Overexpression of lecithin:cholesterol acyltransferase in transgenic rabbits prevents diet-induced atherosclerosis.

Lecithin:cholesterol acyltransferase (LCAT) is a key plasma enzyme in cholesterol and high density lipoprotein (HDL) metabolism. Transgenic rabbits overexpressing human LCAT had 15-fold greater plasma LCAT activity that nontransgenic control rabbits. This degree of overexpression was associated with a 6.7-fold increase in the plasma HDL cholesterol concentration in LCAT transgenic rabbits. On a 0.3% cholesterol diet, the HDL cholesterol concentrations increased from 24 +/- 1 to 39 +/- 3 mg/dl in nontransgenic control rabbits (n = 10; P < 0.05) and increased from 161 +/- 5 to 200 +/- 21 mg/dl (P < 0.001) in the LCAT transgenic rabbits (n = 9). Although the baseline non-HDL concentrations of control (4 +/- 3 mg/dl) and transgenic rabbits (18 +/- 4 mg/dl) were similar, the cholesterol-rich diet raised the non-HDL cholesterol concentrations, reflecting the atherogenic very low density, intermediate density, and low density lipoprotein particles observed by gel filtration chromatography. The non-HDL cholesterol rose to 509 +/- 57 mg/dl in controls compared with only 196 +/- 14 mg/dl in the LCAT transgenic rabbits (P < 0.005). The differences in the plasma lipoprotein response to a cholesterol-rich diet observed in the transgenic rabbits paralleled the susceptibility to developing aortic atherosclerosis. Compared with nontransgenic controls, LCAT transgenic rabbits were protected from diet-induced atherosclerosis with significant reductions determined by both quantitative planimetry (-86%; P < 0.003) and quantitative immunohistochemistry (-93%; P < 0.009). Our results establish the importance of LCAT in the metabolism of both HDL and apolipoprotein B-containing lipoprotein particles with cholesterol feeding and the response to diet-induced atherosclerosis. In addition, these findings identify LCAT as a new target for therapy to prevent atherosclerosis.

A synthetic inhibitor of the mitogen-activated protein kinase cascade.

Treatment of cells with a variety of growth factors triggers a phosphorylation cascade that leads to activation of mitogen-activated protein kinases (MAPKs, also called extracellular signal-regulated kinases, or ERKs). We have identified a synthetic inhibitor of the MAPK pathway. PD 098059 [2-(2'-amino-3'-methoxyphenyl)-oxanaphthalen-4-one] selectively inhibited the MAPK-activating enzyme, MAPK/ERK kinase (MEK), without significant inhibitory activity of MAPK itself. Inhibition of MEK by PD 098059 prevented activation of MAPK and subsequent phosphorylation of MAPK substrates both in vitro and in intact cells. Moreover, PD 098059 inhibited stimulation of cell growth and reversed the phenotype of ras-transformed BALB 3T3 mouse fibroblasts and rat kidney cells. These results indicate that the MAPK pathway is essential for growth and maintenance of the ras-transformed phenotype. Further, PD 098059 is an invaluable tool that will help elucidate the role of the MAPK cascade in a variety of biological settings.

Mouse mammary tumor viruses with functional superantigen genes are selected during in vivo infection.

Mouse mammary tumor virus (MMTV) encodes a superantigen that is important for viral infectivity in vivo. To determine whether superantigen function was required for infection by milk-borne MMTV, we created HYB PRO/Cla transgenic mice. These mice produced a full-length, packaged viral RNA with a frameshift mutation that caused premature termination of the superantigen protein. Young HYB PRO/Cla mice showed no deletion of their cognate V beta 14+ T cells, although they shed virus in their milk. The nontransgenic offspring of the HYB PRO/Cla mice were infected with this virus, since transgene-specific viral transcripts were detected in their mammary glands. Surprisingly, these offspring demonstrated the progressive deletion of V beta 14+ T cells characteristic of exogenous MMTV (C3H) infection. Sequence analysis demonstrated that these newly acquired viruses had reconstituted superantigen open reading frames resulting from recombination between the HYB PRO/Cla and endogenous Mtv-1 proviral RNAs. Thus, there is selection during the infection process for MMTVs with functional superantigen genes.

Charter of 1650, 1650 May 31

Original charter dated May 31, 1650. The charter is engrossed on sheepskin and signed by Thomas Dudley.

[Draft of a committee report, 1790]

Two folio-sized leaves containing a handwritten draft of a report of a committee explaining proposed changes to the academic schedule of Harvard undergraduates. The report discusses the rearrangement of lectures, exercises, disputations, and recitations and the specific reasoning behind the changes. The first page of the report is written on the verso of an essay by student Henry Daingerfield titled, "Wishing of all employments is the worst," and the second page of the report is written on the verso of an essay on the importance of teaching morals to the young by Bradstreet Story (later known as Dudley Story Bradstreet, Harvard AB 1792), dated 1790.

Acknowledgment of Atkins, Dexter, Hall 1, 1780 March 22

One-page handwritten letter to "the Reverent the President, Professors, and Tutors of Harvard College," signed with the last names of Dudley Atkins, Samuel Dexter, and Joseph Hall, asking the President and Tutors for their pardon.

