document_title: List of Interstate Highways

question_text: what is the longest interstate highway in the united states

text: List of Interstate Highways

text: Contiguous United States[edit]

text: There are 70 primary Interstate Highways listed in the table below, and 43 of them have auxiliary routes.

text:
Number

Length (mi)[2]

Length (km)

Southern or western terminus

Northern or eastern terminus

Formed

Removed

Notes

 I0002 !I‑2

46.8
75.3

US 83 in Penitas, Texas
I-69E/US 77/US 83 in Harlingen, Texas

02013-01-012013
current

Texas onlyAssociated routes: none

 I0004 !I‑4

132.3
212.9

I-275 in Tampa, Florida
I-95/SR 400 Daytona Beach, Florida

01959-01-011959
current

Florida onlyAssociated routes: none

 I0005 !I‑5

1,381.29
2,222.97

Fed. 1 at Mexican border in San Ysidro, California
BC 99 at Canadian border in Blaine, Washington

01956-01-011956
current

Serves three states: CA, OR, WAAssociated routes: I-105, I-205, I-405, I-505, I-605, I-705, I-805; Future: I-305, I-905

 I0008 !I‑8

348.25
560.45

Sunset Cliffs Boulevard/Nimitz Boulevard in San Diego, California
I-10 in Casa Grande, Arizona

01964-01-011964
current

Serves two states: CA, AZAssociated routes: none

 I0010 !I‑10

2,460.34
3,959.53

SR 1 in Santa Monica, California
I-95/US 17/SR 228 in Jacksonville, Florida

01957-01-011957
current

Serves eight states: CA, AZ, NM, TX, LA, MS, AL, FLAssociated routes: I-110, I-210, I-310, I-410, I-510, I-610, I-710, I-910

 I0011 !I‑11

15
24

US 93 near Boulder City, Nevada
I-515/US 93/US 95 near Henderson, Nevada

02017-01-012017
current

Nevada only; planned extension north and southAssociated routes: none

 I0012 !I‑12

85.59
137.74

I-10 in Baton Rouge, Louisiana
I-10/I-59 in Slidell, Louisiana

01967-01-011967
current

Louisiana onlyAssociated routes: none

 I0014 !I‑14

25.90
41.68

US 190/SH 9 in Copperas Cove, Texas
I-35 in Belton, Texas

02017-01-262017
current

Texas only; planned extension east and westAssociated routes: none

 I0015 !I‑15

1,433.52
2,307.03

I-8/SR 15 in San Diego, California
Hwy 4 at Canadian border in Sweetgrass, Montana

01957-01-011957
current

Serves six states: CA, NV, AZ, UT, ID, MTAssociated routes: I-115, I-215, I-315, I-515

 I0016 !I‑16

166.81
268.45

I-75 in Macon, Georgia
SR 404 and Montgomery Street/Martin Luther King Jr. Boulevard in Savannah, Georgia

01966-01-011966
current

Georgia onlyAssociated route: I-516

 I0017 !I‑17

145.76
234.58

I-10 in Phoenix, Arizona
I-40/SR 89A in Flagstaff, Arizona

01961-01-011961
current

Arizona onlyAssociated routes: none

 I0019 !I‑19

63.6
102.4

Fed. 15 at Mexican border in Nogales, Arizona
Tucson, Arizona (I-10)

01972-01-011972
current

Arizona onlyAssociated routes: noneUses kilometers instead of miles

 I0020 !I‑20

1,539.38
2,477.39

I-10 between Kent and Toyah, Texas
I-95 in Florence, South Carolina

01957-01-011957
current

Serves six states: TX, LA, MS, AL, GA, SCAssociated routes: I-220, I-520, I-820

 I0022 !I‑22

213.0
342.8

I-269/US 78 near Byhalia
I-65/US 31 in Birmingham, Alabama

02012-01-012012
current

Serves two states: Mississippi, AlabamaPlanned associated routes: I-222, I-422

 I0024 !I‑24

316.36
509.13

I-57 in Pulley's Mill, Illinois
I-75 in Chattanooga, Tennessee

01962-01-011962
current

Serves four states: Illinois, Kentucky, Tennessee, GeorgiaAssociated route: I-124

 I0025 !I‑25

1,062.77
1,710.36

I-10/US 85/US 180 in Las Cruces, New Mexico
I-90/US 87 in Buffalo, Wyoming

01957-01-011957
current

Serves three states: New Mexico, Colorado, WyomingAssociated route: I-225

 I0026 !I‑26

305.62
491.85

US 11W in Kingsport, Tennessee
US 17 in Charleston, South Carolina

01960-01-011960
current

Serves three states: Tennessee, North Carolina, South CarolinaAssociated routes: I-126, I-526

 I0027 !I‑27

124.13
199.77

US 87/Loop 289 in Lubbock, Texas
I-40/US 87/US 287 in Amarillo, Texas

01969-01-011969
current

Texas onlyAssociated routes: none

 I0029 !I‑29

750.58
1,207.94

I-35/I-70 in Kansas City, Missouri
US 81 and PTH 29 at Canadian border in Pembina, North Dakota

01958-01-011958
current

Serves four states: Missouri, Iowa, South Dakota, North DakotaAssociated routes: I-129, I-229

 I0030 !I‑30

366.76
590.24

I-20 in Fort Worth, Texas
I-40/US 65/US 67/US 167 in North Little Rock, Arkansas

01957-01-011957
current

Serves two states: Texas, ArkansasAssociated routes: I-430, I-530, I-630

 I0035 !I‑35

1,569.06
2,525.16

US 83/SH 359/BS I-35 and MX-85 at Mexican border in Laredo, Texas
MN 61/LSCT/26th Avenue in Duluth, Minnesota

01956-01-011956
current

Serves six states: TX, OK, KS, MO, IA, MNAssociated routes: I-35E, I-35W, I-135, I-235, I-335, I-435, I-535, I-635

 I0037 !I‑37

143.00
230.14

US 181 in Corpus Christi, Texas
I-35/US 281 in San Antonio, Texas

01959-01-011959
current

Texas onlyAssociated routes: none

 I0039 !I‑39

306.14
492.68

I-55 in Normal, Illinois
WIS 29/US 51 in Wausau, Wisconsin

01984-01-011984
current

Serves two states: Illinois, WisconsinAssociated routes: none

 I0040 !I‑40

2,555.10
4,112.03

I-15 in Barstow, California
US 117/NC 132 in Wilmington, North Carolina

01964-01-011964
current

Serves eight states: CA, AZ, NM, TX, OK, AR, TN, NCAssociated routes: I-140, I-240, I-440, I-540, I-640, I-840

 I0041 !I‑41

176.33
283.78

I-94/US 41 in Russell, Illinois
I-43 in Howard, Wisconsin

02015-01-012015
current

Serves two states: Illinois, Wisconsin Associated routes: none

 I0043 !I‑43

191.55
308.27

I-39/I-90 in Beloit, Wisconsin
I-41/US 41/US 141 in Howard, Wisconsin

01981-01-011981
current

Wisconsin onlyAssociated routes: none

 I0044 !I‑44

633.79
1,019.99

US 82/US 277/US 281/US 287 in Wichita Falls, Texas
I-70 in St. Louis, Missouri

01958-01-011958
current

Serves three states: Texas, Oklahoma, MissouriAssociated routes: I-244, I-444

 I0045 !I‑45

284.91
458.52

SH 87 in Galveston, Texas
I-30 in Dallas, Texas

01971-01-011971
current

Texas onlyAssociated route: I-345

 I0049 !I‑49

388.25
624.83

I-10 in Lafayette, Louisiana
I-435 in Kansas City, Missouri

01984-01-011984
current

Serves three states: Louisiana, Arkansas, MissouriAssociated routes: none

 I0055 !I‑55

964.25
1,551.81

I-10 in LaPlace, Louisiana
US 41 in Chicago, Illinois

01960-01-011960
current

Serves six states: LA, MS, TN, AR, MO, ILAssociated routes: I-155, I-255, I-355; I-555

 I0057 !I‑57

386.12
621.40

I-55 in Miner, Missouri
I-94 in Chicago, Illinois

01965-01-011965
current

Serves two states: Missouri, Illinois. Planned in 1 more: ArkansasAssociated routes: none

 I0059 !I‑59

445.23
716.53

I-10/I-12 in Slidell, Louisiana
I-24 in Lookout Mountain, Georgia

01960-01-011960
current

Serves four states: Louisiana, Mississippi, Alabama, GeorgiaAssociated routes: I-359, I-459, I-759

 I0064 !I‑64

953.74
1,534.90

I-70 in Wentzville, Missouri
I-264/I-664 in Chesapeake, Virginia

01961-01-011961
current

Serves six states: MO, IL, IN, KY, WV, VAAssociated routes: I-264, I-464, I-564, I-664

 I0065 !I‑65

887.30
1,427.97

I-10 in Mobile, Alabama
I-90, US-12, US-20 in Gary, Indiana

01958-01-011958
current

Serves four states: Alabama, Tennessee, Kentucky, IndianaAssociated routes: I-165, I-265, I-465, I-565, I-865

 I0066 !I‑66

76.28
122.76

I-81 in Front Royal, Virginia
US 29 in Washington, D.C.

