No abstract

Small molecules that directly target MYC and are also well tolerated in vivo will provide invaluable chemical probes and potential anti-cancer therapeutic agents. We developed a series of small-molecule MYC inhibitors that engage MYC inside cells, disrupt MYC/MAX dimers, and impair MYC-driven gene expression. The compounds enhance MYC phosphorylation on threonine-58, consequently increasing proteasome-mediated MYC degradation. The initial lead, MYC inhibitor 361 (MYCi361), suppressed in vivo tumor growth in mice, increased tumor immune cell infiltration, upregulated PD-L1 on tumors, and sensitized tumors to anti-PD1 immunotherapy. However, 361 demonstrated a narrow therapeutic index. An improved analog, MYCi975 showed better tolerability. These findings suggest the potential of small-molecule MYC inhibitors as chemical probes and possible anti-cancer therapeutic agents.

Recently developed classes of ultrasmall, fully implantable devices for optogenetic neuromodulation eliminate physical tethers associated with conventional setups and avoid bulky head-stages and batteries in alternative wireless technologies. The resulting systems enable completely untethered, battery-free operation for high fidelity behavioral studies that eliminate motion constraints and enable experiments in a range of environments and contexts (e.g. social interactions) that would be otherwise difficult or impossible to explore. These devices are, however, purely passive in their electronics design, thereby precluding any form of active control or programmability; independent operation of multiple devices or of multiple active components in a single device is impossible. This paper introduces a series of important concepts in integrated circuit and antenna design which, taken together, enable low power operation, energy efficient and position and angle independent wireless power harvesting with full user-programmability over individual devices or collections of them, in integrated platforms that have sizes and weights not significantly larger than those of previous, passive systems. The results qualitatively expand options in output stabilization, intensity control and multimodal operation, with broad potential applications in neuroscience research, with specific advances in precise dissection of neural circuit function during unconstrained behavioral studies.

Continuous measurements of pressure and temperature within the intracranial, intraocular, and intravascular spaces provide essential diagnostic information for the treatment of traumatic brain injury, glaucoma, and cardiovascular diseases, respectively. Optical sensors are attractive because of their inherent compatibility with magnetic resonance imaging (MRI). Existing implantable optical components use permanent, nonresorbable materials that must be surgically extracted after use. Bioresorbable alternatives, introduced here, bypass this requirement, thereby eliminating the costs and risks of surgeries. Here, millimeter-scale bioresorbable Fabry-Perot interferometers and two dimensional photonic crystal structures enable precise, continuous measurements of pressure and temperature. Combined mechanical and optical simulations reveal the fundamental sensing mechanisms. In vitro studies and histopathological evaluations quantify the measurement accuracies, operational lifetimes, and biocompatibility of these systems. In vivo demonstrations establish clinically relevant performance attributes. The materials, device designs, and fabrication approaches outlined here establish broad foundational capabilities for diverse classes of bioresorbable optical sensors.

No abstract