FasL). The interaction between Fas and FasL results in the formation of the "death-inducing signaling complex" (DISC), which contains the FADD, caspase-8 and caspase-10. In some types of cells (type I), processed caspase-8 directly activates other members of the caspase family, and triggers the execution of apoptosis of the cell. In other types of cells (type II), the "Fas"-DISC starts a feedback loop that spirals into increasing release of proapoptotic factors from mitochondria and the amplified activation of caspase-8.


title: Apoptosis

text: Following "TNF-R1" and "Fas" activation in mammalian cells a balance between proapoptotic (BAX, BID, BAK, or BAD) and anti-apoptotic ("Bcl-Xl" and "Bcl-2") members of the "Bcl-2" family are established. This balance is the proportion of proapoptotic homodimers that form in the outer-membrane of the mitochondrion. The proapoptotic homodimers are required to make the mitochondrial membrane permeable for the release of caspase activators such as cytochrome c and SMAC. Control of proapoptotic proteins under normal cell conditions of nonapoptotic cells is incompletely understood, but in general, Bax or Bak are activated by the activation of BH3-only proteins, part of the Bcl-2 family.


title: Apoptosis

text: Caspases play the central role in the transduction of ER apoptotic signals. Caspases are proteins that are highly conserved, cysteine-dependent aspartate-specific proteases. There are two types of caspases: initiator caspases, caspase 2,8,9,10,11,12, and effector caspases, caspase 3,6,7. The activation of initiator caspases requires binding to specific oligomeric activator protein. Effector caspases are then activated by these active initiator caspases through proteolytic cleavage. The active effector caspases then proteolytically degrade a host of intracellular proteins to carry out the cell death program.


title: Apoptosis

text: There also exists a caspase-independent apoptotic pathway that is mediated by AIF (apoptosis-inducing factor).


title: Apoptosis

text: Amphibian frog "Xenopus laevis" serves as an ideal model system for the study of the mechanisms of apoptosis. In fact, iodine and thyroxine also stimulate the spectacular apoptosis of the cells of the larval gills, tail and fins in amphibians metamorphosis, and stimulate the evolution of their nervous system transforming the aquatic, vegetarian tadpole into the terrestrial, carnivorous frog.


title: Apoptosis

text: Negative regulation of apoptosis inhibits cell death signaling pathways, helping tumors to evade cell death and developing drug resistance. The ratio between anti-apoptotic (Bcl-2) and pro-apoptotic (Bax) proteins determines whether a cell lives or dies. Many families of proteins act as negative regulators categorized into either antiapoptotic factors, such as IAPs and Bcl-2 proteins or prosurvival factors like cFLIP, BNIP3, FADD, Akt, and NF-κB.


title: Apoptosis

text: Many pathways and signals lead to apoptosis, but these converge on a single mechanism that actually causes the death of the cell. After a cell receives stimulus, it undergoes organized degradation of cellular organelles by activated proteolytic caspases. In addition to the destruction of cellular organelles, mRNA is rapidly and globally degraded by a mechanism that is not yet fully characterized. mRNA decay is triggered very early in apoptosis.


title: Apoptosis

text: A cell undergoing apoptosis shows a series of characteristic morphological changes. Early alterations include:


title: Apoptosis

text: Apoptosis progresses quickly and its products are quickly removed, making it difficult to detect or visualize on classical histology sections. During karyorrhexis, endonuclease activation leaves short DNA fragments, regularly spaced in size. These give a characteristic "laddered" appearance on agar gel after electrophoresis. Tests for DNA laddering differentiate apoptosis from ischemic or toxic cell death.


title: Apoptosis

text: Before the apoptotic cell is disposed of, there is a process of disassembly. There are three recognized steps in apoptotic cell disassembly:


title: Apoptosis

text: Dying cells that undergo the final stages of apoptosis display phagocytotic molecules, such as phosphatidylserine, on their cell surface. Phosphatidylserine is normally found on the inner leaflet surface of the plasma membrane, but is redistributed during apoptosis to the extracellular surface by a protein known as scramblase. These molecules mark the cell for phagocytosis by cells possessing the appropriate receptors, such as macrophages. The removal of dying cells by phagocytes occurs in an orderly manner without eliciting an inflammatory response. During apoptosis cellular RNA and DNA are separated from each other and sorted to different apoptotic bodies; separation of RNA is initiated as nucleolar segregation.


title: Apoptosis

text: Many knock-outs have been made in the apoptosis pathways to test the function of each of the proteins. Several caspases, in addition to APAF1 and FADD, have been mutated to determine the new phenotype. In order to create a tumor necrosis factor (TNF) knockout, an exon containing the nucleotides 3704–5364 was removed from the gene . This exon encodes a portion of the mature TNF domain, as well as the leader sequence, which is a highly conserved region necessary for proper intracellular processing. TNF-/- mice develop normally and have no gross structural or morphological abnormalities. However, upon immunization with SRBC (sheep red blood cells), these mice demonstrated a deficiency in the maturation of an antibody response; they were able to generate normal levels of IgM, but could not develop specific IgG levels . Apaf-1 is the protein that turns on caspase 9 by cleavage to begin the caspase cascade that leads to apoptosis . Since a -/- mutation in the APAF-1 gene is embryonic lethal, a gene trap strategy was used in order to generate an APAF-1 -/- mouse. This assay is used to disrupt gene function by creating an intragenic gene fusion. When an APAF-1 gene trap is introduced into cells, many morphological changes occur, such as spina bifida, the persistence of interdigital webs, and open brain . In addition, after embryonic day 12.5, the brain of the embryos showed several structural changes. APAF-1 cells are protected from apoptosis stimuli such as irradiation. A BAX-1 knock-out mouse exhibits normal forebrain formation and a decreased programmed cell death in some neuronal populations and in the spinal cord, leading to an increase in motor neurons .


