RNA aptamers specific for transmembrane p24 trafficking protein 6 and Clusterin for the targeted delivery of imaging reagents and RNA therapeutics to human β cells

The ability to detect and target β cells in vivo can substantially refine how diabetes is studied and treated. However, the lack of specific probes still hampers a precise characterization of human β cell mass and the delivery of therapeutics in clinical settings. Here, we report the identification of two RNA aptamers that specifically and selectively recognize mouse and human β cells. The putative targets of the two aptamers are transmembrane p24 trafficking protein 6 (TMED6) and clusterin (CLUS). When given systemically in immune deficient mice, these aptamers recognize the human islet graft producing a fluorescent signal proportional to the number of human islets transplanted. These aptamers cross-react with endogenous mouse β cells and allow monitoring the rejection of mouse islet allografts. Finally, once conjugated to saRNA specific for X-linked inhibitor of apoptosis (XIAP), they can efficiently transfect non-dissociated human islets, prevent early graft loss, and improve the efficacy of human islet transplantation in immunodeficient in mice

Numerical instability of the Akhmediev breather and a finite-gap model of it

In this paper we study the numerical instabilities of the NLS Akhmediev breather, the simplest space periodic, one-mode perturbation of the unstable background, limiting our considerations to the simplest case of one unstable mode. In agreement with recent theoretical findings of the authors, in the situation in which the round-off errors are negligible with respect to the perturbations due to the discrete scheme used in the numerical experiments, the split-step Fourier method (SSFM), the numerical output is well-described by a suitable genus 2 finite-gap solution of NLS. This solution can be written in terms of different elementary functions in different time regions and, ultimately, it shows an exact recurrence of rogue waves described, at each appearance, by the Akhmediev breather. We discover a remarkable empirical formula connecting the recurrence time with the number of time steps used in the SSFM and, via our recent theoretical findings, we establish that the SSFM opens up a vertical unstable gap whose length can be computed with high accuracy, and is proportional to the inverse of the square of the number of time steps used in the SSFM. This neat picture essentially changes when the round-off error is sufficiently large. Indeed experiments in standard double precision show serious instabilities in both the periods and phases of the recurrence. In contrast with it, as predicted by the theory, replacing the exact Akhmediev Cauchy datum by its first harmonic approximation, we only slightly modify the numerical output. Let us also remark, that the first rogue wave appearance is completely stable in all experiments and is in perfect agreement with the Akhmediev formula and with the theoretical prediction in terms of the Cauchy data.Comment: 27 pages, 8 figures, Formula (30) at page 11 was corrected, arXiv admin note: text overlap with arXiv:1707.0565

Aptamers against mouse and human tumor-infiltrating myeloid cells as reagents for targeted chemotherapy

Local delivery of anticancer agents has the potential to maximize treatment efficacy and minimize the acute and long-term systemic toxicities. Here, we used unsupervised systematic evolution of ligands by exponential enrichment to identify four RNA aptamers that specifically recognized mouse and human myeloid cells infiltrating tumors but not their peripheral or circulating counterparts in multiple mouse models and from patients with head and neck squamous cell carcinoma (HNSCC). The use of these aptamers conjugated to doxorubicin enhanced the accumulation and bystander release of the chemotherapeutic drug in both primary and metastatic tumor sites in breast and fibrosarcoma mouse models. In the 4T1 mammary carcinoma model, these doxorubicin-conjugated aptamers outperformed Doxil, the first clinically approved highly optimized nanoparticle for targeted chemotherapy, promoting tumor regression after just three administrations with no detected changes in weight loss or blood chemistry. These RNA aptamers recognized tumor infiltrating myeloid cells in a variety of mouse tumors in vivo and from human HNSCC ex vivo. This work suggests the use of RNA aptamers for the detection of myeloid-derived suppressor cells in humans and for a targeted delivery of chemotherapy to the tumor microenvironment in multiple malignancies

Magnetostratigraphically-calibrated dinoflagellate cyst bioevents for the uppermost Eocene to lowermost Miocene of the western North Atlantic (IODP Expedition 342, Paleogene Newfoundland sediment drifts)

The Oligocene epoch represents a somewhat neglected chapter in paleoclimate and paleoceanographic history, which is at least partially due to the scarcity of complete Oligocene sedimentary archives and poor biostratigraphic age control. Many of the biotic events registered in Oligocene microfossils are strongly diachronous across latitudes as a response to increased global cooling and enhanced meridional temperature gradients. To improve biostratigraphic age control for the Oligocene of the North Atlantic Ocean, we carried out a high-resolution study of dinoflagellate cysts from Integrated Ocean Drilling Program (IODP) Sites U1405, U1406 and U1411 off Newfoundland. Together the sites comprise an apparently complete uppermost Eocene (34.9 Ma) to lowermost Miocene (21.7 Ma) sequence with good magnetostratigraphic age control. This allows us to firmly tie identified dinoflagellate cyst bioevents to the geomagnetic polarity timescale. In the dinoflagellate cyst assemblages studied we have identified and magnetostratigraphically-calibrated ten first and 19 last appearance datums. Our magnetostratigraphically-calibrated dinocyst-based biostratigraphy, which is based on an average sample resolution of a sample every ~ 150 kyrs, will contribute to an improved age framework for future paleoceanographical studies in the higher-latitude North Atlantic