Loss of Apc heterozygosity and abnormal tissue building in nascent intestinal polyps in mice carrying a truncated Apc gene.

Mutations in the APC (adenomatous polyposis coli) gene appear to be responsible for not only familial adenomatous polyposis but also many sporadic cases of gastrointestinal cancers. Using homologous recombination in mouse embryonic stem cells, we constructed mice that contained a mutant gene encoding a product truncated at a 716 (Apc delta 716). Mendelian transmission of the gene caused most homozygous mice to die in utero before day 8 of gestation. The heterozygotes developed multiple polyps throughout the intestinal tract, mostly in the small intestine. The earliest polyps arose multifocally during the third week after birth, and new polyps continued to appear thereafter. Surprisingly, every nascent polyp consisted of a microadenoma covered with a layer of the normal villous epithelium. These microadenomas originated from single crypts by forming abnormal outpockets into the inner (lacteal) side of the neighboring villi. We carefully dissected such microadenomas from nascent polyps by peeling off the normal epithelium and determined their genotype by PCR: all microadenomas had already lost the wild-type Apc allele, whereas the mutant allele remained unchanged. These results indicate that loss of heterozygosity followed by formation of intravillous microadenomas is responsible for polyposis in Apc delta 716 intestinal mucosa. It is therefore unlikely that the truncated product interacts directly with the wild-type protein and causes the microadenomas by a dominant negative mechanism.

Abnormal junctions between surface membrane and sarcoplasmic reticulum in skeletal muscle with a mutation targeted to the ryanodine receptor.

Junctions that mediate excitation-contraction (e-c) coupling are formed between the sarcoplasmic reticulum (SR) and either the surface membrane or the transverse (T) tubules in normal skeletal muscle. Two structural components of the junctions, the feet of the SR and the tetrads of T tubules, have been identified respectively as ryanodine receptors (RyRs, or SR calcium-release channels), and as groups of four dihydropyridine receptors (DHPRs, or voltage sensors of e-c coupling). A targeted mutation (skrrm1) of the gene for skeletal muscle RyRs in mice results in the absence of e-c coupling in homozygous offspring of transgenic parents. The mutant gene is expected to produce no functional RyRs, and we have named the mutant mice "dyspedic" because they lack feet--the cytoplasmic domain of RyRs anchored in the SR membrane. We have examined the development of junctions in skeletal muscle fibers from normal and dyspedic embryos. Surprisingly, despite the absence of RyRs, junctions are formed in dyspedic myotubes, but the junctional gap between the SR and T tubule is narrow, presumably because the feet are missing. Tetrads are also absent from these junctions. The results confirm the identity of RyRs and feet and a major role for RyRs and tetrads in e-c coupling. Since junctions form in the absence of feet and tetrads, coupling of SR to surface membrane and T tubules appears to be mediated by additional proteins, distinct from either RyRs or DHPRs.

A Return to Little Things: Stories on Motherhood and Mistakes

A Return to Little Things includes three nonfiction pieces that revolve around the mistakes made by mothers and daughters. The collection investigates the idea that our lives are a sum total of the choices we have made. The essays directly address three specific situations that touch on the themes of motherhood, choices, and the human inclination to recall them with bitterness, and offer proof that time often allows us to move forward to forgiveness. Using humor and acceptance, the narrator is led through a labyrinth of emotions to come to peace with these choices. The stories serve as reminders that there are no mistakes, only lessons, and we must seek to understand them to live happy lives. This manuscript is a work in progress.

The Impact of BIM on the Distribution of Cost and Return on Investment in UK Construction Projects

It has been widely documented that when Building Information Modelling (BIM) is used, there is a shift in effort to the design phase. Little investigation into the impact of this shift in effort has been done and how it impacts on costs. It can be difficult to justify the increased expenditure on BIM in a market that is heavily driven by costs. There are currently studies attempting to quantify the return on investment (ROI) for BIM for which these returns can be seen to balance out the shift in efforts and costs to the design phase. The studies however quantify the ROI based on the individual stakeholder’s investment without consideration for the impact that the use of BIM from their project partners may have on their own profitability. In this study, a questionnaire investigated opinions and experience of construction professionals, representing clients, consultants, designers and contractors, to determine fluctuations in costs by their magnitude and when they occur. These factors were examined more closely by interviewing senior members representing each of the stakeholder categories and comparing their experience in using BIM within environments where their project partners were also using BIM and when they were not. This determined the differences in how the use and the investment in BIM impacts on others and how costs are redistributed. This redistribution is not just through time but also between stakeholders and categories of costs. Some of these cost fluctuations and how the cost of BIM is currently financed are also highlighted in several case studies. The results show that the current distribution of costs set for traditional 2D delivery is hindering the potential success of BIM. There is also evidence that stakeholders who don’t use BIM may benefit financially from the BIM use of others and that collaborative BIM is significantly different to the use of ‘lonely’ BIM in terms of benefits and profitability.

"A list of books borrowed from the former Library & not yet return'd," ca. 1764

Lists books borrowed by many individuals, including Governor William Shirley, Colonel Brinley, General Brattle, Secretary Willard, Judge Danforth, Colonel Wendell, Thomas Oliver, Christ Bridge Marsh, and Francis Foxcroft. Entries include the author and title of the borrowed volumes.

Copy of the return of the writ of partition relating to the lands of Peter Weare & others of Casco Bay : manuscript, [1730]

Document concerns how certain lands around Casco Bay, York Co., Maine, were partitioned in accordance with an order of a writ.

Boston, Massachusetts Region LIDAR First Return Elevation Data, 2002

LIDAR (LIght Detection And Ranging) first return elevation data of the Boston, Massachusetts region from MassGIS at 1-meter resolution. This LIDAR data was captured in Spring 2002. LIDAR first return data (which shows the highest ground features, e.g. tree canopy, buildings etc.) can be used to produce a digital terrain model of the Earth's surface. This dataset consists of 74 First Return DEM tiles. The tiles are 4km by 4km areas corresponding with the MassGIS orthoimage index. This data set was collected using 3Di's Digital Airborne Topographic Imaging System II (DATIS II). The area of coverage corresponds to the following MassGIS orthophoto quads covering the Boston region (MassGIS orthophoto quad ID: 229890, 229894, 229898, 229902, 233886, 233890, 233894, 233898, 233902, 233906, 233910, 237890, 237894, 237898, 237902, 237906, 237910, 241890, 241894, 241898, 241902, 245898, 245902). The geographic extent of this dataset is the same as that of the MassGIS dataset: Boston, Massachusetts Region 1:5,000 Color Ortho Imagery (1/2-meter Resolution), 2001 and was used to produce the MassGIS dataset: Boston, Massachusetts, 2-Dimensional Building Footprints with Roof Height Data (from LIDAR data), 2002 [see cross references].