title: Apoptosis

text: The caspase proteins are integral parts of the apoptosis pathway, so it follows that knock-outs made have varying damaging results. A caspase 9 knock-out leads to a severe brain malformation . A caspase 8 knock-out leads to cardiac failure and thus embryonic lethality . However, with the use of cre-lox technology, a caspase 8 knock-out has been created that exhibits an increase in peripheral T cells, an impaired T cell response, and a defect in neural tube closure . These mice were found to be resistant to apoptosis mediated by CD95, TNFR, etc. but not resistant to apoptosis caused by UV irradiation, chemotherapeutic drugs, and other stimuli. Finally, a caspase 3 knock-out was characterized by ectopic cell masses in the brain and abnormal apoptotic features such as membrane blebbing or nuclear fragmentation . A remarkable feature of these KO mice is that they have a very restricted phenotype: Casp3, 9, APAF-1 KO mice have deformations of neural tissue and FADD and Casp 8 KO showed defective heart development, however, in both types of KO other organs developed normally and some cell types were still sensitive to apoptotic stimuli suggesting that unknown proapoptotic pathways exist.


title: Apoptosis

text: Label-free live cell imaging, time-lapse microscopy, flow fluorocytometry, and transmission electron microscopy can be used to compare apoptotic and necrotic cells. There are also various biochemical techniques for analysis of cell surface markers (phosphatidylserine exposure versus cell permeability by flow cytometry), cellular markers such as DNA fragmentation (flow cytometry), caspase activation, Bid cleavage, and cytochrome c release (Western blotting). Supernatant screening for caspases, HMGB1, and cytokeratin 18 release can identify primary from secondary necrotic cells. However, no distinct surface or biochemical markers of necrotic cell death have been identified yet, and only negative markers are available. These include absence of apoptotic markers (caspase activation, cytochrome c release, and oligonucleosomal DNA fragmentation) and differential kinetics of cell death markers (phosphatidylserine exposure and cell membrane permeabilization). A selection of techniques that can be used to distinguish apoptosis from necroptotic cells could be found in these references.


title: Apoptosis

text: The many different types of apoptotic pathways contain a multitude of different biochemical components, many of them not yet understood. As a pathway is more or less sequential in nature, removing or modifying one component leads to an effect in another. In a living organism, this can have disastrous effects, often in the form of disease or disorder. A discussion of every disease caused by modification of the various apoptotic pathways would be impractical, but the concept overlying each one is the same: The normal functioning of the pathway has been disrupted in such a way as to impair the ability of the cell to undergo normal apoptosis. This results in a cell that lives past its "use-by date" and is able to replicate and pass on any faulty machinery to its progeny, increasing the likelihood of the cell's becoming cancerous or diseased.


title: Apoptosis

text: A recently described example of this concept in action can be seen in the development of a lung cancer called NCI-H460. The "X-linked inhibitor of apoptosis protein" (XIAP) is overexpressed in cells of the H460 cell line. XIAPs bind to the processed form of caspase-9 and suppress the activity of apoptotic activator cytochrome c, therefore overexpression leads to a decrease in the number of proapoptotic agonists. As a consequence, the balance of anti-apoptotic and proapoptotic effectors is upset in favour of the former, and the damaged cells continue to replicate despite being directed to die. Defects in regulation of apoptosis in cancer cells occur often at the level of control of transcription factors. As a particular example, defects in molecules that control transcription factor NF-κB in cancer change the mode of transcriptional regulation and the response to apoptotic signals, to curtail dependence on the tissue that the cell belongs. This degree of independence from external survival signals, can enable cancer metastasis.


title: Apoptosis

text: The tumor-suppressor protein p53 accumulates when DNA is damaged due to a chain of biochemical factors. Part of this pathway includes alpha-interferon and beta-interferon, which induce transcription of the "p53" gene, resulting in the increase of p53 protein level and enhancement of cancer cell-apoptosis. p53 prevents the cell from replicating by stopping the cell cycle at G1, or interphase, to give the cell time to repair, however it will induce apoptosis if damage is extensive and repair efforts fail. Any disruption to the regulation of the "p53" or interferon genes will result in impaired apoptosis and the possible formation of tumors.


title: Apoptosis

text: Inhibition of apoptosis can result in a number of cancers, inflammatory diseases, and viral infections. It was originally believed that the associated accumulation of cells was due to an increase in cellular proliferation, but it is now known that it is also due to a decrease in cell death. The most common of these diseases is cancer, the disease of excessive cellular proliferation, which is often characterized by an overexpression of IAP family members. As a result, the malignant cells experience an abnormal response to apoptosis induction: Cycle-regulating genes (such as p53, ras or c-myc) are mutated or inactivated in diseased cells, and further genes (such as bcl-2) also modify their expression in tumors. Some apoptotic factors are vital during mitochondrial respiration e.g. cytochrome C. Pathological inactivation of apoptosis in cancer cells is correlated with frequent respiratory metabolic shifts toward glycolysis (an observation known as the “Warburg hypothesis”.


