Retinal Degeneration: Short-Term Options and Long-Term Vision for Future Therapy.

The leading cause blindness is the loss of retinal ganglion cells which connect the retina to the brain. Degenerative retinal diseases include retinal dystrophy, macular degeneration and diabetic retinopathy, which are currently incurable as the mammalian retina has no intrinsic regenerative capacity. By utilizing insight gained from retinal regeneration in simpler species we define an approach that may unlock regenerative programs in the mammalian retina that potentially facilitate the clinical restoration of retinal function.

LXR-inverse agonism stimulates immune-mediated tumor destruction by enhancing CD8 T-cell activity in triple negative breast cancer.

Triple-negative breast cancer (TNBC) is a highly aggressive subtype that is untreatable with hormonal or HER2-targeted therapies and is also typically unresponsive to checkpoint-blockade immunotherapy. Within the tumor microenvironment dysregulated immune cell metabolism has emerged as a key mechanism of tumor immune-evasion. We have discovered that the Liver-X-Receptors (LXRα and LXRß), nuclear receptors known to regulate lipid metabolism and tumor-immune interaction, are highly activated in TNBC tumor associated myeloid cells. We therefore theorized that inhibiting LXR would induce immune-mediated TNBC-tumor clearance. Here we show that pharmacological inhibition of LXR activity induces tumor destruction primarily through stimulation of CD8+ T-cell cytotoxic activity and mitochondrial metabolism. Our results imply that LXR inverse agonists may be a promising new class of TNBC immunotherapies.

Rheological evaluation of wet masses for the preparation of pharmaceutical pellets by capillary and rotational rheometers.

The rheological properties of wet powder masses used in the preparation of pharmaceutical pellets by extrusion/spheronization were evaluated utilizing capillary and rotational rheometers. A ram extruder was used as a capillary rheometer to construct flow and viscosity curves for each wet mass under different extrusion rates and die geometry. As a result, shear thinning behavior was observed for all wet masses. Among the considered rheological models Power Law and Herschel-Bulkley models fitted well with the experimental results. For the majority of the wet masses, water separation and migration occurred during extrusion which led to uneven water content in the extrudate. The effect of extrusion condition including extrusion speed, die geometry and water content on the occurrence of water separation was investigated and the surface quality of the extrudates was compared. In addition, dynamic rheometry tests were done by a parallel plate rheometer to investigate the viscoelastic properties of the wet masses. The frequency sweep tests showed that as water content of the wet masses decreases storage (G') and loss modulus (G″) increase. The storage modulus values were much higher than those of the loss modulus showing dominated elastic rather than viscous behavior for the wet masses at low deformation rates.

Regional differences in actomyosin contraction shape the primary vesicles in the embryonic chicken brain.

In the early embryo, the brain initially forms as a relatively straight, cylindrical epithelial tube composed of neural stem cells. The brain tube then divides into three primary vesicles (forebrain, midbrain, hindbrain), as well as a series of bulges (rhombomeres) in the hindbrain. The boundaries between these subdivisions have been well studied as regions of differential gene expression, but the morphogenetic mechanisms that generate these constrictions are not well understood. Here, we show that regional variations in actomyosin-based contractility play a major role in vesicle formation in the embryonic chicken brain. In particular, boundaries did not form in brains exposed to the nonmuscle myosin II inhibitor blebbistatin, whereas increasing contractile force using calyculin or ATP deepened boundaries considerably. Tissue staining showed that contraction likely occurs at the inner part of the wall, as F-actin and phosphorylated myosin are concentrated at the apical side. However, relatively little actin and myosin was found in rhombomere boundaries. To determine the specific physical mechanisms that drive vesicle formation, we developed a finite-element model for the brain tube. Regional apical contraction was simulated in the model, with contractile anisotropy and strength estimated from contractile protein distributions and measurements of cell shapes. The model shows that a combination of circumferential contraction in the boundary regions and relatively isotropic contraction between boundaries can generate realistic morphologies for the primary vesicles. In contrast, rhombomere formation likely involves longitudinal contraction between boundaries. Further simulations suggest that these different mechanisms are dictated by regional differences in initial morphology and the need to withstand cerebrospinal fluid pressure. This study provides a new understanding of early brain morphogenesis.