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.

Magnetic susceptibility (MS) measurements on the Sancerre (France) drill-core

The Toarcian Oceanic Anoxic Event (T-OAE) of the early Jurassic period involves one of the largest perturbations of the carbon cycle in the past 250 Ma, recorded by a pronounced negative carbon-isotope excursion (CIE). Numerous studies have focused on potential causes of the T-OAE and CIE, but are hampered by an uncertain timescale. Here we present high-resolution (~2 kyr) magnetic susceptibility (MS) measurements from the marine marls of the Sancerre-Couy drill-core, southern Paris Basin, spanning the entire Toarcian Stage. The MS variations document a rich series of sub-Milankovitch to Milankovitch frequencies (precession, obliquity and eccentricity) with the periodic g2-g5 (405 kyr) and quasi-periodic g4-g3 (~2.4 Myr Cenozoic mean periodicity) eccentricity terms being the most prominent. The MS-related g4-g3 variation reflects third-order eustatic sequences, and constrains the sequence stratigraphic framework of the Toarcian Stage. In addition, MS variations reveal a modulation of g2-g5 by g4-g3 eccentricity related cycles, suggesting that sea-level change was the main control on the deposition of the Toarcian Sancerre marls, in tune with the astro-climatic frequencies. The stable 405 kyr cyclicity constrains a minimum duration of the Toarcian Stage to ~8.3 Myr, and the well documented CIE, associated with the T-OAE, to ~300 to 500 kyr. The 405 kyr MS timescale calibrates the periodicity of the prominent high-frequency d13C cycles that occur in the decreasing part of the CIE to 30 to 34 kyr, consistent with the Toarcian obliquity period predicted for an Earth experiencing sustained tidal dissipation.

Nouveau Dictionnaire Historique, ou Histoire Abrégée de tous les hommes ... : avec des tables chronologiques pour réduire en corps d'Histoire ... /

Mode of access: Internet.

Histoire du Regne de Philippe II, Roi d'Espagne /

Mode of access: Internet.

Istoria del cardinale Ximenes /

Mode of access: Internet.

Timber management plan, Chequamegon National Forest : final environmental statement.

"USDA-FS-R9-FES-Adm-77-01"--P. i.

Timber resource plan : final environmental statement, Hiawatha National Forest.

"USDA-FS-R9-FES-ADM-77-08"--P. 2 of cover.

Timber management plan, Ottawa National Forest : final environmental statement.

"USDA-FS-R9-FES-ADM-76-03"--P. i.

Popular astronomy.

"A review of astronomy and allied sciences."

Within the temple of Isis.

Mode of access: Internet.

The Astrophysical journal

Mode of access: Internet.

Ariadne florentina.

Photocopy. Charlottesville, VA :

Ottawa North and Alligator Eye : two Late Archaic sites on the Ottawa National Forest /

"Document reference number R9-ONF-CRM-002-94"--Cover.

The elements of perspective,

Mode of access: Internet.

Troops marching through the Diagonal

On verso: ASTRO; Co. B-4