Association of terminal deoxynucleotidyl transferase with Ku

Terminal deoxynucleotidyl transferase (TdT) catalyzes the addition of nucleotides at the junctions of rearranging Ig and T cell receptor gene segments, thereby generating antigen receptor diversity. Ku is a heterodimeric protein composed of 70- and 86-kDa subunits that binds DNA ends and is required for V(D)J recombination and DNA double-strand break (DSB) repair. We provide evidence for a direct interaction between TdT and Ku proteins. Studies with a baculovirus expression system show that TdT can interact specifically with each of the Ku subunits and with the heterodimer. The interaction between Ku and TdT is also observed in pre-T cells with endogenously expressed proteins. The protein–protein interaction is DNA independent and occurs at physiological salt concentrations. Deletion mutagenesis experiments reveal that the N-terminal region of TdT (131 amino acids) is essential for interaction with the Ku heterodimer. This region, although not important for TdT polymerization activity, contains a BRCA1 C-terminal domain that has been shown to mediate interactions of proteins involved in DNA repair. The induction of DSBs in Cos-7 cells transfected with a human TdT expression construct resulted in the appearance of discrete nuclear foci in which TdT and Ku colocalize. The physical association of TdT with Ku suggests a possible mechanism by which TdT is recruited to the sites of DSBs such as V(D)J recombination intermediates.

Localization of non-Mhc collagen-induced arthritis susceptibility loci in DBA/1j mice

One approach to understanding common human diseases is to determine the genetic defects responsible for similar diseases in animal models and place those defective genes in their corresponding biochemical pathways. Our laboratory is working with an animal model for human rheumatoid arthritis called collagen-induced arthritis (CIA). We are particularly interested in determining the location of disease-predisposing loci. To that end, we performed experiments to localize susceptibility loci for CIA in an F2 cross between the highly susceptible mouse strain DBA/1j and the highly resistant mouse strain SWR/j. Specifically, a quantitative trait locus analysis was performed to localize regions of the mouse genome responsible for susceptibility/severity to CIA. One susceptibility locus, Cia1 in the major histocompatibility locus, had been identified previously. Two additional loci were detected in our analysis that contribute to CIA severity (Cia2, Cia3) on chromosomes 2 and 6. A third locus was detected that contributes to the age of onset of the disease. This locus (Cia4) was located on chromosome 2 and was linked to the same region as Cia2. Determining the identity of these loci may provide insights into the etiology of human rheumatoid arthritis.

Myocyte-enriched calcineurin-interacting protein, MCIP1, inhibits cardiac hypertrophy in vivo

Signaling events controlled by calcineurin promote cardiac hypertrophy, but the degree to which such pathways are required to transduce the effects of various hypertrophic stimuli remains uncertain. In particular, the administration of immunosuppressive drugs that inhibit calcineurin has inconsistent effects in blocking cardiac hypertrophy in various animal models. As an alternative approach to inhibiting calcineurin in the hearts of intact animals, transgenic mice were engineered to overexpress a human cDNA encoding the calcineurin-binding protein, myocyte-enriched calcineurin-interacting protein-1 (hMCIP1) under control of the cardiac-specific, α-myosin heavy chain promoter (α-MHC). In unstressed mice, forced expression of hMCIP1 resulted in a 5–10% decline in cardiac mass relative to wild-type littermates, but otherwise produced no apparent structural or functional abnormalities. However, cardiac-specific expression of hMCIP1 inhibited cardiac hypertrophy, reinduction of fetal gene expression, and progression to dilated cardiomyopathy that otherwise result from expression of a constitutively active form of calcineurin. Expression of the hMCIP1 transgene also inhibited hypertrophic responses to β-adrenergic receptor stimulation or exercise training. These results demonstrate that levels of hMCIP1 producing no apparent deleterious effects in cells of the normal heart are sufficient to inhibit several forms of cardiac hypertrophy, and suggest an important role for calcineurin signaling in diverse forms of cardiac hypertrophy. The future development of measures to increase expression or activity of MCIP proteins selectively within the heart may have clinical value for prevention of heart failure.

The nuclear receptor PXR is a lithocholic acid sensor that protects against liver toxicity

The pregnane X receptor (PXR) is the molecular target for catatoxic steroids such as pregnenolone 16α-carbonitrile (PCN), which induce cytochrome P450 3A (CYP3A) expression and protect the body from harmful chemicals. In this study, we demonstrate that PXR is activated by the toxic bile acid lithocholic acid (LCA) and its 3-keto metabolite. Furthermore, we show that PXR regulates the expression of genes involved in the biosynthesis, transport, and metabolism of bile acids including cholesterol 7α-hydroxylase (Cyp7a1) and the Na+-independent organic anion transporter 2 (Oatp2). Finally, we demonstrate that activation of PXR protects against severe liver damage induced by LCA. Based on these data, we propose that PXR serves as a physiological sensor of LCA, and coordinately regulates gene expression to reduce the concentrations of this toxic bile acid. These findings suggest that PXR agonists may prove useful in the treatment of human cholestatic liver disease.