01982-01-011982
current

Serves District of Columbia and one state: VirginiaAssociated routes: None, had one proposed auxiliary route, I-266, but was cancelled due to freeway revolts.

 I0068 !I‑68

112.9
181.7

I-79 in Morgantown, West Virginia
I-70 in Hancock, Maryland

01991-01-011991
current

Serves two states: West Virginia, MarylandAssociated routes: None

 I0069 !I‑69

705.40
1,135.23

I-69E/US 77 & I-69W/US 59 in Victoria, Texas (future)
Hwy 402 at Canadian border in Port Huron, Michigan

01957-01-011957
current

Unfinished Texas section: Rosenberg (US-59/Spur 529) to Splendora (US 59/Mandell Road)Unfinished Mississippi-Tennessee section: Banks, Mississippi (MS 304/MS 713) to Frayser, Tennessee (US 51/TN 3)Unfinished Indiana section: Bloomington, Indiana to Indianapolis, IndianaServes six states: TX, MS, TN, KY, IN, MI. Planned/started in 2 more: LA, AR Associated routes: I-69C, I-69E, I-69W, I-169, I-269, I-369, I-469; Planned: I-169 in Tennessee, I-369 in Kentucky

 I0070 !I‑70

2,153.43
3,465.61

I-15 in Cove Fort, Utah
Park and ride in Baltimore, Maryland

01956-01-011956
current

Serves 10 states: UT, CO, KS, MO, IL, IN, OH, WV, PA, MDAssociated routes: I-170, I-270, I-370, I-470, I-670

 I0071 !I‑71

343.78
553.26

I-64 in Louisville, Kentucky
I-90 in Cleveland, Ohio

01959-01-011959
current

Serves two states: Kentucky, OhioAssociated routes: I-271, I-471

 I0072 !I‑72

179.29
288.54

US 61 in Hannibal, Missouri
I-57 in Champaign, Illinois

01970-01-011970
current

Serves two states: Missouri, IllinoisAssociated route: I-172

 I0073 !I‑73

82.4
132.6

US 220 near Ellerbe, North Carolina
I‑840/Bryan Boulevard in Greensboro, North Carolina

01997-01-011997
current

North Carolina onlyAssociated routes: none

 I0074 !I‑74

440.91
709.58

I-80 in Bettendorf, Iowa
NC 41 near Lumberton, North Carolina

01974-01-011974
current

Serves five states: IA, IL, IN, OH, NCAssociated routes: I-474

 I0075 !I‑75

1,786.47
2,875.04

SR 826 near Hialeah, Florida
Sault Ste. Marie, Michigan (Canada)

01958-01-011958
current

Serves six states: FL, GA, TN, KY, OH, MIAssociated routes: I-175, I-275, I-375, I-475, I-575, I-675

 I0076 !I‑76

187.34
301.49

West Denver, Colorado (I-70)
Big Springs, Nebraska (I-80)

01975-01-011975
current

Serves two states: Colorado, NebraskaAssociated routes: none

 I0076 !I‑76

434.36
699.03

East Westfield Center, Ohio (I-71)
Bellmawr, New Jersey (I-295)

01964-01-011964
current

Serves three states: Ohio, Pennsylvania, New JerseyAssociated routes: I-176, I-276, I-376, I-476, I-676; Future: I-576

 I0077 !I‑77

610.10
981.86

Columbia, South Carolina (I-26)
Cleveland, Ohio (I-90)

01958-01-011958
current

Serves five states: South Carolina, North Carolina, Virginia, West Virginia, OhioAssociated route: I-277

 I0078 !I‑78

143.56
231.04

Union Township, Pennsylvania (I-81)
New York City

01957-01-011957
current

Serves three states: Pennsylvania, New Jersey, New YorkAssociated routes: I-278, I-478, I-678, I-878

 I0079 !I‑79

343.24
552.39

Charleston, West Virginia (I-77)
Erie, Pennsylvania (PA-5)

01967-01-011967
current

Serves two states: West Virginia, PennsylvaniaAssociated routes: I-279, I-579

 I0080 !I‑80

2,899.54
4,666.36

San Francisco, California (US 101)
Teaneck, New Jersey (I-95)

01956-01-011956
current

Serves 11 states: CA, NV, UT, WY, NE, IA, IL, IN, OH, PA, NJAssociated routes: I-180, I-238 I-280, I-380, I-480, I-580, I-680, I-780, I-880, I-980

 I0081 !I‑81

854.89
1,375.81

Dandridge, Tennessee (I-40)
Fisher's Landing, New York (Canada)

01961-01-011961
current

Serves six states: TN, VA, WV, MD, PA, NYAssociated routes: I-381, I-481, I-581, I-781

 I0082 !I‑82

143.58
231.07

Ellensburg, Washington (I-90)
Hermiston, Oregon (I-84)

01957-01-011957
current

Serves two states: Washington, OregonAssociated route: I-182

 I0083 !I‑83

85.3
137.3

Baltimore, Maryland
Harrisburg, Pennsylvania (I-81)

01959-01-011959
current

Serves two states: Maryland, PennsylvaniaAssociated route: I-283

 I0084 !I‑84

769.62
1,238.58

West Portland, Oregon (I-5)
Echo, Utah (I-80)

01980-01-011980
current

Serves three states: Oregon, Idaho, UtahAssociated route: I-184

 I0084 !I‑84

232.4
374.0

East Scranton, Pennsylvania (I-81)
Sturbridge, Massachusetts (I-90)

01963-01-011963
current

Serves four states: Pennsylvania, New York, Connecticut, MassachusettsAssociated routes: I-384, I-684

 I0085 !I‑85

668.75
1,076.25

Montgomery, Alabama (I-65)
Petersburg, Virginia (I-95)

01958-01-011958
current

Serves five states: Alabama, Georgia, South Carolina, North Carolina, VirginiaAssociated routes: I-185, I-285, I-385, I-485, I-585, I-785, I-985; Planned: I-685

 I0086 !I‑86

62.85
101.15

West Heyburn, Idaho (I-84)
Pocatello, Idaho (I-15)

01980-01-011980
current

Idaho onlyAssociated routes: none

 I0086 !I‑86

183.56
295.41

East Erie, Pennsylvania (I-90)
Windsor, New York (NY 79)

01999-01-011999
current

Serves two states: Pennsylvania, New YorkAssociated routes: none

 I0087 !I‑87

10.4
16.7

Raleigh, North Carolina (I-440/US 64/US 264)
Wendell, North Carolina (US 64/US 264)

02017-01-012017
current

North Carolina onlyAssociated routes: None, will eventually have one spur route, I-587.