College Book 4, 1686-1750

Regular recording of Corporation meetings began in College Book 4, which includes minutes from July 23, 1686 through September 5, 1750. Its spine title reads "College Book 4 & 5" due to a nineteenth century labeling error. The creation of College Book 4 was precipitated by the English Court of Chancery's October 1684 judgment, which annulled the Royal Charter of the Massachusetts Colony and seemed to render the College Charter of 1650 – and with it the Corporation and Board of Overseers – defunct. In May 1686, Joseph Dudley (Harvard AB 1665) received a commission as the President of the Council of New England, and on July 23, 1686, Dudley and the Council met in Boston to create a provisional College governing board led by Increase Mather as Rector of the College and John Leverett and William Brattle as Tutors. The "Rector and Tutors" mirrored in purpose if not in name the Corporation's "President and Fellows," and the agreements of President Dudley and the Council creating the new governing board comprise the first entry in College Book 4. In June 1692, a new act of incorporation for Harvard College was passed in the Massachusetts Legislature and signed by the Governor. The Charter of 1692 merged the functions of the Board of Overseers and the Corporation into one Corporation consisting of the President, Treasurer, and eight Fellows. As the Corporation created by this 1692 act (and modified in later versions of the Charter) grew unwieldy, its members met less frequently. As a result, the Faculty (known until 1825 as the "Immediate Government") assumed more responsibility in managing the College's daily operations and addressing student discipline. On December 6, 1707 the Massachusetts General Court restored the Charter of 1650, thus reestablishing the Board of Overseers and the Corporation as the governing bodies of Harvard College. The changes in name and composition of the Harvard Corporation between 1686 and 1707 are documented in the proceedings recorded in College Book 4.

A plan of Cambridge Green, 1780 September 14

Small pen-and-ink and watercolor drawing of Cambridge Green created by Harvard senior John Davis, presumably as part of his undergraduate mathematical coursework. The map surveys Cambridge Commons and includes a few rough outlines of College buildings and the Episcopal church, and notes the burying ground, and the roads to Charlestown, Menotomy, the pond, Watertown, and the bridge. The original handwritten text is faded and was annotated with additional text by Davis including the note "[taken in my Senior year at H. College Septr 1780] Surveyed in concert with classmates, Atkins, Hall 1st, Howard, Payne, &c.- J. Davis." There is a note that "Atkins afterwards took the name of Tying." Davis refers to Dudley Atkins Tyng, Joseph Hall, Bezaleel Howard, and Elijah Paine, all members of the Harvard Class of 1781.

Justice of the peace day book, 1797-1816

Contains records of summons and judgements in various court cases, and fines paid.

Correspondence with Judge George Thatcher, 1789-1815

Correspondence from Tyng, who resided in Newburyport and Boston, to Congressman George Thacher of Maine, touching on a variety of political topics such as the judiciary act of 1789, the make-up of the United States Supreme Court, and the judges of the Massachusetts court system.

Mr. Vaughan's case, March 2, 1724

Opinion (or brief or judgement?) delivered in a case involving a claim by the Colony of New Hampshire to a proprietory right in a ferry running between Portsmouth and Kittery (then in Massachusetts) on the Piscataqua River. The ferry was started in 1684 by John Woodman and conveyed by franchise to Colonel Vaughan by Governor Dudley in 1708. Vaughan died in 1724 and the patent passed to his estate. The town of Portsmouth laid claim to the ferry. Read concluded that this action was not well founded since the ferry is not being operated by possession but by franchise and that, furthermore, New Hampshire does not have complete power over the ferry because Massachusetts has power of franchise on the Kittery end of its route.

A proof of Jesus Christ's being the ancient promised Messiah: a sermon preached in the Chapel of Harvard College at Cambridge in New England, June 23, 1756

The hand-sewn notebook contains a 24-page manuscript draft of the second Dudleian lecture, delivered by John Barnard on June 23, 1756. The copy includes a small number of edits and struck-out words adopted in the printed version published by J. Draper of Boston in 1756. The sermon begins with the Biblical text Mark 14:61, 62. The covers are no longer with the item.

Popery a complex falsehood: or an attempt to clear and evidence, that it is so, in a lecture had at Harvard College in Cambridge, New England, on May 10th, 1769

The hand-sewn notebook contains a 30-page manuscript draft of the Dudleian lecture delivered by Samuel Mather on May 10, 1769 at Harvard College. The sermon begins with the Biblical text 2 Thess. 11:11, 12. The copy includes a small number of edits and struck-out words. The item has unattached pages and is in fragile condition. The lecture was never published.

Sermon at the annual Dudleian lecture at Harvard College in Cambridge, May 14th, 1760

The hand-sewn notebook contains a 41-page manuscript draft of the Dudleian lecture delivered by Samuel Wigglesworth on May 14, 1760 at Harvard College. The sermon begins with the Biblical text I Cor. 1:21. The copy includes a small number of edits and struck-out words. The covers are no longer with the item.

Mr. Abbot's sermon at the Dudleian lecture at Harvard College in Cambridge August 29, 1764 pm: being the third in course on the important subject of Reveal'd-religion

The hand-sewn notebook contains a 27-page manuscript draft of the Dudleian lecture delivered by Hull Abbot on August 29, 1764 at Harvard College on the topic of revealed religion. The sermon begins with the Biblical text Zech. 4:6 and Rom. 10:18. The copy includes a small number of edits and struck-out words. The lecture was not printed.