Comparison of Couples' Normal Life Cycle Development and Intimacy Distance Regulation

When conceptualizing healthy couple relationships, it is tempting to use a simple framework as a panacea. Unfortunately, this desire for simplicity can lead to a narrow and naive perspective. Individuals interact and are influenced by a variety of factors (i.e., various social systems, multiple context memberships, complex interconnecting exchanges, etc.); consequently, it is necessary to guard against an overly narrow interpretation when examining healthy couple interactions. It is the purpose of this paper to develop one aspect of a complex perspective for healthy couple relationships by comparing couple life cycle development with couple intimacy-distance regulation.

1794, Catalogus eorum qui in Universitate Harvardiana, Cantabrigiae, in republica Massachusettensi, ab anno MDCXLII, ad annum MDCCXCIV. Alicujus gradû laureâ donati sunt.

Modern hardcover binding around original handsewn paper binding. Missing title page and first page of text. Key to abbreviations titled "Explination" on flyleaf with abbreviations for Massachusetts, New Hampshire, Connecticut, Rhode Island, Long Island, New York, Martha's Vineyard, New Jersey, Pensylvania [sic], Virginia, South Carolina, Georgia, West Indies, Great Britain, Episcopalian, and Baptist. Heavily annotated with residence locations. Asterisks added next to the names of alumni who died after the Catalogue's publication, generally in 1795. Also includes a tipped-in page at front of volume with the names of thirteen alumni of various classes from 1650 through 1756, in one hand, a note "Joseph Lovett was of Beverly, and a minister in a town of Connecticut the name of which I do not recollect. JW" in a different hand, and a final note "I believe there was a Lovett at Norwich" in the original hand.

Alphabetical catalog of Harvard College graduates through 1767, 1767

This hard-bound manuscript catalog alphabetically lists the men who graduated from Harvard College between 1642 and 1767. It is believed to be the first such list compiled. Entries contain each graduate's surname (in English), given name (in Latin), year of graduation, and occasional additional information. Francis Foxcroft (A.B. 1712) compiled the catalog. Entries for those who graduated between 1764 and 1767 have been added at the end of each alphabetical section.

Salutatory address of Abiel Abbot, 1792

Six-unlined pages containing a handwritten copy of the salutatory address composed by Abiel Abbot in Latin for the 1792 Harvard College Commencement. The text includes edits and struck-through words. The first page includes the title "Autore Abiele Abbot" and has a penciled note: "This must be gr. grandfather's Latin oration when he graduated from Harvard, with honors, in 1792."

Coastal Massachusetts, Marblehead to Hampton Harbor, New Hampshire, Nautical Chart, 1776 (Image 1 of 2) (Raster Image)

This layer is a georeferenced raster image of the untitled, historic nautical chart: [A chart of the harbours of Hampton, Newbury, Ipswich, Jebeka, Squam, Cape Ann, Manchester, Beverly, Salem, Marble Head &c.] (sheet originally published in 1776). The map is [sheet 23] from the Atlantic Neptune atlas Vol. 3 : Charts of the coast and harbors of New England, from surveys taken by Samuel Holland and published by J.F.W. Des Barres, 1781. Scale [ca. 1:50,000]. This layer is image 1 of 2 total images of the two sheet source map, representing the southern portion of the map. Covers coastal Massachusetts from Ipswich Harbor to Marblehead. The image is georeferenced to the surface of the earth and fit to the 'World Mercator' (WGS 84) projected coordinate system. All map collar information is also available as part of the raster image, including any inset maps, profiles, statistical tables, directories, text, illustrations, or other information associated with the principal map. This map shows coastal features such as harbors, inlets, rocks, channels, points, coves, shoals, islands, and more. Includes also selected land features such as cities and towns, buildings, and roads. Relief is shown by hachures; depths by soundings. This layer is part of a selection of digitally scanned and georeferenced historic maps from The Harvard Map Collection. The entire Atlantic Neptune atlas Vol. 3 : Charts of the coast and harbors of New England has been scanned and georeferenced as part of this selection.

Coastal Massachusetts, Marblehead to Hampton Harbor, New Hampshire, Nautical Chart, 1776 (Image 2 of 2) (Raster Image)

This layer is a georeferenced raster image of the untitled, historic nautical chart: [A chart of the harbours of Hampton, Newbury, Ipswich, Jebeka, Squam, Cape Ann, Manchester, Beverly, Salem, Marble Head &c.] (sheet originally published in 1776). The map is [sheet 24] from the Atlantic Neptune atlas Vol. 3 : Charts of the coast and harbors of New England, from surveys taken by Samuel Holland and published by J.F.W. Des Barres, 1781. Scale [ca. 1:50,000]. This layer is image 2 of 2 total images of the two sheet source map, representing the northern portion of the map. Covers coastal Massachusetts and New Hampshire from Ipswich Harbor, Massachusetts to Hampton Harbor, New Hampshire. The image is georeferenced to the surface of the earth and fit to the 'World Mercator' (WGS 84) projected coordinate system. All map collar information is also available as part of the raster image, including any inset maps, profiles, statistical tables, directories, text, illustrations, or other information associated with the principal map. This map shows coastal features such as harbors, inlets, rocks, channels, points, coves, shoals, islands, and more. Includes also selected land features such as cities and towns, buildings, and roads. Relief is shown by hachures; depths by soundings. This layer is part of a selection of digitally scanned and georeferenced historic maps from The Harvard Map Collection. The entire Atlantic Neptune atlas Vol. 3 : Charts of the coast and harbors of New England has been scanned and georeferenced as part of this selection.