 I0087 !I‑87

333.49
536.70

New York City (I-278)
Champlain, New York (A-15 at Canadian border)

01957-01-011957
current

New York onlyAssociated routes: I-287, I-587, I-787

 I0088 !I‑88

140.6
226.3

West Barstow, Illinois (I-80)
Hillside, Illinois (I-290)

01987-01-011987
current

Illinois onlyAssociated routes: none

 I0088 !I‑88

117.75
189.50

East Binghamton, New York (I-81)
Schenectady, New York (I-90)

01968-01-011968
current

New York onlyAssociated routes: none

 I0089 !I‑89

191.12
307.58

Bow, New Hampshire (I-93)
Highgate Springs, Vermont (Route 133 at Canadian border/future A-35)

01960-01-011960
current

Serves two states: New Hampshire, VermontAssociated route: I-189

 I0090 !I‑90

3,020.44
4,860.93

Seattle, Washington (WA 519)
Boston, Massachusetts (MA 1A)

01956-01-011956
current

Serves 13 states: WA, ID, MT, WY, SD, MN, WI, IL, IN, OH, PA, NY, MAAssociated routes: I-190, I-290, I-390, I-490, I-590, I-690, I-790, I-890, I-990

 I0091 !I‑91

290.37
467.31

New Haven, Connecticut/North Haven, Connecticut (I-95)
Derby Line, Vermont (A-55 at Canadian border)

01958-01-011958
current

Serves three states: Connecticut, Massachusetts, VermontAssociated routes: I-291, I-391, I-691

 I0093 !I‑93

189.95
305.69

Canton, Massachusetts (I-95)
St. Johnsbury, Vermont (I-91)

01957-01-011957
current

Serves three states: Massachusetts, New Hampshire, VermontAssociated routes: I-293, I-393

 I0094 !I‑94

1,585.20
2,551.13

Billings, Montana (I-90)
Port Huron, Michigan (Hwy 402 at Canadian border)

01956-01-011956
current

Serves seven states: MT, ND, MN, WI, IL, IN, MIAssociated routes: I-194, I-294, I-394, I-494, I-694, I-794, I-894

 I0095 !I‑95

1,925.74
3,099.18

US 1 in Miami, Florida
NB 95 at Canadian border in Houlton, Maine

01957-01-011957
current

Serves DC and 15 states: FL, GA, SC, NC, VA, MD, DE, PA, NJ, NY, CT, RI, MA, NH, MEAssociated routes: I-195, I-295, I-395, I-495, I-595, I-695, I-795, I-895

 I0096 !I‑96

192.06
309.09

Muskegon, Michigan (US 31)
Detroit, Michigan (I-75)

01959-01-011959
current

Michigan onlyAssociated routes: I-196, I-296, I-496, I-696

 I0097 !I‑97

17.62
28.36

Annapolis, Maryland (US 50)
Baltimore, Maryland (I-695/I-895)

01987-01-011987
current

Maryland onlyAssociated routes: None, had 2 auxiliary routes planned, I-197 and I-297, but they were replaced by I-595 and MD Route 3.

 I0099 !I‑99

98.86
159.10

Bedford, Pennsylvania (I-70/I-76)
Painted Post, New York (I-86)

01998-01-011998
current

Unfinished Pennsylvania section: Bellefonte, Pennsylvania (I-80) to New York border near Lawrenceville, Pennsylvania (US 15)Serves two states: Pennsylvania, New YorkAssociated routes: none

tag: table

text: Other jurisdictions[edit]

text: In addition to the 48 contiguous states, Interstate Highways are found in Hawaii, Alaska, and Puerto Rico.  The Federal Highway Administration funds four routes in Alaska and three routes in Puerto Rico under the same program as the rest of the Interstate Highway System. However, these routes are not required to meet the same standards as the mainland routes:

text:
“

Highways on the Interstate System in Alaska and Puerto Rico shall be designed in accordance with such geometric and construction standards as are adequate for current and probable future traffic demands and the needs of the locality of the highway.[3]

”

text: Hawaii[edit]

text: The Interstate Highways in the island of Oʻahu, Hawaii are signed with the standard Interstate Highway shield, with the letter "H-" prefixed before the number. They are fully controlled-access routes built to the same standards as the mainland Interstate Highways.

text:
Number

Length (mi)[2]

Length (km)

Southern or western terminus

Northern or eastern terminus

Formed

Removed

Notes

 I0001 !H-1

27.16
43.71

Route 93 in Kapolei
Route 72 in Honolulu

01959-01-011959
current

Associated route: H-201

 I0002 !H-2

8.33
13.41

H-1 in Pearl City
Route 99 in Wahiawa

01976-01-011976
current

 I0003 !H-3

15.32
24.66

H-1 & H-201 in Halawa
Marine Corps Base Hawaii

01997-01-011997
current

I0004 !H-4

6.5
10.5

—
—

—
—

Was to have provided relief around the congested areas of H-1, but the idea was not popular and was never built.
      Former

text: Alaska[edit]

text: Alaska's Interstate Highways are unsigned as such, although they all have state highway numbers that do not match the Interstate Highway numbers.[4]

text:
Number

Length (mi)[2]

Length (km)

Southern or western terminus

Northern or eastern terminus

Formed

Removed

Notes

 1 !A‑1

408.23
656.98

Anchorage
Canadian border in Alcan Border

01976-01-011976
current

Glenn Highway, Richardson Highway, Tok Cut-Off, Alaska Highway[5][6][7][8]

 2 !A‑2

202.18
325.38

Tok
Fairbanks

01976-01-011976
current

Alaska Highway, Richardson Highway[6][7][8]

 3 !A‑3

148.12
238.38

Anchorage
Soldotna

01976-01-011976
current

Seward Highway, Sterling Highway[5][7][8]

 4 !A‑4

323.69
520.93

Gateway, near Palmer
Fairbanks

01976-01-011976
current

Parks Highway[5][6][7][8]

text: Puerto Rico[edit]

text: Like Alaska, Puerto Rico signs its Interstate Highways as territorial routes, and the numbers do not match their official Interstate Highway designations. Many of the territory's routes are freeway-standard toll roads.[9]

text:
Number

Length (mi)[2]

Length (km)

Southern or western terminus

Northern or eastern terminus

Formed

Removed

Notes

 I0001 !PRI-1

71.08
114.39

PR-2 in Ponce
PR-2 in San Juan

01953-01-011953
current

Follows PR-52

 I0002 !PRI-2

138.13
222.30

PR-1 in Ponce
PR-3 in San Juan

01953-01-011953
current

Follows PR-22

 I0003 !PRI-3

65.27
105.04

PR-3 in Humacao
PR-2 in San Juan

01953-01-011953
current

Follows PR-66

text: In popular culture[edit]

text: The title of interactive fiction I-0 refers to the fictional "Interstate Zero".[10]


document_title: Maid of honour

question_text: what is the meaning of maid of honour

question_tokens: what is the meaning of maid of honour

root

text: Maid of honour

text: This is the current revision of this page, as edited by Volunteer1234 (talk | contribs) at 14:44, 5 August 2017 (→Terminology:  redundancy). The present address (URL) is a permanent link to this version.

text: Maids of honour[1] are the junior attendants of a queen in royal households. The position was and is junior to the lady-in-waiting. The equivalent title and office has historically been used in most European royal courts.

tag: p

text: Role[edit]

text: Traditionally, a queen regnant had eight maids of honour, while a queen consort had four; Queen Anne Boleyn, however, had over 60.

text: A maid of honour was a maiden, meaning that she was unmarried, and was usually young. Maids of honour were commonly in their sixteenth year or older, although Lady Jane Grey, served as a maid of honour to Queen Catherine Parr in about 1546–48, when Jane was only about ten to twelve years old. Under Mary I and Elizabeth I, maids of honour were at court as a kind of finishing school, with the hope of making a good marriage. Elizabeth Knollys was a maid of the court at the age of nine.

text: Some of the maids of honour were paid, while others were not. In the 19th and 20th centuries, the term maid of honour in waiting was sometimes used.

