Low- and high-level transgenic expression of β2-adrenergic receptors differentially affect cardiac hypertrophy and function in Gαq-overexpressing mice

Transgenic overexpression of Gαq in the heart triggers events leading to a phenotype of eccentric hypertrophy, depressed ventricular function, marked expression of hypertrophy-associated genes, and depressed β-adrenergic receptor (βAR) function. The role of βAR dysfunction in the development of this failure phenotype was delineated by transgenic coexpression of the carboxyl terminus of the βAR kinase (βARK), which acts to inhibit the kinase, or concomitant overexpression of the β2AR at low (≈30-fold, Gαq/β2ARL), moderate (≈140-fold, Gαq/β2ARM), and high (≈1,000-fold, Gαq/β2ARH) levels above background βAR density. Expression of the βARK inhibitor had no effect on the phenotype, consistent with the lack of increased βARK levels in Gαq mice. In marked contrast, Gαq/β2ARL mice displayed rescue of hypertrophy and resting ventricular function and decreased cardiac expression of atrial natriuretic factor and α-skeletal actin mRNA. These effects occurred in the absence of any improvement in basal or agonist-stimulated adenylyl cyclase (AC) activities in crude cardiac membranes, although restoration of a compartmentalized β2AR/AC signal cannot be excluded. Higher expression of receptors in Gαq/β2ARM mice resulted in salvage of AC activity, but hypertrophy, ventricular function, and expression of fetal genes were unaffected or worsened. With ≈1,000-fold overexpression, the majority of Gαq/β2ARH mice died with cardiomegaly at 5 weeks. Thus, although it appears that excessive, uncontrolled, or generalized augmentation of βAR signaling is deleterious in heart failure, selective enhancement by overexpressing the β2AR subtype to limited levels restores not only ventricular function but also reverses cardiac hypertrophy.

Fidelity of G protein β-subunit association by the G protein γ-subunit-like domains of RGS6, RGS7, and RGS11

Several regulators of G protein signaling (RGS) proteins contain a G protein γ-subunit-like (GGL) domain, which, as we have shown, binds to Gβ5 subunits. Here, we extend our original findings by describing another GGL-domain-containing RGS, human RGS6. When RGS6 is coexpressed with different Gβ subunits, only RGS6 and Gβ5 interact. The expression of mRNA for RGS6 and Gβ5 in human tissues overlaps. Predictions of α-helical and coiled-coil character within GGL domains, coupled with measurements of Gβ binding by GGL domain mutants, support the contention that Gγ-like regions within RGS proteins interact with Gβ5 subunits in a fashion comparable to conventional Gβ/Gγ pairings. Mutation of the highly conserved Phe-61 residue of Gγ2 to tryptophan, the residue present in all GGL domains, increases the stability of the Gβ5/Gγ2 heterodimer, highlighting the importance of this residue to GGL/Gβ5 association.

Structure-based design of selective and potent G quadruplex-mediated telomerase inhibitors

The telomerase enzyme is a potential therapeutic target in many human cancers. A series of potent inhibitors has been designed by computer modeling, which exploit the unique structural features of quadruplex DNA. These 3,6,9-trisubstituted acridine inhibitors are predicted to interact selectively with the human DNA quadruplex structure, as a means of specifically inhibiting the action of human telomerase in extending the length of single-stranded telomeric DNA. The anilino substituent at the 9-position of the acridine chromophore is predicted to lie in a third groove of the quadruplex. Calculated relative binding energies predict enhanced selectivity compared with earlier 3,6-disubstituted compounds, as a result of this substituent. The ranking order of energies is in accord with equilibrium binding constants for quadruplex measured by surface plasmon resonance techniques, which also show reduced duplex binding compared with the disubstituted compounds. The 3,6,9-trisubstututed acridines have potent in vitro inhibitory activity against human telomerase, with EC50 values of up to 60 nM.

Payment order for Theodore Dehon, 1794 September 26

Handwritten order to John Sale to pay scholarship funds to Theodore Dehon for use by his son Theodore Dehon (Harvard AB 1795), signed by John Clarke, David Tilden, and James Morrill.

1794, Triennial catalogues annotated by William Winthrop, 1794-1812.

