Toward antibody-directed "abzyme" prodrug therapy, ADAPT: carbamate prodrug activation by a catalytic antibody and its in vitro application to human tumor cell killing.

Antibody-directed enzyme prodrug therapy, ADEPT, is a recent approach to targeted cancer chemotherapy intended to diminish the nonspecific toxicity associated with many commonly used chemotherapeutic agents. Most ADEPT systems incorporate a bacterial enzyme, and thus their potential is reduced because of the immunogenicity of that component of the conjugate. This limitation can be circumvented by the use of a catalytic antibody, which can be "humanized," in place of the bacterial enzyme catalyst. We have explored the scope of such antibody-directed "abzyme" prodrug therapy, ADAPT, to evaluate the potential for a repeatable targeted cancer chemotherapy. We report the production of a catalytic antibody that can hydrolyze the carbamate prodrug 4-[N,N-bis(2-chloroethyl)]aminophenyl-N-[(1S)-(1,3- dicarboxy)propyl]carbamate (1) to generate the corresponding cytotoxic nitrogen mustard (Km = 201 microM, kcat = 1.88 min-1). In vitro studies with this abzyme, EA11-D7, and prodrug 1 lead to a marked reduction in viability of cultured human colonic carcinoma (LoVo) cells relative to appropriate controls. In addition, we have found a good correlation between antibody catalysis as determined by this cytotoxicity assay in vitro and competitive binding studies of candidate abzymes to the truncated transition-state analogue ethyl 4-nitrophenylmethylphosphonate. This cell-kill assay heralds a general approach to direct and rapid screening of antibody libraries for catalysts.

[Admittatur of John Alden], 1812 September 23

Published copy of the 1814 College Laws with the admittatur of undergraduate Isaac Boyle lacking a president's signature.

John Winthrop's proposal respecting electrical globes and jars, ca. 1758

In this proposal, John Winthrop explains the need to replace damaged "electric globes" used in the College's collection of scientific apparatus. He states that Benjamin Franklin, at the time residing in London, was willing to seek replacement globes for the College's collection. Winthrop then proceeds to assert that the College should acquire "square bottles, of a moderate size, fitted in a wooden box, like what they call case bottles for spirits" instead of the large jars included in the scientific apparatus, because those jars cracked frequently.

Student notebook of Samuel Dunbar, 1721-1722

This leather-bound volume contains substantial transcriptions copied by Samuel Dunbar from textbooks while he was a student at Harvard in 1721 and 1722. There is a general index to texts at the end of the volume. Dunbar's notebook provides a window into the state of higher education in the eighteenth century and offers a firsthand account of academic life at Harvard College. Notably, he often indicated the number of days spent copying texts into his book.

The Malleable Politics of Welfare-to-Work Reform: Germany's "Hartz" activation compared with Dutch, British and Irish cases. ACES Cases No. 2009.1

We compare the Hartz reforms in Germany with three other major labor market activation reforms carried out by center-left governments. Britain and Germany developed radically neoliberal “mandatory” activation policies, whereas in the Netherlands and Ireland radical activation change took a very different “enabling” form. The Irish and German cases were path deviant, the British and Dutch path dependent. We explain why Germany underwent “mandatory” and path deviant activation by focusing on two features of the policy discourse. First, the elite level discourse was “ensilaged” sealing policy formation off from dissenting actors. This is what the British and German cases had in common and the result was reform that identified long term unemployment as social delinquency rather than market failure. Second, although the German policy-making system lacked the “authoritative” features that facilitated reform in the British case, and the Irish policy-making system lacked the “reflexive” mechanisms that facilitated reform in the Dutch case, in both Germany and Ireland the wider legitimating discourses were reshaped by novel institutional vehicles (the Hartz Commission and FÁS) that served to fundamentally alter system-constitutive perceptions about policy. The findings suggest that major reform of welfare-to-work policy may be much more malleable than previously thought.

Pliocene-Pleistocene stack of globally distributed benthic stable oxygen isotope records

We present a 5.3-Myr stack (the ''LR04'' stack) of benthic d18O records from 57 globally distributed sites aligned by an automated graphic correlation algorithm. This is the first benthic delta18O stack composed of more than three records to extend beyond 850 ka, and we use its improved signal quality to identify 24 new marine isotope stages in the early Pliocene. We also present a new LR04 age model for the Pliocene-Pleistocene derived from tuning the delta18O stack to a simple ice model based on 21 June insolation at 65 N. Stacked sedimentation rates provide additional age model constraints to prevent overtuning. Despite a conservative tuning strategy, the LR04 benthic stack exhibits significant coherency with insolation in the obliquity band throughout the entire 5.3 Myr and in the precession band for more than half of the record. The LR04 stack contains significantly more variance in benthic delta18O than previously published stacks of the late Pleistocene as the result of higher resolution records, a better alignment technique, and a greater percentage of records from the Atlantic. Finally, the relative phases of the stack's 41- and 23-kyr components suggest that the precession component of delta18O from 2.7-1.6 Ma is primarily a deep-water temperature signal and that the phase of d18O precession response changed suddenly at 1.6 Ma.