text: The queen mother often also had maids of honour. In 1912, for example, Ivy Gordon-Lennox was appointed a maid of honour to Queen Alexandra.[2]

text: In 1912, King George V granted maids of honour the style of The Honourable, with precedence next after daughters of barons.[3]

text: At her coronation, Queen Elizabeth II had maids of honour who attended to her throughout the ceremony, especially carrying the trains of her robes. The Queen had six Maids of Honour:

text:
Lady Moyra Hamilton, daughter of James Hamilton, 4th Duke of Abercorn;
Lady Anne Coke, daughter of Thomas Coke, 5th Earl of Leicester;
Lady Jane Vane-Tempest-Stewart, daughter of Robin Vane-Tempest-Stewart, 8th Marquess of Londonderry;
Lady Mary Baillie-Hamilton, daughter of George Baillie-Hamilton, 12th Earl of Haddington;
Lady Jane Heathcote-Drummond-Willoughby, daughter of James Heathcote-Drummond-Willoughby, 3rd Earl of Ancaster; and
Lady Rosemary Spencer-Churchill, daughter of John Spencer-Churchill, 10th Duke of Marlborough.[4]

tag: ul

text: Terminology[edit]

text: A lady-in-waiting is a woman who attends a female member of the Royal Family other than the queen regnant or queen consort. An attendant upon one of the latter is a lady of the bedchamber or woman of the bedchamber, and the senior lady-in-waiting is the mistress of the robes. The women of the bedchamber are in regular attendance, but the mistress of the robes and the ladies of the bedchamber are normally only required for ceremonial occasions.

text: The term maid of honour is the origin of the American English term maid of honor, usually the best friend of a bride who leads her bridal party.


document_title: Continental Army

question_text: when was washington appointed general of the continental army

text: Continental Army

text: Origins[edit]

text: The Continental Army consisted of soldiers from all 13 colonies and, after 1776, from all 13 states. When the American Revolutionary War began at the Battles of Lexington and Concord on April 19, 1775, the colonial revolutionaries did not have an army. Previously, each colony had relied upon the militia, made up of part-time citizen-soldiers, for local defense, or the raising of temporary "provincial regiments" during specific crises such as the French and Indian War of 1754–63. As tensions with Great Britain increased in the years leading to the war, colonists began to reform their militias in preparation for the perceived potential conflict. Training of militiamen increased after the passage of the Intolerable Acts in 1774. Colonists such as Richard Henry Lee proposed forming a national militia force, but the First Continental Congress rejected the idea.[1]

text: On April 23, 1775, the Massachusetts Provincial Congress authorized the raising of a colonial army consisting of 26 company regiments. New Hampshire, Rhode Island, and Connecticut soon raised similar but smaller forces. On June 14, 1775, the Second Continental Congress decided to proceed with the establishment of a Continental Army for purposes of common defense, adopting the forces already in place outside Boston (22,000 troops) and New York (5,000).[2] It also raised the first ten companies of Continental troops on a one-year enlistment, riflemen from Pennsylvania, Maryland, Delaware and Virginia to be used as light infantry,[2] who became the 1st Continental Regiment in 1776.

text: On June 15, 1775, the Congress elected by unanimous vote George Washington as Commander-in-Chief, who accepted and served throughout the war without any compensation except for reimbursement of expenses.[3][4][5][6]

text: On July 18, 1775, the Congress requested all colonies form militia companies from "all able bodied effective men, between sixteen and fifty years of age." It was not uncommon for men younger than sixteen to enlist as most colonies had no requirement of parental consent for those under twenty-one (adulthood).[7]

text: Four major-generals (Artemas Ward, Charles Lee, Philip Schuyler, and Israel Putnam) and eight brigadier-generals (Seth Pomeroy, Richard Montgomery, David Wooster, William Heath, Joseph Spencer, John Thomas, John Sullivan, and Nathanael Greene) were appointed by the Second Continental Congress in the course of a few days.[8][9][10] After Pomeroy did not accept, John Thomas was appointed in his place.[11]

text: As the Continental Congress increasingly adopted the responsibilities and posture of a legislature for a sovereign state, the role of the Continental Army became the subject of considerable debate. Some Americans had a general aversion to maintaining a standing army; but on the other hand the requirements of the war against the British required the discipline and organization of a modern military. As a result, the army went through several distinct phases, characterized by official dissolution and reorganization of units.

text: Soldiers in the Continental Army were citizens who had volunteered to serve in the army (but were paid), and at various times during the war, standard enlistment periods lasted from one to three years. Early in the war the enlistment periods were short, as the Continental Congress feared the possibility of the Continental Army evolving into a permanent army. The army never numbered more than 17,000 men. Turnover proved a constant problem, particularly in the winter of 1776–77, and longer enlistments were approved. Broadly speaking, Continental forces consisted of several successive armies, or establishments:

text:
The Continental Army of 1775, comprising the initial New England Army, organized by Washington into three divisions, six brigades, and 38 regiments. Major General Philip Schuyler's ten regiments in New York were sent to invade Canada.
The Continental Army of 1776, reorganized after the initial enlistment period of the soldiers in the 1775 army had expired. Washington had submitted recommendations to the Continental Congress almost immediately after he had accepted the position of Commander-in-Chief, but the Congress took time to consider and implement these. Despite attempts to broaden the recruiting base beyond New England, the 1776 army remained skewed toward the Northeast both in terms of its composition and of its geographical focus. This army consisted of 36 regiments, most standardized to a single battalion of 768 men strong and formed into eight companies, with a rank-and-file strength of 640.
The Continental Army of 1777–80 evolved out of several critical reforms and political decisions that came about when it became apparent that the British were sending massive forces to put an end to the American Revolution. The Continental Congress passed the "Eighty-eight Battalion Resolve", ordering each state to contribute one-battalion regiments in proportion to their population, and Washington subsequently received authority to raise an additional 16 battalions. Enlistment terms extended to three years or to "the length of the war" to avoid the year-end crises that depleted forces (including the notable near-collapse of the army at the end of 1776, which could have ended the war in a Continental, or American, loss by forfeit).
The Continental Army of 1781–82 saw the greatest crisis on the American side in the war. Congress was bankrupt, making it very difficult to replenish the soldiers whose three-year terms had expired. Popular support for the war reached an all-time low, and Washington had to put down mutinies both in the Pennsylvania Line and in the New Jersey Line. Congress voted to cut funding for the Army, but Washington managed nevertheless to secure important strategic victories.
The Continental Army of 1783–84 was succeeded by the United States Army, which persists to this day. As peace was restored with the British, most of the regiments were disbanded in an orderly fashion, though several had already been diminished.

text: In addition to the Continental Army regulars, local militia units, raised and funded by individual colonies/states, participated in battles throughout the war. Sometimes the militia units operated independently of the Continental Army, but often local militias were called out to support and augment the Continental Army regulars during campaigns. (The militia troops developed a reputation for being prone to premature retreats, a fact that Brigadier-General Daniel Morgan integrated into his strategy at the Battle of Cowpens in 1781.)

text: The financial responsibility for providing pay, food, shelter, clothing, arms, and other equipment to specific units was assigned to states as part of the establishment of these units. States differed in how well they lived up to these obligations. There were constant funding issues and morale problems as the war continued. This led to the army offering low pay, often rotten food, hard work, cold, heat, poor clothing and shelter, harsh discipline, and a high chance of becoming a casualty.

text: Operations[edit]

text: At the time of the Siege of Boston, the Continental Army at Cambridge, Massachusetts, in June 1775, is estimated to have numbered from 14–16,000 men from New England (though the actual number may have been as low as 11,000 because of desertions). Until Washington's arrival, it remained under the command of Artemas Ward, while John Thomas acted as executive officer and Richard Gridley commanded the artillery corps and was chief engineer. It was during this siege that Washington allegedly uttered his famous words, "It is cold out here." This was a poetic representation of the harsh conditions the men endured during the summer of the siege, and a reference to a political cartoon by Benjamin Franklin. It served as a piece of satire as it was a remark about cold conditions, while the men experienced some of the hottest temperatures of that year.

text: The British force in Boston was increasing by fresh arrivals. It numbered then about 10,000 men. Major Generals Howe, Clinton, and Burgoyne, had arrived late in May and joined General Gage in forming and executing plans for dispersing the rebels. Feeling strong with these veteran officers and soldiers around him—and the presence of several Men-of-War under Admiral Graves—the governor issued a proclamation, declaring martial law, branding the entire Continental Army and supporters as "rebels" and "parricides of the Constitution." Amnesty was offered to those who gave up their allegiance to the Continental Army and Congress in favor of the British authorities, though Samuel Adams and John Hancock were still wanted for high treason. This proclamation only served to strengthen the resolve of the Congress and Army.