Leather and marbled hardcover binding. Substantially annotated. The volume consists of pages from the published catalogues pasted into a blank volume. The bulk of the volume is comprised of the printed list of graduate names found in the Triennial Catalogue accompanied by handwritten biographical information, usually a sentence in length. It begins with a handwritten section titled "Settled Ministers (in the first Parish in Cambridge)." The entries generally contain a residence, date of death (abbreviated ob), age of death (abbreviated ae), and professional information. While the 1794 Catalogue comprises the majority of the volume, names were added from Triennial Catalogues through the 1812 edition. An example of an entry, for John Hancock (Harvard AB 1754), reads “Rep. for Boston, Maj. Gen. Militia. Ob. Octo. 8. 1793 AE 57 Son of Rev. John of Brantree [sic]." A March 27, 1798 letter to Judge Richard Cranch (1726-1818) from Jeremy Belknap (1744-1798, Harvard AB 1762) pasted into the back of the volume. Written only two months before his death, Belknap describes his plan to "go thro’ the whole Catalogue of the graduates of Harvard College, & relate all that’s proper to be related." Four leaves of biographical notes for the classes of 1642-1686 towards the beginning of the volume are in a different hand with the note "Rev Dr. Holmes's handwriting."

The standard natural history / ed. by John Sterling Kingsley.

Reptilia (1885)

Harvard College Lottery Book, 1794-1797

The long hardcover account book contains handwritten records of the Harvard College Lottery in the hand of College Treasurer Ebenezer Storer. The volume begins with a transcription of the Massachusetts General Court June 13, 1794 legislation sanctioning the lottery, and a note that the managers of the lottery gave security bonds to the Corporation. The bulk of the volume records the activities of the four classes of the lottery including lists of the individual tickets returned by the managers Benjamin Austin Jr., George R. Minot, Henry Warren, and John Kneeland, and the accounts of prizes drawn and tickets returned. The volume has a table of contents and there is a note pasted onto the third page calculating the sum raised if all tickets had been sold.

Letter from John Russell to William Tudor,

One letter briefly describing Russell’s studies at the home of Rev. Dr. McClintock in Greenland, N.H., where he was staying during a nine-month suspension from Harvard for theft of college property. Tudor, who was also found to be involved, was suspended for six months. Russell also inquires about fellow classmates, some of whom participated in the theft.

Notebook of Moses Appleton, 1794-1837 (inclusive)

Contains notes taken by Moses Appleton (1773-1849) on anatomy lectures delivered at Harvard by John Warren (1753-1815). Other lecture topics included midwifery and surgery. Also includes a transcript of an examination given by Warren to his students on anatomy and surgery, as well as exams given by Harvard Professor Benjamin Waterhouse (1754-1846) and Harvard Professor Aaron Dexter (1750-1829) on the theory and practice of physic, and chemistry, respectively. There are additionally patient case notes and transcriptions of notes and correspondence from physicians Appleton consulted, and a list of operations Appleton performed between 1796 and 1828, primarily repairing dislocated joints and fractured bones. Also includes obituaries of citizens of Waterville, Maine, from 1807 to 1837.

Lenox, Massachusetts, 1854 (Raster Image)

This layer is a georeferenced raster image of the historic paper map entitled: Map of the town of Lenox : Berkshire Co. Massachusetts, surveyed and drawn by E.M. Woodford ; E. Herrlein's lith. It was published by Richard Clark in 1854. Scale [ca. 1:20,000]. The image inside the map neatline is georeferenced to the surface of the earth and fit to the Massachusetts State Plane Coordinate System, Mainland Zone (in Feet) (Fipszone 2001). All map collar and inset information is also available as part of the raster image, including any inset maps, profiles, statistical tables, directories, text, illustrations, index maps, legends, or other information associated with the principal map. This map shows features such as roads, railroads and stations, drainage, public buildings, schools, churches, cemeteries, industry locations (e.g. mills, factories, mines, etc.), private buildings with names of property owners, town district boundaries, and more. Relief shown by hachures. Includes also illustrations and insets: [Cemetery & surrounding residencies] -- Lenox Furnace.This layer is part of a selection of digitally scanned and georeferenced historic maps of Massachusetts from the Harvard Map Collection. These maps typically portray both natural and manmade features. The selection represents a range of regions, originators, ground condition dates (1755-1922), scales, and purposes. The digitized selection includes maps of: the state, Massachusetts counties, town surveys, coastal features, real property, parks, cemeteries, railroads, roads, public works projects, etc.