Essex County, Massachusetts, 1856 (Image 3 of 4) (Raster Image)

This layer is a georeferenced raster image of the historic paper map entitled: A topographical map of Essex County, Massachusetts : based upon the trigonometrical survey of the state the details, from actual surveys under the direction of H.F. Walling, superintendent of state map ; engd. by Geo. Worley & Wm. Bracher. It was published by Smith and Morley in 1856. Scale [ca. 1:50,000]. This layer is image 3 of 4 total images, representing the southwest portion of the four sheet source map.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, drainage, public buildings, schools, churches, cemeteries, industry locations (e.g. mills, factories, mines, etc.), private buildings with names of property owners, town and school district boundaries, and more. Relief shown by hachures. It includes many cadastral insets of individual county towns and villages. It also includes illustrations, business directories, and tables of statistics and distances.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.

Philadelphia, Pennsylvania (East), and vicinity, 1955 (Raster Image) (Image 1 of 2)

This layer is a georeferenced raster image of the United States Geological Survey sheet map set entitled: Philadelphia and vicinity, east, 1955 (and west, 1956) (Pennsylvania - New Jersey) by the Geological Survey. It was published in 1958. Scale 1:24,000. Covers Philadelphia and portions of adjacent counties. Mapped by the Geological Survey, U.S. Coast and Geodetic Survey and Army Map Service. Compiled from 1:24,000 scale maps of Langhorne 1953, Hatboro 1952, Ambler 1952, Germantown 1952, Frankford 1950, Beverly 1955, Moorestown 1953, Camden 1949, Philadelphia 1949, Woodbury 1949, Rennemede 1952, and Clementon 1953 7.5 minute quadrangles. This layer is image 1 of 2 total images of the two sheet source map set representing the eastern portion of the map. The image inside the map neatline is georeferenced to the surface of the earth and fit to the Pennsylvania South State Plane Coordinate System NAD27 (in Feet) (Fipszone 3702). 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. USGS maps are typical topographic maps portraying both natural and manmade features. They show and name works of nature, such as mountains, valleys, lakes, rivers, vegetation, etc. They also identify the principal works of humans, such as roads, railroads, boundaries, transmission lines, major buildings, etc. Relief is shown with standard contour intervals of 10 and 20 feet. Please pay close attention to map collar information on projections, spheroid, sources, dates, and keys to grid numbering and other numbers which appear inside the neatline. This layer is part of a selection of digitally scanned and georeferenced historic maps from The Harvard Map Collection as part of the Imaging the Urban Environment project. Maps selected for this project represent major urban areas and cities of the world, at various time periods. These maps typically portray both natural and manmade features at a large scale. The selection represents a range of regions, originators, ground condition dates, scales, and purposes.

Los Angeles, California (West), and vicinity, 1953 (Raster Image) (Image 2 of 2)

This layer is a georeferenced raster image of the United States Geological Survey sheep map set entitled: Los Angeles and vicinity, East [and West], California. Edition 1953. It was published in 1956. Compiled from 1:24,000 scale maps of the Burbank 1953, Van Nuys 1953, Canoga Park 1952, Topanga 1952, Beverly Hills 1950, Hollywood 1953, Inglewood 1952, and Venice 1950 7.5 minute quadrangles. Hydrography compiled from USC&GS Chart 5144. Scale 1:24,000. This layer is image 2 of 2 total images of the two sheet source map set representing the western portion of the map set. The image inside the map neatline is georeferenced to the surface of the earth and fit to the California State Plane Zone V Coordinate System NAD27 (in Feet) (Fipszone 0405). 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. USGS maps are typical topographic maps portraying both natural and manmade features. They show and name works of nature, such as mountains, valleys, lakes, rivers, vegetation, etc. They also identify the principal works of humans, such as roads, railroads, boundaries, transmission lines, major buildings, etc. Relief is shown with standard contour intervals of 5 and 25 feet. Depth curves in feet. Please pay close attention to map collar information on projections, spheroid, sources, dates, and keys to grid numbering and other numbers which appear inside the neatline. This layer is part of a selection of digitally scanned and georeferenced historic maps from The Harvard Map Collection as part of the Imaging the Urban Environment project. Maps selected for this project represent major urban areas and cities of the world, at various time periods. These maps typically portray both natural and manmade features at a large scale. The selection represents a range of regions, originators, ground condition dates, scales, and purposes.