text: After the British evacuation of Boston (prompted by the placement of Continental artillery overlooking the city in March 1776), the Continental Army relocated to New York. For the next five years, the main bodies of the Continental and British armies campaigned against one another in New York, New Jersey, and Pennsylvania. These campaigns included the notable battles of Trenton, Princeton, Brandywine, Germantown, and Morristown, among many others.

text: The Continental Army was racially integrated, a condition the United States Army would not see again until Truman ordered the desegregation of the military in 1948. African American slaves were promised freedom in exchange for military service in New England, and made up one fifth of the Northern Continental Army.[12]

text: Throughout its existence, the Army was troubled by poor logistics, inadequate training, short-term enlistments, interstate rivalries, and Congress's inability to compel the states to provide food, money or supplies. In the beginning, soldiers enlisted for a year, largely motivated by patriotism; but as the war dragged on, bounties and other incentives became more commonplace. Two major mutinies late in the war drastically diminished the reliability of two of the main units, and there were constant discipline problems.

text: The army increased its effectiveness and success rate through a series of trials and errors, often at great human cost. General Washington and other distinguished officers were instrumental leaders in preserving unity, learning and adapting, and ensuring discipline throughout the eight years of war. In the winter of 1777–1778, with the addition of Baron von Steuben, of Prussian origin, the training and discipline of the Continental Army began to vastly improve. (This was the infamous winter at Valley Forge.) Washington always viewed the Army as a temporary measure and strove to maintain civilian control of the military, as did the Continental Congress, though there were minor disagreements about how this was carried out.

text: Near the end of the war, the Continental Army was augmented by a French expeditionary force (under General Rochambeau) and a squadron of the French navy (under the Comte de Barras), and in the late summer of 1781 the main body of the army travelled south to Virginia to rendezvous with the French West Indies fleet under Admiral Comte de Grasse. This resulted in the Siege of Yorktown, the decisive Battle of the Chesapeake, and the surrender of the British southern army. This essentially marked the end of the land war in America, although the Continental Army returned to blockade the British northern army in New York until the peace treaty went into effect two years later, and battles took place elsewhere between British forces and those of France and its allies.

text: Demobilization[edit]

text: A small residual force remained at West Point and some frontier outposts until Congress created the United States Army by their resolution of June 3, 1784.

text: Planning for the transition to a peacetime force had begun in April 1783 at the request of a congressional committee chaired by Alexander Hamilton. The commander-in-chief discussed the problem with key officers before submitting the army's official views on 2 May. Significantly, there was a broad consensus of the basic framework among the officers. Washington's proposal called for four components: a small regular army, a uniformly trained and organized militia, a system of arsenals, and a military academy to train the army's artillery and engineer officers. He wanted four infantry regiments, each assigned to a specific sector of the frontier, plus an artillery regiment. His proposed regimental organizations followed Continental Army patterns but had a provision for increased strength in the event of war. Washington expected the militia primarily to provide security for the country at the start of a war until the regular army could expand—the same role it had carried out in 1775 and 1776. Steuben and Duportail submitted their own proposals to Congress for consideration.

text: Although Congress declined on May 12 to make a decision on the peace establishment, it did address the need for some troops to remain on duty until the British evacuated New York City and several frontier posts. The delegates told Washington to use men enlisted for fixed terms as temporary garrisons. A detachment of those men from West Point reoccupied New York without incident on November 25. When Steuben's effort in July to negotiate a transfer of frontier forts with Major General Frederick Haldimand collapsed, however, the British maintained control over them, as they would into the 1790s. That failure and the realization that most of the remaining infantrymen's enlistments were due to expire by June 1784 led Washington to order Knox, his choice as the commander of the peacetime army, to discharge all but 500 infantry and 100 artillerymen before winter set in. The former regrouped as Jackson's Continental Regiment under Colonel Henry Jackson of Massachusetts. The single artillery company, New Yorkers under John Doughty, came from remnants of the 2nd Continental Artillery Regiment.

text: Congress issued a proclamation on October 18, 1783, which approved Washington's reductions. On November 2, Washington then released his Farewell Order to the Philadelphia newspapers for nationwide distribution to the furloughed men. In the message he thanked the officers and men for their assistance and reminded them that "the singular interpositions of Providence in our feeble condition were such, as could scarcely escape the attention of the most unobserving; while the unparalleled perseverance of the Armies of the United States, through almost every possible suffering and discouragement for the space of eight long years, was little short of a standing miracle."

text: Washington believed that the blending of persons from every colony into "one patriotic band of Brothers" had been a major accomplishment, and he urged the veterans to continue this devotion in civilian life.

text: Washington said farewell to his remaining officers on December 4 at Fraunces Tavern in New York City. On December 23 he appeared in Congress, then sitting at Annapolis, and returned his commission as commander-in-chief: "Having now finished the work assigned me, I retire from the great theatre of Action; and bidding an Affectionate farewell to this August body under whose orders I have so long acted, I here offer my Commission, and take my leave of all the employments of public life." Congress ended the War of American Independence on January 14, 1784, by ratifying the definitive peace treaty that had been signed in Paris on September 3.

text: Congress had again rejected Washington's concept for a peacetime force in October 1783. When moderate delegates then offered an alternative in April 1784 which scaled the projected army down to 900 men in one artillery and three infantry battalions, Congress rejected it as well, in part because New York feared that men retained from Massachusetts might take sides in a land dispute between the two states. Another proposal to retain 350 men and raise 700 new recruits also failed. On June 2 Congress ordered the discharge of all remaining men except twenty-five caretakers at Fort Pitt and fifty-five at West Point. The next day it created a peace establishment acceptable to all interests.

text: The plan required four states to raise 700 men for one year's service. Congress instructed the Secretary at War to form the troops into eight infantry and two artillery companies. Pennsylvania, with a quota of 260 men, had the power to nominate a lieutenant colonel, who would be the senior officer. New York and Connecticut each were to raise 165 men and nominate a major; the remaining 110 men came from New Jersey. Economy was the watchword of this proposal, for each major served as a company commander, and line officers performed all staff duties except those of chaplain, surgeon, and surgeon's mate. Under Josiah Harmar, the First American Regiment slowly organized and achieved permanent status as an infantry regiment of the new Regular Army. The lineage of the First American Regiment is carried on by the 3rd United States Infantry Regiment (The Old Guard).

text: However the United States military realized it needed a well-trained standing army following St. Clair's Defeat on November 4, 1791, when a force led by General Arthur St. Clair was almost entirely wiped out by the Western Confederacy near Fort Recovery, Ohio. The plans, which were supported by U.S. President George Washington and Henry Knox, Secretary of War, led to the disbandment of the Continental Army and the creation of the Legion of the United States. The command would be based on the 18th-century military works of Henry Bouquet, a professional Swiss soldier who served as a colonel in the British army, and French Marshal Maurice de Saxe. In 1792 Anthony Wayne, a renowned hero of the American Revolutionary War, was encouraged to leave retirement and return to active service as Commander-in-Chief of the Legion with the rank of Major General.

text: The legion was recruited and raised in Pittsburgh, Pennsylvania. It was formed into four sub-legions. These were created from elements of the 1st and 2nd Regiments from the Continental Army. These units then became the First and Second Sub-Legions. The Third and Fourth Sub-Legions were raised from further recruits. From June 1792 to November 1792, the Legion remained cantoned at Fort LaFayette in Pittsburgh. Throughout the winter of 1792–93, existing troops along with new recruits were drilled in military skills, tactics and discipline at Legionville on the banks of the Ohio River near present-day Baden, Pennsylvania. The following Spring the newly named Legion of the United States left Legionville for the Northwest Indian War, a struggle between American Indian tribes affiliated with the Western Confederacy in the area south of the Ohio River. The overwhelmingly successful campaign was concluded with the decisive victory at the Battle of Fallen Timbers on August 20, 1794, Maj. Gen. Anthony Wayne applied the techniques of wilderness operations perfected by Sullivan's 1779 expedition against the Iroquois. The training the troops received at Legionville was also seen as an instrumental to this overwhelming victory.

