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A PEG-based cyclized vinyl polymer was synthesized via one-step RAFT polymerization and used as a precursor of injectable hydrogels. Dithiol linkers including laminin-derived peptides containing IKVAV and YIGSR sequences and DTT were used for gelation. Fast and adjustable gelation rate was achieved through nucleophile-initiated thiol-Michael reaction under physiological conditions. Low swelling ratio and moderate degradation rate of the formed hydrogels were observed. 3D encapsulation of neural progenitor cells in the synthetic hydrogel showed good cell viability over 8 days. The long-term cell survival and proliferation were promoted by the introduction of laminin-derived peptides. This hydrogel platform based on peptide-cross-linked, cyclized vinyl polymers can be used as a universal hydrogel template for 3D cell encapsulation. [ABSTRACT FROM AUTHOR]

The primary transcript of the mammalian Fragile X Mental Retardation-1 gene (Fmr1), like many transcripts in the central nervous system, is alternatively spliced to yield mRNAs encoding multiple proteins, which can possess quite different biochemical properties. Despite the fact that the relative levels of the 12 Fmr1 transcript isoforms examined here vary by as much as two orders of magnitude amongst themselves in both adult and embryonic mouse brain, all are associated with polyribosomes, consistent with translation into the corresponding isoforms of the protein product, FMRP (Fragile X Mental Retardation Protein). Employing the RiboTag methodology developed in our laboratory, the relative proportions of the 7 most abundant transcript isoforms were measured specifically in neurons and found to be similar to those identified in whole brain. Measurements of isoform profiles across 11 regions of adult brain yielded similar distributions, with the exceptions of the hippocampus and the olfactory bulb. These two regions differ from most of the brain in relative amounts of transcripts encoding an alternate form of one of the KH RNA binding domains. A possible relationship between patterns of expression in the hippocampus and olfactory bulb and the presence of neuroblasts in these two regions is suggested by the isoform patterns in early embryonic brain and in cultured neural progenitor cells. These results demonstrate that the relative levels of the Fmr1 isoforms are modulated according to developmental stage, highlighting the complex ramifications of losing all the protein isoforms in individuals with Fragile X Syndrome. It should also be noted that, of the eight most prominent FMRP isoforms (1–3, 6–9 and 12) in mouse, only two have the major site of phosphorylation at Ser-499, which is thought to be involved in some of the regulatory interactions of this protein. [ABSTRACT FROM AUTHOR]

Selective therapeutic targeting of T-cell malignancies is difficult due to the shared lineage between healthy and malignant T cells. Current front-line chemotherapy for these cancers is largely nonspecific, resulting in frequent cases of relapsed/refractory disease. The development of targeting approaches for effectively treating T-cell leukemia and lymphoma thus remains a critical goal for the oncology field. Here, we report the discovery of a DNA aptamer, named HR7A1, that displays low nanomolar affinity for the integrin α4β1 (VLA-4), a marker associated with chemoresistance and relapse in leukemia patients. After truncation of HR7A1 to a minimal binding motif, we demonstrate elevated binding of the aptamer to T-lineage cancer cells over healthy immune cells. Using cryo-EM and competition studies, we find that HR7A1 shares an overlapping binding site on α4β1 with fibronectin and VCAM-1, which has implications for sensitizing blood cancers to chemotherapy. We last characterize barriers to in vivo aptamer translation, including serum stability, temperature-sensitive binding, and short circulation half-life, and synthesize an aptamer-polymer conjugate that addresses these challenges. Future work will seek to validate in vivo targeting of α4β1 + tumors with the conjugate, establishing an aptamer-based biomaterial that can be readily adapted for targeted treatment of T-cell malignancies.