The promise of oligonucleotide therapeutic agents to perturb expression of disease-related genes remains unrealized, in part due to challenges with functional cellular delivery of these agents. Herein, we describe disulfide-constrained cyclic amphipathic peptides that complex with short-interfering RNA (siRNA) and affect functional cytosolic delivery and knockdown of target gene products in cell culture and in vivo to mouse lung. Reduction of the constraining disulfide bond and subsequent proteolytic clearance of the peptide are key design features that allow unmasking of the siRNA cargo and presentation to the RNA interference machinery.

Holocene relative sea-level (RSL) change is investigated at Nyland Hill (Somerset Levels). The lithostratigraphy comprises turfa peat underlying marine clay, both onlapping a sloping Upper Palaeozoic basement. The altitude of the peat-clay contact ranges from 2.42 to 4.52 m OD, becoming lower down basement slope, yet 14C dates of three samples taken laterally along the contact at different altitudes yield similar ages (3640-3330, 3715-3460, 3725-3465 cal. yrs BP), suggesting either very rapid (‘instantaneous’) RSL rise or sediment compaction. Biostratigraphic data indicate a gradual transition to marine conditions across the peat-clay contact. Therefore, the height difference is interpreted as evidence for significant compaction. We consider 4.64 m OD the minimum pre-compaction altitude, indicating maximum observed compaction of 2.22 m. The clay surface, reclaimed during Roman occupation, represents an anthropogenically induced negative tendency and is dated chemostratigraphically to 1776 ± 46, using a datum related to the onset of local Roman lead mining AD 43-49. Sedimentation rates of the marine clay are established: 1.58-1.92 mm yr-1 and 0.8-0.96 mm yr-1 at sites of maximum and less severe compaction respectively. RSL continued to rise throughout the deposition of the clay unit at a rate of 0.41-0.82 mm yr-1, a view that disagrees with previous models that imply stabilised RSL by 3000 BP. These earlier studies underestimate compaction with implications for subsequent studies employing these sea-level data, particularly in crustal studies where the apparent trend of subsidence is overestimated/increased.

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