text: Nevertheless, Steuben's Blue Book remained the official manual for the legion, as well as for the militia of most states, until Winfield Scott in 1835. In 1796, the United States Army was raised following the discontinuation with the legion of the United States. This preceded the graduation of the first cadets from United States Military Academy at West Point, New York, which was established in 1802.

text: Rank insignia[edit]

text: During the American Revolutionary War, the Continental Army initially wore ribbons, cockades and epaulettes of various colors as an ad hoc form of rank insignia, as General George Washington wrote in 1775:

text: "As the Continental Army has unfortunately no uniforms, and consequently many inconveniences must arise from not being able to distinguish the commissioned officers from the privates, it is desired that some badge of distinction be immediately provided; for instance that the field officers may have red or pink colored cockades in their hats, the captains yellow or buff, and the subalterns green."

text: In 1776 captains were to have buff or white cockades.

text:
Rank insignia of the Continental Army 1775 [13]

Ribands across the breast
Cockades in the hats
Epaulettes or stripes on the right shoulder

General
and
commander-in-chief
Major general
Brigadier general
Aide-de-camp
Colonel,
Lieutenant colonel,
Major
Captain
Lieutenant, Ensign
Sergeant
Corporal

text: Later on in the war, the Continental Army established its own uniform with a black cockade (as used in much of the British Army) among all ranks and the following insignia:

text:
Ranks and insignia of the Continental Army 1780[14]

General and
Commander-in-Chief
Major general
Brigadier general
Colonel
Lieutenant colonel
Aide-de-camp
Major
Captain
Subaltern
Lieutenant
Ensign
Sergeant major
Sergeant
Corporal
Private

Gold epaulets
Jacket with gold trim
Silver epaulets
Gold epaulets
Hat with green cockade
Gold epaulets
Gold epaulet
(Right shoulder)
Gold epaulet
(Left shoulder)
No epaulets
Red epaulets
Red epaulet
(Right shoulder)
Green epaulet
(Right shoulder)
No epaulets

text: Major battles[edit]

text:
Siege of Boston
Battle of Long Island
Battle of Harlem Heights
Battle of Trenton
Battle of Princeton
Battle of Brandywine
Battle of Germantown
Battle of Saratoga
Battle of Monmouth
Siege of Charleston
Battle of Camden
Battle of Cowpens
Battle of Guilford Court House
Siege of Yorktown


document_title: Cell cycle

question_text: dna replication occurs in which phase of the cell cycle

text: Cell cycle

text: Phases[edit]

text: The cell cycle consists of four distinct phases: G1 phase, S phase (synthesis), G2 phase (collectively known as interphase) and M phase (mitosis or meiosis). M phase is itself composed of two tightly coupled processes: karyokinesis, in which the cell's chromosomes are divided, and cytokinesis, in which the cell's cytoplasm divides forming two daughter cells. Activation of each phase is dependent on the proper progression and completion of the previous one. Cells that have temporarily or reversibly stopped dividing are said to have entered a state of quiescence called G0 phase.

text:
State

Phase

Abbreviation

Description

Resting

Gap 0

G0

A phase where the cell has left the cycle and has stopped dividing.

Interphase

Gap 1

G1

Cells increase in size in Gap 1. The G1 checkpoint control mechanism ensures that everything is ready for DNA synthesis.

Synthesis

S

DNA replication occurs during this phase.

Gap 2

G2

During the gap between DNA synthesis and mitosis, the cell will continue to grow. The G2 checkpoint control mechanism ensures that everything is ready to enter the M (mitosis) phase and divide.

Cell division

Mitosis

M

Cell growth stops at this stage and cellular energy is focused on the orderly division into two daughter cells. A checkpoint in the middle of mitosis (Metaphase Checkpoint) ensures that the cell is ready to complete cell division.

text: After cell division, each of the daughter cells begin the interphase of a new cycle. Although the various stages of interphase are not usually morphologically distinguishable, each phase of the cell cycle has a distinct set of specialized biochemical processes that prepare the cell for initiation of cell division.

text: G0 phase (quiescence)[edit]

text: G0 is a resting phase where the cell has left the cycle and has stopped dividing.  The cell cycle starts with this phase.  The word "post-mitotic" is sometimes used to refer to both quiescent and senescent cells. Non-proliferative (non-dividing) cells in multicellular eukaryotes generally enter the quiescent G0 state from G1 and may remain quiescent for long periods of time, possibly indefinitely (as is often the case for neurons). This is very common for cells that are fully differentiated. Cellular senescence occurs in response to DNA damage and external stress and usually constitutes an arrest in G1. Some cells enter the G0 phase semi-permanently and are considered post-mitotic, e.g., some liver, kidney, and stomach cells. Many cells do not enter G0 and continue to divide throughout an organism's life, e.g., epithelial cells.

text: Cellular senescence is also a state that occurs in response to DNA damage or degradation that would make a cell's progeny nonviable; it is often a biochemical alternative to the self-destruction of such a damaged cell by apoptosis.

text: Interphase (intermitosis)[edit]

text: Before a cell can enter cell division, it needs to take in nutrients. All of the preparations are done during interphase. Interphase is a series of changes that takes place in a newly formed cell and its nucleus, before it becomes capable of division again. It is also called preparatory phase or intermitosis. Previously it was called resting stage because there is no apparent activity related to cell division.Typically interphase lasts for at least 91% of the total time required for the cell cycle.

text: Interphase proceeds in three stages, G1, S, and G2, followed by the cycle of mitosis and cytokinesis. The cell's nuclear DNA contents are duplicated during S phase but may continue till G2 in case of heterochromatin.

text: G1 phase (First growth phase or Post mitotic gap phase)[edit]

text:
The first phase within interphase, from the end of the previous M phase until the beginning of DNA synthesis, is called G1 (G indicating gap). It is also called the growth phase. During this phase, the biosynthetic activities of the cell, which are considerably slowed down during M phase, resume at a high rate. The duration of G1 is highly variable, even among different cells of the same species.[3] In this phase, the cell increases its supply of proteins, increases the number of organelles (such as mitochondria, ribosomes), and grows in size. In G1 phase, a cell has three options.
(1) To continue cell cycle and enter S phase
(2) Stop cell cycle and enter G0 phase for undergoing differentiation.
(3) Get arrested in G1 phase hence it may enter G0 phase or re-enter cell cycle.
The deciding factor is availability of nutrients and storage of energy rich compounds at the deciding point called check point (Restriction point). This check point is called the restriction point or START and is regulated by G1/S cyclins, which cause transition from G1 to S phase. Passage through the  G1 check point commits the cell to division.

text: S phase (DNA replication)[edit]

text: The ensuing S phase starts when DNA synthesis commences; when it is complete, all of the chromosomes have been replicated, i.e., each chromosome has two (sister) chromatids. Thus, during this phase, the amount of DNA in the cell has effectively doubled, though the ploidy of the cell remains the same. Rates of RNA transcription and protein synthesis are very low during this phase. An exception to this is histone production, most of which occurs during the S phase.[4][5][6]

text: G2 phase (growth)[edit]

text:
G2 phase occurs after DNA replication and is a period of protein synthesis and rapid cell growth to prepare the cell for mitosis.
During this phase microtubules begin to reorganize to form a spindle.

text: Mitotic phase (chromosome separation)[edit]

text: The relatively brief M phase consists of nuclear division (karyokinesis). It is a relatively short period of the cell cycle. M phase is complex and highly regulated. The sequence of events is divided into phases, corresponding to the completion of one set of activities and the start of the next. These phases are sequentially known as:

text:
prophase,
metaphase,
anaphase,
telophase

text: Mitosis is the process by which a eukaryotic cell separates the chromosomes in its cell nucleus into two identical sets in two nuclei.[7] During the process of mitosis the pairs of chromosomes condense and attach to fibers that pull the sister chromatids to opposite sides of the cell.[8]

text: Mitosis occurs exclusively in eukaryotic cells, but occurs in different ways in different species. For example, animals undergo an "open" mitosis, where the nuclear envelope breaks down before the chromosomes separate, while fungi such as Aspergillus nidulans and Saccharomyces cerevisiae (yeast) undergo a "closed" mitosis, where chromosomes divide within an intact cell nucleus.[9] Prokaryotic cells, which lack a nucleus, divide by a process called binary fission.