title: Apoptosis

text: Apoptosis in HeLa cells is inhibited by proteins produced by the cell; these inhibitory proteins target retinoblastoma tumor-suppressing proteins. These tumor-suppressing proteins regulate the cell cycle, but are rendered inactive when bound to an inhibitory protein. HPV E6 and E7 are inhibitory proteins expressed by the human papillomavirus, HPV being responsible for the formation of the cervical tumor from which HeLa cells are derived. HPV E6 causes p53, which regulates the cell cycle, to become inactive. HPV E7 binds to retinoblastoma tumor suppressing proteins and limits its ability to control cell division. These two inhibitory proteins are partially responsible for HeLa cells' immortality by inhibiting apoptosis to occur. Canine distemper virus (CDV) is able to induce apoptosis despite the presence of these inhibitory proteins. This is an important oncolytic property of CDV: this virus is capable of killing canine lymphoma cells. Oncoproteins E6 and E7 still leave p53 inactive, but they are not able to avoid the activation of caspases induced from the stress of viral infection. These oncolytic properties provided a promising link between CDV and lymphoma apoptosis, which can lead to development of alternative treatment methods for both canine lymphoma and human non-Hodgkin lymphoma. Defects in the cell cycle are thought to be responsible for the resistance to chemotherapy or radiation by certain tumor cells, so a virus that can induce apoptosis despite defects in the cell cycle is useful for cancer treatment.


title: Apoptosis

text: The main method of treatment for potential death from signaling-related diseases involves either increasing or decreasing the susceptibility of apoptosis in diseased cells, depending on whether the disease is caused by either the inhibition of or excess apoptosis. For instance, treatments aim to restore apoptosis to treat diseases with deficient cell death and to increase the apoptotic threshold to treat diseases involved with excessive cell death. To stimulate apoptosis, one can increase the number of death receptor ligands (such as TNF or TRAIL), antagonize the anti-apoptotic Bcl-2 pathway, or introduce Smac mimetics to inhibit the inhibitor (IAPs). The addition of agents such as Herceptin, Iressa, or Gleevec works to stop cells from cycling and causes apoptosis activation by blocking growth and survival signaling further upstream. Finally, adding p53-MDM2 complexes displaces p53 and activates the p53 pathway, leading to cell cycle arrest and apoptosis. Many different methods can be used either to stimulate or to inhibit apoptosis in various places along the death signaling pathway.


title: Apoptosis

text: Apoptosis is a multi-step, multi-pathway cell-death programme that is inherent in every cell of the body. In cancer, the apoptosis cell-division ratio is altered. Cancer treatment by chemotherapy and irradiation kills target cells primarily by inducing apoptosis.


title: Apoptosis

text: On the other hand, loss of control of cell death (resulting in excess apoptosis) can lead to neurodegenerative diseases, hematologic diseases, and tissue damage. It is of interest to note that neurons that rely on mitochondrial respiration undergo apoptosis in neurodegenerative diseases such as Alzheimer's and Parkinson's. (an observation known as the “Inverse Warburg hypothesis”). Moreover, there is an inverse epidemiological comorbidity between neurodegenerative diseases and cancer. The progression of HIV is directly linked to excess, unregulated apoptosis. In a healthy individual, the number of CD4+ lymphocytes is in balance with the cells generated by the bone marrow; however, in HIV-positive patients, this balance is lost due to an inability of the bone marrow to regenerate CD4+ cells. In the case of HIV, CD4+ lymphocytes die at an accelerated rate through uncontrolled apoptosis, when stimulated.


title: Apoptosis

text: At the molecular level, hyperactive apoptosis can be caused by defects in signaling pathways that regulate the Bcl-2 family proteins. Increased expression of apoptotic proteins such as BIM, or their decreased proteolysis, leads to cell death and can cause a number of pathologies, depending on the cells where excessive activity of BIM occurs. Cancer cells can escape apoptosis through mechanisms that suppress BIM expression or by increased proteolysis of BIM.


title: Apoptosis

text: Treatments aiming to inhibit works to block specific caspases. Finally, the Akt protein kinase promotes cell survival through two pathways. Akt phosphorylates and inhibits Bad (a Bcl-2 family member), causing Bad to interact with the 14-3-3 scaffold, resulting in Bcl dissociation and thus cell survival. Akt also activates IKKα, which leads to NF-κB activation and cell survival. Active NF-κB induces the expression of anti-apoptotic genes such as Bcl-2, resulting in inhibition of apoptosis. NF-κB has been found to play both an antiapoptotic role and a proapoptotic role depending on the stimuli utilized and the cell type.


title: Apoptosis

text: The progression of the human immunodeficiency virus infection into AIDS is due primarily to the depletion of CD4+ T-helper lymphocytes in a manner that is too rapid for the body's bone marrow to replenish the cells, leading to a compromised immune system. One of the mechanisms by which T-helper cells are depleted is apoptosis, which results from a series of biochemical pathways:


title: Apoptosis

text: Cells may also die as direct consequences of viral infections. HIV-1 expression induces tubular cell G2/M arrest and apoptosis. The progression from HIV to AIDS is not immediate or even necessarily rapid; HIV's cytotoxic activity toward CD4+ lymphocytes is classified as AIDS once a given patient's CD4+ cell count falls below 200.


title: Apoptosis

text: Researchers from Kumamoto University in Japan have developed a new method to eradicate HIV in viral reservoir cells, named "Lock-in and apoptosis." Using the synthesized compound Heptanoylphosphatidyl L-Inositol Pentakisphophate (or L-Hippo) to bind strongly to the HIV protein PR55Gag, they were able to suppress viral budding. By suppressing viral budding, the researchers were able to trap the HIV virus in the cell and allow for the cell to undergo apoptosis (natural cell death). Associate Professor Mikako Fujita has stated that the approach is not yet available to HIV patients because the research team has to conduct further research on combining the drug therapy that currently exists with this "Lock-in and apoptosis" approach to lead to complete recovery from HIV.


