The design, synthesis, and evaluation of molecules that enable or enhance cellular uptake: Peptoid molecular transporters

Certain proteins contain subunits that enable their active translocation across the plasma membrane into cells. In the specific case of HIV-1, this subunit is the basic domain Tat49–57 (RKKRRQRRR). To establish the optimal structural requirements for this translocation process, and thereby to develop improved molecular transporters that could deliver agents into cells, a series of analogues of Tat49–57 were prepared and their cellular uptake into Jurkat cells was determined by flow cytometry. All truncated and alanine-substituted analogues exhibited diminished cellular uptake, suggesting that the cationic residues of Tat49–57 play a principal role in its uptake. Charge alone, however, is insufficient for transport as oligomers of several cationic amino acids (histidine, lysine, and ornithine) are less effective than Tat49–57 in cellular uptake. In contrast, a 9-mer of l-arginine (R9) was 20-fold more efficient than Tat49–57 at cellular uptake as determined by Michaelis–Menton kinetic analysis. The d-arginine oligomer (r9) exhibited an even greater uptake rate enhancement (>100-fold). Collectively, these studies suggest that the guanidinium groups of Tat49–57 play a greater role in facilitating cellular uptake than either charge or backbone structure. Based on this analysis, we designed and synthesized a class of polyguanidine peptoid derivatives. Remarkably, the subset of peptoid analogues containing a six-methylene spacer between the guanidine head group and backbone (N-hxg), exhibited significantly enhanced cellular uptake compared to Tat49–57 and even to r9. Overall, a transporter has been developed that is superior to Tat49–57, protease resistent, and more readily and economically prepared.

Ficción y realidad en "Les Bienveillantes" de Jonathan Littell

En el presente trabajo se analiza "Les Bienveillantes", novela que ficciona las memorias atormentadas de un nazi. A través de su lectura se viaja a los infiernos del holocausto, de la guerra y de una conciencia sin anclajes éticos ni estéticos, narrados por una mente perversa que apenas se conmueve ante las atrocidades más profundas. Tras contrastar a lo largo de su trama ficción y realidad, se destaca, a la luz de los debates sobre la reescritura de la Historia, la operatividad de esta novela para captar y transmitir la verdad de lo ocurrido favoreciendo de ese modo el desarrollo de una conciencia responsable y la no repetición de los hechos.

Dissolution of partnership with Charles Turner, 1808

This folder contains two handwritten documents, dated January 27, 1808, and April 22, 1808, related to the dissolution of the partnership between William Croswell and Charles Turner.

Letter from E. Carter to William Croswell, [1808]

One-page letter regarding payment.