text: Cytokinesis phase (separation of all cell components)[edit]

text: Mitosis is immediately followed by cytokinesis, which divides the nuclei, cytoplasm, organelles and cell membrane into two cells containing roughly equal shares of these cellular components. Mitosis and cytokinesis together define  the division of the mother cell into two daughter cells, genetically identical to each other and to their parent cell. This accounts for approximately 10% of the cell cycle.

text: Because cytokinesis usually occurs in conjunction with mitosis, "mitosis" is often used interchangeably with "M phase". However, there are many cells where mitosis and cytokinesis occur separately, forming single cells with multiple nuclei in a process called endoreplication. This occurs most notably among the fungi and slime moulds, but is found in various groups. Even in animals, cytokinesis and mitosis may occur independently, for instance during certain stages of fruit fly embryonic development.[10] Errors in mitosis can either kill a cell through apoptosis or cause mutations that may lead to cancer.

text: The process of mitosis is complex and highly regulated. The sequence of events is divided into phases, corresponding to the completion of one set of activities and the start of the next. These stages are prophase, prometaphase, metaphase, anaphase and telophase. During the process of mitosis the pairs of chromosomes condense and attach to fibers that pull the sister chromatids to opposite sides of the cell. The cell then divides in cytokinesis, to produce two identical daughter cells.[8]

text: Regulation of eukaryotic cell cycle[edit]

text: Regulation of the cell cycle involves processes crucial to the survival of a cell, including the detection and repair of genetic damage as well as the prevention of uncontrolled cell division. The molecular events that control the cell cycle are ordered and directional; that is, each process occurs in a sequential fashion and it is impossible to "reverse" the cycle.

text: Role of cyclins and CDKs[edit]

text:
Nobel LaureatePaul Nurse

Nobel LaureateTim Hunt

text: Two key classes of regulatory molecules, cyclins and cyclin-dependent kinases (CDKs), determine a cell's progress through the cell cycle.[11] Leland H. Hartwell, R. Timothy Hunt, and Paul M. Nurse won the 2001 Nobel Prize in Physiology or Medicine for their discovery of these central molecules.[12] Many of the genes encoding cyclins and CDKs are conserved among all eukaryotes, but in general more complex organisms have more elaborate cell cycle control systems that incorporate more individual components. Many of the relevant genes were first identified by studying yeast, especially Saccharomyces cerevisiae;[13] genetic nomenclature in yeast dubs many of these genes cdc (for "cell division cycle") followed by an identifying number, e.g. cdc25 or cdc20.

text: Cyclins form the regulatory subunits and CDKs the catalytic subunits of an activated heterodimer; cyclins have no catalytic activity and CDKs are inactive in the absence of a partner cyclin. When activated by a bound cyclin, CDKs perform a common biochemical reaction called phosphorylation that activates or inactivates target proteins to orchestrate coordinated entry into the next phase of the cell cycle. Different cyclin-CDK combinations determine the downstream proteins targeted. CDKs are constitutively expressed in cells whereas cyclins are synthesised at specific stages of the cell cycle, in response to various molecular signals.[14]

text: General mechanism of cyclin-CDK interaction[edit]

text: Upon receiving a pro-mitotic extracellular signal, G1 cyclin-CDK complexes become active to prepare the cell for S phase, promoting the expression of transcription factors that in turn promote the expression of S cyclins and of enzymes required for DNA replication. The G1 cyclin-CDK complexes also promote the degradation of molecules that function as S phase inhibitors by targeting them for ubiquitination. Once a protein has been ubiquitinated, it is targeted for proteolytic degradation by the proteasome. However, results from a recent study of E2F transcriptional dynamics at the single-cell level argue that the role of G1 cyclin-CDK activities, in particular cyclin D-CDK4/6, is to tune the timing rather than the commitment of cell cycle entry.[15]

text: Active S cyclin-CDK complexes phosphorylate proteins that make up the pre-replication complexes assembled during G1 phase on DNA replication origins. The phosphorylation serves two purposes: to activate each already-assembled pre-replication complex, and to prevent new complexes from forming. This ensures that every portion of the cell's genome will be replicated once and only once. The reason for prevention of gaps in replication is fairly clear, because daughter cells that are missing all or part of crucial genes will die. However, for reasons related to gene copy number effects, possession of extra copies of certain genes is also deleterious to the daughter cells.

text: Mitotic cyclin-CDK complexes, which are synthesized but inactivated during S and G2 phases, promote the initiation of mitosis by stimulating downstream proteins involved in chromosome condensation and mitotic spindle assembly. A critical complex activated during this process is a ubiquitin ligase known as the anaphase-promoting complex (APC), which promotes degradation of structural proteins associated with the chromosomal kinetochore. APC also targets the mitotic cyclins for degradation, ensuring that telophase and cytokinesis can proceed.[16]

text: Specific action of cyclin-CDK complexes[edit]

text:
Cyclin D is the first cyclin produced in the cell cycle, in response to extracellular signals (e.g. growth factors). Cyclin D binds to existing CDK4, forming the active cyclin D-CDK4 complex. Cyclin D-CDK4 complex in turn phosphorylates the retinoblastoma susceptibility protein (Rb). The hyperphosphorylated Rb dissociates from the E2F/DP1/Rb complex (which was bound to the E2F responsive genes, effectively "blocking" them from transcription), activating E2F. Activation of E2F results in transcription of various genes like cyclin E, cyclin A, DNA polymerase, thymidine kinase, etc. Cyclin E thus produced binds to CDK2, forming the cyclin E-CDK2 complex, which pushes the cell from G1 to S phase (G1/S, which initiates the G2/M transition).[17] Cyclin B-cdk1 complex activation causes breakdown of nuclear envelope and initiation of prophase, and subsequently, its deactivation causes the cell to exit mitosis.[14]
A quantitative study of E2F transcriptional dynamics at the single-cell level by using engineered fluorescent reporter cells provided a quantitative framework for understanding the control logic of cell cycle entry, challenging the canonical textbook model. Genes that regulate the amplitude of E2F accumulation, such as Myc, determine the commitment in cell cycle and S phase entry. G1 cyclin-CDK activities are not the driver of cell cycle entry. Instead, they primarily tune the timing of E2F increase, thereby modulating the pace of cell cycle progression.[15]

text: Inhibitors[edit]

text: Two families of genes, the cip/kip (CDK interacting protein/Kinase inhibitory protein) family and the INK4a/ARF (Inhibitor of Kinase 4/Alternative Reading Frame) family, prevent the progression of the cell cycle. Because these genes are instrumental in prevention of tumor formation, they are known as tumor suppressors.

text: The cip/kip family includes the genes p21, p27 and p57. They halt cell cycle in G1 phase, by binding to, and inactivating, cyclin-CDK complexes. p21 is activated by p53 (which, in turn, is triggered by DNA damage e.g. due to radiation). p27 is activated by Transforming Growth Factor of β (TGF β), a growth inhibitor.

text: The INK4a/ARF family includes p16INK4a, which binds to CDK4 and arrests the cell cycle in G1 phase, and p14ARF which prevents p53 degradation.