title: Apoptosis

text: Viral induction of apoptosis occurs when one or several cells of a living organism are infected with a virus, leading to cell death. Cell death in organisms is necessary for the normal development of cells and the cell cycle maturation. It is also important in maintaining the regular functions and activities of cells.


title: Apoptosis

text: Canine distemper virus (CDV) is known to cause apoptosis in central nervous system and lymphoid tissue of infected dogs in vivo and in vitro.


title: Apoptosis

text: Apoptosis caused by CDV is typically induced via the extrinsic pathway, which activates caspases that disrupt cellular function and eventually leads to the cells death. In normal cells, CDV activates caspase-8 first, which works as the initiator protein followed by the executioner protein caspase-3. However, apoptosis induced by CDV in HeLa cells does not involve the initiator protein caspase-8. HeLa cell apoptosis caused by CDV follows a different mechanism than that in vero cell lines. This change in the caspase cascade suggests CDV induces apoptosis via the intrinsic pathway, excluding the need for the initiator caspase-8. The executioner protein is instead activated by the internal stimuli caused by viral infection not a caspase cascade.


title: Apoptosis

text: The Oropouche virus (OROV) is found in the family "Bunyaviridae". The study of apoptosis brought on by "Bunyaviridae" was initiated in 1996, when it was observed that apoptosis was induced by the La Crosse virus into the kidney cells of baby hamsters and into the brains of baby mice.


title: Apoptosis

text: OROV is a disease that is transmitted between humans by the biting midge ("Culicoides paraensis"). It is referred to as a zoonotic arbovirus and causes febrile illness, characterized by the onset of a sudden fever known as Oropouche fever.


title: Apoptosis

text: The Oropouche virus also causes disruption in cultured cells – cells that are cultivated in distinct and specific conditions. An example of this can be seen in HeLa cells, whereby the cells begin to degenerate shortly after they are infected.


title: Apoptosis

text: With the use of gel electrophoresis, it can be observed that OROV causes DNA fragmentation in HeLa cells. It can be interpreted by counting, measuring, and analyzing the cells of the Sub/G1 cell population. When HeLA cells are infected with OROV, the cytochrome C is released from the membrane of the mitochondria, into the cytosol of the cells. This type of interaction shows that apoptosis is activated via an intrinsic pathway.


title: Apoptosis

text: In order for apoptosis to occur within OROV, viral uncoating, viral internalization, along with the replication of cells is necessary. Apoptosis in some viruses is activated by extracellular stimuli. However, studies have demonstrated that the OROV infection causes apoptosis to be activated through intracellular stimuli and involves the mitochondria.


title: Apoptosis

text: Many viruses encode proteins that can inhibit apoptosis. Several viruses encode viral homologs of Bcl-2. These homologs can inhibit proapoptotic proteins such as BAX and BAK, which are essential for the activation of apoptosis. Examples of viral Bcl-2 proteins include the Epstein-Barr virus BHRF1 protein and the adenovirus E1B 19K protein. Some viruses express caspase inhibitors that inhibit caspase activity and an example is the CrmA protein of cowpox viruses. Whilst a number of viruses can block the effects of TNF and Fas. For example, the M-T2 protein of myxoma viruses can bind TNF preventing it from binding the TNF receptor and inducing a response. Furthermore, many viruses express p53 inhibitors that can bind p53 and inhibit its transcriptional transactivation activity. As a consequence, p53 cannot induce apoptosis, since it cannot induce the expression of proapoptotic proteins. The adenovirus E1B-55K protein and the hepatitis B virus HBx protein are examples of viral proteins that can perform such a function.


title: Apoptosis

text: Viruses can remain intact from apoptosis in particular in the latter stages of infection. They can be exported in the "apoptotic bodies" that pinch off from the surface of the dying cell, and the fact that they are engulfed by phagocytes prevents the initiation of a host response. This favours the spread of the virus.


title: Apoptosis

text: Programmed cell death in plants has a number of molecular similarities to that of animal apoptosis, but it also has differences, notable ones being the presence of a cell wall and the lack of an immune system that removes the pieces of the dead cell. Instead of an immune response, the dying cell synthesizes substances to break itself down and places them in a vacuole that ruptures as the cell dies. Additionally, plants do not contain phagocytic cells, which are essential in the process of breaking down and removing apoptotic bodies. Whether this whole process resembles animal apoptosis closely enough to warrant using the name "apoptosis" (as opposed to the more general "programmed cell death") is unclear.


title: Apoptosis

text: The characterization of the caspases allowed the development of caspase inhibitors, which can be used to determine whether a cellular process involves active caspases. Using these inhibitors it was discovered that cells can die while displaying a morphology similar to apoptosis without caspase activation. Later studies linked this phenomenon to the release of AIF (apoptosis-inducing factor) from the mitochondria and its translocation into the nucleus mediated by its NLS (nuclear localization signal). Inside the mitochondria, AIF is anchored to the inner membrane. In order to be released, the protein is cleaved by a calcium-dependent calpain protease.


title: North German Confederation

text: The North German Confederation () was initially a German military alliance established in August 1866 under the leadership of the Kingdom of Prussia, which was transformed in the subsequent year into a confederated state (a "de facto" federal state) that existed from July 1867 to December 1870. A milestone of the German Unification, it was the earliest continual legal predecessor of the modern German nation-state known today as the Federal Republic of Germany.


