Delivery of nucleic acids can be hindered by multiple factors including nuclease susceptibility, endosome trapping, and clearance. Multiple nanotechnology scaffolds have offered promising solutions, and among these, lipid-based systems are advantageous because of their high biocompatibility and low toxicity. However, many lipid nanoparticle systems still have issues regarding stability, rapid clearance, and cargo leakage. Herein, we demonstrate the use of a synthetic nanodisc (ND) scaffold functionalized with an anti-HIF-1-α antisense oligonucleotide (ASO) to reduce HIF-1-α mRNA transcript levels. We prepared ND conjugates by using a mixture of phosphoglycerolipids with phosphocholine and phosphothioethanol headgroups that selfassemble into a ∼13 × 5 nm discoidal structure upon addition of a 22-amino-acid ApoA1 mimetic peptide. Optimized reaction conditions yield 15 copies of the anti-HIF-1-α ASO DNA covalently conjugated to the thiolated phospholipids using maleimide−thiol chemistry. We show that DNA-ND conjugates are active, nuclease resistant, and rapidly internalized into cells to regulate HIF-1-α mRNA levels without the use of transfection agents. DNA-ND uptake is partially mediated through Scavenger Receptor B1 and the ND conjugates show enhanced knockdown of HIF-1-α compared to that of the soluble ASOs in multiple cell lines. Our results demonstrate that covalently functionalized NDs may offer an improved platform for ASO therapeutics.

The menstrual cycle impacts mood and neural response to reward-phenomena that may be related to natural fluctuations in ovarian hormones. Using a within-subject design, the present study examined ovarian hormones (i.e., estradiol and progesterone) and ERPs in response to feedback indicating gains and losses in both the follicular and luteal phases of the menstrual cycle. We examined whether hormone levels and variation in neural response to reward and loss across menstrual cycle phases were associated with depressive symptoms. Participants high in depressive symptoms showed a reduced reward positivity (RewP) to monetary gains during the luteal phase of the menstrual cycle as compared to the follicular phase, while those low in depressive symptoms showed no change in the RewP to monetary gains between phases. Thus, increased fluctuation in the neural response to gains (but not losses) across menstrual cycle phases was associated with greater depression symptoms. Overall, findings indicate that hormonal fluctuations associated with the menstrual cycle may relate to depressive symptoms by altering reward sensitivity. Furthermore, fluctuation in the neural response to rewards over the menstrual cycle may play an important role in the expression of depressive symptoms.

Significantly increased genomic instability in players of both sports was observed. Both repaired and repairable genetic damage cells were observed in different tissues of the same subject. The presence of such genetic damage implies that these players are at an individual risk from cancer- and age-related diseases.

Antisense oligonucleotides (ASOs) are single-stranded short nucleic acids that silence the expression of target mRNAs and show increasing therapeutic potential. Since ASOs are internalized by many cell types, both normal and diseased cells, gene silencing in unwanted cells is a significant challenge for their therapeutic use. To address this challenge, we created conditional ASOs that become active only upon detecting transcripts unique to the target cell. As a proof-of-concept, we modified an HIF1α ASO (EZN2968) to generate miRNA-specific conditional ASOs, which can inhibit HIF1α in the presence of a hepatocyte-specific miRNA, miR-122, via a toehold exchange reaction. We characterized a library of nucleic acids, testing how the conformation, thermostability, and chemical composition of the conditional ASO impact the specificity and efficacy in response to miR-122 as a trigger signal. Optimally designed conditional ASOs demonstrated knockdown of HIF1α in cells transfected with exogenous miR-122 and in hepatocytes expressing endogenous miR-122. We confirmed that conditional ASO activity was mediated by toehold exchange between miR-122 and the conditional ASO duplex, and the magnitude of the knockdown depended on the toehold length and miR-122 levels. Using the same concept, we further generated another conditional ASO that can be triggered by miR-21. Our results suggest that conditional ASOs can be custom-designed with any miRNA to control ASO activation in targeted cells while reducing unwanted effects in nontargeted cells.

Highlights Radial artery access for cardiac catherization can have complications, rarely a pseudoanuerysm can form. Imaging modalities to diagnose a pseudoaneursym including arterial ultrasound can computed tomography can help with diagnosis. Management of a pseudoaneurysm depends on the severity and can involve compression techniques, thrombin injections, or surgical repair.