text: Synthetic inhibitors of Cdc25 could also be useful for the arrest of cell cycle and therefore be useful as antineoplastic and anticancer agents.[18]

text: Transcriptional regulatory network[edit]

text: Current evidence suggests that a semi-autonomous transcriptional network acts in concert with the CDK-cyclin machinery to regulate the cell cycle. Several gene expression studies in Saccharomyces cerevisiae have identified 800–1200 genes that change expression over the course of the cell cycle.[13][19][20] They are transcribed at high levels at specific points in the cell cycle, and remain at lower levels throughout the rest of the  cycle. While the set of identified genes differs between studies due to the computational methods and criteria used to identify them, each study indicates that a large portion of yeast genes are temporally regulated.[21]

text: Many periodically expressed genes are driven by transcription factors that are also periodically expressed. One screen of single-gene knockouts identified 48 transcription factors (about 20% of all non-essential transcription factors) that show cell cycle progression defects.[22] Genome-wide studies using high throughput technologies have identified the transcription factors that bind to the promoters of yeast genes, and correlating these findings with temporal expression patterns have allowed the identification of transcription factors that drive phase-specific gene expression.[19][23] The expression profiles of these transcription factors are driven by the transcription factors that peak in the prior phase, and computational models have shown that a CDK-autonomous network of these transcription factors is sufficient to produce steady-state oscillations in gene expression).[20][24]

text: Experimental evidence also suggests that gene expression can oscillate with the period seen in dividing wild-type cells independently of the CDK machinery. Orlando et al. used microarrays to measure the expression of a set of 1,271 genes that they identified as periodic in both wild type cells and cells lacking all S-phase and mitotic cyclins (clb1,2,3,4,5,6). Of the 1,271 genes assayed, 882 continued to be expressed in the cyclin-deficient cells at the same time as in the wild type cells, despite the fact that the cyclin-deficient cells arrest at the border between G1 and S phase. However, 833 of the genes assayed changed behavior between the wild type and mutant cells, indicating that these genes are likely directly or indirectly regulated by the CDK-cyclin machinery. Some genes that continued to be expressed on time in the mutant cells were also expressed at different levels in the mutant and wild type cells. These findings suggest that while the transcriptional network may oscillate independently of the CDK-cyclin oscillator, they are coupled in a manner that requires both to ensure the proper timing of cell cycle events.[20] Other work indicates that phosphorylation, a post-translational modification, of cell cycle transcription factors by Cdk1 may alter the localization or activity of the transcription factors in order to tightly control timing of target genes.[22][25][26]

text: While oscillatory transcription plays a key role in the progression of the yeast cell cycle, the CDK-cyclin machinery operates independently in the early embryonic cell cycle. Before the midblastula transition, zygotic transcription does not occur and all needed proteins, such as the B-type cyclins, are translated from maternally loaded mRNA.[27]

text: DNA replication and DNA replication origin activity[edit]

text: Analyses of synchronized cultures of Saccharomyces cerevisiae under conditions that prevent DNA replication initiation without delaying cell cycle progression showed that origin licensing decreases the expression of genes with origins near their 3' ends, revealing that downstream origins can regulate the expression of upstream genes.[28] This confirms previous predictions from mathematical modeling of a global causal coordination between DNA replication origin activity and mRNA expression,[29][30][31] and shows that mathematical modeling of DNA microarray data can be used to correctly predict previously unknown biological modes of regulation.

text: Checkpoints[edit]

text: Cell cycle checkpoints are used by the cell to monitor and regulate the progress of the cell cycle.[32] Checkpoints prevent cell cycle progression at specific points, allowing verification of necessary phase processes and repair of DNA damage. The cell cannot proceed to the next phase until checkpoint requirements have been met.  Checkpoints typically consist of a network of regulatory proteins that monitor and dictate the progression of the cell through the different stages of the cell cycle.

text: There are several checkpoints to ensure that damaged or incomplete DNA is not passed on to daughter cells. Three main checkpoints exist: the G1/S checkpoint, the G2/M checkpoint and the metaphase (mitotic) checkpoint.

text: G1/S transition is a rate-limiting step in the cell cycle and is also known as restriction point.[14] This is where the cell checks whether it has enough raw materials to fully replicate its DNA (nucleotide bases, DNA synthase, chromatin, etc.). An unhealthy or malnourished cell will get stuck at this checkpoint.

text: The G2/M checkpoint is where the cell ensures that it has enough cytoplasm and phospholipids for two daughter cells. But sometimes more importantly, it checks to see if it is the right time to replicate. There are some situations where many cells need to all replicate simultaneously (for example, a growing embryo should have a symmetric cell distribution until it reaches the mid-blastula transition). This is done by controlling the G2/M checkpoint.

text: The metaphase checkpoint is a fairly minor checkpoint, in that once a cell is in metaphase, it has committed to undergoing mitosis. However that's not to say it isn't important. In this checkpoint, the cell checks to ensure that the spindle has formed and that all of the chromosomes are aligned at the spindle equator before anaphase begins.[33]

text: While these are the three "main" checkpoints, not all cells have to pass through each of these checkpoints in this order to replicate. Many types of cancer are caused by mutations that allow the cells to speed through the various checkpoints or even skip them altogether. Going from S to M to S phase almost consecutively. Because these cells have lost their checkpoints, any DNA mutations that may have occurred are disregarded and passed on to the daughter cells. This is one reason why cancer cells have a tendency to exponentially accrue mutations. Aside from cancer cells, many fully differentiated cell types no longer replicate so they leave the cell cycle and stay in G0 until their death. Thus removing the need for cellular checkpoints. An alternative model of the cell cycle response to DNA damage has also been proposed, known as the postreplication checkpoint.

text: Checkpoint regulation plays an important role in an organism's development. In sexual reproduction, when egg fertilization occurs, when the sperm binds to the egg, it releases signalling factors that notify the egg that it has been fertilized. Among other things, this induces the now fertilized oocyte to return from its previously dormant, G0, state back into the cell cycle and on to mitotic replication and division.

text: p53 plays an important role in triggering the control mechanisms at both G1/S and G2/M checkpoints. In addition to p53, checkpoint regulators are being heavily researched for their roles in cancer growth and proliferation.

text: Fluorescence imaging of the cell cycle[edit]

text: Pioneering work by Atsushi Miyawaki and coworkers developed the fluorescent ubiquitination-based cell cycle indicator (FUCCI), which enables fluorescence imaging of the cell cycle.  Originally, a green fluorescent protein, mAG, was fused to hGem(1/110) and an orange fluorescent protein (mKO2) was fused to hCdt1(30/120).  Note, these fusions are fragments that contain a nuclear localization signal and ubiquitination sites for degradation, but are not functional proteins.  The green fluorescent protein is made during the S, G2, or M phase and degraded during the G0 or G1 phase, while the orange fluorescent protein is made during the G0 or G1 phase and destroyed during the S, G2, or M phase.[34] A far-red and near-infrared FUCCI was developed using a cyanobacteria-derived fluorescent protein (smURFP) and a bacteriophytochrome-derived fluorescent protein (movie found at this link).[35]

text: Role in tumor formation[edit]

text: A disregulation of the cell cycle components may lead to tumor formation.[36] As mentioned above, when some genes like the cell cycle inhibitors, RB, p53 etc. mutate, they may cause the cell to multiply uncontrollably, forming a tumor. Although the duration of cell cycle in tumor cells is equal to or longer than that of normal cell cycle, the proportion of cells that are in active cell division (versus quiescent cells in G0 phase) in tumors is much higher than that in normal tissue.[citation needed] Thus there is a net increase in cell number as the number of cells that die by apoptosis or senescence remains the same.

text: The cells which are actively undergoing cell cycle are targeted in cancer therapy as the DNA is relatively exposed during cell division and hence susceptible to damage by drugs or radiation. This fact is made use of in cancer treatment; by a process known as debulking, a significant mass of the tumor is removed which pushes a significant number of the remaining tumor cells from G0 to G1 phase (due to increased availability of nutrients, oxygen, growth factors etc.). Radiation or chemotherapy following the debulking procedure kills these cells which have newly entered the cell cycle.[14]

text: The fastest cycling mammalian cells in culture, crypt cells in the intestinal epithelium, have a cycle time as short as 9 to 10 hours. Stem cells in resting mouse skin may have a cycle time of more than 200 hours. Most of this difference is due to the varying length of G1, the most variable phase of the cycle. M and S do not vary much.

text: In general, cells are most radiosensitive in late M and G2 phases and most resistant in late S phase.

text: For cells with a longer cell cycle time and a significantly long G1 phase, there is a second peak of resistance late in G1.

text: The pattern of resistance and sensitivity correlates with the level of sulfhydryl compounds in the cell. Sulfhydryls are natural substances that protect cells from radiation damage and tend to be at their highest levels in S and at their lowest near mitosis.