title: North German Confederation

text: The Confederation came into existence following the Prussian victory in the Austro-Prussian War of 1866 over the lordship of two small Danish duchies (Schleswig-Holstein) resulting in the Peace of Prague, where Prussia pressured Austria and its allies into accepting the dissolution of the existing German Confederation (an association of German states under the leadership of the Austrian Empire), thus paving the way for the Lesser German version of German unification in the form of a federal state in Northern Germany. Construction of such state became a reality in August 1866, following the North German Confederation Treaty, initially as a military alliance only, while its first federal constitution establishing a constitutional monarchy with the Prussian king holding as the head of state the ' was adopted on 1 July 1867. Laws could only be enabled with the consent of the ' (a parliament based on universal male suffrage) and the Federal Council (, a representation of the states). During the initial three and a half years of the Confederation, a conservative-liberal cooperation undertook important steps to unify (Northern) Germany with regard to law and infrastructure. The designed political system and the political parties remained essentially the same also after 1870.


title: North German Confederation

text: Shortly after its inception, tensions emerged between the North German Confederation and the Second French Empire, which was ruled by the French Emperor Napoleon III. In Summer 1870, a dispute over a new king for Spain escalated into the Franco-Prussian War. At the time, the original Confederation had nearly 30 million inhabitants of whom 80% lived in Prussia, thus making up roughly 75% of the population of the future German Empire. Under these circumstances, the South German states of Baden, Hesse-Darmstadt, Württemberg and Bavaria previously opposed to the Confederation ultimately decided to join it. A new short-lived constitution subsequently entered into force on 1 January 1871 proclaiming in its preamble and article 11 the "German Empire" despite being titled as one of a new "German Confederation", but it lasted only four months. Following the victory in the war with France, the German princes and senior military commanders proclaimed Wilhelm "German Emperor" in the Hall of Mirrors at the Palace of Versailles. Transition from the Confederation to the Empire was completed when the Constitution of the German Empire which prevailed until the demise of the monarchy entered into force on 4 May 1871, while France recognised the empire on 10 May 1871 in the Treaty of Frankfurt.


title: North German Confederation

text: For most of 1815–1833, Austria and Prussia worked together and used the German Confederation as a tool to suppress liberal and national ambitions in the German population.


title: North German Confederation

text: The first major step towards a Lesser German solution was the "Zollverein", a customs union formed by the treaties of 1833, with Prussia being the primary driver behind the customs union. Although it was formally inaugurated on 1 January 1834, its origins may be traced to a variety of custom unions among the German states, formed beginning from 1818. The "Zollverein" was not subordinate to the Austrian-led German Confederation (1815-1866) and Austria itself was excluded because of its highly protectionist trade policy, the unwillingness to split its customs territory into the separate Austrian, Hungarian and Galician-Lodomerian ones, as well as due to opposition of Prince von Metternich to the idea. Nevertheless, the "Zollverein" managed to include by 1866 the majority of the German states.


title: North German Confederation

text: In 1849, the National Assembly in Frankfurt elected the Prussian king as the Emperor of a Lesser Germany (a Germany without Austria). The king refused and tried to unite Germany with the Erfurt Union of 1849–1850. When the union parliament met in early 1850 to discuss the constitution, the participating states were mainly only those in Northern and Central Germany. Austria and the southern German states Württemberg and Bavaria forced Prussia to give up its union plans in late 1850.


title: North German Confederation

text: In April and June 1866, Prussia proposed a Lesser Germany again. A corner stone of the proposal was the election of a German parliament based on universal male suffrage. The proposal explicitly mentioned the Frankfurt election law of 1849. Otto von Bismarck, the minister-president of Prussia, wanted to gain sympathy within the national and liberal movement of the time. Austria and its allies refused the proposal. In summer 1866 Austria and Prussia fought with their respective allies in the Austro-Prussian War.


title: North German Confederation

text: Prussia and Austria signed a Nikolsburg preliminary (26 July) and a final peace treaty of Prague (23 August). Austria accepted the Prussian demand for the German Confederation to be dissolved. Prussia was allowed to create instead a "closer federation" () in Germany north of the river Main. Bismarck had already agreed on this limitation with the French emperor Napoleon III prior to the peace talks.


title: North German Confederation

text: On 18 August 1866, Prussia and a larger number of North and Central German states signed the North German Confederation Treaty establishing a (alliance). The treaty created a military alliance for one year. It also affirmed that the states wanted to form a federal state based on the Prussian proposals of June 1866. They agreed to have a parliament elected to discuss a draft constitution. At the same time, the original East Prussian craddle of the Prussian statehood as well as the Prussian-held Polish- or Kashubian-speaking territories of Province of Posen, West Prussia, the Lauenburg and Bütow Land and Draheim were formally ′annexed into Germany. Saxony and Hesse-Darmstadt, former enemies in the war of 1866, had to agree their accession to the new federation in their respective peace treaties (Hesse-Darmstadt only joined with its northern province, Upper Hesse). Later in 1866, other states joined the treaty. The liberals in the Prussian parliament favored a wholesale annexation of all North German territories by Prussia. In a similar way, Sardinia–Piedmont had created the Kingdom of Italy. But Bismarck chose a different approach. Prussia incorporated (in October 1866) only the former military opponents Hannover, Hesse-Kassel, Nassau, the free city of Frankfurt, and the Hesse-Homburg area of Hesse Darmstadt. These areas were combined into the two new Prussian provinces of Hannover and Hesse-Nassau. Schleswig and Holstein also became a Prussian province.


title: North German Confederation

text: Bismarck sought advice from conservative and democratic politicians and finally presented a draft constitution to the other state governments. At the same time, in late 1866, Prussia and the other states prepared the election of a North German parliament. This was elected in February 1867 based on state laws. The gathered from February to April. In close talks with Bismarck, it altered the draft constitution in some significant points. The was not a parliament but only an organ to discuss and accept the draft constitution. After that, the state parliaments (June 1867) ratified it so that on 1 July the constitution was enabled. In August, the first Reichstag of the new federal state was elected.


title: North German Confederation

text: A major factor in determining the form the new federal government would take was the aftermath of the recently concluded American Civil War, which had seen the southern states forcibly re-incorporated into the United States of America and slavery abolished. While few Germans were particularly sympathetic toward the precise institution (i.e., slavery) which had precipitated civil war in America, the prevailing viewpoint outside the U.S. at this time was that the slaves had only been emancipated as a reprisal for Southern secession from the American Union. With this in mind, many Catholics especially in Southern Germany feared that Prussia might one day might attempt to engineer a similar sort of secession crisis within a united Germany and use it as a pretext to launch a violent repression against Catholicism throughout Germany. Thus, it was Bismarck's intention to make the new federal state look like a confederation in the tradition of the German Confederation and explains the name of the country and several provisions in the draft constitution — Bismarck needed to make the federal state more attractive (or at least less repulsive) to southern German states which might later join.


title: North German Confederation

text: During the roughly three and a half years of the North German Confederation its major action existed in legislation unifying Northern Germany. The Reichstag decided on laws concerning, for example:


title: North German Confederation

text: The North German Constitution of 16 April 1867 created a national parliament with universal suffrage (for men above the age of 25), the . Another important organ was the , the 'federal council' of the representatives of the state governments. To adopt a law, a majority in the Reichstag and in the Bundesrat was necessary. This gave the allied governments, meaning the states (and, depending on the state, their princes), an important veto.


title: North German Confederation

text: Executive power was vested in a chancellor, being the only responsible federal minister of the country. There was no formal cabinet, and in the time of the North German Confederation there were only two government departments anyway: the as the general office of the chancellor, and, since early 1870, the foreign office.


title: North German Confederation

text: The chancellor was installed and dismissed by the . This office belonged automatically to the Prussian king (art. 11). The holder was de facto the head of state of the North German Confederation. (Bismarck wanted to avoid the title with its republican air.)


title: North German Confederation

text: For all intents and purposes, the Confederation was dominated by Prussia. It had four-fifths of the confederation's territory and population – more than the other 21 members combined. The Prussian king was a kind of head of state. Chancellor Bismarck was also prime minister and foreign minister of Prussia. In that role he instructed the Prussian votes in the Bundesrat. Prussia had 17 of 43 votes in the Bundesrat despite being by far the largest state but could easily get a majority by making alliances with the smaller states.


title: North German Confederation

text: In June 1867 a conference took place between Prussia and the south German states, who were not members of the North German Confederation. After pressure from Prussia, new Customs Union () treaties were signed the following month. Henceforth, the governing bodies of the Customs Union were the Bundesrat and Reichstag of the North German Confederation, augmented by representatives of the south German governments in the former and members from these states elected in the same way as the others in the latter. When augmented thus for customs matters, the institutions were known as the Federal Customs Council and the Customs Parliament ().


title: North German Confederation

text: On 1 January 1868, the new institutions came into force. Bismarck hoped that the might become the vehicle of German unification. But in the 1868 election the South Germans voted mainly for anti-Prussian parties.


title: North German Confederation

text: On the other hand, the two Mecklenburg duchies and three Hanseatic cities were initially not members of the Customs Union. The Mecklenburgs and Lübeck joined soon after the North German Confederation was formed. Eventually, after heavy Prussian pressure, Hamburg acceded to the Customs Union in 1888. Bremen joined at the same time. Despite this, all these states fully participated in the federal institutions, even while outside the Customs Union and not directly affected by their decisions in that regard.


title: North German Confederation

text: In mid-1870, a diplomatic crisis concerning the Spanish throne led eventually to the Franco-Prussian War. During the war, in November 1870, the south German states of Bavaria, Württemberg, and Baden (together with the parts of Hesse-Darmstadt that were left out of the Confederation) joined the North German Confederation. On this occasion, the country adopted a new constitution, and the name of the federal state was changed to (German Empire).


title: North German Confederation

text: According to a minority among German experts, the North German Confederation and the southern states created a new federal state (the German Empire). Indeed, Bismarck allowed the south German states to save face and therefore used terminology suggesting a new creation. But Kotulla emphasizes that legally only accession of the southern states to the North German Confederation was possible; the legal basis for such an accession was art. 79 of the North German federal constitution.


title: North German Confederation

text: On 10 December 1870 the Reichstag of the North German Confederation had adopted a new constitution, still titled as one of the (German Confederation) in spite of establishing for the state a new name (German Realm or German Empire) and granting the title of German Emperor to the King of Prussia holding the of the Confederation; it entered into force on 1 January 1871, but lasted only four months.


title: North German Confederation

text: Following the victory in the war with France, the German princes and senior military commanders proclaimed Wilhelm "German Emperor" in the Hall of Mirrors at the Palace of Versailles. This latter date was later customarily celebrated as the symbolic day of 'foundation of the German Empire' (), although it had no constitutional meaning.


title: North German Confederation

text: After a new Reichstag was elected on 3 March 1871, the transition from the Confederation to the Empire was completed when the permanent Constitution of the German Empire prevailing until the demise of the monarchy entered into force on 4 May 1871, while France recognised the empire on 10 May 1971 in the Treaty of Frankfurt.


title: North German Confederation

text: The three constitutions (1867, January 1871, and April 1871) were nearly identical. It took roughly a decade to develop the country into a fully grown federal state, with several governmental departments (a kind of ministries), responsible state secretaries (a kind of ministers, 1878), and an imperial court (, 1879).


title: North German Confederation

text: All of the member states had already belonged to the German Confederation of 1815-66. Austria and the south German states Bavaria, Württemberg, Baden and the Grand Duchy of Hesse (Hesse-Darmstadt) remained outside of the North German Confederation. Though, the northern province of the Grand Duchy of Hesse did join.


title: North German Confederation

text: Lauenburg is sometimes mentioned as one of the member states, sometimes not. It was one of the three duchies that had earlier belong to Denmark. Lauenburg was a state with the Prussian king as duke until 1876, when it became a part of the Prussian province of Schleswig-Holstein.


title: Jimmy Doolittle

text: James Harold Doolittle (December 14, 1896 – September 27, 1993) was an American military general and aviation pioneer who received the Medal of Honor for his daring raid on Japan during World War II. He also made early coast-to-coast flights, record-breaking speed flights, won many flying races, and helped develop and flight-test instrument flying.


title: Jimmy Doolittle

text: Raised in Nome, Alaska, Doolittle studied as an undergraduate at University of California, Berkeley, graduating with a Bachelor of Arts in 1922. He also earned a doctorate in aeronautics from the Massachusetts Institute of Technology in 1925, the first issued in the United States. In 1929, he pioneered the use of "blind flying", where a pilot relies on flight instruments alone, which later won him the Harmon Trophy and made all-weather airline operations practical. He was a flying instructor during World War I and a reserve officer in the United States Army Air Corps, but he was recalled to active duty during World War II. He was awarded the Medal of Honor for personal valor and leadership as commander of the Doolittle Raid, a bold long-range retaliatory air raid on some of the Japanese main islands on April 18, 1942, four months after the attack on Pearl Harbor. The raid used 16 B-25B Mitchell medium bombers with reduced armament to decrease weight and increase range, each with a crew of five and no escort fighter aircraft. It was a major morale booster for the United States and Doolittle was celebrated as a hero, making him one of the most important national figures of the war.


title: Jimmy Doolittle

text: Doolittle was promoted to lieutenant general and commanded the Twelfth Air Force over North Africa, the Fifteenth Air Force over the Mediterranean, and the Eighth Air Force over Europe. He retired from the Air Force in 1959 but remained active in many technical fields. Doolittle was inducted into the National Aviation Hall of Fame in 1967, eight years after retirement and only five years after the Hall was founded. He was eventually promoted to general in 1985, presented to him by President Ronald Reagan 43 years after the Doolittle Raid. In 2003, he topped "Air & Space/Smithsonian" magazine's list of the greatest pilots of all time, and ten years later, "Flying" magazine ranked Doolittle sixth on its list of the 51 Heroes of Aviation. He died in 1993 at the age of 96, and was buried at Arlington National Cemetery.


title: Jimmy Doolittle

text: Doolittle was born December 14, 1896, in Alameda, California, and spent his youth in Nome, Alaska, where he earned a reputation as a boxer. His parents were Frank Henry Doolittle (1869–1918) and Rosa (Rose) Cerenah Doolittle (; 1869–1930). By 1910, Jimmy Doolittle was attending school in Los Angeles. When his school attended the 1910 Los Angeles International Air Meet at Dominguez Field, Doolittle saw his first airplane. He attended Los Angeles City College after graduating from Manual Arts High School in Los Angeles, and later won admission to the University of California, Berkeley where he studied at the College of Mines. He was a member of Theta Kappa Nu fraternity, which would merge into Lambda Chi Alpha during the later stages of the Great Depression.


title: Jimmy Doolittle

text: Doolittle took a leave of absence in October 1917 to enlist in the Signal Corps Reserve as a flying cadet; he received ground training at the School of Military Aeronautics (an Army school) on the campus of the University of California, and flight-trained at Rockwell Field, California. Doolittle received his Reserve Military Aviator rating and was commissioned a second lieutenant in the Signal Officers Reserve Corps of the U.S. Army on March 11, 1918.


title: Jimmy Doolittle

text: During World War I, Doolittle stayed in the United States as a flight instructor and performed his war service at Camp John Dick Aviation Concentration Center ("Camp Dick"), Texas; Wright Field, Ohio; Gerstner Field, Louisiana; Rockwell Field, California; Kelly Field, Texas and Eagle Pass, Texas.


title: Jimmy Doolittle

text: Doolittle served at Rockwell as a flight leader and gunnery instructor. At Kelly Field, he served with the 104th Aero Squadron and with the 90th Aero Squadron of the 1st Surveillance Group. His detachment of the 90th Aero Squadron was based at Eagle Pass, patrolling the Mexican border. Recommended by three officers for retention in the Air Service during demobilization at the end of the war, Doolittle qualified by examination and received a Regular Army commission as a 1st Lieutenant, Air Service, on July 1, 1920.


title: Jimmy Doolittle

text: On May 10, 1921, he was engineering officer and pilot for an expedition recovering a plane that had force-landed in a Mexican canyon on February 10 during a transcontinental flight attempt by Alexander Pearson Jr. Doolittle reached the plane on May 3 and found it serviceable, then returned May 8 with a replacement motor and four mechanics. The oil pressure of the new motor was inadequate and Doolittle requested two pressure gauges, using carrier pigeons to communicate. The additional parts were dropped by air and installed, and Doolittle flew the plane to Del Rio, Texas himself, taking off from a 400-yard airstrip hacked out of the canyon floor.


title: Jimmy Doolittle

text: Subsequently, he attended the Air Service Mechanical School at Kelly Field and the Aeronautical Engineering Course at McCook Field, Ohio. Having at last returned to complete his college degree, he earned a Bachelor of Arts from the University of California, Berkeley in 1922, and joined the Lambda Chi Alpha fraternity.


title: Jimmy Doolittle

text: Doolittle was one of the most famous pilots during the inter-war period. On September 4, 1922, he made the first of many pioneering flights, flying a de Havilland DH-4 – which was equipped with early navigational instruments – in the first cross-country flight, from Pablo Beach (now Jacksonville Beach), Florida, to Rockwell Field, San Diego, California, in 21 hours and 19 minutes, making only one refueling stop at Kelly Field. The U.S. Army awarded him the Distinguished Flying Cross.


title: Jimmy Doolittle

text: Within days after the transcontinental flight, he was at the Air Service Engineering School (a precursor to the Air Force Institute of Technology) at McCook Field, Dayton, Ohio. For Doolittle, the school assignment had special significance: "In the early 1920s, there was not complete support between the flyers and the engineers. The pilots thought the engineers were a group of people who zipped slide rules back and forth, came out with erroneous results and bad aircraft; and the engineers thought the pilots were crazy – otherwise they would not be pilots. So some of us who had previous engineering training were sent to the engineering school at old McCook Field. After a year's training there in practical aeronautical engineering, some of us were sent on to MIT where we took advanced degrees in aeronautical engineering. I believe that the purpose was served, that there was thereafter a better understanding between pilots and engineers."


title: Jimmy Doolittle

text: In July 1923, after serving as a test pilot and aeronautical engineer at McCook Field, Doolittle entered the Massachusetts Institute of Technology. In March 1924, he conducted aircraft acceleration tests at McCook Field, which became the basis of his master's thesis and led to his second Distinguished Flying Cross. He received his MS degree in Aeronautics from MIT in June 1924. Because the Army had given him two years to get his degree and he had done it in just one, he immediately started working on his Sc.D. in Aeronautics, which he received in June 1925. His doctorate in aeronautical engineering was the first issued in the United States. He said that he considered his master's work more significant than his doctorate.


title: Jimmy Doolittle

text: Following graduation, Doolittle attended special training in high-speed seaplanes at Naval Air Station Anacostia in Washington, D.C. He also served with the Naval Test Board at Mitchel Field, Long Island, New York, and was a familiar figure in air speed record attempts in the New York area. He won the Schneider Cup race in a Curtiss R3C in 1925 with an average speed of 232 MPH. For that feat, Doolittle was awarded the Mackay Trophy in 1926.


title: Jimmy Doolittle

text: In April 1926, Doolittle was given a leave of absence to go to South America to perform demonstration flights for Curtiss Aircraft. In Chile, he broke both ankles while demonstrating his acrobatic abilities in an incident that was known as Night of the Pisco Sours. Despite having both ankles in casts, Doolittle put his Curtiss P-1 Hawk through aerial maneuvers that outdid the competition. He returned to the United States, and was confined to Walter Reed Army Hospital for his injuries until April 1927. He was then assigned to McCook Field for experimental work, with additional duty as an instructor pilot to the 385th Bomb Squadron of the Air Corps Reserve. During this time, in 1927 he was the first to perform an outside loop, previously thought to be a fatal maneuver. Carried out in a Curtiss fighter at Wright Field in Ohio, Doolittle executed the dive from 10,000 feet, reached 280 mph, bottomed out upside down, then climbed and completed the loop.


title: Jimmy Doolittle

text: Doolittle's most important contribution to aeronautical technology was his early advancement of instrument flying. He was the first to recognize that true operational freedom in the air could not be achieved until pilots developed the ability to control and navigate aircraft in flight from takeoff run to landing rollout, regardless of the range of vision from the cockpit. Doolittle was the first to envision that a pilot could be trained to use instruments to fly through fog, clouds, precipitation of all forms, darkness, or any other impediment to visibility; and in spite of the pilot's own possibly convoluted motion sense inputs. Even at this early stage, the ability to control aircraft was getting beyond the motion sense capability of the pilot. That is, as aircraft became faster and more maneuverable, pilots could become seriously disoriented without visual cues from outside the cockpit, because aircraft could move in ways that pilots' senses could not accurately decipher.


title: Jimmy Doolittle

text: Doolittle was also the first to recognize these psycho-physiological limitations of the human senses (particularly the motion sense inputs, "i.e.", up, down, left, right). He initiated the study of the relationships between the psychological effects of visual cues and motion senses. His research resulted in programs that trained pilots to read and understand navigational instruments. A pilot learned to "trust his instruments," not his senses, as visual cues and his motion sense inputs (what he sensed and "felt") could be incorrect or unreliable.


title: Jimmy Doolittle

text: In 1929, he became the first pilot to take off, fly and land an airplane using instruments alone, without a view outside the cockpit. Having returned to Mitchell Field that September, he helped develop blind-flying equipment. He helped develop, and was then the first to test, the now universally used artificial horizon and directional gyroscope. He attracted wide newspaper attention with this feat of "blind" flying and later received the Harmon Trophy for conducting the experiments. These accomplishments made all-weather airline operations practical.


title: Jimmy Doolittle

text: In January 1930, he advised the Army on the construction of Floyd Bennett Field in New York City. Doolittle resigned his regular commission on February 15, 1930, and was commissioned a Major in the Air Reserve Corps a month later, being named manager of the Aviation Department of Shell Oil Company, in which capacity he conducted numerous aviation tests. While in the Reserve, he also returned to temporary active duty with the Army frequently to conduct tests.


title: Jimmy Doolittle

text: Doolittle helped influence Shell Oil Company to produce the first quantities of 100 octane aviation gasoline. High octane fuel was crucial to the high-performance planes that were developed in the late 1930s.


title: Jimmy Doolittle

text: In 1931, Doolittle won the first Bendix Trophy race from Burbank, California, to Cleveland, in a Laird Super Solution biplane.